farmacos en personalidad
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8112019 Farmacos en Personalidad
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Luis H Ripoll Joseph Triebwasser
Larry J Siever Evidence-Based Pharmacotherapy forPersonality Disorders
Abstract Patients with personality disorders are prescribed psychotropic medications with greater frequency than almost
any other diagnostic group Prescribing practices in these populations are often based on anecdotal evidence rather than
rigorous data Although evidence-based psychotherapy remains an integral part of treatment Axis II psychopathology is
increasingly conceptualized according to neurobiological substrates that correspond to speci1047297c psychopharmacological
strategies We summarize the best available evidence regarding medication treatment of personality disordered patients and
provide optimal strategies for evidence-based practice Most available evidence is concentrated around borderline and
schizotypal personality disorders with some additional evidence concerning the treatment of avoidant and antisocial
personality disorders Although maladaptive personality symptoms respond to antidepressants antipsychotics mood
stabilizers and other medications evidence-based pharmacotherapy is most useful in treating circumscribed symptom
domains and induces only partial improvement Most available evidence supports use of medication in reducing impulsivity
and aggression characteristic of borderline and antisocial psychopathology Efforts have also begun to reduce psychotic-like
symptoms and improve cognitive de1047297cits characteristic of schizotypy Indirect evidence is also provided for
psychopharmacological reduction of social anxiety central to avoidant personality disorder Evidence-based practice requires
attention to domains of expected clinical improvement associated with a medication relative to the potential risks The
development of future rational pharmacotherapy will require increased understanding of the neurobiological underpinnings
of personality disorders and their component dimensions Increasing efforts to translate personality theory and social
cognitive neuroscience into increasingly speci1047297c neurobiological substrates may provide more effective targets for
pharmacotherapy
(Reprinted with permission from International Journal of Neuropsychopharmacology 2011 141257 ndash1288)
INTRODUCTION
Personality disorders are de1047297nedbyan lsquoenduring
pattern of inner experience and behavior thathellip
isin1047298exible and pervasive across a broad range of personal and social situationsrsquo with symptomaticdisturbances in cognition affect impulsivity and interpersonal functioning leading to distress (APA1994) Until recently guidelines recommended sparing use of pharmacotherapy and expectationsremained guarded regarding expected bene1047297ts frommedications Since then distinctions between Axis Idisorders considered lsquo genetichellip biologicalhellip braindisordersrsquo treated with medications and Axis II dis-orders alternatively considered lsquopsychologicalrsquo and
therefore treated with psychotherapy has undergonea paradigm shift (Siever amp Davis 1991) In this at-
mosphere clinicians must rely on the most up-to-
date evidence-based practices for pharmacotherapy to be effective
Component dimensions of personality such as im-pulsivity or aggressiveness have demonstrable neuro-biologicalcorrelatesasshownviaavarietyofendocrineelectrophysiological and neuroimaging measures(Brambilla et al 2004 Goodman et al 2004Houston et al 2004 Juengling et al 2003 Levittet al 2004 Minzenberg et al 2006 New et al
1997 2004 Ogiso et al 1993 Oquendo et al
2005 Prossin et al 2010 Rusch et al 2003 Russ
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et al 1991 Simeon et al 1992 Soderstrom ampForesman 2004) Identifying neurobiological sub-strates of personality has allowed for increasingly speci1047297c pharmacotherapy Nevertheless improvementfrom effective pharmacotherapeutic interventions isoften transient andor restricted to several symptom
domains In the USA there are no FDA-approved medications for treating personality disorders Thuspharmacotherapy for personality disorders remainsoff-label and psychopharmacological strategies for evidence-based practices remain lacking
Themajorityofpsychopharmacologicalresearchon personality disorders has focused on borderlinepersonality disorder (BPD) In the most recenttreatment guidelines for BPD the AmericanPsychiatric Association (APA 2001) acknowl-edges that lsquopharmacotherapy has an importantadjunctive rolersquo along with lsquoextended psycho-
therapy to attain and maintain lasting improvementinhellip personality interpersonal problems and overallfunctioning rsquo Similarly others have described psy-chopharmacological treatment of BPD as resulting only in lsquoa mild degree of symptom relief rsquo (Paris2005) Moreover there remainsa dearth of evidence-based medication treatments for other personality disorders
Often pharmacotherapy for severe personality disorders is used to stabilize patientsrsquo symptomssuf 1047297ciently in order to facilitate psychosocial inter-ventions and foster re1047298ective functioning Close
communication between psychotherapists and psychopharmacologists remains crucial Althoughfunctional gains can be expected from medicationsthe magnitude and time-course vary There is littleevidence regarding distinctions between acute and maintenance pharmacotherapy or how long to
continue patients on a medication Empirical data on recurrence or relapse is similarly scarce There-fore evidence-based practices must be judged case-by-case weighing clinical risks and bene1047297ts
Clinicians canreferto accompanyingtables forthebest available evidence regarding pharmacotherapy for personality disorders (see Tables 1ndash4) This data
was compiled by searching the Medline database with the main combinations pharmacotherapy and each of the various DSM-IV personality disorder diagnoses In addition we paid particularly closeattention to randomized placebo-controlled trials
(along with some lower-level evidence if this type of evidence was severely limited) We focused onstudies published in the past 3 years since thepublication of the last World Federation of Societiesof Biological Psychiatry Guidelines for the BiologicalTreatment of Personality Disorders (Herpertz et al
2007) Additional research regarding medicationsfor treating impulsive aggression was found via a similar Medline search on impulsivity aggressionand pharmacotherapy
Unfortunately only a few novel trials of pharmaco-therapy for personality disorders have been published
Table 1 Schizotypal Personality Disorder (SPD)
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Koenigsberg
et al (2003)
SPD 25 males
and
females
Risperidone Started
at 025 mgd
titrated up to
2 mgd
Parallel
design
9 wk
Significantly lower scores on PANSS
negative and general symptom scales
by week 3 and positive symptoms by
week 7
McClureet al (2007b )
SPD 29 malesand
females
Guanfacine Titrated up to2 mgd within
first 2 wk
Paralleldesign
4 wk
After 4 wk greater improvements frombaseline in neuropsychological
measures of working memory (Modified
AX-Continuous Performance Task)
compared to placebo
McClure
et al (2010)
SPD 25 males
and
females
Pergolide 0025 mgd for
first 3 d then
005 mgd for 4 d
then 01 mgd for 1 wk
then 02 mgd for 1 wk
then 03 mgd
Parallel
design
4 wk
Greater improvement from baseline in
tasks measuring executive function
(Trail-Making Test Part B) verbal
memory (Word List Learning-
immediate and delayed recall) verbal
working memory (Letter Number Span)
long-term visuospatial memory
(Wechsler Memory Scale Visual
Reproduction Test) and visuospatial
working memory (Dot Test) comparedto placebo Dot findings were largely
driven by worsening in placebo group
PANSS Positive and Negative Symptom Scale
226 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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8112019 Farmacos en Personalidad
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during this recent period Several recent meta-analyses have been published in this time which we utilized to establish areas of consensus for evidence-basedpracticeandidentifygapsthatneed to be addressed with future research Many prior reviews cover only BPD but we expanded our scope to include all personality disorders Thus
we include a comprehensive summary of the bestcurrent evidence with commentary on recentconsensus and recommendations for evidence-based practices and future directions regarding pharmacotherapeutic strategies that have been in-
suf 1047297
ciently tested but appear promising for further research This situates this review as a nexuscompiling evidence-based practices for treating personality disorders for interested clinicians as
well as providing avenues for future psychophar-macological research
SCHIZOTYPAL PERSONALITY DISORDER
(SPD)
SPD is characterized by interpersonal de1047297citsand psychotic-like symptoms Like schizophrenia
Table 2 Antisocial Personality Disorder
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Sheard
(1971)
Inmates of
maximum security
prison with verbal
and physical
aggression whilein prison
12 males Lithium
carbonate
Lithium levels of
06ndash15 meql
mean dose
1200 mgd
Crossoversingle-
blind three
4-wk phases
Decrease in serious incidents of verbal
or physical aggression Improvements
in self-rated anger and tension
Single-blind Aggressive incidents
scored on basis of prison guardsrsquo
issuing of punitive tickets not by
psychiatristsrsquo ratings
Sheard
et al
(1976)
Prisoners
convicted of
lsquoserious
aggressive
crimesrsquo
80 males Lithium
carbonate
Lithium levels of
06ndash10 meql
mean lithium level
during last week
of medication
phase 089 meql
Parallel design
5 months with
first and
last months
medication
free and 3
months lithium
vs placebo
Decrease in violent infractions of prison
rules in lithium group
Lion
(1979)
lsquo All patients had
past histories of
temper outbursts
belligerenceassaultive
behaviour and
impulsiveness
had experienced
legal difficulties
and some
had committed
criminal actsrsquo
65 males
and females
Chlordiazepoxide
oxazepam
Chlordiazepoxide
100 mgd for 2 wk
then 200 mgd for
2 wk Oxazepam120 mgd for 2 wk
then 240 mgd
for 2wk
Parallel design
4 wk
Oxazepam superior to chlordiazepoxide
and placebo for indirect hostility
(Buss-Durkee Hostility Scale) anxiety
Barratt
et al
(1991)
Maximum security
prison inmates
with impulsive
aggression
while in prison
19 males Phenytoin 100 mgd or
300 mgd
Crossover design
three 4-wk
phases
Significant reduction in aggressive
acts at 300 mgd but not
100 mgd Improvements in
tension-anxiety and
depression-dejection at 300 mgd
but not anger-hostility
Barratt
et al
(1997)
Prison inmates
with aggression
while in prison
150 total but only
30 males with
primarily impulsive
aggression and
30 males with
primarily
pre-meditated
aggression included
in analysis (other
66 had mixture
of both types)
Phenytoin 300 mgd Crossover
design two
6-wk phases
Significant reduction in frequency
and intensity of aggressive acts
in impulsive aggressive group
but not pre-meditated aggressive
group
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Table 3 Borderline Personality Disorder (BPD)
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Rifkin et al
(1972)
EUCD (emotionally
unstable character
disorder
characterized by
rsquochronic maladaptivebehaviour patternshellip
poor acceptance of
reasonable authority
truancy poor
work history
manipulativenesshellip
with a core
psychopathological
disturbance of
depressive and
hypomanic mood
swings lasting hours
to daysrsquo)
21 (sex
distribution
not specified)
Lithium
carbonate
Dosed to levels
between 06ndash15
meql
Crossover
design
two 6-wk
phases
Mood swings and overall clinical
status judged better on lithium
Leone (1982) BPD 80 males and
females
Loxapine
succinate
chlorpromazine
Mean doses
loxapine
145 mgd
chlorpromazine
110 mgd
Parallel design but
not placebo-
controlled 6 wk
Both groups with significant
improvements Loxapine group
improved more especially in
depression and anger-hostility
Montgomery
amp Montgomery
(1982)
BPD DPD andor
HPD all hospitalized
after a suicidal act
with history of at
least 2 prior suicidal
acts
Not specified 30
males and
females
completed the
study 23 with
BPD 15 with
HPD and 2
with DPD
Depot
flupenthixol
20 mg IM every
4 wk
Parallel design
6 months
Flupenthixol group showed reduction
in number of suicidal acts
Montgomery
et al (1983)
BPD andor HPD all
hospitalized after
a suicidal act with
history of at least 2
prior suicidal acts
Not specified
38 male
and female
subjects
completed
30 with BPD and
12 with HPD
Mianserin 30 mg qhs Parallel design
6 months
Mianserin group showed less
suicidal acts but this did not
reach trend levels
Serban amp
Siegel (1984)
BPD SPD 52 males and
females
Thiothixene
haloperidol
Thiothexene began at
2 mgd then adjusted
up or down mean
dose 94 mgd
Haloperidol began at
08 mg bid then
adjusted dose up
or down mean
dose 3 mgd
Parallel design
but not
placebo-
controlled
3 months
Final drop-out rate unspecified
but 19 dropped out during
the first month 84 of all
subjects moderately to markedly
improved (mainly in cognitive
disturbance derealization ideas of
reference anxiety depression
Thiothixene superior to haloperidol
BPD vs SPD diagnoses did not
predict outcome
Goldberg
et al (1986)
BPD andor SPD
all subjects with
at least one
psychotic symptom
50 males and
females
Thiothixene Started at 5 mgd then
increased gradually to
maximum of 35 mgd
Parallel design
12 wk
48 drop-out rate Significant
improvement in ideas of reference
illusions phobic anxiety
psychoticism and obsessive-
compulsive symptoms but not
depression (SCL-90) Predictors of
response from pre-treatment MMPI
discussed in Goldberg et al (1986)
Soloff et al
(1986b )
BPD andor SPD 64 total with 28
BPD only 4 SPD
only and 32
Haloperidol
amitryptiline
Amitryptiline began
at 25 mgd then
titrated upward to
Parallel design
5 wk
Observer-rated measures did
not demonstrate significant
medication effects
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
comorbid BPD and
SPD
mean final dose of
14762 mgd
Haloperidol began
at 2 mgd then
titrated upward tomean final dose of
724 mgd
Haloperidol superior to amitryptiline
in self-report measures of hostility
paranoia anxiety and depression
Little benefit from amitryptiline
even on depression Resultspresented again in Soloff et al
(1989) but outpatients deleted
from analyses (N 5 13)
Soloff et al
(1986c )
See above See above See above See above See above Haloperidol better than both
amitryptiline and placebo for overall
symptom severity Improvements
described as lsquomodest rsquo more
apparent in self-rated than
observer-rated measures
No differences between
amitryptiline and placebo
Soloff et al
(1986a
1987)
See above Papers analyse
paradoxical
response toamitryptiline
during study first
described in
Soloff et al
(1986b )
Compared 15
amitryptiline non-
responders
14 placebo
non-responders
13 amitryptiline
responders and
10 placebo
responders
Amitryptiline See above Mean final
amitryptiline1
nortryptiline bloodlevels were 246 ngml
for responders and
2459 ngml for non-
responders
See above Amitrypti line associated with
paradoxical increases in hostility
irritability impulsivity paranoiasuicide threats and demanding
and assaultive behaviour in
non-responders
Cowdry amp
Gardner
(1988)
BPD with lsquoprominent
behavioural
dyscontrolrsquo
16 females Alprazolam
carbamazepine
trifluoperazine
hydrochloride
tranylcypromine
sulfate
Mean doses of
alprazolam 47 mgd
carbamazepine
820 mgd
trifluoperazine
78 mgd and
tranylcypromine
40 mgd
Crossover design
each phase
lasting 6 wk
Tranylcypromine and carbamazepine
had lowest drop-out rates (25 and
33 respectively compared to
average 45) and were associated
with physician-rated improvements
Tranylcypromine also associated
with patient-rated improvements
Trifluoperazine completers showed
some improvements Carbamazepine
group showed improvement
especially in behavioural dyscontrol
(Gardner amp Cowdry 1986b )
Alprazolam group showed
worsening behavioural dyscontrol
(Cowdry amp Gardner 1988)3 subjects on carbamazepine
developed worsening melancholia
that remitted on discontinuation
(Gardner amp Cowdry 1986a )
Parsons et al
(1989)
BPD and atypical
depression
First sample of
subjects were
required to meet
5 BPD criteria
(N 5 40) second
sample met 4
Phenelzine
imipramine
Phenelzine titration to
60 mgd with
option to increase to
90 mgd if no
response by week 5
Imipramine titration
to 200 mgd with
Crossover
design two
6-wk phases
Greater proportion of subjects
responded to phenelzine than
imipramine Presence of BPD
symptoms was negative predictor
of response to imipramine in
subjects with 4 or more BPD
symptoms higher number
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
BPD criteria
(N 5 19)
option to increase
to 300 mgd if no
response by week 5
of symptoms predicted superiority
of phenelzine
Soloff et al
(1989)
Same as Soloff
et al (1986 b)
90 total with 35
lsquounstablersquo BPD
4 SPD and 51
lsquomixedrsquo BPD
and SPD
Same as Soloff
et al (1986b )
Same procedure as
Soloff et al (1986b )
Mean dose of
haloperidol was 48
mgd and mean dose
of amitryptiline was
1491 mgd on
day 35
Parallel design
5 wk
Significant differences between
haloperidol and placebo in global
functioning depression hostility
schizotypy and impulsivity
Differences between amitryptiline
and placebo limited to depressive
symptoms Final results of 4-year
study only analyzed data from
inpatients deleting data from
outpatients in prior reports
Links et al
(1990)
BPD 17 males and
females
Lithium
carbonate
desipramine
Not spe ci fi ed Cr ossover d es ig n
two 6-wk phases
No statistically significant effects on
depression Trend towards decrease
in anger and suicidality in lithium
group relative to desipramine
Therapistsrsquo perceptions favored
lithium over placebo Trendtowards favoring lithium over
desipramine Therapists did not find
desipramine superior to placebo
Soloff et al
(1993)
BPD 108 males and
females
Haloperidol
phenelzine
Haloperidol began at
1 mgd then titrated
up to mean dose of
4 mgd Phenelzine
began at 15 mgd
then titrated up to
mean dose of 60
mgd
Parallel design
5 wk
Improvements observed with
haloperidol in Soloff et al
(1986a ndashc 19871989) were not
replicated Phenelzine associated
with improvements in depression
borderline symptoms anxiety
anger and hostility but not
atypical depressionhysteroid
dysphoria
Cornelius
et al (1993)
BPD 54 males and
females
Haloperidol
phenelzine
Haloperidol up to 6
mgd phenelzine upto 90 mgd Doses
generally did not
change from final
dose of prior 5-wk
acute phase
(Soloff et al 1993)
Parallel design
16 wk following 5-wk
acute phase
(Soloff et al
1993)
Drop-out rate during entire 22-wk
study acute phase (Soloff et al1993) and continuation was
73 (79108) Only benefit in
haloperidol group was decreased
irritability Haloperidol contributed
to worsening depression leaden
paralysis and hypersomnia
Phenelzine showed modest
efficacy on depression and
irritability but unpleasant activation
de la Fuente
amp Lotstra
(1994)
BPD 20 males and
females
Carbamazepine Dosed to obtain
therapeutic blood
levels
Parallel design
32 days
No significant benefit
Salzman
et al (1995)
BPD 27 males and
females
Fluoxet ine Started at 20 mgd
titrated up toa maximum of
60 mgd with mean
dose of 40 mgd
Parallel design
12 wk
Decrease in anger with fluoxetine
but high placebo response rateSubjects from outpatient sample
without Axis I comorbidity limiting
generalizability
Coccaro amp
Kavoussi
(1997)
All subjects had at
least one PD as
well as current
problems with
impulsive aggression
and irritability Most
frequent PD was
BPD
40 males and
females
Fluoxet ine Started at 20 mgd
and after end of 4th
week could be
increased to
40 mgd with further
increase to 60 mgd
possible after end of
8th week
Parallel design
12 wk
Reduction in irritability and
aggression subscales of OAS-M
Higher proportion of CGI
responders in fluoxetine group
relative to placebo
D-fenfluramine challenge of subset
of 15 subjects showed positive
correlation in fluoxetine-treated but
not placebo-treated subjects
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
between improvement in OAS-M
subscales and pre-treatment
prolactin response (Coccaro
amp Kavoussi 1997)
Verkes et al
(1998)
Non-depressed
subjects who had
recently attempted
suicide for at least
the second time
81 met criteria
for a Cluster B PD
91 males and
females
Paroxet ine Started at 20 mgd
increased to
40 mgd after
1 wk
Parallel design
52 wk
79 (7291) dropped out prematurely
Significant efficacy in preventing
suicidal behaviour after controlling
for number of prior suicide
attempts Paroxetine more effective
in patients who met fewer than
15 Cluster B PD criteria Paroxetine
group did not differ from placebo
in depressed mood
hopelessness or anger
Battaglia
et al (1999)
Multiple suicide
attempters 85
had BPD
58 males and
females
Fluphenazine
decanoate
125 mg IM monthly
or 15 mg IM
monthly
Parallel design
but not placebo-
controlled
6 months
60 (3558) dropped out
prematurely Marked reduction in
self-harm behaviours but 125 mg
dose did not significantly differ from
15 mg dose According to authorslsquoThe lsquoultra-lowrsquo 15 mg dose was
chosen to represent the extreme
low end of possible
pharmacological effect for
fluphenazine treatment The
investigators believed that the
ethics review board would not
approve a study with the use of a
placebo in such a critically ill
group of patients
Hollander
et al (2001)
BPD 16 males and
females
Divalproex
sodium
Started at 250 mg qhs
increased gradually
to maintain valproate
levels of 80 mgml or
highest tolerable
dose Mean
endpoint valproate
level 6457 mgml
Parallel design
10 wk
50 (612) of medication group
and 100 (612) of placebo
group dropped out No statistically
significant benefits in ITT
analyses Among completers
significant improvements from
baseline in CGI and GAS ITT
data showed changes in expected
directions in BDI and AQ scores
Zanarini amp
Frankenburg
(2001)
BPD 28 females Olanzapine Started with
125 mgd then
titrated up to
mean dose of
533 mgd at
endpoint
Parallel design
6 months
68 (1928) dropped out
prematurely Improvements in
olanzapine group in anxiety
paranoia angerhostility and
interpersonal sensitivity
subscales but not depression
subscale of SCL-90
Frankenburg
amp Zanarini
(2002)
BPD and bipolar
disorder type II
30 females Divalproex
sodium
Started at 250 mg bid
then titrated to target
serum levels of
50ndash100 mgl
Parallel design 6
months
63 (1930) dropped out
prematurely Improvements in
medication group in
interpersonal sensitivity anger
hostility and overall aggression
Rinne et al
(2002)
BPD 38 females Fluvoxamine Began with 150 mgd
then titrated up to
a maximum of 250
mgd after 10th
week if insufficient
response
6-wk double-blind
placebo-controlled
phase followed by
6-wk singleblind
half-crossover
phase in which all
subjects received
fluvoxamine This
was followed by
Significant reduction in BPD
Severity Index rapid mood
shift subscale but not in
