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Contents lists available atScienceDirect
Primary Care Diabetes
j o u r n a l h o m e p a g e : h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / p c d
Review
Clinical monitoring and management of the metabolic
syndrome in patients receiving atypical antipsychotic
medications
Mehrul Hasnain a,, W. Victor R. Vieweg b,c,e,f, Sonja K. Fredrickson c,f,
Mary Beatty-Brooksd
, Antony Fernandezb,e
, Anand K. Pandurangie
a Department of Psychiatry, Western Regional Integrated Health Authority, Sir Thomas Roddick Hospital,
Stephenville, Newfoundland, Canadab Psychiatry Services, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, United Statesc Medical Services, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, United Statesd Medical Media, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, United Statese Department of Psychiatry, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, United Statesf Department of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, United States
a r t i c l e i n f o
Article history:
Received 26 June 2008Received in revised form
23 October 2008
Accepted 24 October 2008
Keywords:
Antipsychotic drugs
Overweight
Obesity
Diabetes mellitus
Dyslipidemia
Metabolic syndrome
Primary care
a b s t r a c t
Individuals with major mental illness are a high-risk group for cardio-metabolic derange-
ments due to genetic predisposition, developmental and environmental stressors, andlifestyle. This risk is compounded when they receive antipsychotic medications. Guidelines
for screening, monitoring, and managing thesepatients for metabolicproblems have beenin
place for severalyears. Despite this, recentreports document that this population continues
to receive poor care in this regard. In this article, we review the metabolic profile of atypical
antipsychotic medications and offer guidelines to reduce the metabolic complications of
these agents.
2008 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Metabolic syndrome and cardio-metabolic risk factors .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Corresponding author at: Sir Thomas Roddick Hospital, 142 Minnesota Drive, Stephenville, Newfoundland A2N 2V6, Canada.Tel.: +1 709 643 1973; fax: +1 709 643 7911.
E-mail address:mehrul [email protected](M. Hasnain).1751-9918/$ see front matter 2008 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.pcd.2008.10.005
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Please cite this article in press as: M. Hasnain, et al., Clinical monitoring and management of the metabolic syndrome in patients receivingatypical antipsychotic medications, Prim. Care Diab. (2008), doi:10.1016/j.pcd.2008.10.005
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3. Atypical antipsychotic medications and metabolic disturbances .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 00
3.1. Weight gain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Insulin and glucose metabolism abnormalities and diabetes mellitus. . .. . .. .. .. . .. .. .. . .. .. . .. .. .. . .. .. . .. .. .. . .. . 00
3.4. Metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Atypical antipsychotics and the metabolic syndrome: pathogenesis.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . 00
5. Assessing, monitoring, and managing patients receiving atypical antipsychotic medications . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Baseline assessment and follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.2. Liaison between the primary care physician and the psychiatrist. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 00
5.3. Selection of atypical antipsychotic medication.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.4. Patient education and interventions for modifiable risk factors. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 00
6. Pharmacological interventions for antipsychotic-induced metabolic derangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction
The prevalence of the metabolic syndrome and individual
cardiovascular risk factors including obesity, dyslipidemia,
diabetes mellitus, cigarette smoking, and hypercortisolemia
are greater in individuals with major mental illness compared
with the general population [16].While unhealthy lifestyle
[1,7,8]and apparent genetic predisposition[911]contribute
to this, there is growing evidence that treatment with antipsy-
chotic medications maybe a factor in the increased prevalence
of the cardio-metabolic problems among patients with major
mental illness[1215].
Guidelines to screen and monitor patients receiving atypi-
cal antipsychotic drugs have emerged over the last few years
[16,17].Despite these guidelines, screening for, monitoring of,and managing metabolic disturbances among patients with
major mental illness remains poor [1821],underscoring the
need to further improve awareness among clinicians on this
important subject. In this article, we review the metabolic
side effects of atypical antipsychotic medications, discuss
the mechanisms that mayunderliethe medication-associated
metabolic effects, and recommend monitoring and manage-
ment strategies.
