schizophr bull 2012 kishimoto schbul sbs150

8/10/2019 Schizophr Bull 2012 Kishimoto Schbul Sbs150

1/22

Page 1 of 22

Schizophrenia Bulletin

doi:10.1093/schbul/sbs150

The Author 2012. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.For permissions, please email: [email protected]

Long-Acting Injectable vs Oral Antipsychotics for Relapse Prevention inSchizophrenia: A Meta-Analysis of Randomized Trials

Taishiro Kishimoto1,2, Alfred Robenzadeh1, Claudia Leucht3, Stefan Leucht3, Koichiro Watanabe2,4, Masaru Mimura2,Michael Borenstein5, John M. Kane1,6,7,8, and Christoph U. Correll*,1,6,7,8

1The Zucker Hillside Hospital, Psychiatry Research, North Shore Long Island Jewish Health System, Glen Oaks, NY; 2Keio UniversitySchool of Medicine, Neuropsychiatry, Shinjuku-ku, Tokyo, Japan; 3Department of Psychiatry and Psychotherapy, Klinikum rechts derIsar der Technischen Universitt Mnchen, Mnchen, Germany; 4Kyorin University School of Medicine, Neuropsychiatry, Mitaka,Tokyo, Japan; 5Biostat, Inc, Englewood, NJ; 6Hofstra North Shore LIJ School of Medicine, Department of Psychiatry and MolecularMedicine, Hempstead, NY; 7Albert Einstein College of Medicine, Deparment of Psychiatry and Behavioral Sciences, Bronx, NY;8The Feinstein Institute for Medical Research, Manhasset, NY

*To whom correspondence should be addressed; Division of Psychiatry Research, the Zucker Hillside Hospital, 75-59 263rd Street, GlenOaks, NY 11004, US; tel: (718) 470-4812, fax: (718) 343-1659, e-mail: [email protected]

Results from this study were presented at the Schizophrenia International Research Society 3rd biennial meeting, April 1418, Florence,Italy, and the NCDEU 52nd Annual meeting, May 29-June 1, 2012 Arizona, USA.

Background: While long-acting injectable antipsychotics(LAIs) are hoped to reduce high relapse rates in schizophre-nia, recent randomized controlled trials (RCTs) challengedthe benefits of LAIs over oral antipsychotics (OAPs).

Methods:Systematic review/meta-analysis of RCTs thatlasted 6 months comparing LAIs and OAPs. Primaryoutcome was study-defined relapse at the longest timepoint; secondary outcomes included relapse at 3, 6, 12, 18,

and 24 months, all-cause discontinuation, discontinuationdue to adverse events, drug inefficacy (ie, relapse + discon-tinuation due to inefficacy), hospitalization, and nonad-

herence. Results:Across 21 RCTs (n= 5176), LAIs weresimilar to OAPs for relapse prevention at the longest timepoint (studies = 21, n= 4950, relative risk [RR] = 0.93,95% confidence interval [CI]: 0.801.08, P = .35). Thefinding was confirmed restricting the analysis to outpa-tient studies lasting 1 year (studies = 12, RR = 0.93, 95%CI:0.711.07, P= .31). However, studies using first-gener-

ation antipsychotic (FGA)-LAIs (studies = 10, RR = 0.82,95% CI:0.690.97, P = .02) and those published 1991

(consisting exclusively of all 8 fluphenazine-LAI studies;RR = 0.79, 95% CI: 0.650.96, P= 0.02) were superior toOAPs regarding the primary outcome. Pooled LAIs alsodid not separate from OAPs regarding any secondary out-comes. Again, studies using FGA-LAIs and those published

1991 were associated with LAI superiority over OAPs, eg,hospitalization and drug inefficacy. Conclusions:In RCTs,which are less representative of real-world patients than nat-uralistic studies, pooled LAIs did not reduce relapse com-pared with OAPs in schizophrenia patients. The exceptions

were FGA-LAIs, mostly consisting of fluphenazine-LAIstudies, which were all conducted through 1991. Because

this finding is vulnerable to a cohort bias, studies compar-ing FGA-LAI vs second-generation antipsychotics-LAIand LAI vs OAP RCTs in real-world patients are needed.

Key words:antipsychotics/adherence/depot/long-actinginjection/meta-analysis/relapse/schizophrenia/treatment

discontinuation

Introduction

Because psychopathology and social functioning canworsen with repeated psychotic episodes in patients withschizophrenia,1,2 relapse prevention is critical. There isstrong evidence of antipsychotic efficacy for relapse preven-tion in chronic and first-episode patients,3,4in that the risk ofrelapse is 26 times higher without medication.36However,because nonadherence rates as high as 50% can limit theefficacy of pharmacotherapy,7,8 the use of long-acting

injectable antipsychotics (LAIs) is an important option.9

Inpractice, patients and clinicians are sometimes reluctant touse LAIs because of stigma, needle pain, time constraints,side effect concerns, and cost.10Given these drawbacks tothe use of LAIs, convincing data showing the superiority ofLAI over oral antipsychotics (OAPs) is needed to supportthe use of LAIs. The first LAI was introduced in the 1960s.Since then, at least 5 first-generation antipsychotics (FGAs)-LAIs and 3 second-generation antipsychotics (SGA)-LAIshave become available. Our previous meta-analysis found

Schizophrenia Bulletin Advance Access published January 2, 2013
mailto:[email protected]:[email protected]


2/22


3/22

Page 3 of 22

Table1.DescriptionofIncludedStu

dies

Study/Country

na

Study

Design

D

uration

(wks)

InclusionCriteria

Definition

ofRelapse-

Related

Outcome

Mean

Age(Range)

(y.o.)