impulsivity or aggression
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
12-wk open label
study of
fluvoxamine
Hollander
et al (2003)
Cluster B PD IED or
PTSD with OAS-M
Aggression score
15
Males and females
Cluster B PD 96
with 55 BPD
13 NPD 10
AsPD 1 HPD
PD NOS 21) IED
116 PTSD 34
Divalproex
sodium
Began with 250 mg
bid then increased
by 250 mgd every
3ndash7d during first
3 wk Recommended
valproate levels were
80ndash120mgml by third
week Maximum dose
30 mgkgd
Parallel design
12 wk
44 (54124) divalproex group
and 39 (47122) placebo group
dropped out No differences in ITT
data sets when all subjects
included In Cluster B PD subjects
significant decreases in CGI
scores OAS-M irritability scores
and verbal assault and assault
against objects items of OAS-M
aggression scale in medication
group Secondary analysis
(Hollander et al 2005) revealed
improvements in impulsive
aggression in a subset of BPD
subjects and that high BIS
scores and high OAS-M
aggression scores predicted
better responses
Zanarini amp
Frankenburg
(2003)
BPD 30 females Ethyl-eicosa-
pentaenoic acid
(E-EPA)
500 mg b i d Pa ral le l d es ig n
8 wk
Better than placebo in reducing
aggression and severity of
depressive symptoms
Bogenschutz
amp Nurnberg
(2004)
BPD 40 males and
females
Olanzapine Started at 25 mgd
then increased by
25ndash5 mgdwk up to
10 mgd After week 8
dose could be further
increased to
maximum of 20 mgd
Most patients received
less than 10 mgd
Parallel design
12 wk
Superior to placebo on CGI
and CGI-BPD
Nickel et al
(2004)
BPD 31 females Topiramate Began with 50 mgd
then increased to
250 mgd by last
3 wk
Parallel design
8 wk
Significant improvements in
State-Anger Trait-Anger
Anger-Out and Anger-
Control subscales of STAXI
Philipsen
et al
(2004a )
BPD 22 females Clonidine 75 mg or l50 mg Crossov er design in
which each subject
received one 75 mg
dose and one
150 mg dose in
randomized
crossover fashion
during separate
episodes of lsquostrong
aversive inner
tension and urge
to commit
self-injurious
behaviourrsquo no
placebo-control
single-blind
Significant decreases in aversive
inner tension dissociative
symptoms suicidal ideation
and urges to commit
self-injurious behaviour
30ndash60 min after clonidine for
both doses Dose did not affect
response no placebo-control
Philipsen
et al (2004b )
BPD 9 females Naloxone
hydrochloride
04 mg IV administered
over 30 s
Crossover design in
which each subject
received one dose
of naloxone and
onedose of placebo
in randomized
Dissociative symptoms decreased
after both naloxone and placebo
but no difference between groups
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
crossover fashion
during separate
acute dissociative
episodes
Simpson
et al (2004)
BPD 25 females Fluoxetine plus
concurrent DBT
Started at 20 mgd
increased to 40 mgd
at week 3
Parallel design
12 wk
No significant group differences
from pre-treatment to
post-treatment
Zanarini et al
(2004b )
BPD 45 females Fluoxetine
olanzapine and
olanzapine-
fluoxetine
combination
(OFC)
Fluoxetine started at
10 mgd with endpoint
mean dose of 15 mgd
Olanzapine started at
25 mgd with endpoint
mean dose of 33 mgd
OFC started at
olanzapine 25 mgd
and fluoxetine 10 mgd
with endpoint mean
doses of 32 mgd and
127 mgd respectively
Parallel design but
not placebo-
controlled 8 wk
Olanzapine and OFC superior to
fluoxetine for depression and
impulsive aggression although
patients on fluoxetine improved
in both as well Weight gain
greater in olanzapine group than
fluoxetine or OFC groups
Nickel et al
(2005)
BPD 44 males Topiramate Began with 50 mgd
then increased to
250 mgd by last 3 wk
Parallel design
8 wk
Significant improvements for
medication group in State-Anger
Trait-Anger Anger-Out and
Anger-Control subscales of STAXI
Subsequent open-label follow-up
(Nickel amp Loew 2008)
demonstrated continued
benefits in topiramate group
in ITT analysis
Soler et al
(2005)
BPD 60 males and
females
Olanzapine with
concurrent DBT
Flexible dosing from 5ndash
20 mgd with mean
dose 883 mgd
Parallel design
12 wk
Olanzapine superior to placebo
for depression anxiety and
impulsive aggression
Tritt et al
(2005)
BPD 27 females Lamotrigine Started at 50 mgd then
increased to 100 mgd
during week 3
150 mgd during wk 4
and 5 and 200 mgd
during wk 6ndash8
Parallel design
8 wk
Significant improvement on
State-Anger Trait-Anger
Anger-Out and Anger-Control
subscales of STAXI in
medication group
Nickel et al
(2006)
BPD 52 males and
females
Aripiprazole 15 mgd Parallel design
8 wk
Aripiprazole group evidenced
greater improvements in SCL-90
subscales of obsessive-compulsive
symptoms insecurity in social
contacts depression anxiety
hostility phobic anxiety paranoia
and psychoticism as well as
global psychological stress
Medication group also improved
on HAMD and HAMA as well asall subscales of the STAXI Less
selfinjurious behaviour
observed in medication group
Loew et al
(2006)
BPD 59 females Topiramate Began with 25 mgd
increasing to a target
dose of 200 mgd by
the 6th week
Parallel design
10 wk
Significant improvements in
medication group in SCL-90
subscales of somatization
symptoms interpersonal sensitivity
anxiety hostility phobic anxiety
and global stress but not in
obsessive-compulsive
depression paranoia or
psychoticism subscales
Medication group significantly
(Continued)
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patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
240 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
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Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
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R IPOLL ET AL
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Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2424
Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 224
et al 1991 Simeon et al 1992 Soderstrom ampForesman 2004) Identifying neurobiological sub-strates of personality has allowed for increasingly speci1047297c pharmacotherapy Nevertheless improvementfrom effective pharmacotherapeutic interventions isoften transient andor restricted to several symptom
domains In the USA there are no FDA-approved medications for treating personality disorders Thuspharmacotherapy for personality disorders remainsoff-label and psychopharmacological strategies for evidence-based practices remain lacking
Themajorityofpsychopharmacologicalresearchon personality disorders has focused on borderlinepersonality disorder (BPD) In the most recenttreatment guidelines for BPD the AmericanPsychiatric Association (APA 2001) acknowl-edges that lsquopharmacotherapy has an importantadjunctive rolersquo along with lsquoextended psycho-
therapy to attain and maintain lasting improvementinhellip personality interpersonal problems and overallfunctioning rsquo Similarly others have described psy-chopharmacological treatment of BPD as resulting only in lsquoa mild degree of symptom relief rsquo (Paris2005) Moreover there remainsa dearth of evidence-based medication treatments for other personality disorders
Often pharmacotherapy for severe personality disorders is used to stabilize patientsrsquo symptomssuf 1047297ciently in order to facilitate psychosocial inter-ventions and foster re1047298ective functioning Close
communication between psychotherapists and psychopharmacologists remains crucial Althoughfunctional gains can be expected from medicationsthe magnitude and time-course vary There is littleevidence regarding distinctions between acute and maintenance pharmacotherapy or how long to
continue patients on a medication Empirical data on recurrence or relapse is similarly scarce There-fore evidence-based practices must be judged case-by-case weighing clinical risks and bene1047297ts
Clinicians canreferto accompanyingtables forthebest available evidence regarding pharmacotherapy for personality disorders (see Tables 1ndash4) This data
was compiled by searching the Medline database with the main combinations pharmacotherapy and each of the various DSM-IV personality disorder diagnoses In addition we paid particularly closeattention to randomized placebo-controlled trials
(along with some lower-level evidence if this type of evidence was severely limited) We focused onstudies published in the past 3 years since thepublication of the last World Federation of Societiesof Biological Psychiatry Guidelines for the BiologicalTreatment of Personality Disorders (Herpertz et al
2007) Additional research regarding medicationsfor treating impulsive aggression was found via a similar Medline search on impulsivity aggressionand pharmacotherapy
Unfortunately only a few novel trials of pharmaco-therapy for personality disorders have been published
Table 1 Schizotypal Personality Disorder (SPD)
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Koenigsberg
et al (2003)
SPD 25 males
and
females
Risperidone Started
at 025 mgd
titrated up to
2 mgd
Parallel
design
9 wk
Significantly lower scores on PANSS
negative and general symptom scales
by week 3 and positive symptoms by
week 7
McClureet al (2007b )
SPD 29 malesand
females
Guanfacine Titrated up to2 mgd within
first 2 wk
Paralleldesign
4 wk
After 4 wk greater improvements frombaseline in neuropsychological
measures of working memory (Modified
AX-Continuous Performance Task)
compared to placebo
McClure
et al (2010)
SPD 25 males
and
females
Pergolide 0025 mgd for
first 3 d then
005 mgd for 4 d
then 01 mgd for 1 wk
then 02 mgd for 1 wk
then 03 mgd
Parallel
design
4 wk
Greater improvement from baseline in
tasks measuring executive function
(Trail-Making Test Part B) verbal
memory (Word List Learning-
immediate and delayed recall) verbal
working memory (Letter Number Span)
long-term visuospatial memory
(Wechsler Memory Scale Visual
Reproduction Test) and visuospatial
working memory (Dot Test) comparedto placebo Dot findings were largely
driven by worsening in placebo group
PANSS Positive and Negative Symptom Scale
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during this recent period Several recent meta-analyses have been published in this time which we utilized to establish areas of consensus for evidence-basedpracticeandidentifygapsthatneed to be addressed with future research Many prior reviews cover only BPD but we expanded our scope to include all personality disorders Thus
we include a comprehensive summary of the bestcurrent evidence with commentary on recentconsensus and recommendations for evidence-based practices and future directions regarding pharmacotherapeutic strategies that have been in-
suf 1047297
ciently tested but appear promising for further research This situates this review as a nexuscompiling evidence-based practices for treating personality disorders for interested clinicians as
well as providing avenues for future psychophar-macological research
SCHIZOTYPAL PERSONALITY DISORDER
(SPD)
SPD is characterized by interpersonal de1047297citsand psychotic-like symptoms Like schizophrenia
Table 2 Antisocial Personality Disorder
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Sheard
(1971)
Inmates of
maximum security
prison with verbal
and physical
aggression whilein prison
12 males Lithium
carbonate
Lithium levels of
06ndash15 meql
mean dose
1200 mgd
Crossoversingle-
blind three
4-wk phases
Decrease in serious incidents of verbal
or physical aggression Improvements
in self-rated anger and tension
Single-blind Aggressive incidents
scored on basis of prison guardsrsquo
issuing of punitive tickets not by
psychiatristsrsquo ratings
Sheard
et al
(1976)
Prisoners
convicted of
lsquoserious
aggressive
crimesrsquo
80 males Lithium
carbonate
Lithium levels of
06ndash10 meql
mean lithium level
during last week
of medication
phase 089 meql
Parallel design
5 months with
first and
last months
medication
free and 3
months lithium
vs placebo
Decrease in violent infractions of prison
rules in lithium group
Lion
(1979)
lsquo All patients had
past histories of
temper outbursts
belligerenceassaultive
behaviour and
impulsiveness
had experienced
legal difficulties
and some
had committed
criminal actsrsquo
65 males
and females
Chlordiazepoxide
oxazepam
Chlordiazepoxide
100 mgd for 2 wk
then 200 mgd for
2 wk Oxazepam120 mgd for 2 wk
then 240 mgd
for 2wk
Parallel design
4 wk
Oxazepam superior to chlordiazepoxide
and placebo for indirect hostility
(Buss-Durkee Hostility Scale) anxiety
Barratt
et al
(1991)
Maximum security
prison inmates
with impulsive
aggression
while in prison
19 males Phenytoin 100 mgd or
300 mgd
Crossover design
three 4-wk
phases
Significant reduction in aggressive
acts at 300 mgd but not
100 mgd Improvements in
tension-anxiety and
depression-dejection at 300 mgd
but not anger-hostility
Barratt
et al
(1997)
Prison inmates
with aggression
while in prison
150 total but only
30 males with
primarily impulsive
aggression and
30 males with
primarily
pre-meditated
aggression included
in analysis (other
66 had mixture
of both types)
Phenytoin 300 mgd Crossover
design two
6-wk phases
Significant reduction in frequency
and intensity of aggressive acts
in impulsive aggressive group
but not pre-meditated aggressive
group
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Table 3 Borderline Personality Disorder (BPD)
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Rifkin et al
(1972)
EUCD (emotionally
unstable character
disorder
characterized by
rsquochronic maladaptivebehaviour patternshellip
poor acceptance of
reasonable authority
truancy poor
work history
manipulativenesshellip
with a core
psychopathological
disturbance of
depressive and
hypomanic mood
swings lasting hours
to daysrsquo)
21 (sex
distribution
not specified)
Lithium
carbonate
Dosed to levels
between 06ndash15
meql
Crossover
design
two 6-wk
phases
Mood swings and overall clinical
status judged better on lithium
Leone (1982) BPD 80 males and
females
Loxapine
succinate
chlorpromazine
Mean doses
loxapine
145 mgd
chlorpromazine
110 mgd
Parallel design but
not placebo-
controlled 6 wk
Both groups with significant
improvements Loxapine group
improved more especially in
depression and anger-hostility
Montgomery
amp Montgomery
(1982)
BPD DPD andor
HPD all hospitalized
after a suicidal act
with history of at
least 2 prior suicidal
acts
Not specified 30
males and
females
completed the
study 23 with
BPD 15 with
HPD and 2
with DPD
Depot
flupenthixol
20 mg IM every
4 wk
Parallel design
6 months
Flupenthixol group showed reduction
in number of suicidal acts
Montgomery
et al (1983)
BPD andor HPD all
hospitalized after
a suicidal act with
history of at least 2
prior suicidal acts
Not specified
38 male
and female
subjects
completed
30 with BPD and
12 with HPD
Mianserin 30 mg qhs Parallel design
6 months
Mianserin group showed less
suicidal acts but this did not
reach trend levels
Serban amp
Siegel (1984)
BPD SPD 52 males and
females
Thiothixene
haloperidol
Thiothexene began at
2 mgd then adjusted
up or down mean
dose 94 mgd
Haloperidol began at
08 mg bid then
adjusted dose up
or down mean
dose 3 mgd
Parallel design
but not
placebo-
controlled
3 months
Final drop-out rate unspecified
but 19 dropped out during
the first month 84 of all
subjects moderately to markedly
improved (mainly in cognitive
disturbance derealization ideas of
reference anxiety depression
Thiothixene superior to haloperidol
BPD vs SPD diagnoses did not
predict outcome
Goldberg
et al (1986)
BPD andor SPD
all subjects with
at least one
psychotic symptom
50 males and
females
Thiothixene Started at 5 mgd then
increased gradually to
maximum of 35 mgd
Parallel design
12 wk
48 drop-out rate Significant
improvement in ideas of reference
illusions phobic anxiety
psychoticism and obsessive-
compulsive symptoms but not
depression (SCL-90) Predictors of
response from pre-treatment MMPI
discussed in Goldberg et al (1986)
Soloff et al
(1986b )
BPD andor SPD 64 total with 28
BPD only 4 SPD
only and 32
Haloperidol
amitryptiline
Amitryptiline began
at 25 mgd then
titrated upward to
Parallel design
5 wk
Observer-rated measures did
not demonstrate significant
medication effects
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
comorbid BPD and
SPD
mean final dose of
14762 mgd
Haloperidol began
at 2 mgd then
titrated upward tomean final dose of
724 mgd
Haloperidol superior to amitryptiline
in self-report measures of hostility
paranoia anxiety and depression
Little benefit from amitryptiline
even on depression Resultspresented again in Soloff et al
(1989) but outpatients deleted
from analyses (N 5 13)
Soloff et al
(1986c )
See above See above See above See above See above Haloperidol better than both
amitryptiline and placebo for overall
symptom severity Improvements
described as lsquomodest rsquo more
apparent in self-rated than
observer-rated measures
No differences between
amitryptiline and placebo
Soloff et al
(1986a
1987)
See above Papers analyse
paradoxical
response toamitryptiline
during study first
described in
Soloff et al
(1986b )
Compared 15
amitryptiline non-
responders
14 placebo
non-responders
13 amitryptiline
responders and
10 placebo
responders
Amitryptiline See above Mean final
amitryptiline1
nortryptiline bloodlevels were 246 ngml
for responders and
2459 ngml for non-
responders
See above Amitrypti line associated with
paradoxical increases in hostility
irritability impulsivity paranoiasuicide threats and demanding
and assaultive behaviour in
non-responders
Cowdry amp
Gardner
(1988)
BPD with lsquoprominent
behavioural
dyscontrolrsquo
16 females Alprazolam
carbamazepine
trifluoperazine
hydrochloride
tranylcypromine
sulfate
Mean doses of
alprazolam 47 mgd
carbamazepine
820 mgd
trifluoperazine
78 mgd and
tranylcypromine
40 mgd
Crossover design
each phase
lasting 6 wk
Tranylcypromine and carbamazepine
had lowest drop-out rates (25 and
33 respectively compared to
average 45) and were associated
with physician-rated improvements
Tranylcypromine also associated
with patient-rated improvements
Trifluoperazine completers showed
some improvements Carbamazepine
group showed improvement
especially in behavioural dyscontrol
(Gardner amp Cowdry 1986b )
Alprazolam group showed
worsening behavioural dyscontrol
(Cowdry amp Gardner 1988)3 subjects on carbamazepine
developed worsening melancholia
that remitted on discontinuation
(Gardner amp Cowdry 1986a )
Parsons et al
(1989)
BPD and atypical
depression
First sample of
subjects were
required to meet
5 BPD criteria
(N 5 40) second
sample met 4
Phenelzine
imipramine
Phenelzine titration to
60 mgd with
option to increase to
90 mgd if no
response by week 5
Imipramine titration
to 200 mgd with
Crossover
design two
6-wk phases
Greater proportion of subjects
responded to phenelzine than
imipramine Presence of BPD
symptoms was negative predictor
of response to imipramine in
subjects with 4 or more BPD
symptoms higher number
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
BPD criteria
(N 5 19)
option to increase
to 300 mgd if no
response by week 5
of symptoms predicted superiority
of phenelzine
Soloff et al
(1989)
Same as Soloff
et al (1986 b)
90 total with 35
lsquounstablersquo BPD
4 SPD and 51
lsquomixedrsquo BPD
and SPD
Same as Soloff
et al (1986b )
Same procedure as
Soloff et al (1986b )
Mean dose of
haloperidol was 48
mgd and mean dose
of amitryptiline was
1491 mgd on
day 35
Parallel design
5 wk
Significant differences between
haloperidol and placebo in global
functioning depression hostility
schizotypy and impulsivity
Differences between amitryptiline
and placebo limited to depressive
symptoms Final results of 4-year
study only analyzed data from
inpatients deleting data from
outpatients in prior reports
Links et al
(1990)
BPD 17 males and
females
Lithium
carbonate
desipramine
Not spe ci fi ed Cr ossover d es ig n
two 6-wk phases
No statistically significant effects on
depression Trend towards decrease
in anger and suicidality in lithium
group relative to desipramine
Therapistsrsquo perceptions favored
lithium over placebo Trendtowards favoring lithium over
desipramine Therapists did not find
desipramine superior to placebo
Soloff et al
(1993)
BPD 108 males and
females
Haloperidol
phenelzine
Haloperidol began at
1 mgd then titrated
up to mean dose of
4 mgd Phenelzine
began at 15 mgd
then titrated up to
mean dose of 60
mgd
Parallel design
5 wk
Improvements observed with
haloperidol in Soloff et al
(1986a ndashc 19871989) were not
replicated Phenelzine associated
with improvements in depression
borderline symptoms anxiety
anger and hostility but not
atypical depressionhysteroid
dysphoria
Cornelius
et al (1993)
BPD 54 males and
females
Haloperidol
phenelzine
Haloperidol up to 6
mgd phenelzine upto 90 mgd Doses
generally did not
change from final
dose of prior 5-wk
acute phase
(Soloff et al 1993)
Parallel design
16 wk following 5-wk
acute phase
(Soloff et al
1993)
Drop-out rate during entire 22-wk
study acute phase (Soloff et al1993) and continuation was
73 (79108) Only benefit in
haloperidol group was decreased
irritability Haloperidol contributed
to worsening depression leaden
paralysis and hypersomnia
Phenelzine showed modest
efficacy on depression and
irritability but unpleasant activation
de la Fuente
amp Lotstra
(1994)
BPD 20 males and
females
Carbamazepine Dosed to obtain
therapeutic blood
levels
Parallel design
32 days
No significant benefit
Salzman
et al (1995)
BPD 27 males and
females
Fluoxet ine Started at 20 mgd
titrated up toa maximum of
60 mgd with mean
dose of 40 mgd
Parallel design
12 wk
Decrease in anger with fluoxetine
but high placebo response rateSubjects from outpatient sample
without Axis I comorbidity limiting
generalizability
Coccaro amp
Kavoussi
(1997)
All subjects had at
least one PD as
well as current
problems with
impulsive aggression
and irritability Most
frequent PD was
BPD
40 males and
females
Fluoxet ine Started at 20 mgd
and after end of 4th
week could be
increased to
40 mgd with further
increase to 60 mgd
possible after end of
8th week
Parallel design
12 wk
Reduction in irritability and
aggression subscales of OAS-M
Higher proportion of CGI
responders in fluoxetine group
relative to placebo
D-fenfluramine challenge of subset
of 15 subjects showed positive
correlation in fluoxetine-treated but
not placebo-treated subjects
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
between improvement in OAS-M
subscales and pre-treatment
prolactin response (Coccaro
amp Kavoussi 1997)
Verkes et al
(1998)
Non-depressed
subjects who had
recently attempted
suicide for at least
the second time
81 met criteria
for a Cluster B PD
91 males and
females
Paroxet ine Started at 20 mgd
increased to
40 mgd after
1 wk
Parallel design
52 wk
79 (7291) dropped out prematurely
Significant efficacy in preventing
suicidal behaviour after controlling
for number of prior suicide
attempts Paroxetine more effective
in patients who met fewer than
15 Cluster B PD criteria Paroxetine
group did not differ from placebo
in depressed mood
hopelessness or anger
Battaglia
et al (1999)
Multiple suicide
attempters 85
had BPD
58 males and
females
Fluphenazine
decanoate
125 mg IM monthly
or 15 mg IM
monthly
Parallel design
but not placebo-
controlled
6 months
60 (3558) dropped out
prematurely Marked reduction in
self-harm behaviours but 125 mg