2. Metabolic syndrome andcardio-metabolic risk factors
Metabolic syndrome refers to a group of metabolic distur-bances that interact synergistically to increase the risk of
atherosclerotic cardiovascular disease. The syndrome also
predisposes to diabetes mellitus, onset of which increases
cardiovascular risk even further, such that diabetes is
considered a cardiovascular risk equivalent [22,23]. Core
features of metabolic syndrome are overweight including
increased abdominal (visceral) fat, atherogenic dyslipidemia,
insulin resistance, and hypertension. Pro-thrombotic and pro-
inflammatory states are found in this setting. Organizations
vary in their definition of the metabolic syndrome (Table 1).
Questions remain as to whether the metabolic syndrome
can predict cardiovascular disease and diabetes mellitus more
accurately than its components[24,25].For purposes of this
review, we will embrace the clinical utility of this syndrome.
For a detailed discussion of the metabolic syndrome and its
components, please see the reports by the National Heart,Lung, andBlood Institute and the American Heart Association
[23,26].
Cardiovascular risk factors expand beyond the various def-
initions of the metabolic syndrome. The National Cholesterol
Education Programs Adult Treatment Panel (ATP III) cate-
gorizes cardiovascular risk factors into underlying, major,
and emerging risk factors [23]. The underlying risk factors
are obesity (especially abdominal), physical inactivity, and
atherogenic diet. The majorrisk factors are cigarette-smoking,
hypertension, elevated LDL, low HDL, family history of pre-
mature coronary heart disease, and aging. The emerging
risk factors include elevated triglycerides, small LDL parti-
cles, insulin resistance, glucose intolerance, pro-inflammatorystate, and pro-thrombotic state.
3. Atypical antipsychotic medications andmetabolic disturbances
Atypical antipsychotics currently available in the United
States (in order of market approval) are: clozapine (1990),
risperidone (1994), olanzapine (1996), quetiapine (1997),
ziprasidone (2000), aripiprazole (2001), and paliperidone [the
main active metabolite of risperidone] (2006). All these agents
are available in Europe as well. Atypical antipsychotics avail-
able in Europe but not in the United States are amisulpride,melperone, sertindole, sulpiride, and zotepine. The relative
potential for these agents to cause metabolic disturbances is
reviewed below and is summarized in Table 2. Information
available for melperone, sertindole, sulpiride, and zotepine is
very limited. Preliminary findings suggest that paliperidone
has low metabolic liability[27].
3.1. Weight gain
The risk and magnitude of short-term and long-term weight
gain are highest for clozapine and lowest for ziprasidone
[12,28,29]. For other antipsychotics the risk can be quanti-
fied for short-term use with olanzapine having high risk,
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Pleasecitethisarticlein
pressas:M
Hasnain
etalClinicalmonitoringandmanagementofthemetabolicsyndromeinpatientsreceiving
Table 1 The metabolic syndrome as defined by the World Health Organization [100,101],Adult Treatment Panel III[22,26],Internat
World Health Organization (1998) Adult Treatment Panel III (2001) In
2 or more of the following 3 or more of the following
Abdominal girth Waist-to-hip ratio >0.9 in men, >0.85 in
women AND/OR BMI >30 kg/m2Waist circumference 102cm (40 in.) for
men and 88cm (35in.) for women
C
E
h
Microalbuminuria Urinary albumin excretion rate
20g/min OR albumin-to-creatinine
ratio30mg/g
Hypertriglyceridemia Serum triglycerides 1.7mmol/L
(150mg/dL)
Triglycerides 1.7mmol/L (150 mg/dL)a
Low high density l ipoproteins HDL
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Table 2 Approximate relative likelihood of metabolic disturbances with atypical antipsychotic medications (see text fordiscussion).
Medication Weight gain Glucose metabolism abnormalities Dyslipidemia Metabolic syndrome
Amisulpride Low Low Low
Aripiprazole Low Low Low Low
Clozapine High High High High
Melperone Olanzapine High High High High
Paliperidone
Risperidone Medium Medium to low Low
Sulpiride
Quetiapine Medium Medium to low High
Sertindole Low
Ziprasidone Low Low Low Low
Zotepine Medium
quetiapine and possibly zotepine having moderate risk, and
risperidone, sertindole, amisulpride, aripiprazole, and ziprasi-
done having mild risk. With long-term use, differencesin weight-gain liability of these agents are not as great
[29].