dose did not significantly differ from
15 mg dose According to authorslsquoThe lsquoultra-lowrsquo 15 mg dose was
chosen to represent the extreme
low end of possible
pharmacological effect for
fluphenazine treatment The
investigators believed that the
ethics review board would not
approve a study with the use of a
placebo in such a critically ill
group of patients
Hollander
et al (2001)
BPD 16 males and
females
Divalproex
sodium
Started at 250 mg qhs
increased gradually
to maintain valproate
levels of 80 mgml or
highest tolerable
dose Mean
endpoint valproate
level 6457 mgml
Parallel design
10 wk
50 (612) of medication group
and 100 (612) of placebo
group dropped out No statistically
significant benefits in ITT
analyses Among completers
significant improvements from
baseline in CGI and GAS ITT
data showed changes in expected
directions in BDI and AQ scores
Zanarini amp
Frankenburg
(2001)
BPD 28 females Olanzapine Started with
125 mgd then
titrated up to
mean dose of
533 mgd at
endpoint
Parallel design
6 months
68 (1928) dropped out
prematurely Improvements in
olanzapine group in anxiety
paranoia angerhostility and
interpersonal sensitivity
subscales but not depression
subscale of SCL-90
Frankenburg
amp Zanarini
(2002)
BPD and bipolar
disorder type II
30 females Divalproex
sodium
Started at 250 mg bid
then titrated to target
serum levels of
50ndash100 mgl
Parallel design 6
months
63 (1930) dropped out
prematurely Improvements in
medication group in
interpersonal sensitivity anger
hostility and overall aggression
Rinne et al
(2002)
BPD 38 females Fluvoxamine Began with 150 mgd
then titrated up to
a maximum of 250
mgd after 10th
week if insufficient
response
6-wk double-blind
placebo-controlled
phase followed by
6-wk singleblind
half-crossover
phase in which all
subjects received
fluvoxamine This
was followed by
Significant reduction in BPD
Severity Index rapid mood
shift subscale but not in
impulsivity or aggression
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
12-wk open label
study of
fluvoxamine
Hollander
et al (2003)
Cluster B PD IED or
PTSD with OAS-M
Aggression score
15
Males and females
Cluster B PD 96
with 55 BPD
13 NPD 10
AsPD 1 HPD
PD NOS 21) IED
116 PTSD 34
Divalproex
sodium
Began with 250 mg
bid then increased
by 250 mgd every
3ndash7d during first
3 wk Recommended
valproate levels were
80ndash120mgml by third
week Maximum dose
30 mgkgd
Parallel design
12 wk
44 (54124) divalproex group
and 39 (47122) placebo group
dropped out No differences in ITT
data sets when all subjects
included In Cluster B PD subjects
significant decreases in CGI
scores OAS-M irritability scores
and verbal assault and assault
against objects items of OAS-M
aggression scale in medication
group Secondary analysis
(Hollander et al 2005) revealed
improvements in impulsive
aggression in a subset of BPD
subjects and that high BIS
scores and high OAS-M
aggression scores predicted
better responses
Zanarini amp
Frankenburg
(2003)
BPD 30 females Ethyl-eicosa-
pentaenoic acid
(E-EPA)
500 mg b i d Pa ral le l d es ig n
8 wk
Better than placebo in reducing
aggression and severity of
depressive symptoms
Bogenschutz
amp Nurnberg
(2004)
BPD 40 males and
females
Olanzapine Started at 25 mgd
then increased by
25ndash5 mgdwk up to
10 mgd After week 8
dose could be further
increased to
maximum of 20 mgd
Most patients received
less than 10 mgd
Parallel design
12 wk
Superior to placebo on CGI
and CGI-BPD
Nickel et al
(2004)
BPD 31 females Topiramate Began with 50 mgd
then increased to
250 mgd by last
3 wk
Parallel design
8 wk
Significant improvements in
State-Anger Trait-Anger
Anger-Out and Anger-
Control subscales of STAXI
Philipsen
et al
(2004a )
BPD 22 females Clonidine 75 mg or l50 mg Crossov er design in
which each subject
received one 75 mg
dose and one
150 mg dose in
randomized
crossover fashion
during separate
episodes of lsquostrong
aversive inner
tension and urge
to commit
self-injurious
behaviourrsquo no
placebo-control
single-blind
Significant decreases in aversive
inner tension dissociative
symptoms suicidal ideation
and urges to commit
self-injurious behaviour
30ndash60 min after clonidine for
both doses Dose did not affect
response no placebo-control
Philipsen
et al (2004b )
BPD 9 females Naloxone
hydrochloride
04 mg IV administered
over 30 s
Crossover design in
which each subject
received one dose
of naloxone and
onedose of placebo
in randomized
Dissociative symptoms decreased
after both naloxone and placebo
but no difference between groups
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
crossover fashion
during separate
acute dissociative
episodes
Simpson
et al (2004)
BPD 25 females Fluoxetine plus
concurrent DBT
Started at 20 mgd
increased to 40 mgd
at week 3
Parallel design
12 wk
No significant group differences
from pre-treatment to
post-treatment
Zanarini et al
(2004b )
BPD 45 females Fluoxetine
olanzapine and
olanzapine-
fluoxetine
combination
(OFC)
Fluoxetine started at
10 mgd with endpoint
mean dose of 15 mgd
Olanzapine started at
25 mgd with endpoint
mean dose of 33 mgd
OFC started at
olanzapine 25 mgd
and fluoxetine 10 mgd
with endpoint mean
doses of 32 mgd and
127 mgd respectively
Parallel design but
not placebo-
controlled 8 wk
Olanzapine and OFC superior to
fluoxetine for depression and
impulsive aggression although
patients on fluoxetine improved
in both as well Weight gain
greater in olanzapine group than
fluoxetine or OFC groups
Nickel et al
(2005)
BPD 44 males Topiramate Began with 50 mgd
then increased to
250 mgd by last 3 wk
Parallel design
8 wk
Significant improvements for
medication group in State-Anger
Trait-Anger Anger-Out and
Anger-Control subscales of STAXI
Subsequent open-label follow-up
(Nickel amp Loew 2008)
demonstrated continued
benefits in topiramate group
in ITT analysis
Soler et al
(2005)
BPD 60 males and
females
Olanzapine with
concurrent DBT
Flexible dosing from 5ndash
20 mgd with mean
dose 883 mgd
Parallel design
12 wk
Olanzapine superior to placebo
for depression anxiety and
impulsive aggression
Tritt et al
(2005)
BPD 27 females Lamotrigine Started at 50 mgd then
increased to 100 mgd
during week 3
150 mgd during wk 4
and 5 and 200 mgd
during wk 6ndash8
Parallel design
8 wk
Significant improvement on
State-Anger Trait-Anger
Anger-Out and Anger-Control
subscales of STAXI in
medication group
Nickel et al
(2006)
BPD 52 males and
females
Aripiprazole 15 mgd Parallel design
8 wk
Aripiprazole group evidenced
greater improvements in SCL-90
subscales of obsessive-compulsive
symptoms insecurity in social
contacts depression anxiety
hostility phobic anxiety paranoia
and psychoticism as well as
global psychological stress
Medication group also improved
on HAMD and HAMA as well asall subscales of the STAXI Less
selfinjurious behaviour
observed in medication group
Loew et al
(2006)
BPD 59 females Topiramate Began with 25 mgd
increasing to a target
dose of 200 mgd by
the 6th week
Parallel design
10 wk
Significant improvements in
medication group in SCL-90
subscales of somatization
symptoms interpersonal sensitivity
anxiety hostility phobic anxiety
and global stress but not in
obsessive-compulsive
depression paranoia or
psychoticism subscales
Medication group significantly
(Continued)
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patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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8112019 Farmacos en Personalidad
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
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Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
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R IPOLL ET AL
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I C A T
I O
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S
8112019 Farmacos en Personalidad
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Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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U E N
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B L
I C A T
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8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 324
during this recent period Several recent meta-analyses have been published in this time which we utilized to establish areas of consensus for evidence-basedpracticeandidentifygapsthatneed to be addressed with future research Many prior reviews cover only BPD but we expanded our scope to include all personality disorders Thus
we include a comprehensive summary of the bestcurrent evidence with commentary on recentconsensus and recommendations for evidence-based practices and future directions regarding pharmacotherapeutic strategies that have been in-
suf 1047297
ciently tested but appear promising for further research This situates this review as a nexuscompiling evidence-based practices for treating personality disorders for interested clinicians as
well as providing avenues for future psychophar-macological research
SCHIZOTYPAL PERSONALITY DISORDER
(SPD)
SPD is characterized by interpersonal de1047297citsand psychotic-like symptoms Like schizophrenia
Table 2 Antisocial Personality Disorder
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Sheard
(1971)
Inmates of
maximum security
prison with verbal
and physical
aggression whilein prison
12 males Lithium
carbonate
Lithium levels of
06ndash15 meql
mean dose
1200 mgd
Crossoversingle-
blind three
4-wk phases
Decrease in serious incidents of verbal
or physical aggression Improvements
in self-rated anger and tension
Single-blind Aggressive incidents
scored on basis of prison guardsrsquo
issuing of punitive tickets not by
psychiatristsrsquo ratings
Sheard
et al
(1976)
Prisoners
convicted of
lsquoserious
aggressive
crimesrsquo
80 males Lithium
carbonate
Lithium levels of
06ndash10 meql
mean lithium level
during last week
of medication
phase 089 meql
Parallel design
5 months with
first and
last months
medication
free and 3
months lithium
vs placebo
Decrease in violent infractions of prison
rules in lithium group
Lion
(1979)
lsquo All patients had
past histories of
temper outbursts
belligerenceassaultive
behaviour and
impulsiveness
had experienced
legal difficulties
and some
had committed
criminal actsrsquo
65 males
and females
Chlordiazepoxide
oxazepam
Chlordiazepoxide
100 mgd for 2 wk
then 200 mgd for
2 wk Oxazepam120 mgd for 2 wk
then 240 mgd
for 2wk
Parallel design
4 wk
Oxazepam superior to chlordiazepoxide
and placebo for indirect hostility
(Buss-Durkee Hostility Scale) anxiety
Barratt
et al
(1991)
Maximum security
prison inmates
with impulsive
aggression
while in prison
19 males Phenytoin 100 mgd or
300 mgd
Crossover design
three 4-wk
phases
Significant reduction in aggressive
acts at 300 mgd but not
100 mgd Improvements in
tension-anxiety and
depression-dejection at 300 mgd
but not anger-hostility
Barratt
et al
(1997)
Prison inmates
with aggression
while in prison
150 total but only
30 males with
primarily impulsive
aggression and
30 males with
primarily
pre-meditated
aggression included
in analysis (other
66 had mixture
of both types)
Phenytoin 300 mgd Crossover
design two
6-wk phases
Significant reduction in frequency
and intensity of aggressive acts
in impulsive aggressive group
but not pre-meditated aggressive
group
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 227
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Table 3 Borderline Personality Disorder (BPD)
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Rifkin et al
(1972)
EUCD (emotionally
unstable character
disorder
characterized by
rsquochronic maladaptivebehaviour patternshellip
poor acceptance of
reasonable authority
truancy poor
work history
manipulativenesshellip
with a core
psychopathological
disturbance of
depressive and
hypomanic mood
swings lasting hours
to daysrsquo)
21 (sex
distribution
not specified)
Lithium
carbonate
Dosed to levels
between 06ndash15
meql
Crossover
design
two 6-wk
phases
Mood swings and overall clinical
status judged better on lithium
Leone (1982) BPD 80 males and
females
Loxapine
succinate
chlorpromazine
Mean doses
loxapine
145 mgd
chlorpromazine
110 mgd
Parallel design but
not placebo-
controlled 6 wk
Both groups with significant
improvements Loxapine group
improved more especially in
depression and anger-hostility
Montgomery
amp Montgomery
(1982)
BPD DPD andor
HPD all hospitalized
after a suicidal act
with history of at
least 2 prior suicidal
acts
Not specified 30
males and
females
completed the
study 23 with
BPD 15 with
HPD and 2
with DPD
Depot
flupenthixol
20 mg IM every
4 wk
Parallel design
6 months
Flupenthixol group showed reduction
in number of suicidal acts
Montgomery
et al (1983)
BPD andor HPD all
hospitalized after
a suicidal act with
history of at least 2
prior suicidal acts
Not specified
38 male
and female
subjects
completed
30 with BPD and
12 with HPD
Mianserin 30 mg qhs Parallel design
6 months
Mianserin group showed less
suicidal acts but this did not
reach trend levels
Serban amp
Siegel (1984)
BPD SPD 52 males and
females
Thiothixene
haloperidol
Thiothexene began at
2 mgd then adjusted
up or down mean
dose 94 mgd
Haloperidol began at
08 mg bid then
adjusted dose up
or down mean
dose 3 mgd
Parallel design
but not
placebo-
controlled
3 months
Final drop-out rate unspecified
but 19 dropped out during
the first month 84 of all
subjects moderately to markedly
improved (mainly in cognitive
disturbance derealization ideas of
reference anxiety depression
Thiothixene superior to haloperidol
BPD vs SPD diagnoses did not
predict outcome
Goldberg
et al (1986)
BPD andor SPD
all subjects with
at least one
psychotic symptom
50 males and
females
Thiothixene Started at 5 mgd then
increased gradually to
maximum of 35 mgd
Parallel design
12 wk
48 drop-out rate Significant
improvement in ideas of reference
illusions phobic anxiety
psychoticism and obsessive-
compulsive symptoms but not
depression (SCL-90) Predictors of
response from pre-treatment MMPI
discussed in Goldberg et al (1986)
Soloff et al
(1986b )
BPD andor SPD 64 total with 28
BPD only 4 SPD
only and 32
Haloperidol
amitryptiline
Amitryptiline began
at 25 mgd then
titrated upward to
Parallel design
5 wk
Observer-rated measures did
not demonstrate significant
medication effects
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
comorbid BPD and
SPD
mean final dose of
14762 mgd
Haloperidol began
at 2 mgd then
titrated upward tomean final dose of
724 mgd
Haloperidol superior to amitryptiline
in self-report measures of hostility
paranoia anxiety and depression
Little benefit from amitryptiline
even on depression Resultspresented again in Soloff et al
(1989) but outpatients deleted
from analyses (N 5 13)
Soloff et al
(1986c )
See above See above See above See above See above Haloperidol better than both
amitryptiline and placebo for overall
symptom severity Improvements
described as lsquomodest rsquo more
apparent in self-rated than
observer-rated measures
No differences between
amitryptiline and placebo
Soloff et al
(1986a
1987)
See above Papers analyse
paradoxical
response toamitryptiline
during study first
described in
Soloff et al
(1986b )
Compared 15
amitryptiline non-
responders
14 placebo
non-responders
13 amitryptiline
responders and
10 placebo
responders
Amitryptiline See above Mean final
amitryptiline1
nortryptiline bloodlevels were 246 ngml
for responders and
2459 ngml for non-
responders
See above Amitrypti line associated with
paradoxical increases in hostility
irritability impulsivity paranoiasuicide threats and demanding
and assaultive behaviour in
non-responders
Cowdry amp
Gardner
(1988)
BPD with lsquoprominent
behavioural
dyscontrolrsquo
16 females Alprazolam
carbamazepine
trifluoperazine
hydrochloride
tranylcypromine
sulfate
Mean doses of
alprazolam 47 mgd
carbamazepine
820 mgd
trifluoperazine
78 mgd and
tranylcypromine
40 mgd
Crossover design
each phase
lasting 6 wk
Tranylcypromine and carbamazepine
had lowest drop-out rates (25 and
33 respectively compared to
average 45) and were associated
with physician-rated improvements
Tranylcypromine also associated
with patient-rated improvements
Trifluoperazine completers showed
some improvements Carbamazepine
group showed improvement
especially in behavioural dyscontrol
(Gardner amp Cowdry 1986b )
Alprazolam group showed
worsening behavioural dyscontrol
(Cowdry amp Gardner 1988)3 subjects on carbamazepine
developed worsening melancholia
that remitted on discontinuation
(Gardner amp Cowdry 1986a )
Parsons et al
(1989)
BPD and atypical
depression
First sample of
subjects were
required to meet
5 BPD criteria
(N 5 40) second
sample met 4
Phenelzine
imipramine
Phenelzine titration to
60 mgd with
option to increase to
90 mgd if no
response by week 5
Imipramine titration
to 200 mgd with
Crossover
design two
6-wk phases
Greater proportion of subjects
responded to phenelzine than
imipramine Presence of BPD
symptoms was negative predictor
of response to imipramine in
subjects with 4 or more BPD
symptoms higher number
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
BPD criteria
(N 5 19)
option to increase
to 300 mgd if no
response by week 5
of symptoms predicted superiority
of phenelzine
Soloff et al
(1989)
Same as Soloff
et al (1986 b)
90 total with 35
lsquounstablersquo BPD
4 SPD and 51
lsquomixedrsquo BPD
and SPD
Same as Soloff
et al (1986b )
Same procedure as
Soloff et al (1986b )
Mean dose of
haloperidol was 48
mgd and mean dose
of amitryptiline was
1491 mgd on
day 35
Parallel design
5 wk
Significant differences between
haloperidol and placebo in global
functioning depression hostility
schizotypy and impulsivity
Differences between amitryptiline
and placebo limited to depressive
symptoms Final results of 4-year
study only analyzed data from
inpatients deleting data from
outpatients in prior reports
Links et al
(1990)
BPD 17 males and
females
Lithium
carbonate
desipramine
Not spe ci fi ed Cr ossover d es ig n
two 6-wk phases
No statistically significant effects on
depression Trend towards decrease
in anger and suicidality in lithium
group relative to desipramine
Therapistsrsquo perceptions favored
lithium over placebo Trendtowards favoring lithium over
desipramine Therapists did not find
desipramine superior to placebo
Soloff et al
(1993)
BPD 108 males and
females
Haloperidol
phenelzine
Haloperidol began at
1 mgd then titrated
up to mean dose of
4 mgd Phenelzine
began at 15 mgd
then titrated up to
mean dose of 60
mgd
Parallel design
5 wk
Improvements observed with
haloperidol in Soloff et al
(1986a ndashc 19871989) were not
replicated Phenelzine associated
with improvements in depression
borderline symptoms anxiety
anger and hostility but not
atypical depressionhysteroid
dysphoria
Cornelius
et al (1993)
BPD 54 males and
females
Haloperidol
phenelzine
Haloperidol up to 6
mgd phenelzine upto 90 mgd Doses
generally did not
change from final
dose of prior 5-wk
acute phase
(Soloff et al 1993)
Parallel design
16 wk following 5-wk
acute phase
(Soloff et al
1993)
Drop-out rate during entire 22-wk
study acute phase (Soloff et al1993) and continuation was
73 (79108) Only benefit in
haloperidol group was decreased
irritability Haloperidol contributed
to worsening depression leaden
paralysis and hypersomnia
Phenelzine showed modest
efficacy on depression and
irritability but unpleasant activation
de la Fuente
amp Lotstra
(1994)
BPD 20 males and
females
Carbamazepine Dosed to obtain
therapeutic blood
levels
Parallel design
32 days
No significant benefit
Salzman
et al (1995)
BPD 27 males and
females
Fluoxet ine Started at 20 mgd
titrated up toa maximum of
60 mgd with mean
dose of 40 mgd
Parallel design
12 wk
Decrease in anger with fluoxetine
but high placebo response rateSubjects from outpatient sample
without Axis I comorbidity limiting
generalizability
Coccaro amp
Kavoussi
(1997)
All subjects had at
least one PD as
well as current
problems with
impulsive aggression
and irritability Most
frequent PD was
BPD
40 males and
females
Fluoxet ine Started at 20 mgd
and after end of 4th
week could be
increased to
40 mgd with further
increase to 60 mgd
possible after end of
8th week
Parallel design
12 wk
Reduction in irritability and
aggression subscales of OAS-M
Higher proportion of CGI
responders in fluoxetine group
relative to placebo
D-fenfluramine challenge of subset
of 15 subjects showed positive
correlation in fluoxetine-treated but
not placebo-treated subjects
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
between improvement in OAS-M
subscales and pre-treatment
prolactin response (Coccaro
amp Kavoussi 1997)
Verkes et al
(1998)
Non-depressed
subjects who had
recently attempted
suicide for at least
the second time
81 met criteria
for a Cluster B PD
91 males and
females
Paroxet ine Started at 20 mgd
increased to
40 mgd after
1 wk
Parallel design
52 wk
79 (7291) dropped out prematurely
Significant efficacy in preventing
suicidal behaviour after controlling
for number of prior suicide
attempts Paroxetine more effective
in patients who met fewer than
15 Cluster B PD criteria Paroxetine
group did not differ from placebo
in depressed mood
hopelessness or anger
Battaglia
et al (1999)
Multiple suicide
attempters 85
had BPD
58 males and
females
Fluphenazine
decanoate
125 mg IM monthly
or 15 mg IM
monthly
Parallel design
but not placebo-
controlled
6 months
60 (3558) dropped out
prematurely Marked reduction in
self-harm behaviours but 125 mg
dose did not significantly differ from
15 mg dose According to authorslsquoThe lsquoultra-lowrsquo 15 mg dose was
chosen to represent the extreme
low end of possible
pharmacological effect for
fluphenazine treatment The
investigators believed that the
ethics review board would not
approve a study with the use of a
placebo in such a critically ill
group of patients
Hollander
et al (2001)
BPD 16 males and
females
Divalproex
sodium
Started at 250 mg qhs
increased gradually
to maintain valproate
levels of 80 mgml or
highest tolerable
dose Mean
endpoint valproate
level 6457 mgml
Parallel design
10 wk
50 (612) of medication group
and 100 (612) of placebo
group dropped out No statistically
significant benefits in ITT
analyses Among completers
significant improvements from
baseline in CGI and GAS ITT
data showed changes in expected
directions in BDI and AQ scores
Zanarini amp
Frankenburg
(2001)
BPD 28 females Olanzapine Started with
125 mgd then
titrated up to
mean dose of
533 mgd at
endpoint
Parallel design
6 months
68 (1928) dropped out
prematurely Improvements in
olanzapine group in anxiety
paranoia angerhostility and
interpersonal sensitivity
subscales but not depression
subscale of SCL-90
Frankenburg
amp Zanarini
(2002)
BPD and bipolar
disorder type II
30 females Divalproex
sodium
Started at 250 mg bid
then titrated to target
serum levels of
50ndash100 mgl
Parallel design 6
months
63 (1930) dropped out
prematurely Improvements in
medication group in
interpersonal sensitivity anger
hostility and overall aggression
Rinne et al
(2002)
BPD 38 females Fluvoxamine Began with 150 mgd
then titrated up to
a maximum of 250
mgd after 10th
week if insufficient
response
6-wk double-blind
placebo-controlled
phase followed by
6-wk singleblind
half-crossover
phase in which all
subjects received
fluvoxamine This
was followed by
Significant reduction in BPD
Severity Index rapid mood
shift subscale but not in
impulsivity or aggression
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
12-wk open label
study of
fluvoxamine
Hollander
et al (2003)
Cluster B PD IED or
PTSD with OAS-M
Aggression score
15
Males and females
Cluster B PD 96
with 55 BPD
13 NPD 10
AsPD 1 HPD
PD NOS 21) IED
116 PTSD 34
Divalproex
sodium
Began with 250 mg
bid then increased
by 250 mgd every
3ndash7d during first
3 wk Recommended
valproate levels were
80ndash120mgml by third
week Maximum dose
30 mgkgd
Parallel design
12 wk
44 (54124) divalproex group
and 39 (47122) placebo group
dropped out No differences in ITT
data sets when all subjects
included In Cluster B PD subjects
significant decreases in CGI
scores OAS-M irritability scores
and verbal assault and assault
against objects items of OAS-M
aggression scale in medication
group Secondary analysis
(Hollander et al 2005) revealed
improvements in impulsive
aggression in a subset of BPD
subjects and that high BIS
scores and high OAS-M
aggression scores predicted
better responses
Zanarini amp
Frankenburg
(2003)
BPD 30 females Ethyl-eicosa-
pentaenoic acid
(E-EPA)
500 mg b i d Pa ral le l d es ig n
8 wk
Better than placebo in reducing
aggression and severity of
depressive symptoms
Bogenschutz
amp Nurnberg
(2004)
BPD 40 males and
females
Olanzapine Started at 25 mgd
then increased by
25ndash5 mgdwk up to
10 mgd After week 8
dose could be further
increased to
maximum of 20 mgd
Most patients received
less than 10 mgd
Parallel design
12 wk
Superior to placebo on CGI
and CGI-BPD
Nickel et al
(2004)
BPD 31 females Topiramate Began with 50 mgd
then increased to
250 mgd by last
3 wk
Parallel design
8 wk
Significant improvements in
State-Anger Trait-Anger
Anger-Out and Anger-
Control subscales of STAXI
Philipsen
et al
(2004a )
BPD 22 females Clonidine 75 mg or l50 mg Crossov er design in
which each subject
received one 75 mg
dose and one
150 mg dose in
randomized
crossover fashion
during separate
episodes of lsquostrong
aversive inner
tension and urge
to commit
self-injurious
behaviourrsquo no
placebo-control
single-blind
Significant decreases in aversive
inner tension dissociative
symptoms suicidal ideation
and urges to commit
self-injurious behaviour
30ndash60 min after clonidine for
both doses Dose did not affect
response no placebo-control
Philipsen
et al (2004b )
BPD 9 females Naloxone
hydrochloride
04 mg IV administered
over 30 s
Crossover design in
which each subject
received one dose
of naloxone and
onedose of placebo
in randomized
Dissociative symptoms decreased
after both naloxone and placebo
but no difference between groups
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
crossover fashion
during separate
acute dissociative
episodes
Simpson
et al (2004)
BPD 25 females Fluoxetine plus
concurrent DBT
Started at 20 mgd
increased to 40 mgd
at week 3
Parallel design
12 wk
No significant group differences
from pre-treatment to
post-treatment
Zanarini et al
(2004b )
BPD 45 females Fluoxetine
olanzapine and
olanzapine-
fluoxetine
combination
(OFC)
Fluoxetine started at
10 mgd with endpoint
mean dose of 15 mgd
Olanzapine started at
25 mgd with endpoint
mean dose of 33 mgd
OFC started at
olanzapine 25 mgd
and fluoxetine 10 mgd
with endpoint mean
doses of 32 mgd and
127 mgd respectively
Parallel design but
not placebo-
controlled 8 wk
Olanzapine and OFC superior to
fluoxetine for depression and
impulsive aggression although
patients on fluoxetine improved
in both as well Weight gain
greater in olanzapine group than
fluoxetine or OFC groups
Nickel et al
(2005)
BPD 44 males Topiramate Began with 50 mgd
then increased to
250 mgd by last 3 wk
Parallel design
8 wk
Significant improvements for
medication group in State-Anger
Trait-Anger Anger-Out and
Anger-Control subscales of STAXI
Subsequent open-label follow-up
(Nickel amp Loew 2008)
demonstrated continued
benefits in topiramate group
in ITT analysis
Soler et al
(2005)
BPD 60 males and
females
Olanzapine with
concurrent DBT
Flexible dosing from 5ndash
20 mgd with mean
dose 883 mgd
Parallel design
12 wk
Olanzapine superior to placebo
for depression anxiety and
impulsive aggression
Tritt et al
(2005)
BPD 27 females Lamotrigine Started at 50 mgd then
increased to 100 mgd
during week 3
150 mgd during wk 4
and 5 and 200 mgd
during wk 6ndash8
Parallel design
8 wk
Significant improvement on
State-Anger Trait-Anger
Anger-Out and Anger-Control
subscales of STAXI in
medication group
Nickel et al
(2006)
BPD 52 males and
females
Aripiprazole 15 mgd Parallel design
8 wk
Aripiprazole group evidenced
greater improvements in SCL-90
subscales of obsessive-compulsive
symptoms insecurity in social
contacts depression anxiety
hostility phobic anxiety paranoia
and psychoticism as well as
global psychological stress
Medication group also improved
on HAMD and HAMA as well asall subscales of the STAXI Less
selfinjurious behaviour
observed in medication group
Loew et al
(2006)
BPD 59 females Topiramate Began with 25 mgd
increasing to a target
dose of 200 mgd by
the 6th week
Parallel design
10 wk
Significant improvements in
medication group in SCL-90
subscales of somatization
symptoms interpersonal sensitivity
anxiety hostility phobic anxiety
and global stress but not in
obsessive-compulsive
depression paranoia or
psychoticism subscales
Medication group significantly
(Continued)
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patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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I C A T
I O
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S
8112019 Farmacos en Personalidad
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Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
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Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
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I O
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S
8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 424
Table 3 Borderline Personality Disorder (BPD)
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Rifkin et al
(1972)
EUCD (emotionally
unstable character
disorder
characterized by
rsquochronic maladaptivebehaviour patternshellip
poor acceptance of
reasonable authority
truancy poor
work history
manipulativenesshellip
with a core
psychopathological
disturbance of
depressive and
hypomanic mood
swings lasting hours
to daysrsquo)
21 (sex
distribution
not specified)
Lithium
carbonate
Dosed to levels
between 06ndash15
meql
Crossover
design
two 6-wk
phases
Mood swings and overall clinical
status judged better on lithium
Leone (1982) BPD 80 males and
females
Loxapine
succinate
chlorpromazine
Mean doses
loxapine
145 mgd
chlorpromazine
110 mgd
Parallel design but
not placebo-
controlled 6 wk
Both groups with significant
improvements Loxapine group
improved more especially in
depression and anger-hostility
Montgomery
amp Montgomery
(1982)
BPD DPD andor
HPD all hospitalized
after a suicidal act
with history of at
least 2 prior suicidal
acts
Not specified 30
males and
females
completed the
study 23 with
BPD 15 with
HPD and 2
with DPD
Depot
flupenthixol
20 mg IM every
4 wk
Parallel design
6 months
Flupenthixol group showed reduction
in number of suicidal acts
Montgomery
et al (1983)
BPD andor HPD all
hospitalized after
a suicidal act with
history of at least 2
prior suicidal acts
Not specified
38 male
and female
subjects
completed
30 with BPD and
12 with HPD
Mianserin 30 mg qhs Parallel design
6 months
Mianserin group showed less
suicidal acts but this did not
reach trend levels
Serban amp
Siegel (1984)
BPD SPD 52 males and
females
Thiothixene
haloperidol
Thiothexene began at
2 mgd then adjusted
up or down mean
dose 94 mgd
Haloperidol began at
08 mg bid then
adjusted dose up
or down mean
dose 3 mgd
Parallel design
but not
placebo-
controlled
3 months
Final drop-out rate unspecified
but 19 dropped out during
the first month 84 of all
subjects moderately to markedly
improved (mainly in cognitive
disturbance derealization ideas of
reference anxiety depression
Thiothixene superior to haloperidol
BPD vs SPD diagnoses did not
predict outcome
Goldberg
et al (1986)
BPD andor SPD
all subjects with
at least one
psychotic symptom
50 males and
females
Thiothixene Started at 5 mgd then
increased gradually to
maximum of 35 mgd
Parallel design
12 wk
48 drop-out rate Significant
improvement in ideas of reference
illusions phobic anxiety
psychoticism and obsessive-
compulsive symptoms but not
depression (SCL-90) Predictors of
response from pre-treatment MMPI
discussed in Goldberg et al (1986)
Soloff et al
(1986b )
BPD andor SPD 64 total with 28
BPD only 4 SPD
only and 32
Haloperidol
amitryptiline
Amitryptiline began
at 25 mgd then
titrated upward to
Parallel design
5 wk
Observer-rated measures did
not demonstrate significant
medication effects
(Continued)
228 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 524
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
comorbid BPD and
SPD
mean final dose of
14762 mgd
Haloperidol began
at 2 mgd then
titrated upward tomean final dose of
724 mgd
Haloperidol superior to amitryptiline
in self-report measures of hostility
paranoia anxiety and depression
Little benefit from amitryptiline
even on depression Resultspresented again in Soloff et al
(1989) but outpatients deleted
from analyses (N 5 13)
Soloff et al
(1986c )
See above See above See above See above See above Haloperidol better than both
amitryptiline and placebo for overall
symptom severity Improvements
described as lsquomodest rsquo more
apparent in self-rated than
observer-rated measures
No differences between
amitryptiline and placebo
Soloff et al
(1986a
1987)
See above Papers analyse
paradoxical
response toamitryptiline
during study first
described in
Soloff et al
(1986b )
Compared 15
amitryptiline non-
responders
14 placebo
non-responders
13 amitryptiline
responders and
10 placebo
responders
Amitryptiline See above Mean final
amitryptiline1
nortryptiline bloodlevels were 246 ngml
for responders and
2459 ngml for non-
responders
See above Amitrypti line associated with
paradoxical increases in hostility
irritability impulsivity paranoiasuicide threats and demanding
and assaultive behaviour in
non-responders
Cowdry amp
Gardner
(1988)
BPD with lsquoprominent
behavioural
dyscontrolrsquo
16 females Alprazolam
carbamazepine
trifluoperazine
hydrochloride
tranylcypromine
sulfate
Mean doses of
alprazolam 47 mgd
carbamazepine
820 mgd
trifluoperazine
78 mgd and
tranylcypromine
40 mgd
Crossover design
each phase
lasting 6 wk
Tranylcypromine and carbamazepine
had lowest drop-out rates (25 and
33 respectively compared to
average 45) and were associated
with physician-rated improvements
Tranylcypromine also associated
with patient-rated improvements
Trifluoperazine completers showed
some improvements Carbamazepine
group showed improvement
especially in behavioural dyscontrol
(Gardner amp Cowdry 1986b )
Alprazolam group showed
worsening behavioural dyscontrol
(Cowdry amp Gardner 1988)3 subjects on carbamazepine
developed worsening melancholia
that remitted on discontinuation
(Gardner amp Cowdry 1986a )
Parsons et al
(1989)
BPD and atypical
depression
First sample of
subjects were
required to meet
5 BPD criteria
(N 5 40) second
sample met 4
Phenelzine
imipramine
Phenelzine titration to
60 mgd with
option to increase to
90 mgd if no
response by week 5
Imipramine titration
to 200 mgd with
Crossover
design two
6-wk phases
Greater proportion of subjects
responded to phenelzine than
imipramine Presence of BPD
symptoms was negative predictor
of response to imipramine in
subjects with 4 or more BPD
symptoms higher number
(Continued)
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 229
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
BPD criteria
(N 5 19)
option to increase
to 300 mgd if no
response by week 5
of symptoms predicted superiority
of phenelzine
Soloff et al
(1989)
Same as Soloff
et al (1986 b)
90 total with 35
lsquounstablersquo BPD
4 SPD and 51
lsquomixedrsquo BPD
and SPD
Same as Soloff
et al (1986b )
Same procedure as
Soloff et al (1986b )
Mean dose of
haloperidol was 48
mgd and mean dose
of amitryptiline was
1491 mgd on
day 35
Parallel design
5 wk
Significant differences between
haloperidol and placebo in global
functioning depression hostility
schizotypy and impulsivity
Differences between amitryptiline
and placebo limited to depressive
symptoms Final results of 4-year
study only analyzed data from
inpatients deleting data from
outpatients in prior reports
Links et al
(1990)
BPD 17 males and
females
Lithium
carbonate
desipramine
Not spe ci fi ed Cr ossover d es ig n
two 6-wk phases
No statistically significant effects on
depression Trend towards decrease
in anger and suicidality in lithium
group relative to desipramine
Therapistsrsquo perceptions favored
lithium over placebo Trendtowards favoring lithium over
desipramine Therapists did not find
desipramine superior to placebo
Soloff et al
(1993)
BPD 108 males and
females
Haloperidol
phenelzine
Haloperidol began at
1 mgd then titrated
up to mean dose of
4 mgd Phenelzine
began at 15 mgd
then titrated up to
mean dose of 60
mgd
Parallel design
5 wk
Improvements observed with
haloperidol in Soloff et al
(1986a ndashc 19871989) were not
replicated Phenelzine associated
with improvements in depression
borderline symptoms anxiety
anger and hostility but not
atypical depressionhysteroid
dysphoria
Cornelius
et al (1993)
BPD 54 males and
females
Haloperidol
phenelzine
Haloperidol up to 6
mgd phenelzine upto 90 mgd Doses
generally did not
change from final
dose of prior 5-wk
acute phase
(Soloff et al 1993)
Parallel design
16 wk following 5-wk
acute phase
(Soloff et al
1993)
Drop-out rate during entire 22-wk
study acute phase (Soloff et al1993) and continuation was
73 (79108) Only benefit in
haloperidol group was decreased
irritability Haloperidol contributed
to worsening depression leaden
paralysis and hypersomnia
Phenelzine showed modest
efficacy on depression and
irritability but unpleasant activation
de la Fuente
amp Lotstra
(1994)
BPD 20 males and
females
Carbamazepine Dosed to obtain
therapeutic blood
levels
Parallel design
32 days
No significant benefit
Salzman
et al (1995)
BPD 27 males and
females
Fluoxet ine Started at 20 mgd
titrated up toa maximum of
60 mgd with mean
dose of 40 mgd
Parallel design
12 wk
Decrease in anger with fluoxetine
but high placebo response rateSubjects from outpatient sample
without Axis I comorbidity limiting
generalizability
Coccaro amp
Kavoussi
(1997)
All subjects had at
least one PD as
well as current
problems with
impulsive aggression
and irritability Most
frequent PD was
BPD
40 males and
females
Fluoxet ine Started at 20 mgd
and after end of 4th
week could be
increased to
40 mgd with further
increase to 60 mgd
possible after end of
8th week
Parallel design
12 wk
Reduction in irritability and
aggression subscales of OAS-M
Higher proportion of CGI
responders in fluoxetine group
relative to placebo
D-fenfluramine challenge of subset
of 15 subjects showed positive
correlation in fluoxetine-treated but
not placebo-treated subjects
(Continued)
230 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
between improvement in OAS-M
subscales and pre-treatment
prolactin response (Coccaro
amp Kavoussi 1997)
Verkes et al
(1998)
Non-depressed
subjects who had
recently attempted
suicide for at least
the second time
81 met criteria
for a Cluster B PD
91 males and
females
Paroxet ine Started at 20 mgd
increased to
40 mgd after
1 wk
Parallel design
52 wk
79 (7291) dropped out prematurely
Significant efficacy in preventing
suicidal behaviour after controlling
for number of prior suicide
attempts Paroxetine more effective
in patients who met fewer than
15 Cluster B PD criteria Paroxetine
group did not differ from placebo
in depressed mood
hopelessness or anger
Battaglia
et al (1999)
Multiple suicide
attempters 85
had BPD
58 males and
females
Fluphenazine
decanoate
125 mg IM monthly
or 15 mg IM
monthly
Parallel design
but not placebo-
controlled
6 months
60 (3558) dropped out
prematurely Marked reduction in
self-harm behaviours but 125 mg
dose did not significantly differ from
15 mg dose According to authorslsquoThe lsquoultra-lowrsquo 15 mg dose was
chosen to represent the extreme
low end of possible
pharmacological effect for
fluphenazine treatment The
investigators believed that the
ethics review board would not
approve a study with the use of a
placebo in such a critically ill
group of patients
Hollander
et al (2001)
BPD 16 males and
females
Divalproex
sodium
Started at 250 mg qhs
increased gradually
to maintain valproate
levels of 80 mgml or
highest tolerable
dose Mean
endpoint valproate
level 6457 mgml
Parallel design
10 wk
50 (612) of medication group
and 100 (612) of placebo
group dropped out No statistically
significant benefits in ITT
analyses Among completers
significant improvements from
baseline in CGI and GAS ITT
data showed changes in expected
directions in BDI and AQ scores
Zanarini amp
Frankenburg
(2001)
BPD 28 females Olanzapine Started with
125 mgd then
titrated up to
mean dose of
533 mgd at
endpoint
Parallel design
6 months
68 (1928) dropped out
prematurely Improvements in
olanzapine group in anxiety
paranoia angerhostility and
interpersonal sensitivity
subscales but not depression
subscale of SCL-90
Frankenburg
amp Zanarini
(2002)
BPD and bipolar
disorder type II
30 females Divalproex
sodium
Started at 250 mg bid
then titrated to target
serum levels of
50ndash100 mgl
Parallel design 6
months
63 (1930) dropped out
prematurely Improvements in
medication group in
interpersonal sensitivity anger
hostility and overall aggression
Rinne et al
(2002)
BPD 38 females Fluvoxamine Began with 150 mgd
then titrated up to
a maximum of 250
mgd after 10th
week if insufficient
response
6-wk double-blind
placebo-controlled
phase followed by
6-wk singleblind
half-crossover
phase in which all
subjects received
fluvoxamine This
was followed by
Significant reduction in BPD
Severity Index rapid mood
shift subscale but not in
impulsivity or aggression
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
12-wk open label
study of
fluvoxamine
Hollander
et al (2003)
Cluster B PD IED or
PTSD with OAS-M
Aggression score
15
Males and females
Cluster B PD 96
with 55 BPD
13 NPD 10
AsPD 1 HPD
PD NOS 21) IED
116 PTSD 34
Divalproex
sodium
Began with 250 mg
bid then increased
by 250 mgd every
3ndash7d during first
3 wk Recommended
valproate levels were
80ndash120mgml by third
week Maximum dose
30 mgkgd
Parallel design
12 wk
44 (54124) divalproex group
and 39 (47122) placebo group
dropped out No differences in ITT
data sets when all subjects
included In Cluster B PD subjects
significant decreases in CGI
scores OAS-M irritability scores
and verbal assault and assault
against objects items of OAS-M
aggression scale in medication
group Secondary analysis
(Hollander et al 2005) revealed
improvements in impulsive
aggression in a subset of BPD
subjects and that high BIS
scores and high OAS-M
aggression scores predicted
better responses
Zanarini amp
Frankenburg
(2003)
BPD 30 females Ethyl-eicosa-
pentaenoic acid
(E-EPA)
500 mg b i d Pa ral le l d es ig n
8 wk
Better than placebo in reducing
aggression and severity of
depressive symptoms
Bogenschutz
amp Nurnberg
(2004)
BPD 40 males and
females
Olanzapine Started at 25 mgd
then increased by
25ndash5 mgdwk up to
10 mgd After week 8
dose could be further
increased to
maximum of 20 mgd
Most patients received
less than 10 mgd
Parallel design
12 wk
Superior to placebo on CGI
and CGI-BPD
Nickel et al
(2004)
BPD 31 females Topiramate Began with 50 mgd
then increased to
250 mgd by last
3 wk
Parallel design
8 wk
Significant improvements in
State-Anger Trait-Anger
Anger-Out and Anger-
Control subscales of STAXI
Philipsen
et al
(2004a )
BPD 22 females Clonidine 75 mg or l50 mg Crossov er design in
which each subject
received one 75 mg
dose and one
150 mg dose in
randomized
crossover fashion
during separate
episodes of lsquostrong
aversive inner
tension and urge
to commit
self-injurious
behaviourrsquo no
placebo-control
single-blind
Significant decreases in aversive
inner tension dissociative
symptoms suicidal ideation
and urges to commit
self-injurious behaviour
30ndash60 min after clonidine for
both doses Dose did not affect
response no placebo-control
Philipsen
et al (2004b )
BPD 9 females Naloxone
hydrochloride
04 mg IV administered
over 30 s
Crossover design in
which each subject
received one dose
of naloxone and
onedose of placebo
in randomized
Dissociative symptoms decreased
after both naloxone and placebo
but no difference between groups
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
crossover fashion
during separate
acute dissociative
episodes
Simpson
et al (2004)
BPD 25 females Fluoxetine plus
concurrent DBT
Started at 20 mgd
increased to 40 mgd
at week 3
Parallel design
12 wk
No significant group differences
from pre-treatment to
post-treatment
Zanarini et al
(2004b )
BPD 45 females Fluoxetine
olanzapine and
olanzapine-
fluoxetine
combination
(OFC)
Fluoxetine started at
10 mgd with endpoint
mean dose of 15 mgd
Olanzapine started at
25 mgd with endpoint
mean dose of 33 mgd
OFC started at
olanzapine 25 mgd
and fluoxetine 10 mgd
with endpoint mean
doses of 32 mgd and
127 mgd respectively
Parallel design but
not placebo-
controlled 8 wk
Olanzapine and OFC superior to
fluoxetine for depression and
impulsive aggression although
patients on fluoxetine improved
in both as well Weight gain
greater in olanzapine group than
fluoxetine or OFC groups
Nickel et al
(2005)
BPD 44 males Topiramate Began with 50 mgd
then increased to
250 mgd by last 3 wk
Parallel design
8 wk
Significant improvements for
medication group in State-Anger
Trait-Anger Anger-Out and
Anger-Control subscales of STAXI
Subsequent open-label follow-up
(Nickel amp Loew 2008)
demonstrated continued
benefits in topiramate group
in ITT analysis
Soler et al
(2005)
BPD 60 males and
females
Olanzapine with
concurrent DBT
Flexible dosing from 5ndash
20 mgd with mean
dose 883 mgd
Parallel design
12 wk
Olanzapine superior to placebo
for depression anxiety and
impulsive aggression
Tritt et al
(2005)
BPD 27 females Lamotrigine Started at 50 mgd then
increased to 100 mgd
during week 3
150 mgd during wk 4
and 5 and 200 mgd
during wk 6ndash8
Parallel design
8 wk
Significant improvement on
State-Anger Trait-Anger
Anger-Out and Anger-Control
subscales of STAXI in
medication group
Nickel et al
(2006)
BPD 52 males and
females
Aripiprazole 15 mgd Parallel design
8 wk
Aripiprazole group evidenced
greater improvements in SCL-90
subscales of obsessive-compulsive
symptoms insecurity in social
contacts depression anxiety
hostility phobic anxiety paranoia
and psychoticism as well as
global psychological stress
Medication group also improved
on HAMD and HAMA as well asall subscales of the STAXI Less
selfinjurious behaviour
observed in medication group
Loew et al
(2006)
BPD 59 females Topiramate Began with 25 mgd
increasing to a target
dose of 200 mgd by
the 6th week
Parallel design
10 wk
Significant improvements in
medication group in SCL-90