Clozapine administration may lead to weight gain of
412kg in 1385% of patients[30]. In a recent review, New-
comer and Haupt[12] based on pooled multiple doses data
from the clinical trial programs reported that mean weight
gain over one year is about 1 kg with aripiprazole and ziprasi-
done, about 1.5kg with amisulpride, 23kg with quetiapine
and risperidone, and over 6kg with olanzapine (>10kg in
patients who received a daily dose between 12.5 mg and
17.5mg). The authors of this review noted that their find-
ings paralleled the results of recent prospective randomized
comparisons of individual agents. In another recent reviewof pivotal trials, Conley and Kelly [31] reported that 29% of
patients receiving olanzapine, 25% taking quetiapine, 18%
receiving risperidone, 10% taking ziprasidone, and 7% of
patients taking aripiprazole can expect greater than 7%
increase in their baseline body weight in the short-term.
Some assert that with the exception of clozapine, atypical
antipsychoticdrug-induced weight tends to stabilizein several
months to a year[32].
3.2. Dyslipidemia
Dyslipidemia associated with atypical antipsychotic drug
administration was comprehensively reviewed by Meyer andKoro[33]a few years ago and several studies on this subject
have appeared since then [3441]. This literature suggests that
administration of atypical antipsychotic drugs may result in
dyslipidemia including reduced HDL and elevated cholesterol,
triglycerides, and LDL. The risk of dyslipidemia appears to
be high with clozapine, olanzapine, and quetiapine and mild
with risperidone and amisulpride. Ziprasidone and aripipra-
zoleare least likely (or unlikely) to cause dyslipidemiaand may
improve the lipid profile of patients switched from another
antipsychotic drug to one of these agents [38,42]. Weight
gain associated with atypical antipsychotic drug administra-
tion may explain dyslipidemia, but this lipid disturbance may
occur independent of weight gain[41,43].
3.3. Insulin and glucose metabolism abnormalities
and diabetes mellitus
Atypical antipsychotic medications may have unfavorable
effects on insulin and glucose regulation[12,40,4447].Specif-
ically, the risk of insulin resistance and hyperglycemia is high
with clozapine and olanzapine, moderate to low with quetiap-
ine and risperidone, and low with aripiprazole, amisulpride,
and ziprasidone.
Treatment with antipsychotic medications may be asso-
ciated with sudden onset of hyperglycemia with or without
complications[12].Bayesian data-mining analysis of the FDA
adverse event reporting system (19682004)[48]showed that
on average, therankingof association strength in this regard is
strong for clozapine and olanzapine, medium for quetiapine,
and low for ziprasidone, aripiprazole and risperidone.Literature describing the association between antipsy-
chotic medications and new onset diabetes mellitus or
worsening of existing diabetes mellitus [12,15,4952] is dif-
ficult to interpret and evidence for a causative association
between use of antipsychotic medications and diabetes melli-
tus is inconclusive[53].We have drawn a few generalizations
fromthe literature. (1) Atypical antipsychotics associated with
greater weight gain are generally associated with a higher
risk for type 2 diabetes mellitus. Some studies, however,
report a comparable diabetogenic effect for clozapine, olan-
zapine, risperidone, and quetiapine[54],especially in young
adults [55]. (2) Age appears to be a factor contributing to
antipsychotic-induced diabetes mellitus, with younger adultsbeing at greater risk than older adults[49,5658]. (3) Although
most new-onset type 2 diabetes mellitus cases are associated
with substantial weight gain or obesity, about 25% are not [12],
implyingthat adiposityalone doesnot explain the association.
(4) In somecases, medication-induced diabetesmellitusmight
remit after switching from a high potential medication to
one with a low potential.
3.4. Metabolic syndrome
Several recent studies looked at the risk of the metabolic syn-
drome among patients taking atypical antipsychotic drugs.