subscales of somatization
symptoms interpersonal sensitivity
anxiety hostility phobic anxiety
and global stress but not in
obsessive-compulsive
depression paranoia or
psychoticism subscales
Medication group significantly
(Continued)
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patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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I C A T
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
comorbid BPD and
SPD
mean final dose of
14762 mgd
Haloperidol began
at 2 mgd then
titrated upward tomean final dose of
724 mgd
Haloperidol superior to amitryptiline
in self-report measures of hostility
paranoia anxiety and depression
Little benefit from amitryptiline
even on depression Resultspresented again in Soloff et al
(1989) but outpatients deleted
from analyses (N 5 13)
Soloff et al
(1986c )
See above See above See above See above See above Haloperidol better than both
amitryptiline and placebo for overall
symptom severity Improvements
described as lsquomodest rsquo more
apparent in self-rated than
observer-rated measures
No differences between
amitryptiline and placebo
Soloff et al
(1986a
1987)
See above Papers analyse
paradoxical
response toamitryptiline
during study first
described in
Soloff et al
(1986b )
Compared 15
amitryptiline non-
responders
14 placebo
non-responders
13 amitryptiline
responders and
10 placebo
responders
Amitryptiline See above Mean final
amitryptiline1
nortryptiline bloodlevels were 246 ngml
for responders and
2459 ngml for non-
responders
See above Amitrypti line associated with
paradoxical increases in hostility
irritability impulsivity paranoiasuicide threats and demanding
and assaultive behaviour in
non-responders
Cowdry amp
Gardner
(1988)
BPD with lsquoprominent
behavioural
dyscontrolrsquo
16 females Alprazolam
carbamazepine
trifluoperazine
hydrochloride
tranylcypromine
sulfate
Mean doses of
alprazolam 47 mgd
carbamazepine
820 mgd
trifluoperazine
78 mgd and
tranylcypromine
40 mgd
Crossover design
each phase
lasting 6 wk
Tranylcypromine and carbamazepine
had lowest drop-out rates (25 and
33 respectively compared to
average 45) and were associated
with physician-rated improvements
Tranylcypromine also associated
with patient-rated improvements
Trifluoperazine completers showed
some improvements Carbamazepine
group showed improvement
especially in behavioural dyscontrol
(Gardner amp Cowdry 1986b )
Alprazolam group showed
worsening behavioural dyscontrol
(Cowdry amp Gardner 1988)3 subjects on carbamazepine
developed worsening melancholia
that remitted on discontinuation
(Gardner amp Cowdry 1986a )
Parsons et al
(1989)
BPD and atypical
depression
First sample of
subjects were
required to meet
5 BPD criteria
(N 5 40) second
sample met 4
Phenelzine
imipramine
Phenelzine titration to
60 mgd with
option to increase to
90 mgd if no
response by week 5
Imipramine titration
to 200 mgd with
Crossover
design two
6-wk phases
Greater proportion of subjects
responded to phenelzine than
imipramine Presence of BPD
symptoms was negative predictor
of response to imipramine in
subjects with 4 or more BPD
symptoms higher number
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
BPD criteria
(N 5 19)
option to increase
to 300 mgd if no
response by week 5
of symptoms predicted superiority
of phenelzine
Soloff et al
(1989)
Same as Soloff
et al (1986 b)
90 total with 35
lsquounstablersquo BPD
4 SPD and 51
lsquomixedrsquo BPD
and SPD
Same as Soloff
et al (1986b )
Same procedure as
Soloff et al (1986b )
Mean dose of
haloperidol was 48
mgd and mean dose
of amitryptiline was
1491 mgd on
day 35
Parallel design
5 wk
Significant differences between
haloperidol and placebo in global
functioning depression hostility
schizotypy and impulsivity
Differences between amitryptiline
and placebo limited to depressive
symptoms Final results of 4-year
study only analyzed data from
inpatients deleting data from
outpatients in prior reports
Links et al
(1990)
BPD 17 males and
females
Lithium
carbonate
desipramine
Not spe ci fi ed Cr ossover d es ig n
two 6-wk phases
No statistically significant effects on
depression Trend towards decrease
in anger and suicidality in lithium
group relative to desipramine
Therapistsrsquo perceptions favored
lithium over placebo Trendtowards favoring lithium over
desipramine Therapists did not find
desipramine superior to placebo
Soloff et al
(1993)
BPD 108 males and
females
Haloperidol
phenelzine
Haloperidol began at
1 mgd then titrated
up to mean dose of
4 mgd Phenelzine
began at 15 mgd
then titrated up to
mean dose of 60
mgd
Parallel design
5 wk
Improvements observed with
haloperidol in Soloff et al
(1986a ndashc 19871989) were not
replicated Phenelzine associated
with improvements in depression
borderline symptoms anxiety
anger and hostility but not
atypical depressionhysteroid
dysphoria
Cornelius
et al (1993)
BPD 54 males and
females
Haloperidol
phenelzine
Haloperidol up to 6
mgd phenelzine upto 90 mgd Doses
generally did not
change from final
dose of prior 5-wk
acute phase
(Soloff et al 1993)
Parallel design
16 wk following 5-wk
acute phase
(Soloff et al
1993)
Drop-out rate during entire 22-wk
study acute phase (Soloff et al1993) and continuation was
73 (79108) Only benefit in
haloperidol group was decreased
irritability Haloperidol contributed
to worsening depression leaden
paralysis and hypersomnia
Phenelzine showed modest
efficacy on depression and
irritability but unpleasant activation
de la Fuente
amp Lotstra
(1994)
BPD 20 males and
females
Carbamazepine Dosed to obtain
therapeutic blood
levels
Parallel design
32 days
No significant benefit
Salzman
et al (1995)
BPD 27 males and
females
Fluoxet ine Started at 20 mgd
titrated up toa maximum of
60 mgd with mean
dose of 40 mgd
Parallel design
12 wk
Decrease in anger with fluoxetine
but high placebo response rateSubjects from outpatient sample
without Axis I comorbidity limiting
generalizability
Coccaro amp
Kavoussi
(1997)
All subjects had at
least one PD as
well as current
problems with
impulsive aggression
and irritability Most
frequent PD was
BPD
40 males and
females
Fluoxet ine Started at 20 mgd
and after end of 4th
week could be
increased to
40 mgd with further
increase to 60 mgd
possible after end of
8th week
Parallel design
12 wk
Reduction in irritability and
aggression subscales of OAS-M
Higher proportion of CGI
responders in fluoxetine group
relative to placebo
D-fenfluramine challenge of subset
of 15 subjects showed positive
correlation in fluoxetine-treated but
not placebo-treated subjects
(Continued)
230 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
between improvement in OAS-M
subscales and pre-treatment
prolactin response (Coccaro
amp Kavoussi 1997)
Verkes et al
(1998)
Non-depressed
subjects who had
recently attempted
suicide for at least
the second time
81 met criteria
for a Cluster B PD
91 males and
females
Paroxet ine Started at 20 mgd
increased to
40 mgd after
1 wk
Parallel design
52 wk
79 (7291) dropped out prematurely
Significant efficacy in preventing
suicidal behaviour after controlling
for number of prior suicide
attempts Paroxetine more effective
in patients who met fewer than
15 Cluster B PD criteria Paroxetine
group did not differ from placebo
in depressed mood
hopelessness or anger
Battaglia
et al (1999)
Multiple suicide
attempters 85
had BPD
58 males and
females
Fluphenazine
decanoate
125 mg IM monthly
or 15 mg IM
monthly
Parallel design
but not placebo-
controlled
6 months
60 (3558) dropped out
prematurely Marked reduction in
self-harm behaviours but 125 mg
dose did not significantly differ from
15 mg dose According to authorslsquoThe lsquoultra-lowrsquo 15 mg dose was
chosen to represent the extreme
low end of possible
pharmacological effect for
fluphenazine treatment The
investigators believed that the
ethics review board would not
approve a study with the use of a
placebo in such a critically ill
group of patients
Hollander
et al (2001)
BPD 16 males and
females
Divalproex
sodium
Started at 250 mg qhs
increased gradually
to maintain valproate
levels of 80 mgml or
highest tolerable
dose Mean
endpoint valproate
level 6457 mgml
Parallel design
10 wk
50 (612) of medication group
and 100 (612) of placebo
group dropped out No statistically
significant benefits in ITT
analyses Among completers
significant improvements from
baseline in CGI and GAS ITT
data showed changes in expected
directions in BDI and AQ scores
Zanarini amp
Frankenburg
(2001)
BPD 28 females Olanzapine Started with
125 mgd then
titrated up to
mean dose of
533 mgd at
endpoint
Parallel design
6 months
68 (1928) dropped out
prematurely Improvements in
olanzapine group in anxiety
paranoia angerhostility and
interpersonal sensitivity
subscales but not depression
subscale of SCL-90
Frankenburg
amp Zanarini
(2002)
BPD and bipolar
disorder type II
30 females Divalproex
sodium
Started at 250 mg bid
then titrated to target
serum levels of
50ndash100 mgl
Parallel design 6
months
63 (1930) dropped out
prematurely Improvements in
medication group in
interpersonal sensitivity anger
hostility and overall aggression
Rinne et al
(2002)
BPD 38 females Fluvoxamine Began with 150 mgd
then titrated up to
a maximum of 250
mgd after 10th
week if insufficient
response
6-wk double-blind
placebo-controlled
phase followed by
6-wk singleblind
half-crossover
phase in which all
subjects received
fluvoxamine This
was followed by
Significant reduction in BPD
Severity Index rapid mood
shift subscale but not in
impulsivity or aggression
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
12-wk open label
study of
fluvoxamine
Hollander
et al (2003)
Cluster B PD IED or
PTSD with OAS-M
Aggression score
15
Males and females
Cluster B PD 96
with 55 BPD
13 NPD 10
AsPD 1 HPD
PD NOS 21) IED
116 PTSD 34
Divalproex
sodium
Began with 250 mg
bid then increased
by 250 mgd every
3ndash7d during first
3 wk Recommended
valproate levels were
80ndash120mgml by third
week Maximum dose
30 mgkgd
Parallel design
12 wk
44 (54124) divalproex group
and 39 (47122) placebo group
dropped out No differences in ITT
data sets when all subjects
included In Cluster B PD subjects
significant decreases in CGI
scores OAS-M irritability scores
and verbal assault and assault
against objects items of OAS-M
aggression scale in medication
group Secondary analysis
(Hollander et al 2005) revealed
improvements in impulsive
aggression in a subset of BPD
subjects and that high BIS
scores and high OAS-M
aggression scores predicted
better responses
Zanarini amp
Frankenburg
(2003)
BPD 30 females Ethyl-eicosa-
pentaenoic acid
(E-EPA)
500 mg b i d Pa ral le l d es ig n
8 wk
Better than placebo in reducing
aggression and severity of
depressive symptoms
Bogenschutz
amp Nurnberg
(2004)
BPD 40 males and
females
Olanzapine Started at 25 mgd
then increased by
25ndash5 mgdwk up to
10 mgd After week 8
dose could be further
increased to
maximum of 20 mgd
Most patients received
less than 10 mgd
Parallel design
12 wk
Superior to placebo on CGI
and CGI-BPD
Nickel et al
(2004)
BPD 31 females Topiramate Began with 50 mgd
then increased to
250 mgd by last
3 wk
Parallel design
8 wk
Significant improvements in
State-Anger Trait-Anger
Anger-Out and Anger-
Control subscales of STAXI
Philipsen
et al
(2004a )
BPD 22 females Clonidine 75 mg or l50 mg Crossov er design in
which each subject
received one 75 mg
dose and one
150 mg dose in
randomized
crossover fashion
during separate
episodes of lsquostrong
aversive inner
tension and urge
to commit
self-injurious
behaviourrsquo no
placebo-control
single-blind
Significant decreases in aversive
inner tension dissociative
symptoms suicidal ideation
and urges to commit
self-injurious behaviour
30ndash60 min after clonidine for
both doses Dose did not affect
response no placebo-control
Philipsen
et al (2004b )
BPD 9 females Naloxone
hydrochloride
04 mg IV administered
over 30 s
Crossover design in
which each subject
received one dose
of naloxone and
onedose of placebo
in randomized
Dissociative symptoms decreased
after both naloxone and placebo
but no difference between groups
(Continued)
232 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
crossover fashion
during separate
acute dissociative
episodes
Simpson
et al (2004)
BPD 25 females Fluoxetine plus
concurrent DBT
Started at 20 mgd
increased to 40 mgd
at week 3
Parallel design
12 wk
No significant group differences
from pre-treatment to
post-treatment
Zanarini et al
(2004b )
BPD 45 females Fluoxetine
olanzapine and
olanzapine-
fluoxetine
combination
(OFC)
Fluoxetine started at
10 mgd with endpoint
mean dose of 15 mgd
Olanzapine started at
25 mgd with endpoint
mean dose of 33 mgd
OFC started at
olanzapine 25 mgd
and fluoxetine 10 mgd
with endpoint mean
doses of 32 mgd and
127 mgd respectively
Parallel design but
not placebo-
controlled 8 wk
Olanzapine and OFC superior to
fluoxetine for depression and
impulsive aggression although
patients on fluoxetine improved
in both as well Weight gain
greater in olanzapine group than
fluoxetine or OFC groups
Nickel et al
(2005)
BPD 44 males Topiramate Began with 50 mgd
then increased to
250 mgd by last 3 wk
Parallel design
8 wk
Significant improvements for
medication group in State-Anger
Trait-Anger Anger-Out and
Anger-Control subscales of STAXI
Subsequent open-label follow-up
(Nickel amp Loew 2008)
demonstrated continued
benefits in topiramate group
in ITT analysis
Soler et al
(2005)
BPD 60 males and
females
Olanzapine with
concurrent DBT
Flexible dosing from 5ndash
20 mgd with mean
dose 883 mgd
Parallel design
12 wk
Olanzapine superior to placebo
for depression anxiety and
impulsive aggression
Tritt et al
(2005)
BPD 27 females Lamotrigine Started at 50 mgd then
increased to 100 mgd
during week 3
150 mgd during wk 4
and 5 and 200 mgd
during wk 6ndash8
Parallel design
8 wk
Significant improvement on
State-Anger Trait-Anger
Anger-Out and Anger-Control
subscales of STAXI in
medication group
Nickel et al
(2006)
BPD 52 males and
females
Aripiprazole 15 mgd Parallel design
8 wk
Aripiprazole group evidenced
greater improvements in SCL-90
subscales of obsessive-compulsive
symptoms insecurity in social
contacts depression anxiety
hostility phobic anxiety paranoia
and psychoticism as well as
global psychological stress
Medication group also improved
on HAMD and HAMA as well asall subscales of the STAXI Less
selfinjurious behaviour
observed in medication group
Loew et al
(2006)
BPD 59 females Topiramate Began with 25 mgd
increasing to a target
dose of 200 mgd by
the 6th week
Parallel design
10 wk
Significant improvements in
medication group in SCL-90
subscales of somatization
symptoms interpersonal sensitivity
anxiety hostility phobic anxiety
and global stress but not in
obsessive-compulsive
depression paranoia or
psychoticism subscales
Medication group significantly
(Continued)
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patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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httpslidepdfcomreaderfullfarmacos-en-personalidad 1924
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
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P U
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8112019 Farmacos en Personalidad
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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8112019 Farmacos en Personalidad
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
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Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2424
Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 624
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
BPD criteria
(N 5 19)
option to increase
to 300 mgd if no
response by week 5
of symptoms predicted superiority
of phenelzine
Soloff et al
(1989)
Same as Soloff
et al (1986 b)
90 total with 35
lsquounstablersquo BPD
4 SPD and 51
lsquomixedrsquo BPD
and SPD
Same as Soloff
et al (1986b )
Same procedure as
Soloff et al (1986b )
Mean dose of
haloperidol was 48
mgd and mean dose
of amitryptiline was
1491 mgd on
day 35
Parallel design
5 wk
Significant differences between
haloperidol and placebo in global
functioning depression hostility
schizotypy and impulsivity
Differences between amitryptiline
and placebo limited to depressive
symptoms Final results of 4-year
study only analyzed data from
inpatients deleting data from
outpatients in prior reports
Links et al
(1990)
BPD 17 males and
females
Lithium
carbonate
desipramine
Not spe ci fi ed Cr ossover d es ig n
two 6-wk phases
No statistically significant effects on
depression Trend towards decrease
in anger and suicidality in lithium
group relative to desipramine
Therapistsrsquo perceptions favored
lithium over placebo Trendtowards favoring lithium over
desipramine Therapists did not find
desipramine superior to placebo
Soloff et al
(1993)
BPD 108 males and
females
Haloperidol
phenelzine
Haloperidol began at
1 mgd then titrated
up to mean dose of
4 mgd Phenelzine
began at 15 mgd
then titrated up to
mean dose of 60
mgd
Parallel design
5 wk
Improvements observed with
haloperidol in Soloff et al
(1986a ndashc 19871989) were not
replicated Phenelzine associated
with improvements in depression
borderline symptoms anxiety
anger and hostility but not
atypical depressionhysteroid
dysphoria
Cornelius
et al (1993)
BPD 54 males and
females
Haloperidol
phenelzine
Haloperidol up to 6
mgd phenelzine upto 90 mgd Doses
generally did not
change from final
dose of prior 5-wk
acute phase
(Soloff et al 1993)
Parallel design
16 wk following 5-wk
acute phase
(Soloff et al
1993)
Drop-out rate during entire 22-wk
study acute phase (Soloff et al1993) and continuation was
73 (79108) Only benefit in
haloperidol group was decreased
irritability Haloperidol contributed
to worsening depression leaden
paralysis and hypersomnia
Phenelzine showed modest
efficacy on depression and
irritability but unpleasant activation
de la Fuente
amp Lotstra
(1994)
BPD 20 males and
females
Carbamazepine Dosed to obtain
therapeutic blood
levels
Parallel design
32 days
No significant benefit
Salzman
et al (1995)
BPD 27 males and
females
Fluoxet ine Started at 20 mgd
titrated up toa maximum of
60 mgd with mean
dose of 40 mgd
Parallel design
12 wk
Decrease in anger with fluoxetine
but high placebo response rateSubjects from outpatient sample
without Axis I comorbidity limiting
generalizability
Coccaro amp
Kavoussi
(1997)
All subjects had at
least one PD as
well as current
problems with
impulsive aggression
and irritability Most
frequent PD was
BPD
40 males and
females
Fluoxet ine Started at 20 mgd
and after end of 4th
week could be
increased to
40 mgd with further
increase to 60 mgd
possible after end of
8th week
Parallel design
12 wk
Reduction in irritability and
aggression subscales of OAS-M
Higher proportion of CGI
responders in fluoxetine group
relative to placebo
D-fenfluramine challenge of subset
of 15 subjects showed positive
correlation in fluoxetine-treated but
not placebo-treated subjects
(Continued)
230 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 724
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
between improvement in OAS-M
subscales and pre-treatment
prolactin response (Coccaro
amp Kavoussi 1997)
Verkes et al
(1998)
Non-depressed
subjects who had
recently attempted
suicide for at least
the second time
81 met criteria
for a Cluster B PD
91 males and
females
Paroxet ine Started at 20 mgd
increased to
40 mgd after
1 wk
Parallel design
52 wk
79 (7291) dropped out prematurely
Significant efficacy in preventing
suicidal behaviour after controlling
for number of prior suicide
attempts Paroxetine more effective
in patients who met fewer than
15 Cluster B PD criteria Paroxetine
group did not differ from placebo
in depressed mood
hopelessness or anger
Battaglia
et al (1999)
Multiple suicide
attempters 85
had BPD
58 males and
females
Fluphenazine
decanoate
125 mg IM monthly
or 15 mg IM
monthly
Parallel design
but not placebo-
controlled
6 months
60 (3558) dropped out
prematurely Marked reduction in
self-harm behaviours but 125 mg
dose did not significantly differ from
15 mg dose According to authorslsquoThe lsquoultra-lowrsquo 15 mg dose was
chosen to represent the extreme
low end of possible
pharmacological effect for
fluphenazine treatment The
investigators believed that the
ethics review board would not
approve a study with the use of a
placebo in such a critically ill
group of patients
Hollander
et al (2001)
BPD 16 males and
females
Divalproex
sodium
Started at 250 mg qhs
increased gradually
to maintain valproate
levels of 80 mgml or
highest tolerable
dose Mean
endpoint valproate
level 6457 mgml
Parallel design
10 wk
50 (612) of medication group
and 100 (612) of placebo
group dropped out No statistically
significant benefits in ITT
analyses Among completers
significant improvements from
baseline in CGI and GAS ITT
data showed changes in expected
directions in BDI and AQ scores
Zanarini amp
Frankenburg
(2001)
BPD 28 females Olanzapine Started with
125 mgd then
titrated up to
mean dose of
533 mgd at
endpoint
Parallel design
6 months
68 (1928) dropped out
prematurely Improvements in
olanzapine group in anxiety
paranoia angerhostility and
interpersonal sensitivity
subscales but not depression
subscale of SCL-90
Frankenburg
amp Zanarini
(2002)
BPD and bipolar
disorder type II
30 females Divalproex
sodium
Started at 250 mg bid
then titrated to target
serum levels of
50ndash100 mgl
Parallel design 6
months
63 (1930) dropped out
prematurely Improvements in
medication group in
interpersonal sensitivity anger
hostility and overall aggression
Rinne et al
(2002)
BPD 38 females Fluvoxamine Began with 150 mgd
then titrated up to
a maximum of 250
mgd after 10th
week if insufficient
response
6-wk double-blind
placebo-controlled
phase followed by
6-wk singleblind
half-crossover
phase in which all
subjects received
fluvoxamine This
was followed by
Significant reduction in BPD
Severity Index rapid mood
shift subscale but not in
impulsivity or aggression
(Continued)
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 231
R IPOLL ET AL
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 824
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
12-wk open label
study of
fluvoxamine
Hollander
et al (2003)
Cluster B PD IED or
PTSD with OAS-M
Aggression score
15
Males and females
Cluster B PD 96
with 55 BPD
13 NPD 10
AsPD 1 HPD
PD NOS 21) IED
116 PTSD 34
Divalproex
sodium
Began with 250 mg
bid then increased
by 250 mgd every
3ndash7d during first
3 wk Recommended
valproate levels were
80ndash120mgml by third
week Maximum dose
30 mgkgd
Parallel design
12 wk
44 (54124) divalproex group
and 39 (47122) placebo group
dropped out No differences in ITT
data sets when all subjects
included In Cluster B PD subjects
significant decreases in CGI
scores OAS-M irritability scores
and verbal assault and assault
against objects items of OAS-M
aggression scale in medication
group Secondary analysis
(Hollander et al 2005) revealed
improvements in impulsive
aggression in a subset of BPD
subjects and that high BIS
scores and high OAS-M
aggression scores predicted
better responses
Zanarini amp
Frankenburg
(2003)
BPD 30 females Ethyl-eicosa-
pentaenoic acid
(E-EPA)