Again, this risk is high with clozapine and olanzapine and
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Fig. 1 Interplay of cardio-metabolic risks associated with major mental illness and the metabolic effects of atypical
antipsychotic medications.
low with aripiprazole[2,5961]. The risk also appears to be
low with ziprasidone[62].We know less about the relation-
ship between quetiapine and risperidone and the metabolic
syndrome[13,59].
4. Atypical antipsychotics and themetabolic syndrome: pathogenesis
Metabolic risk factors associated with major mental illness
among patients taking atypical antipsychotic medications
appear inFig. 1.Certain antipsychotic medications increase
appetite and this leads to adiposity. Affinity of the antipsy-
chotic drugs for histamine-1 (H1) receptors closely correlates
with their weight-gainingpotential [63] and appears to involve
H1 receptor-linked activation of hypothalamic AMP-kinase
[64]. Also, 5-HT2C receptor antagonism may contribute to
weight gain[65]. The effect atypical antipsychotics have on
hormones involved in appetite regulation is not clear [66].
However, the H1 and 5HT2C blocking effects of antipsychotic
medications may interfere with leptin-mediated appetite sup-
pression[65,67].Adiposity alone does not explain the diabetogenic poten-
tial of atypical antipsychotic medications [12]. Animal and
human studies describe the acute adverse effect of clozap-
ine and olanzapine on insulin and glucose metabolism[68].
Significant insulin resistance has also been documented in
non-obese individuals receiving clozapine or olanzapine ver-
sus those receiving risperidone[45].Diminished or inefficient
insulin release from pancreatic beta cells as well as periph-
eral insulin resistance may underlie the diabetogenic effect of
certain antipsychoticmedications. Blocking muscarinic type 3
(M3) and5-HT1A receptors may be a factor to diminished pan-
creatic beta-cell responsiveness and blocking 5HT2A receptor
may suppress glucose uptake in skeletal muscle[63].
Some antipsychotic medications may impair and/or alter
the action of insulin on adipocytes leading to progres-
sive lipid accumulation [69]. The impaired effect of insulin
on adipocytes may partly explain weight-gain independent
dyslipidemia [41,43]. Increased food intake and periph-
eral insulin resistance perpetuate adiposity and release of
several adipocytokinessome of which contribute to cardio-
metabolic risk[70].
5. Assessing, monitoring, and managingpatients receiving atypical antipsychoticmedications
We will use consensus guidelines (Table 3)developed jointly
by the American Diabetes Association, American Psychiatric
Association, American Association of Clinical Endocrinolo-
gists,and North American Association forthe Studyof Obesity
[71]to monitor patients taking atypical antipsychotic drugs.
We are mindful of other guidelines[16,17].
5.1. Baseline assessment and follow-up
Besides guidelines provided in Table 3, consider ethnicity,
dietary habits, physical activity, support system, cigarette
smoking, and alcohol and drug abuse. Consider previous
response to and side effects of medications that the patient is
using or has used. Keep in mindthat psychotropicmedications
other than antipsychotic drugs such as some antidepressants
and mood stabilizers may link to weight gain[7274].
Even for patients free of metabolic disturbances, monitor
potential risk factors as show inTable 3.Weight gain may not
be dose-dependent and individuals with low body mass index
(BMI) at baseline may be particularly vulnerable to weight
gain[31]. Glucose and lipid metabolism abnormalities may
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Table 3 American Diabetes Association (ADA) and American Psychiatric Association (APA) consensus guidelines forbaseline assessment and monitoring of patients receiving atypical antipsychotic medications[71]a.
Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years
Personal/family historyb X X
Weight (body mass index) X X X X X
Waist circumference X X
Blood pressure X X XFasting plasma glucose X X X
Fasting lipid profile X X X
a More frequent assessments may be warranted based on clinical status.b Personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease.
occur without weight gain[12,41,43]. For patients who gain
significant weight (greater than 7% of baseline body weight)
and were free of metabolic abnormalities at the beginning of
treatment, we recommend checking fasting lipid profile and
fasting glucose after 6 months as well. Patients who have
cardio-metabolic risk factors should have their fasting lipid
profile checkedevery 2 years instead of every 5 yearsand most
patients with diabetes mellitus should have their fasting lipid
profile measured at least once a year. Central obesity is a bet-
ter predictor of metabolic derangements than BMI. Because
antipsychotic-induced weight gain can be significant early in
treatment, we recommend measuring waist circumference
3 and 6 months after starting treatment and then annually.