500 mg b i d Pa ral le l d es ig n
8 wk
Better than placebo in reducing
aggression and severity of
depressive symptoms
Bogenschutz
amp Nurnberg
(2004)
BPD 40 males and
females
Olanzapine Started at 25 mgd
then increased by
25ndash5 mgdwk up to
10 mgd After week 8
dose could be further
increased to
maximum of 20 mgd
Most patients received
less than 10 mgd
Parallel design
12 wk
Superior to placebo on CGI
and CGI-BPD
Nickel et al
(2004)
BPD 31 females Topiramate Began with 50 mgd
then increased to
250 mgd by last
3 wk
Parallel design
8 wk
Significant improvements in
State-Anger Trait-Anger
Anger-Out and Anger-
Control subscales of STAXI
Philipsen
et al
(2004a )
BPD 22 females Clonidine 75 mg or l50 mg Crossov er design in
which each subject
received one 75 mg
dose and one
150 mg dose in
randomized
crossover fashion
during separate
episodes of lsquostrong
aversive inner
tension and urge
to commit
self-injurious
behaviourrsquo no
placebo-control
single-blind
Significant decreases in aversive
inner tension dissociative
symptoms suicidal ideation
and urges to commit
self-injurious behaviour
30ndash60 min after clonidine for
both doses Dose did not affect
response no placebo-control
Philipsen
et al (2004b )
BPD 9 females Naloxone
hydrochloride
04 mg IV administered
over 30 s
Crossover design in
which each subject
received one dose
of naloxone and
onedose of placebo
in randomized
Dissociative symptoms decreased
after both naloxone and placebo
but no difference between groups
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
crossover fashion
during separate
acute dissociative
episodes
Simpson
et al (2004)
BPD 25 females Fluoxetine plus
concurrent DBT
Started at 20 mgd
increased to 40 mgd
at week 3
Parallel design
12 wk
No significant group differences
from pre-treatment to
post-treatment
Zanarini et al
(2004b )
BPD 45 females Fluoxetine
olanzapine and
olanzapine-
fluoxetine
combination
(OFC)
Fluoxetine started at
10 mgd with endpoint
mean dose of 15 mgd
Olanzapine started at
25 mgd with endpoint
mean dose of 33 mgd
OFC started at
olanzapine 25 mgd
and fluoxetine 10 mgd
with endpoint mean
doses of 32 mgd and
127 mgd respectively
Parallel design but
not placebo-
controlled 8 wk
Olanzapine and OFC superior to
fluoxetine for depression and
impulsive aggression although
patients on fluoxetine improved
in both as well Weight gain
greater in olanzapine group than
fluoxetine or OFC groups
Nickel et al
(2005)
BPD 44 males Topiramate Began with 50 mgd
then increased to
250 mgd by last 3 wk
Parallel design
8 wk
Significant improvements for
medication group in State-Anger
Trait-Anger Anger-Out and
Anger-Control subscales of STAXI
Subsequent open-label follow-up
(Nickel amp Loew 2008)
demonstrated continued
benefits in topiramate group
in ITT analysis
Soler et al
(2005)
BPD 60 males and
females
Olanzapine with
concurrent DBT
Flexible dosing from 5ndash
20 mgd with mean
dose 883 mgd
Parallel design
12 wk
Olanzapine superior to placebo
for depression anxiety and
impulsive aggression
Tritt et al
(2005)
BPD 27 females Lamotrigine Started at 50 mgd then
increased to 100 mgd
during week 3
150 mgd during wk 4
and 5 and 200 mgd
during wk 6ndash8
Parallel design
8 wk
Significant improvement on
State-Anger Trait-Anger
Anger-Out and Anger-Control
subscales of STAXI in
medication group
Nickel et al
(2006)
BPD 52 males and
females
Aripiprazole 15 mgd Parallel design
8 wk
Aripiprazole group evidenced
greater improvements in SCL-90
subscales of obsessive-compulsive
symptoms insecurity in social
contacts depression anxiety
hostility phobic anxiety paranoia
and psychoticism as well as
global psychological stress
Medication group also improved
on HAMD and HAMA as well asall subscales of the STAXI Less
selfinjurious behaviour
observed in medication group
Loew et al
(2006)
BPD 59 females Topiramate Began with 25 mgd
increasing to a target
dose of 200 mgd by
the 6th week
Parallel design
10 wk
Significant improvements in
medication group in SCL-90
subscales of somatization
symptoms interpersonal sensitivity
anxiety hostility phobic anxiety
and global stress but not in
obsessive-compulsive
depression paranoia or
psychoticism subscales
Medication group significantly
(Continued)
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patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
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borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
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R IPOLL ET AL
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Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2424
Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 724
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
between improvement in OAS-M
subscales and pre-treatment
prolactin response (Coccaro
amp Kavoussi 1997)
Verkes et al
(1998)
Non-depressed
subjects who had
recently attempted
suicide for at least
the second time
81 met criteria
for a Cluster B PD
91 males and
females
Paroxet ine Started at 20 mgd
increased to
40 mgd after
1 wk
Parallel design
52 wk
79 (7291) dropped out prematurely
Significant efficacy in preventing
suicidal behaviour after controlling
for number of prior suicide
attempts Paroxetine more effective
in patients who met fewer than
15 Cluster B PD criteria Paroxetine
group did not differ from placebo
in depressed mood
hopelessness or anger
Battaglia
et al (1999)
Multiple suicide
attempters 85
had BPD
58 males and
females
Fluphenazine
decanoate
125 mg IM monthly
or 15 mg IM
monthly
Parallel design
but not placebo-
controlled
6 months
60 (3558) dropped out
prematurely Marked reduction in
self-harm behaviours but 125 mg
dose did not significantly differ from
15 mg dose According to authorslsquoThe lsquoultra-lowrsquo 15 mg dose was
chosen to represent the extreme
low end of possible
pharmacological effect for
fluphenazine treatment The
investigators believed that the
ethics review board would not
approve a study with the use of a
placebo in such a critically ill
group of patients
Hollander
et al (2001)
BPD 16 males and
females
Divalproex
sodium
Started at 250 mg qhs
increased gradually
to maintain valproate
levels of 80 mgml or
highest tolerable
dose Mean
endpoint valproate
level 6457 mgml
Parallel design
10 wk
50 (612) of medication group
and 100 (612) of placebo
group dropped out No statistically
significant benefits in ITT
analyses Among completers
significant improvements from
baseline in CGI and GAS ITT
data showed changes in expected
directions in BDI and AQ scores
Zanarini amp
Frankenburg
(2001)
BPD 28 females Olanzapine Started with
125 mgd then
titrated up to
mean dose of
533 mgd at
endpoint
Parallel design
6 months
68 (1928) dropped out
prematurely Improvements in
olanzapine group in anxiety
paranoia angerhostility and
interpersonal sensitivity
subscales but not depression
subscale of SCL-90
Frankenburg
amp Zanarini
(2002)
BPD and bipolar
disorder type II
30 females Divalproex
sodium
Started at 250 mg bid
then titrated to target
serum levels of
50ndash100 mgl
Parallel design 6
months
63 (1930) dropped out
prematurely Improvements in
medication group in
interpersonal sensitivity anger
hostility and overall aggression
Rinne et al
(2002)
BPD 38 females Fluvoxamine Began with 150 mgd
then titrated up to
a maximum of 250
mgd after 10th
week if insufficient
response
6-wk double-blind
placebo-controlled
phase followed by
6-wk singleblind
half-crossover
phase in which all
subjects received
fluvoxamine This
was followed by
Significant reduction in BPD
Severity Index rapid mood
shift subscale but not in
impulsivity or aggression
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
12-wk open label
study of
fluvoxamine
Hollander
et al (2003)
Cluster B PD IED or
PTSD with OAS-M
Aggression score
15
Males and females
Cluster B PD 96
with 55 BPD
13 NPD 10
AsPD 1 HPD
PD NOS 21) IED
116 PTSD 34
Divalproex
sodium
Began with 250 mg
bid then increased
by 250 mgd every
3ndash7d during first
3 wk Recommended
valproate levels were
80ndash120mgml by third
week Maximum dose
30 mgkgd
Parallel design
12 wk
44 (54124) divalproex group
and 39 (47122) placebo group
dropped out No differences in ITT
data sets when all subjects
included In Cluster B PD subjects
significant decreases in CGI
scores OAS-M irritability scores
and verbal assault and assault
against objects items of OAS-M
aggression scale in medication
group Secondary analysis
(Hollander et al 2005) revealed
improvements in impulsive
aggression in a subset of BPD
subjects and that high BIS
scores and high OAS-M
aggression scores predicted
better responses
Zanarini amp
Frankenburg
(2003)
BPD 30 females Ethyl-eicosa-
pentaenoic acid
(E-EPA)
500 mg b i d Pa ral le l d es ig n
8 wk
Better than placebo in reducing
aggression and severity of
depressive symptoms
Bogenschutz
amp Nurnberg
(2004)
BPD 40 males and
females
Olanzapine Started at 25 mgd
then increased by
25ndash5 mgdwk up to
10 mgd After week 8
dose could be further
increased to
maximum of 20 mgd
Most patients received
less than 10 mgd
Parallel design
12 wk
Superior to placebo on CGI
and CGI-BPD
Nickel et al
(2004)
BPD 31 females Topiramate Began with 50 mgd
then increased to
250 mgd by last
3 wk
Parallel design
8 wk
Significant improvements in
State-Anger Trait-Anger
Anger-Out and Anger-
Control subscales of STAXI
Philipsen
et al
(2004a )
BPD 22 females Clonidine 75 mg or l50 mg Crossov er design in
which each subject
received one 75 mg
dose and one
150 mg dose in
randomized
crossover fashion
during separate
episodes of lsquostrong
aversive inner
tension and urge
to commit
self-injurious
behaviourrsquo no
placebo-control
single-blind
Significant decreases in aversive
inner tension dissociative
symptoms suicidal ideation
and urges to commit
self-injurious behaviour
30ndash60 min after clonidine for
both doses Dose did not affect
response no placebo-control
Philipsen
et al (2004b )
BPD 9 females Naloxone
hydrochloride
04 mg IV administered
over 30 s
Crossover design in
which each subject
received one dose
of naloxone and
onedose of placebo
in randomized
Dissociative symptoms decreased
after both naloxone and placebo
but no difference between groups
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
crossover fashion
during separate
acute dissociative
episodes
Simpson
et al (2004)
BPD 25 females Fluoxetine plus
concurrent DBT
Started at 20 mgd
increased to 40 mgd
at week 3
Parallel design
12 wk
No significant group differences
from pre-treatment to
post-treatment
Zanarini et al
(2004b )
BPD 45 females Fluoxetine
olanzapine and
olanzapine-
fluoxetine
combination
(OFC)
Fluoxetine started at
10 mgd with endpoint
mean dose of 15 mgd
Olanzapine started at
25 mgd with endpoint
mean dose of 33 mgd
OFC started at
olanzapine 25 mgd
and fluoxetine 10 mgd
with endpoint mean
doses of 32 mgd and
127 mgd respectively
Parallel design but
not placebo-
controlled 8 wk
Olanzapine and OFC superior to
fluoxetine for depression and
impulsive aggression although
patients on fluoxetine improved
in both as well Weight gain
greater in olanzapine group than
fluoxetine or OFC groups
Nickel et al
(2005)
BPD 44 males Topiramate Began with 50 mgd
then increased to
250 mgd by last 3 wk
Parallel design
8 wk
Significant improvements for
medication group in State-Anger
Trait-Anger Anger-Out and
Anger-Control subscales of STAXI
Subsequent open-label follow-up
(Nickel amp Loew 2008)
demonstrated continued
benefits in topiramate group
in ITT analysis
Soler et al
(2005)
BPD 60 males and
females
Olanzapine with
concurrent DBT
Flexible dosing from 5ndash
20 mgd with mean
dose 883 mgd
Parallel design
12 wk
Olanzapine superior to placebo
for depression anxiety and
impulsive aggression
Tritt et al
(2005)
BPD 27 females Lamotrigine Started at 50 mgd then
increased to 100 mgd
during week 3
150 mgd during wk 4
and 5 and 200 mgd
during wk 6ndash8
Parallel design
8 wk
Significant improvement on
State-Anger Trait-Anger
Anger-Out and Anger-Control
subscales of STAXI in
medication group
Nickel et al
(2006)
BPD 52 males and
females
Aripiprazole 15 mgd Parallel design
8 wk
Aripiprazole group evidenced
greater improvements in SCL-90
subscales of obsessive-compulsive
symptoms insecurity in social
contacts depression anxiety
hostility phobic anxiety paranoia
and psychoticism as well as
global psychological stress
Medication group also improved
on HAMD and HAMA as well asall subscales of the STAXI Less
selfinjurious behaviour
observed in medication group
Loew et al
(2006)
BPD 59 females Topiramate Began with 25 mgd
increasing to a target
dose of 200 mgd by
the 6th week
Parallel design
10 wk
Significant improvements in
medication group in SCL-90
subscales of somatization
symptoms interpersonal sensitivity
anxiety hostility phobic anxiety
and global stress but not in
obsessive-compulsive
depression paranoia or
psychoticism subscales
Medication group significantly
(Continued)
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patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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I C A T
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
12-wk open label
study of
fluvoxamine
Hollander
et al (2003)
Cluster B PD IED or
PTSD with OAS-M
Aggression score
15
Males and females
Cluster B PD 96
with 55 BPD
13 NPD 10
AsPD 1 HPD
PD NOS 21) IED
116 PTSD 34
Divalproex
sodium
Began with 250 mg
bid then increased
by 250 mgd every
3ndash7d during first
3 wk Recommended
valproate levels were
80ndash120mgml by third
week Maximum dose
30 mgkgd
Parallel design
12 wk
44 (54124) divalproex group
and 39 (47122) placebo group
dropped out No differences in ITT
data sets when all subjects
included In Cluster B PD subjects
significant decreases in CGI
scores OAS-M irritability scores
and verbal assault and assault
against objects items of OAS-M
aggression scale in medication
group Secondary analysis
(Hollander et al 2005) revealed
improvements in impulsive
aggression in a subset of BPD
subjects and that high BIS
scores and high OAS-M
aggression scores predicted
better responses
Zanarini amp
Frankenburg
(2003)
BPD 30 females Ethyl-eicosa-
pentaenoic acid
(E-EPA)
500 mg b i d Pa ral le l d es ig n
8 wk
Better than placebo in reducing
aggression and severity of
depressive symptoms
Bogenschutz
amp Nurnberg
(2004)
BPD 40 males and
females
Olanzapine Started at 25 mgd
then increased by
25ndash5 mgdwk up to
10 mgd After week 8
dose could be further
increased to
maximum of 20 mgd
Most patients received
less than 10 mgd
Parallel design
12 wk
Superior to placebo on CGI
and CGI-BPD
Nickel et al
(2004)
BPD 31 females Topiramate Began with 50 mgd
then increased to
250 mgd by last
3 wk
Parallel design
8 wk
Significant improvements in
State-Anger Trait-Anger
Anger-Out and Anger-
Control subscales of STAXI
Philipsen
et al
(2004a )
BPD 22 females Clonidine 75 mg or l50 mg Crossov er design in
which each subject
received one 75 mg
dose and one
150 mg dose in
randomized
crossover fashion
during separate
episodes of lsquostrong
aversive inner
tension and urge
to commit
self-injurious
behaviourrsquo no
placebo-control
single-blind
Significant decreases in aversive
inner tension dissociative
symptoms suicidal ideation
and urges to commit
self-injurious behaviour
30ndash60 min after clonidine for
both doses Dose did not affect
response no placebo-control
Philipsen
et al (2004b )
BPD 9 females Naloxone
hydrochloride
04 mg IV administered
over 30 s
Crossover design in
which each subject
received one dose
of naloxone and
onedose of placebo
in randomized
Dissociative symptoms decreased
after both naloxone and placebo
but no difference between groups
(Continued)
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
crossover fashion
during separate
acute dissociative
episodes
Simpson
et al (2004)
BPD 25 females Fluoxetine plus
concurrent DBT
Started at 20 mgd
increased to 40 mgd
at week 3
Parallel design
12 wk
No significant group differences
from pre-treatment to
post-treatment
Zanarini et al
(2004b )
BPD 45 females Fluoxetine
olanzapine and
olanzapine-
fluoxetine
combination
(OFC)
Fluoxetine started at
10 mgd with endpoint
mean dose of 15 mgd
Olanzapine started at
25 mgd with endpoint
mean dose of 33 mgd
OFC started at
olanzapine 25 mgd
and fluoxetine 10 mgd
with endpoint mean
doses of 32 mgd and
127 mgd respectively
Parallel design but
not placebo-
controlled 8 wk
Olanzapine and OFC superior to
fluoxetine for depression and
impulsive aggression although
patients on fluoxetine improved
in both as well Weight gain
greater in olanzapine group than
fluoxetine or OFC groups
Nickel et al
(2005)
BPD 44 males Topiramate Began with 50 mgd
then increased to
250 mgd by last 3 wk
Parallel design
8 wk
Significant improvements for
medication group in State-Anger
Trait-Anger Anger-Out and
Anger-Control subscales of STAXI
Subsequent open-label follow-up
(Nickel amp Loew 2008)
demonstrated continued
benefits in topiramate group
in ITT analysis
Soler et al
(2005)
BPD 60 males and
females
Olanzapine with
concurrent DBT
Flexible dosing from 5ndash
20 mgd with mean
dose 883 mgd
Parallel design
12 wk
Olanzapine superior to placebo
for depression anxiety and
impulsive aggression
Tritt et al
(2005)
BPD 27 females Lamotrigine Started at 50 mgd then
increased to 100 mgd
during week 3
150 mgd during wk 4
and 5 and 200 mgd
during wk 6ndash8
Parallel design
8 wk
Significant improvement on
State-Anger Trait-Anger
Anger-Out and Anger-Control
subscales of STAXI in
medication group
Nickel et al
(2006)
BPD 52 males and
females
Aripiprazole 15 mgd Parallel design
8 wk
Aripiprazole group evidenced
greater improvements in SCL-90
subscales of obsessive-compulsive
symptoms insecurity in social
contacts depression anxiety
hostility phobic anxiety paranoia
and psychoticism as well as
global psychological stress
Medication group also improved
on HAMD and HAMA as well asall subscales of the STAXI Less
selfinjurious behaviour
observed in medication group
Loew et al
(2006)
BPD 59 females Topiramate Began with 25 mgd
increasing to a target
dose of 200 mgd by
the 6th week
Parallel design
10 wk
Significant improvements in
medication group in SCL-90
subscales of somatization
symptoms interpersonal sensitivity
anxiety hostility phobic anxiety
and global stress but not in
obsessive-compulsive
depression paranoia or
psychoticism subscales
Medication group significantly
(Continued)
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patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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I C A T
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
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Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
crossover fashion
during separate
acute dissociative
episodes
Simpson
et al (2004)
BPD 25 females Fluoxetine plus
concurrent DBT
Started at 20 mgd
increased to 40 mgd
at week 3
Parallel design
12 wk
No significant group differences
from pre-treatment to
post-treatment
Zanarini et al
(2004b )
BPD 45 females Fluoxetine
olanzapine and
olanzapine-
fluoxetine
combination
(OFC)
Fluoxetine started at
10 mgd with endpoint
mean dose of 15 mgd
Olanzapine started at
25 mgd with endpoint
mean dose of 33 mgd
OFC started at
olanzapine 25 mgd
and fluoxetine 10 mgd
with endpoint mean
doses of 32 mgd and
127 mgd respectively
Parallel design but
not placebo-
controlled 8 wk
Olanzapine and OFC superior to
fluoxetine for depression and
impulsive aggression although
patients on fluoxetine improved
in both as well Weight gain
greater in olanzapine group than
fluoxetine or OFC groups
Nickel et al
(2005)
BPD 44 males Topiramate Began with 50 mgd
then increased to
250 mgd by last 3 wk
Parallel design
8 wk
Significant improvements for
medication group in State-Anger
Trait-Anger Anger-Out and
Anger-Control subscales of STAXI
Subsequent open-label follow-up
(Nickel amp Loew 2008)
demonstrated continued
benefits in topiramate group
in ITT analysis
Soler et al
(2005)
BPD 60 males and
females
Olanzapine with
concurrent DBT
Flexible dosing from 5ndash
20 mgd with mean
dose 883 mgd
Parallel design
12 wk
Olanzapine superior to placebo
for depression anxiety and
impulsive aggression
Tritt et al
(2005)
BPD 27 females Lamotrigine Started at 50 mgd then
increased to 100 mgd
during week 3
150 mgd during wk 4
and 5 and 200 mgd
during wk 6ndash8
Parallel design
8 wk
Significant improvement on
State-Anger Trait-Anger
Anger-Out and Anger-Control
subscales of STAXI in
medication group
Nickel et al
(2006)
BPD 52 males and
females
Aripiprazole 15 mgd Parallel design
8 wk
Aripiprazole group evidenced
greater improvements in SCL-90
subscales of obsessive-compulsive
symptoms insecurity in social
contacts depression anxiety
hostility phobic anxiety paranoia
and psychoticism as well as
global psychological stress
Medication group also improved
on HAMD and HAMA as well asall subscales of the STAXI Less
selfinjurious behaviour
observed in medication group
Loew et al
(2006)
BPD 59 females Topiramate Began with 25 mgd
increasing to a target
dose of 200 mgd by
the 6th week
Parallel design
10 wk
Significant improvements in
medication group in SCL-90
subscales of somatization
symptoms interpersonal sensitivity
anxiety hostility phobic anxiety
and global stress but not in
obsessive-compulsive
depression paranoia or
psychoticism subscales
Medication group significantly
(Continued)
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patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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P U
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I C A T
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
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patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
240 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
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and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
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Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
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Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
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parallel-group comparison with paroxetine Human Psychopharmacology 19
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APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
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APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
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Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2424
Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 1124
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
Table 3 Continued
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Shafti amp
Shahveisi
(2010)
BPD 28 females
recruited shortly
after inpatient
psychiatric
admission andsubsequent 7d
washout
Olanzapine
haloperidol
Both medications began
at 25 mgd and
increased weekly by
25 mgd as needed or
tolerated toa maximum of 10
mgd by week 4
Doses at week 4 were
maintained for
remainder of study
Parallel design
but no placebo-
control 8 wk
Olanzapine group trended
towards greater
improvement in Bussndash
Durkee Hostility scores
Haloperidol trended towardsgreater improvement in
CGI scores No significant
between-group differences
Olanzapine group associated
with worsening metabolic
profile Higher rates of
extrapyramidal symptoms in
haloperidol group
AQ Aggression Questionnaire AsPD antis ocial personality disorder AvPD avoidant personality disorder BDI Beck Depression Inventory BPD borderline personality disorder CGI Clinical Global
ImpressionCGI-BPD ClinicalGlobal Impressionfor Borderline PersonalityDisorder DPDdependent personalitydisorder GASGlobalAssessmentScale HAMAHamilton Anxiety Scale HAMDHamilton
Depression Scale HPD histrionic personality disorder MMPI Minnesota Multiphasic Personality Inventory OAS-M Modified Overt Aggression Scale PANSS Positive and Negative Symptom Scale PD
personality disorder PTSD post-traumatic stress disorder SCL-90 Symptom Checklist-90 STAXI State-Trait Anger Expression Inventory ZAN-PBD Zanarini Rating Scale for Borderline Personality
Disorder
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 1924
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
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P U
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I C A T
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8112019 Farmacos en Personalidad
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2124
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
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Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
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criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2124
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
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borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
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and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
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resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
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has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
240 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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8112019 Farmacos en Personalidad
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
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Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
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R IPOLL ET AL
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I C A T
I O
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S
8112019 Farmacos en Personalidad
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Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2424
Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 1424
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 1524
Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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I C A T
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
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Table 4 Avoidant Personality Disorder (AvPD)
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Versiani et al
(1992)
Social
phobia
78 males and
females (percent
AvPD or
generalized
type not reported)
Moclobemide
phenelzine
Moclobemide started with
100 mg bid with flexible
dose increases after 4d
again after 4 wk and 5 wk
Mean dose 580 mgdPhenelzine started with
15 mg bid with flexible
dose increases after 4d
again after 4 wk 5 wk
Mean dose 675 mgd
Parallel design 16 wk
(with 8 additional wk
follow-up in which
half of each
medication groupgradually
switched to placebo
others continued on
last dosage)
Both agents better than
placebo in reducing
social anxiety and
improving social
function 82 responserate for moclobemide
group 91 for
phenelzine group
Moclobemide better
tolerated than
phenelzine
Van Vliet
et al (1994)
Social
phobia
30 males and
females (53
generalized
subtype)
Fluvoxamine 150 mgd Parallel design 12 wk Reduction of social and
general anxiety but not
phobic avoidance
Fahlen
(1995)
Social
phobia
63 males and
females (34 with
comorbid AvPD
1 with comorbidDPD)
Brofaromine Started at 50 mgd then
increased to 100 mgd in
2nd week and 150 mgd
in 3rd week
Parallel design 12 wk Improvement in social
anxiety More marked
improvements in
maladaptive personalitytraits 23 of subjects in
medication group with
comorbid AvPD and 1
DPD comorbid subject
no longer met criteria
Katzelnick
et al (1995)
Social
phobia
12 males and
females (percent
AvPD or
generalized type
not reported)
Sertral ine Began with 50 mgd with
flexible increases by
50 mg every 2 wk if no
clinical response to
maximum of 200 mg
Mean dose 1335 mgd at
endpoint
Parallel design 10 wk Reduction of social
anxiety bodily pain and
improvement in social
functioning 50 of
sertraline group rated
moderately or markedly
improved vs 9 of
placebo group
IMCTGMSPand
Katschnig
(1997)
Socialphobia
578 males andfemales (78
generalized type
49 comorbid
AvPD)
Moclobemide 300 mgd vs 600 mgd(after 4d of 300 mg initial
dose)
Parallel design 12 wk Reduction of social anxietyand improved social
functioning in 600 mg
group (47 responders
vs 34 in placebo
group) No differences
between groups with
without AvPD in
response but comorbid
AvPD patients
responded less to
placebo
Lott et al
(1997)
Social
phobia
102 males and
females
(percent
AvPD or
generalized type
not reported)
Brofaromine After 1ndash8 wk washout
started on 50 mgd with
flexible dosing to
maximum of 150 mgd
Parallel design 10 wk Reduction of social anxiety
but no significant effect
in social functioning
50 response rate vs
19 in placebo group
Noyes et al
(1997)
Social
phobia
583 males and
females (625
generalized
type
478
comorbid
AvPD)
Moclobemide Fixed dose comparison of
75 mgd vs 150 mgd vs
300 mgd vs 600 mgd
vs 900 mgd 75ndash150
mg d began with full
dose other groups began
with 150 mgd and
increased by 150 mg q4d
to target dosage
Parallel design 12 wk No improvement
independent of dose at
12 wk only at 8 wk
35 much improved but
high placebo response
rate As above no
difference between
groups withwithout
AvPD but less drug
(Continued)
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
240 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2124
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
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and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
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double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
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Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
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study Paroxetine Study British Journal of Psychiatry 175 120ndash126
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in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
placebo difference in
comorbid AvPD patients
Heimberg
et al (1998)
Social
phobia
133 males and
females (707
generalized
type)
Phenelzine Began with 15 mgd with
increases to 30 mg after
4d then 45 mg after 8d
then 60 mg after 15d
Further flexible dose
increases possible after
4 wk to 75 mgd and after
5 wk to 90 mgd
Parallel design but
non-randomized
comparing
medication to group
cognitivebehavioural
therapy (CBT) or
supportive
educational
therapy or placebo
12 wk
Phenelzine and CBT better
than both comparison
conditions Phenelzine
effect earlier and on more
subscales 77 response
rate to phenelzine and 75
to CBT Phenelzine group
showed trend towards
greater relapse in subsequent
treatment-free follow-up
(Liebowitz et al 1999)
Schneier
et al (1998)
Social
phobia
77 males and
females (85
generalized
type 38
comorbid AvPD)
Moclobemide Began with 100 mg bid
flexibly dosed to
a maximum of 400 mg
bid Mean dose 728
mgd at endpoint
Parallel design 8 wk Reduction of 2 of 10
subscores of social
anxiety (total fear avoidance)
175 response rate vs
135 in placebo group
Stein et al
(1998)
Social
phobia
183 males and
females (100
generalized
subtype)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every 2 wk to a maximum
of 50 mgd Mean dose
366 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Allgulander
(1999)
Social
phobia
99 males and
females
(percent
with comorbid
AvPD or
generalized type
not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement in social
functioning 705 response
rate vs 83 in placebo
group Rate of response lower
amongst those with comorbid
dysthymia
Baldwin et al
(1999)
Social
phobia
290 males and
females
(percent with
comorbid AvPD
or generalized
type not reported)
Paroxet ine Began with 20 mgd with
possible 10 mg increases
every week to maximum
of 50 mgd Mean dose
347 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Stein et al
(1999)
Social
phobia
92 males and
females (913
generalized
type)
Fluvoxamine Began with 50 mgd with
further weekly 50 mgd
increases possible after
week 1 to maximum of
300 mgd Mean dose
202 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 657
response rate vs 324
in placebo group
Blomhoff
et al (2001)
Social
phobia
387 males and
females (100
generalized
type)
Se rtr al in e B eg an wit h 50 mg d
increased to 100 mgd
after 4 wk if insufficient
improvement noted
Further dose escalationto 150 mgd allowed
after 8 or 12wk
Parallel design
comparing
sertraline1general
medical care
sertraline1
prolonged
exposure therapy
(PE) placebo1PE
and placebo1
general medical
care 24 wk
Sertraline and combined
sertralinePE groups
superior to placebo
groups in reduction of
social anxiety Greatest improvement in
combination group
though not significantly
different than sertraline
alone
van
Ameringen
et al (2001)
Social
phobia
204 males and
females (100
generalized
type 61
comorbid AvPD)
Sertral ine Began with 50 mgd with
option to increase after 4
wk by 50 mg every 3 wk
to maximum of
200 mg d Mean dose
1467 mgd at endpoint
Parallel design 20 wk Reduction of social anxiety
and improvement in
social functioning 53
response rate vs 29 in
placebo group
(Continued)
240 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2124
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
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and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
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Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
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Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
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study Paroxetine Study British Journal of Psychiatry 175 120ndash126
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in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
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Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Liebowitz
et al (2002)
Social
phobia
384 males and
females (100
generalized
type)
Paroxet ine Fixed dose comparison of
20 mgd vs 40 mgd vs
60 mgd All groups
began with 20 mgd
increasing to 40 mgdafter 1 wk and to
60 mgd after 2 wk in
each respective group
Parallel design 12 wk Greatest improvement of
baseline social anxiety in
20 mg group Highest
response rate (based on
CGI) in 40 mg group
Stein et al
(2002)
Social
phobia
257 males and
females (100
generalized
type)
Par oxeti ne B eg an with 20 mgd
flexibly increased by 10
mg at 2 3 4 and 8 wk to
maximum of 50 mgd
Parallel design single-
blind 12-wk acute
phase with those
whose CGI
decreased by at least
2 entering 24-wk
double-blind
continuation
phase
Relapse in paroxetine
group 14 compared to
39 in placebo group
Davidson
et al(2004b )
Social
phobia
279 males and
females (100generalized
type)
Fluvoxamine CR Began with 100 mgd and
flexibly increased by50 mg every week to
maximum of 300 mgd
Mean dose 174 mgd
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning
Davidson
et al
(2004a )
Social
phobia
295 (100
generalized
type)
F lu oxeti ne B eg an with 10 mgd
increasing to 20 mgd on
day 8 to 30 mgd on day
15 and to 40 mgd on
day 29 Dose could be
further increased to
50ndash60 mgd on days
43 and 57 if insufficient
improvement
Parallel design
comparing
fluoxetine group
CBT fluoxetine1
group CBT placebo
placebo1group CBT
14 wk
All treatments superior to
placebo No differences
between treatments at
14 wk Combined
treatment without further
advantage
Lepola et al
(2004)
Social
phobia
372 males and
females(percent
with comorbid
AvPD or
generalized
type not
reported)
Paroxetine CR Began with 125 mgd for 2
wk with flexibleincreases by 125 mg
every week to maximum
of 375 mgd Mean dose
323 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement insocial functioning 57
response rate vs 304
in placebo group
Rickels et al
(2004)
Social
phobia
272 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd with
increase to 150 mg after
1 wk and possible further
increase to maximum of
225 mgd after at least
one more week
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
Lader et al
(2004)
Social
phobia
839 males and
females (100generalized
type)
Escitalopram
paroxetine
Escitalopram fixed dose
comparison of 5 mgd vs10 mgd vs 20 mgd
Paroxetine 20 mgd
Parallel design 12 wk
with 24 wk continuation and
follow-up
Reduction of social anxiety
and improvement insocial functioning for all
doses of escitalopram
and paroxetine
Escitalopram 20 mgd
superior to paroxetine
20 mgd
Allgulander
et al (2004)
Social
phobia
434 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd with flexible
increases by 75 mg after
1 wk and after 3 wk to
maximum of 225 mgd
Parallel design 12 wk Both venlafaxine and
paroxetine groups
similarly efficacious in
reducing social anxiety
and improvement in
(Continued)
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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I C A T
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
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an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
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Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
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Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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I C A T
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S
8112019 Farmacos en Personalidad
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Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2424
Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 1924
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
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8112019 Farmacos en Personalidad
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antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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8112019 Farmacos en Personalidad
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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I C A T
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8112019 Farmacos en Personalidad
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Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
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Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2024
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
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Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
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Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
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Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
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parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
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Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
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Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
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Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
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Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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I C A T
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8112019 Farmacos en Personalidad
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Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2124
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
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antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
phobiasocial anxiety disorder Randomised double-blind placebo-controlled
study Paroxetine Study British Journal of Psychiatry 175 120ndash126
Barratt ES Kent TA Bryant SG Felthous AR (1991) A controlled trial of phenytoin
in impulsive aggression Journal of Clinical Psychopharmacology 11 388ndash389
Barratt ES Stanford MS Felthous AR Kent TA (1997) The effects of phenytoin on
impulsive and pre-meditated aggression a controlled study Journal of Clinical
Psychopharmacology 17 341ndash349
Battaglia J Wolff TK Wagner-Johnson DS Rush AJ et al (1999) Structured
diagnostic assessment and depot fluphenazine treatment of multiple suicide
attempters in the emergency department International Clinical Psychopharma-
cology 14 361ndash372
Bender DS Skodol AE (2007) Borderline personality as a self-other representa-
tional disturbance Journal of Personality Disorders 21 500ndash517
Bergida H Lenzenweger MF (2006) Schizotypy and sustained attention con-
firming evidence from an adult community sample Journal of Abnormal Psychol- ogy 115 545ndash551
Blair RJR (2005) Responding to the emotions of others dissociating forms of
empathy through the study of typical and psychiatric populations Consciousness
and Cognition 14 698ndash718
Blomhoff S Haug TT Hellstrom K Holme I et al (2001) Randomised controlled
general practice trial of sertraline exposure therapy and combined treatment in
generalised social phobia British Journal of Psychiatry 179 23ndash30
Bogenschutz MP Nurnberg PH (2004) Olanzapine vs placebo in the treatment of
borderline personality disorder Journal of Clinical Psychiatry 65 104ndash109
Bohus MJ Landwehrmeyer GB Stiglmayr CE Limberger MF et al (1999)
Naltrexone in the treatment of dissociative symptoms in patients with borderline
personality disorder an open-label trial Journal of Clinical Psychiatry 60598ndash603
Bolton S Gunderson JG (1996) Distinguishing borderline personality disorder
from bipolar disorder differential diagnosis and implications American Journal of
Psychiatry 153 1202ndash1207
Brambilla P Soloff PH Sala M Nicoletti MA et al (2004) Anatomical MRI
study of borderline personality disorder patients Psychiatry Research 131125ndash133
Coccaro EF Kavoussi RJ (1997) Fluoxetine and impulsive aggressive behavior in
personality-disordered subjects Archives of General Psychiatry 54 1081ndash1088
Coccaro EF Kavoussi RJ Hauger RL (1995) Physiological responses to
d-fenfluramine and ipsapirone challenge correlate with indices of aggression in
males with personality disorder International Clinical Psychopharmacology 10
177ndash179
Coccaro EF Lee RJ Kavoussi RJ (2009) A double-blind randomized placebo-
controlled trial of fluoxetine in patients with intermittent explosive disorder Jour-
nal of Clinical Psychiatry 70 653ndash662
Coccaro EF Siever LJ Klar HM Maurer G et al (1989) Serotonergic studies
in patients with affective and personality disorders correlates with suicidal
and impulsive aggressive behavior Archives of General Psychiatry 46 587ndash599
Cornelius JR Soloff PH Perel JM Ulrich RF (1993) Continuation pharmacother-
apy of borderline personality disorder with haloperidol and phenelzine American
Journal of Psychiatry 150 1843ndash1848
Cowdry RW Gardner DL (1988) Pharmacotherapy of borderline personality dis-order alprazolam carbamazepine trifluoperazine and tranylcypromine
Archives of General Psychiatry 45 111ndash119
Davidson J Yaryura-Tobias J DuPont R Stallings L et al (2004b ) Fluvoxamine-
controlled release formulation for the treatment of generalized social anxiety
disorder Journal of Clinical Psychopharmacology 24 118ndash125
Davidson JR Foa EB Huppert JD Keefe FJ et al (2004a ) Fluoxetine compre-
hensive cognitive behavioral therapy and placebo in generalized social phobia
Archives of General Psychiatry 61 1005ndash1013
de la Fuente JM Lotstra F (1994) A trial of carbamazepine in borderline person-
ality disorder European Neuropsychopharmacology 4 479ndash486
Depue RA Morrone-Strupinsky JV (2005) A neurobehavioral model of affiliative
bonding implications for conceptualizing a human trait of affiliation Behavioral
and Brain Sciences 28 313ndash395
Deutsch H (1942) Some forms of emotional disturbance and their relationship to
schizophrenia Psychoanalytic Quarterly 11 301ndash321
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 245
R IPOLL ET AL
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P U
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I C A T
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8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
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8112019 Farmacos en Personalidad
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Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2224
Ekselius L von Knorring L (1998) Personality disorder comorbidity with major
depression and response to treatment with sertraline or citalopram International
Clinical Psychopharmacology 13 205ndash211
Evenden J (1999) Impulsivity a discussion of clinical and experimental findings
Journal of Psychopharmacology 13 180ndash192
Fahlen T (1995) Personality traits in social phobia II changes during drug
treatment Journal of Clinical Psychiatry 56 569ndash573
Faltus FJ (1984) The positive effect of alprazolam in the treatment of three
patients with borderline personality disorder American Journal of Psychiatry
141 802ndash803
Fonagy P Luyten P (2009) A developmental mentalization-based approach to
the understanding and treatment of borderline personality disorder Development and Psychopathology 21 1355ndash1381
Frankenburg FR Zanarini MC (2002) Divalproex sodium treatment of women
with borderline personality disorder and bipolar II disorder a double-blind
placebo-controlled pilot study Journal of Clinical Psychiatry 63 442ndash446
Frankenburg FR Zanarini MC (2006) Obesity and obesity-related illnesses in
borderline patients Journal of Personality Disorders 20 71ndash80
Gardner DL Cowdry RW (1986a ) Development of melancholia during carbama-
zepine treatment in borderline personality disorder Journal of Clinical Psycho-
pharmacology 6 236ndash239
Gardner DL Cowdry RW (1986b ) Positive effectsof carbamazepineon behavioral
dyscontrolin borderlinepersonalitydisorder American Journal of Psychiatry 143
519ndash522
Goldberg SC Schulz SC Schulz PM Resnick RJ et al (1986) Borderline and
schizotypal personality disorders treated with low-dose thiothixene vs placebo
Archives of General Psychiatry 43 680ndash686
Goodman M New A Siever L (2004) Trauma genes and the neurobiology of
personality disorders Annals of the New York Academy of Sciences 1032104ndash116