Antipsychotic medications may contribute to hypertension by
causing weight gain and/or insulin resistance. Blood pressure
should be monitored yearly or more often if indicated. Look for
symptoms and signs of diabetes mellitus and diabetic ketoaci-
dosis during the first several months, especially in patients
taking clozapine, olanzapine or quetiapine. Checking glycosy-
lated hemoglobin (HbA1c) levels may identify those patients
who are developing glucose metabolism problems[75].Check
at risk patients 3 and 6 monthsafter starting treatment. The
frequency of monitoring will be different for those patients
who develop metabolic derangement and will be dictated by
the treatment guidelines for that specific derangement.
5.2. Liaison between the primary care physician and
the psychiatrist
Current studies indicate that patients with major mental
illness do not receive adequate evaluation and effective
treatment of their cardio-metabolic problems [1821,7679].
Effective communication between the primary care physician
and the psychiatrist is particularly important for the chronicmentally ill because of their impaired capacity to care for
themselves. Such communication will improve monitoring,
help early detection of metabolic derangements, and limit
duplication of clinical or laboratory workup. Monitoring for
metabolic side effects is primarily the responsibility of the
physician prescribing antipsychotic medication and in most
cases that would be a psychiatrist. If the primary care physi-
cian observes that the patient is being prescribed such drugs
without being monitored effectively, he/she should discuss
this with the psychiatrist. The psychiatrist may not have the
expertise to manage any abnormalities that are detected and
in such situations the primary care physician will most likely
take over both monitoring and management. Liaison should
extend to any healthcare professionals involved in the care
of patients with chronic mental illness and cardio-metabolic
problems.
5.3. Selection of atypical antipsychotic medication
Atypical antipsychotic drugs have comparable efficacy and
largely differ based on their side-effect profile[80,81].There-
fore choosing a drug would be based on risk factors and
metabolic state of the patient, metabolic side-effect profile
of the drug (Table 2),responses and side effects to previous
treatments, and patient preference. Combining medications
associated with weight gain will increase the likelihood of
weight gain [73]. If a patient requires several psychotropic
medications (for example, a mood stabilizer or an antide-
pressant plus an antipsychotic), try to avoid combining drugs
associated with weight gain.
5.4. Patient education and interventions for modifiable
risk factors
Educationof the patient and, when possible, significant others
and other care-providers (e.g., case manager, respite worker)
optimizes treatment and drug compliance, and reduces unfa-
vorable metabolic side effects. Patient education is an ongoing
process and should be provided in a manner and at a pace
manageable for the patient. It should cover topics including
those related to the patients illness, what to expect from the
medication(s)in termsof response and sideeffects, symptoms
and signs of diabetes and diabetic ketoacidosis, modifiable
cardio-metabolic risk factors, and importance of treatment
compliance.
Modifiable cardio-metabolic risk factors such as, over-
weight/obesity, cigarettesmoking,lack of physical activity and
unhealthy diet are common in patients with major mental ill-
ness [1,7,8,82,83] and should be addressed even in patients free
of metabolic derangements. If resources allow, educate other
relevant health professionals (dietitian, psychologist, activity-
recreational therapist, and addiction counselor, etc.).
6. Pharmacological interventions forantipsychotic-induced metabolic derangements
The primary care physician is central to managing and moni-
toring the physical health of patientsrequiring treatment with
antipsychotic drugs [71,84]. The patient benefits when there is
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a collaborative approach between the psychiatrist and physi-
cian. Such collaboration may require psychiatrists to improve
their knowledge of physical treatments.
There is a growing body of literature [38,42,8588] docu-
menting the benefits of switching from an antipsychotic drug
with high risk of metabolic side effects (including weight gain)
to one with low risk (Table 2).This option has been suggested
byBarnett et al. [17] based on the joint guidelines of the Amer-ican Diabetes Association, American Psychiatric Association,
American Association of Clinical Endocrinologists, and the
North American Association for the Study of Obesity[71].We
strongly recommend this course as the initial intervention
when possible in all patients who show worsening metabolic
profile including significant weight gain. Specific guidelines
for switching antipsychotic medications have been developed
[89].
Various agents including ephedrine, sibutramine, orlistat,
topiramate, nizatidine, cimetidine, naltrexone, amantadine,
reboxetine, fluoxetine, and topiramate have been studied
as potential anti-obesity treatments in antipsychotic-treated
patientsdevelopingmetabolic derangements. Two recent pub-lications[90,91], found insufficient evidence to support the
general use of any of these agents to limit or reverse the
metabolic complications associated with antipsychotic-drug
therapy. However, trial of one or more of these medica-
tions may be advisable if more conservative interventions
like switching to a metabolically safer antipsychotic is not
possible and lifestyle interventions have failed[92].Insulin-
sensitizing agent, Metformin, has been shown to prevent or
attenuate weight gain and insulin resistance associated with
antipsychoticuse in several recent studies of short-term dura-
tion (816 weeks) [9397]. Most of these studies used adult
patients receiving olanzapine. However, one study on chil-
dren and adolescents also had subjects taking quetiapine andrisperidone [95]. Another study included patients receiving
clozapine, risperidone, and sulpiride[96].Dose range of met-
formin in these studies was 7502550mg per day and the drug
was tolerated reasonably well.
The beneficial effect of metformin administration on
weight and glucose metabolism may be more pronounced in
patients who undergo lifestyle intervention consisting of psy-
choeducation, dietary modification based on the American
Heart Association step 2 diet (less than 30% of total energy
fraction from fat), and an individualized exercise program
[96].In this study of 12-weeks duration metformin use alone
was more effective than lifestyle intervention plus placebo in
increasing insulin sensitivity and reversing weight gain butmetformin along with lifestyle intervention offered the great-
est benefit. A large multicenter study using individuals from
the general US population showed that either metformin use
or intensive lifestyle intervention may delay or prevent the
onset of diabetes mellitus in patients with impaired glucose
tolerance[98].In this study, the metformin group lost weight
during the first year of treatment. However, this loss was not
as pronounced or sustained as that observed for the inten-
sive lifestyle group. Taken together, these findings suggest the
potential use of metformin in patients with major mental ill-
ness receiving antipsychotic medications. However, we need
long-term studies to clearly establish the utility of metformin
plus lifestyle modification. Thiazolidinedions (rosiglitazone
and pioglitazone) may improve cardiovascular risk factors
through multiple mechanisms[99]but so far they have not
been systematically studied for treatment of antipsychotic-
induced weight gain and metabolic derangements.
If the metabolic derangement evolves into a disorder, then
treatment guidelines specific to that disorder dictate man-
agement. Pharmacological interventions should not exclude
non-pharmacologic strategies.
7. Conclusions
Despite the availability of well-published clinical guide-
lines, patients with chronic mental illness receiving atypical
antipsychotic medications remain vulnerable to the cardio-
metabolic complications of these drugs. In general, patients
taking clozapine and olanzapine are most vulnerable and
those taking aripiprazole and ziprasidone are least vulnerable
to these complications. Preliminary data on paliperidone also
suggests it to have low metabolic risk. Patients taking amisul-
pride, risperidone, and quetiapine fall in between. We haveemphasized the need for screening, monitoring, and manage-
ment of these patients. Management includes close liaison
between the primary care provider and the psychiatrist.
We recommend large-scale studies using present guide-
lines that include the primary care provider and the
psychiatrist working together. New strategies and technolo-
gies might emerge from such studies, facilitate cooperation
and enhance patient care.
Conflict of interest
Dr Pandurangi is on the speakers bureau of Astra-Zeneca,Bristol Myers Squibb, Janssen and Pfizer Pharmaceuticals.
Other authors do not have any conflict of interest to declare.
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