GoodwinGM Bowden CLCalabrese JRGrunzeH etal (2004) A pooled analysis
of 2 placebo-controlled18-month trials of lamotrigine andlithium maintenance in
bipolar I disorder Journal of Clinical Psychiatry 65 432ndash441
Griengl H Sendera A Dantendorfer K (2001) Naltrexone as a treatment of
self-injurious behavior ndash a case report Acta Psychiatrica Scandinavica 103
234ndash236
Hamazaki T Sawazaki S Itomura M Asaoka E et al (1996) The effect of
docosahexaenoic acid on aggression in young adults A placebo-controlled
double-blind study Journal of Clinical Investigation 97 1129ndash1133
Hamazaki T Thienprasert A Kheovichai K Samuhaseneetoo S et al (2002) The
effect of docosahexaenoic acidon aggression in elderly Thaisubjects ndash a placebo-
controlled double-blind study Nutritional Neuroscience 5 37ndash41
Heimberg RG Liebowitz MR Hope DA Schneier FR et al (1998) Cognitive
behavioral group therapy vs phenelzine therapy for social phobia 12-week out-
come Archives of General Psychiatry 55 1133ndash1141
Henry C Mitropoulou V New AS Koenigsberg HW et al (2001) Affectiveinstability and impulsivity in borderline personality and bipolar II disor-
ders similarities and differences Journal of Psychiatric Research 35
307 ndash312
Herpertz SC Zanarini M Schulz CS Siever L et al (2007) World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of
Personality Disorders World Journal of Biological Psychiatry 8 212ndash244
Higgins GA Enderlin M Haman M Fletcher PJ (2003) The 5-HT2A receptor
antagonist M100907 attenuates motor and lsquo impulsive-typersquo behaviours pro-
duced by NMDA receptor antagonism Psychopharmacology (Berlin) 170
309ndash319
Hollander E Allen A Lopez RP Bienstock CA et al (2001) A preliminary double-
blind placebo-controlled trial of divalproex sodium in borderline personality dis-
order Journal of Clinical Psychiatry 62 199ndash203
Hollander E Swann AC Coccaro EF Jiang P et al (2005) Impact of trait impul-
sivity and state aggression on divalproex vs placebo response in borderline
personality disorder American Journal of Psychiatry 162 621ndash624
Hollander E Tracy KA Swann AC Coccaro EF et al (2003) Divalproex in thetreatment of impulsive aggression efficacy in cluster B personality disorders
Neuropsychopharmacology 28 1185ndash1197
Houston RJ Bauer LO Hesselbrock VM (2004) Effects of borderline personality
disorder features and a family history of alcohol or drug dependence on P300 in
adolescents International Journal of rsquo Psychophysiology 53 57ndash70
Huband N FerriterM Nathan R Jones H (2010) Antiepileptics foraggression and
associated impulsivity Cochrane Database for Systematic Reviews Issue 2 Art
No CD003499
IMCTGMSP Katschnig H (1997) The International Multicenter Clinical Trial Group
on Moclobemide in Social Phobia Moclobemide in social phobia a double-blind
placebo-controlled clinical study European Archives of Psychiatry and Clinical
Neuroscience 247 71ndash80
Ingenhoven T Lafay P Rinne T Passchier J et al (2010) Effectiveness of
pharmacotherapy for severe personality disorders meta-analyses of randomized
controlled trials Journal of Clinical Psychiatry 71 14ndash25
Jensen HV Andersen J (1989) An open noncomparative study of amoxapine in
borderline disorders Acta Psychiatrica Scandinavica 79 89ndash93
Juengling FD Schmahl C Hesslinger B Ebert D et al (2003) Positron emission
tomography in female patients with borderline personality disorder Journal of
Psychiatric Research 37 109ndash115
Kasper S Stein DJ Loft H Nil R (2005) Escitalogram in the treatment of social
anxiety disorder randomised placebo-controlled flexible-dosage study British
Journal of Psychiatry 186 222ndash226
Katzelnick DJ Kobak KA Greist JH Jefferson JW et al (1995) Sertraline for
social phobia a double-blind placebo-controlled crossover study American
Journal of Psychiatry 152 1368ndash1371
Kayser A Robinson DS Nies A Howard D (1985) Respons to phenelzine amongdepressed patients with features of hysteroid dysphoria American Journal of
Psychiatry 142 486ndash488
Keck P Buffenstein A Ferguson J Feighner J et al (1998) Ziprasidone 40 and
120 mgday in the acute exacerbation of schizophrenia and schizoaffective dis-
order a 4-week placebo-controlled trial Psychopharmacology 140 173ndash184
Koenigsberg HW Reynolds D Goodman M New AS et al (2003) Risperidone in
the treatment of schizotypal personality disorder Journal of Clinical Psychiatry
64 628ndash634
Lader M Stender K Burger V Nil R (2004) Efficacy and tolerability of escitalo-
pram in 12- and 24-week treatment of social anxiety disorder randomised
double-blind placebo-controlled fixed-dose study Depression and Anxiety 19
241ndash248
Langdon R Coltheart M (2004) Recognition of metaphor and irony in young
adults the impact of schizotypal personality traits Psychiatry Research 125
9ndash20
Leiberich P Nickel MK Tritt K Pedrosa Gil F (2008) Lamotrigine treatment of
aggression in female borderline patients part II an 18-month follow-up Journal of Psychopharmacology 22 805ndash808
Leone NF (1982) Response of borderline patients to loxapine and chlorproma-
zine Journal of Clinical Psychiatry 43 148ndash150
Lepola U Bergtholdt B St Lambert J Davy KL et al (2004) Controlled-release
paroxetine in the treatment of patients with social anxiety disorder Journal of
Clinical Psychiatry 65 222ndash229
Levitt JJ Westin CF Nestor PG Estepar RS et al (2004) Shape of caudate
nucleus and its cognitive correlates in neuroleptic-naiumlve schizotypal personality
disorder Biological Psychiatry 55 177ndash184
Lieb K Vollm B Rucker G Timmer A et al (2010) Pharmacotherapy for border-
linepersonalitydisorder Cochranesystematic review of randomized trials British
Journal of Psychiatry 196 4ndash12
Lieb K ZanariniMC Schmahl CLinehanMM etal (2004) Borderlinepersonality
disorder Lancet 364 453ndash461
Liebowitz MR Gelenberg AJ Munjack D (2005a ) Venlafaxine extended release
vs placebo and paroxetine in social anxiety disorder Archives of General Psy-
chiatry 62 190ndash198Liebowitz MR Heimberg RG Schneier FR Hope DA et al (1999) Cognitive-
behavioral group therapy versus phenelzine in social phobia long-term outcome
Depression and Anxiety 10 89ndash98
Liebowitz MR Klein DF (1981) Interrelationship of hysteroid dysphoria and bor-
derline personality disorder Psychiatric Clinics of North America 4 67ndash87
Liebowitz MR Mangano RM Bradwejn J Asnis G et al (2005b ) A randomized
controlled trial of venlafaxine extended release in generalized social anxiety
disorder Journal of Clinical Psychiatry 66 238ndash247
Liebowitz MR Stein MB Tancer M Carpenter D et al (2002) A randomized
double-blind fixed-dose comparison of paroxetine and placebo in the treat-
ment of generalized social anxiety disorder Journal of Clinical Psychiatry 63
66ndash74
Links PS Steiner M Boiago I Irwin D (1990) Lithium therapy for borderline
patients preliminary findings Journal of Personality Disorders 4 173ndash181
Lion JR (1979) Benzodiazepines in the treatment of aggressive patients Journal
of Clinical Psychiatry 40 70ndash71
Loew TH Nickel MK (2008) Topiramate treatment of women with borderlinepersonality disorder part II an open 18-month follow-up Journal of Clinical
Psychopharmacology 28 355ndash357
Loew TH Nickel MK Muehlbacher M Kaplan P et al (2006) Topiramate treat-
ment of women with borderline personality disorder a double-blind placebo-
controlled study Journal of Clinical Psychopharmacology 26 61ndash66
Loranger AW Sartorius N Andreoli A Berger P et al (1994) The international
personality disorders examination The world health organizationalcohol drug
abuse and mental health administration international pilot study of personality
disorders Archives of General Psychiatry 51 215ndash224
Lott M Greist JH Jefferson JW Kobak KA et al (1997) Brofaromine for social
phobia a multicenter placebo-controlled double-blind study Journal of Clinical
Psychophamacology 17 255ndash260
Malone KM Corbitt EM Li S Mann JJ (1996) Prolactin response to fenfluramine
and suicide attempt lethality in major depression British Journal of Psychiatry
168 324ndash329
246 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2424
Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2324
Markovitz PJ Calabrese JR Schulz SC Meltzer HY (1991) Fluoxetine in the
treatment of borderline and schizotypal personality disorders American Journal
of Psychiatry 148 1064ndash1067
Mattes JA (2005) Oxcarbazepine in patients with impulsive aggression
a double-blind placebo-controlled trial Journal of Clinical Psychopharmacology
25 575ndash579
Mattes JA (2008) Levetiracetam in patients with impulsive aggression a double-
blind placebo-controlled trial Journal of Clinical Psychiatry 69 310ndash315
Mauchnik J Schmahl C (2010) The latest neuroimaging findings in borderline
personality disorder Current Psychiatry Reports 12 46ndash55
McClure MM Barch DM Romero MJ Minzenberg MJ et al (2007b ) The effects
of guanfacine on context-processing abnormalities in schizotypal personalitydisorder Biological Psychiatry 61 1157ndash1160
McClure MM Harvey PD Goodman M Triebwasser J et al (2010) Pergolide
treatment of cognitive deficits associated with schizotypal personality disorder
continued evidence of the importance of the dopamine system in the schizophre-
nia spectrum Neuropsychopharmacology 35 1356ndash1362
McClure MM Romero MJ Bowie CR Reichenberg A etal (2007a ) Visual-spatial
learning and memory in schizotypal personality disorder continued evidence for
the importance of working memory in the schizophrenia spectrum Archives of
Clinical Neuropsychology 22 109ndash116
McGee MD (1997) Cessation of self-mutilation in a patient with borderline per-
sonalitydisordertreated withnaltrexoneJournalof ClinicalPsychiatry 5832ndash33
Mehlman PT Higley JD Faucher I Lilly AA et al (1994) Low CSF 5-HIAA
concentrations andsevere aggression andimpairedimpulsecontrol in nonhuman
primates American Journal of Psychiatry 151 1485ndash1491
Mercer D Douglass AB Links PS (2009) Meta-analyses of mood stabilizers
antidepressants and antipsychotics in the treatment of borderline personality
disorder effectiveness for depression and anger symptoms Journal of Person- ality Disorders 23 156ndash174
Minzenberg MJ Grossman R New AS Mitropoulou V et al (2006) Blunted
hormone responses to ipsapirone are associated with trait impulsivity in person-
ality disorder patients Neuropsychopharmacology 31 197ndash203
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
metabolite levels Biological Psychiatry 50 783ndash791
Posner MI Rothbart MK Vizueta N Levy KN et al (2002) Attentional mecha-
nisms of borderline personality disorder Proceedings of the National Academy of
Sciences USA 99 16366ndash16370
Prossin AR Love TM Koeppe RA Zubieta JK et al (2010) Dysregulation of
regional endogenous opioid function in borderline personality disorder American
Journal of Psychiatry 167 925ndash933
Reich DB Zanarini MC Bieri KA (2009) A preliminary study of lamotrigine in the
treatment of affective instability in borderline personality disorder International Clinical Psychopharmacology 24 270ndash275
Reich J (2002) Drug treatment of personality disorder traits Psychiatric Annals
32 590ndash596
Rickels K Mangano R KhanA (2004) A double-blindplacebo-controlled studyof
a flexible dose of venlafaxine ER in adult outpatients with generalized social
anxiety disorder Journal of Clinical Psychopharmacology 24 488ndash496
Rifkin A Quitkin F Carrillo C Blumberg AG et al (1972) Lithium carbonate
in emotionally unstable character disorder Archives of General Psychiatry 27
519ndash523
Rinne T van den Brink W Wouters L van Dyck R (2002) SSRI treatment of
borderline personality disorder a randomized placebo-controlled clinical trial for
female patients with borderline personality disorder American Journal of Psy-
chiatry 159 2048ndash2054
Roth AS Rostroff RB Hoffman RE (1996) Naltrexone as a treatment for repetitive
self-injurious behavior an open-label trial Journal of Clinical Psychiatry 57
233ndash237
Rusch N van Elst LT Ludaescher P Wilke M et al (2003) A voxel-basedmorphometric MRI study in female patients with borderline personality disorder
Neuroimage 20 385ndash392
Russ MJ Campbell SS Kakuma T Harrison K etal (1991) EEGtheta activity and
pain insensitivity in self-injurious borderline patients Psychiatry Research 89
201ndash214
Salzman C WolfsonAN Schatzberg A Looper J etal (1995) Effectsof fluoxetine
on anger in symptomatic volunteers with borderline personality disorder Journal
of Clinical Psychopharmacology 15 23ndash29
Samuelsson M Jokinen J Nordstrom AL Nordstrom P (2006) CSF 5-HIAA
suicide intent and hopelessness in the prediction of early suicide in male high-
risk suicide attempters Acta Psychiatrica Scandinavica 113 44ndash47
Saper JR (2000) Borderline personality opioids and naltrexone Headache 40
765ndash766
Schneier FR Gortz D Campeas R Fallon B et al (1998) Placebo-controlled trial
of moclobemide in social phobia British Journal of Psychiatry 172 70ndash77
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 247
R IPOLL ET AL
I N
F L
U E N
T
I A L
P U
B L
I C A T
I O
N
S
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2424
Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
anxious before dental surgery Journal of Clinical Psychopharmacology 22
206ndash210
Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
5-HT2C receptor antagonists have opposing effects on a measure of impulsivity
Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
376ndash385
Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
personality disorderpatients a double-blindplacebo-controlled pilot study Jour-
nal of Clinical Psychiatry 62 849ndash854
Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
with borderline personality disorder a double-blind placebo-controlled pilot
study American Journal of Psychiatry 160 167ndash169
Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission American Journal of Psychiatry 161
2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
trial of fluoxetine olanzapine and the olanzapine-fluoxetine combination in
women with borderline personality disorder Journal of Clinical Psychiatry 7
903ndash907
Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
comorbidity of borderline personality disorder Description of six-year course
and prediction to time-to-remission Acta Psychiatrica Scandinavica 110
416ndash420
Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
ing borderline personality disorder from other axis II disorders American Journal
of Psychiatry 147 161ndash167
Ziegenhorn AA Roepke S Schommer NC Merkl A et al (2009) Clonidine
improves hyperarousal in borderline personality disorder with or without
comorbid post-traumatic stress disorder a randomized double-blind
placebo-controlled trial Journal of Clinical Psychopharmacology 29
170ndash173
R IPOLL ET AL
8112019 Farmacos en Personalidad
httpslidepdfcomreaderfullfarmacos-en-personalidad 2424
Schulz SC Zanarini MC Bateman A Bohus M et al (2008) Olanzapine for the
treatment of borderline personality disorder variable-dose 12-week random-
ized double-blind placebo-controlled study British Journal of Psychiatry 193
485ndash492
Serban G Siegel S (1984) Response of borderline and schizotypal patients to
small doses of thiothixene and haloperidol American Journal of Psychiatry 141
1455ndash1458
Shafti SS Shahveisi B (2010) Olanzapine vs haloperidol in the management of
borderline personality disorder a randomized double-blind trial Journal of Clin-
ical Psychopharmacology 30 44ndash47
Sheard MH (1971) Effect of lithium on human aggression Nature 230 113ndash114
Sheard MH Marini JL Bridges CI Wagner E (1976) The effect of lithium onimpulsive aggressive behavior in man American Journal of Psychiatry 133
1409ndash1413
Siever LJ Buchsbaum MS New AS Spiegel-Cohen J et al (1999) D L-
fenfluramine response in impulsive personality disorder assessed with [18F]
fluorodeoxyglucose positron emission tomography Neuropsychopharmacology
20 413ndash423
Siever LJ Davis KL (1991) A psychobiological perspective on the personality
disorders American Journal of Psychiatry 148 1647ndash1658
Siever LJ Davis KL (2004) The pathophysiology of schizophrenia disorders
perspectives from the spectrum American Journal of Psychiatry 161 398ndash413
Simeon D Stanley B Frances A Mann JJ et al (1992) Self-mutilation in per-
sonality disorders psychological and biological correlates American Journal of
Psychiatry 149 221ndash226
Simpson EB Yen S Costello E Rosen K et al (2004) Combined dialectical
behavior therapy and fluoxetine in the treatment of borderline personality disor-
der Journal of Clinical Psychiatry 65 379ndash385
Skodol AE Gunderson JG Shea MT McGlashan TH et al (2005) The collabo-rative longitudinal personality disorders study (CLPS) overview and implications
Journal of Personality Disorders 19 487ndash504
Smith DJ Muir WJ Blackwood DH (2004) Is borderline personality disorder part
of the bipolar spectrum Harvard Review of Psychiatry 12 133ndash139
Soderstrom H Foresman A (2004) Elevated triiodothyronine in psychopathy ndash
possible physiological mechanisms Journal of NeuralTransmission 111739ndash744
Soler J PascualJC CampinsJ BarrachinaJ etal (2005)Double-blindplacebo-
controlled study of dialectical behavior therapy plus olanzapine for border-
line personality disorder American Journal of Psychiatry 162 1221ndash1224
Soloff PH Cornelius J George A Nathan S et al (1993) Efficacy of phenelzine
and haloperidol in borderline personality disorder Archives of General Psychiatry
50 377ndash385
Soloff PH George A Nathan RS Schulz PM et al (1986a ) Paradoxical effects
of amitryptiline on borderline patients American Journal of Psychiatry 143 1603ndash
1605
Soloff PH George A Nathan RS Schulz PM et al (1986b ) Amitryptiline and
haloperidol in unstable and schizotypal borderline disorders Psychopharmacol-
ogy Bulletin 22 177ndash182
Soloff PH George A Nathan RS Schulz PM et al (1986c ) Progress in
pharmacotherapy of borderline disorders Archives of General Psychiatry
43 691ndash697
Soloff PH George A Nathan RS Schulz PM etal (1987) Behavioral dyscontrol in
borderline patients treated with amitryptiline Psychopharmacology Bulletin 23
177ndash181
Soloff PH George A Nathan RS Schulz PM et al (1989) Amitryptiline vs
haloperidol in borderlines final outcomes and predictors of response Journal
of Clinical Psychopharmacology 9 238ndash246
Southwick SM Bremner JD Rasmusson A Morgan CA et al (1999) Role of
norepinephrine in the pathophysiology and treatment of posttraumatic stress
disorder Biological Psychiatry 46 1192ndash1204
Stanley B Siever LJ (2010) Theinterpersonal dimension of borderline personality
disorder toward a neuropeptide model American Journal of Psychiatry 167
24ndash39
Stein DJ Versiani M Hair T Kumar R (2002) Efficacy of paroxetine for relapse
preventionin social anxiety disorder Archives of General Psychiatry 591111ndash1118
Stein MB Fyer AJ Davidson JR Pollack MH etal (1999) Fluvoxamine treatment
of social phobia (social anxiety disorder) a double-blind placebo-controlled
study American Journal of Psychiatry 156 756ndash760
Stein MB Liebowitz MR Lydiard RB Pitts CD et al (1998) Paroxetine treatment
of gereralized social phobia (social anxiety disorder) a randomized controlled
trial Journal of the American Medical Association 280 708ndash713
Stein MB Pollack MH Bystritsky A Kelsey JE et al (2005) Efficacy of low
and higher dose extended-release venlafaxine in generalized social anxiety
disorder a 6-month randomized controlled trial Psychopharmalogy 177
280ndash288
Strawn JR Geracioti TD (2008) Noradrenergic dysfunction and the psycho-
pharmacology of posttraumatic stress disorder Depression and Anxiety 25
260ndash271
Tandon R (2000) Introduction ziprasidone appears to offer important therapeutic
and tolerability advantages over conventional and some novel antipsychotics
British Journal of Clinical Pharmacology 49(Suppl 1) 1Sndash3S
Thurauf NJ Washeim HA (2000) The effects of exogenous analgesia in a patient
with borderline personality disorder (BPD) and severe self-injurious behavior
European Journal of Pain 4 107ndash109
Traskman L Asberg M Bertilsson L Sjostrand L (1981) Monoamine metabolitesin CSF and suicidal behavior Archives of General Psychiatry 38 631ndash636
Tritt K Nickel C Lahmann C Leiberich PK et al (2005) Lamotrigine treatment of
aggression in female borderline patients a randomized double-blind placebo-
controlled study Journal of Psychopharmacology 19 287ndash291
van Ameringen M Oakman J Mancini C Pipe B et al (2004) Predictors of
response in generalized social phobia effect of age of onset Journal of Clinical
Psychopharmacology 24 42ndash48
van Ameringen MA Lane RM Walker JR Bowen RC et al (2001) Sertraline
treatment of generalized social phobia a 20ndashweek doubleblind placebo-
controlled study American Journal of Psychiatry 158 275ndash281
van Vliet IM den Boer JA Westenberg HG (1994) Psychopharmacological treat-
ment of social phobia a double blind placebo controlled study with fluvoxamine
Psychopharmacology (Berlin) 115 128ndash134
Verkes RJ van der Mast RC Hengeveld MW Tuyl JP et al (1998) Reduction by
paroxetine of suicidal behavior in patients with repeated suicide attempts but not
major depression American Journal of Psychiatry 155 543ndash547
Versiani M Nardi AE Mundim FD Alves AB et al (1992) Pharmacotherapy of social phobia A controlled study with moclobemide and phenelzine British Jour-
nal of Psychiatry 161 353ndash360
Virkkunen M Raw lings R Tokola R Polan d RE et al (1994) CSF biochemis-
tries glucose metabolism and diurnal activity rhythms in alcoholic violent
offenders fire setters and healthy volunteers Archives of General Psychiatry
51 20ndash27
Welch SS Linehan MM (2002) High-risk situations associated with parasuicide
and drug use in borderline personality disorder Journal of Personality Disorders
16 561ndash569
Wilner KD Anziano RJ Johnson AC Miceli JJ et al (2002) The anxiolytic effect
of the novel antipsychotic ziprasidone compared with diazepam in subjects
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Winstanley CA Theobald DE Dalley JW Glennon JC et al (2004) 5-HT2A and
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Interactions with global 5-HT depletion Psychopharmacology (Berlin) 176
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Zanarini MC Frankenburg FR (2001) Olanzapine treatment of female borderline
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Zanarini MC Frankenburg FR (2003) Omega-3 fatty acid treatment of women
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Zanarini MC Frankenburg FR Hennen J Reich DB et al (2004a ) Axis I
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2108ndash2114
Zanarini MC Frankenburg FR Parachini EA (2004b ) A preliminary randomized
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Zanarini MC Frankenburg FR Vujanovic AA Hennen J et al (2004c ) Axis II
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Zanarini MC Gunderson JG Frankenburg FR Chauncey DL (1990) Discriminat-
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R IPOLL ET AL
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