%Male

%Hpat

BaselineI

nformation

R

egarding

C

hronicity

(#Hp,

D

urationof

illnessetc.)

Medication

Randomized#

Safety/

Efficacy#

MeanDose

(Range)

First-generationantipsychoticLAIs

Fulphenazinedepot

Crawfordand

Forrest4574/UK

31

DBDD40

Stableand

cooperativeOPs

withSCZwho

areadherentto

medicationand

attendingthe

clinic

Withdraw

alb:

terminationof

thetriald

ueto

significan

tSx

thatwarranted

unblindin

gthe

treatmentin

ordertoinform

futurePt

managem

ent

NR(2065)

29

0

N

R

FPZdecanoate

14

14

NR(Same

doseas

beforethe

trial)

Triflu-

operazine

17

15

10mg/d

(fixed)

DelGiudice

etal.2

575/USA

88

DBDD/

RMc

69

IPswithSCZwho

respondedtooral

FPZandwere

discharged

Re-Hpb

NR(2050)

100

0

4

8.8%had

5

10Hpsin

thepast

FPZEnanthate

27

27

25mg/2

wks(fixed)

FPZ

61

61

21.7mg

(580mg)

Rifkinetal.2

7

77/USA

73d

DBDD52

StableOPseon

FPZdepotororal

for4wks,nomore

thanminorside

effects,cooperative

andcompliant

Relapse:clinical

deterioration

withmarked

social

impairme

nt

23.7(1738)

67

0

M

ean#of

H

psinthe

p

ast:1.79

FPZdecanoate

23

23

NR(0.52ml/

2wks)

FPZ

28

28

NR(520mg)

Falloonetal.2

6

78/UK

53

DBDD52

SCZPtsreturning

tothecommunity

followingHpofan

acuteschizophrenic

episode

Relapse:

reappearanceor

exacerbationof

schizophrenic

featuresthatled

towithdrawal

fromthetrial,

regardlessof

re-Hp

39(1760)

45

0

8

1%had2

H

psinthe

p

ast

FPZdecanoate

NR

20

25mg/2

wksf

(flexible)

Pimozide

NR

24

8mg/df

(flexible)


4/22

Page 4 of 22

Study/Country

na

Study

Design

D

uration

(w

ks)

InclusionCriteria

Definition

ofRelapse-

Related

Outcome

Mean

Age(Range)

(y.o.)

%Male

%Hpat

BaselineI

nformation

R

egarding

C

hronicity

(#Hp,

D

urationof

illnessetc.)

Medication

Randomized#

Safety/

Efficacy#

MeanDose

(Range)

Hogartyetal.4

6

79/USA

105

DBDD104

PtswithSCZ

whoreceived

majorneuroleptic

treatmentduring

theHpandwas

discharged

Relapse:

unequivocal

clinicaldeterio-

rationof

such

magnitud

ethat

Hpappea

red

imminentafter

allreason

able

attemptsto

maintain

Pts

withstudy

medicatio

n

failedorsuicide

34.2(1855)

46

0

8

8%had1

H

pinthe

p

ast

FPZdecanoate

55

55

34mg/2

wks(12.5

125mg/2

wks)

FPZ

50

50

9.9mg/d

(2.5

40mg/d)

Schooleretal.4

3

80/USA

290

DBDD52

PtswithSCZdis-

chargedafteracute

phasetreatment

andbeingtreated

incommunity

Relapse:

deterioration

thatcouldnot

managed

sat-

isfactoryafter

adjustmentof

dosagewithin

protocollimits

29(1855)

59

100/0g1

00%newly

H

p

FPZdecanoate

143

107h

34.2mg/3

wks(12.5

100mg/3

wks)

FPZ

147

107h

24.8mg/d

(2.5-

60mg/d)

Barnesetal.4

7

83/UK

36

DBDD52

OPswithSCZ

(PSE)regu-

larlyreceiving

depotFPZfor

6months,and

willingtopartici-

patethetrial

Relapse:

marked

exacerbation

ofpsycho

tic

featuresrequir-

ingincrea

se

medicatio

nand

re-Hp

49.5(NR)50

0

77.8%

h

avesocial

p

erformance

limitations

FPZdecanoate

19

19

NR(same

doseas

beforethe

trial)

Pimozide

17

17

NR(dose

equivalent

beforethe

trial)

Kanenoetal.4

8

91/Japan

263

DBDD24

ChronicPts

withSCZwho

needlong-term

treatment

Treatmen

t

discontinuation

duetowo

rsen-

ingofpsychiat-

ricSxb

NR(NR)i65

NR

D

urationof

illnesswas

10yearsin

8

1%

FPZdecanoate

130

127

12.6

50mg/4

wksf

(75mg/4

wks)

HAL

133

132

3.112.0mg/df

(18mg/d)

Table1.Continued


5/22

Page 5 of 22

Study/Country

na

Study

Design

D

uration

(wks)

InclusionCriteria

Definition

ofRelapse-

Related

Outcome

Mean

Age(Range)

(y.o.)

%Male

%Hpat

BaselineI

nformation

R

egarding

C

hronicity

(

#Hp,

D

urationof

illnessetc.)

Medication

Randomized#

Safety/

Efficacy#

MeanDose

(Range)

Haloperidoldepot

Glicketal.4

905/

USA

35

OL

48

OPswithSCZor

SzADj (DSM-IV)

whorequirelong-

termtherapy

Ptswhowere

nolongerexac-

erbationfreeb

42.3(NR)80

0

M

ean

d

uration

o

fillness:

1

6.5years

HAL

decanoate

14

10/9

170mg/4

wks(200mg/4

wksk)

QUE

21

19/16

493mg/d

(500mg/dk)

Zuclopenthixoldepot

Arangoetal.2

406/

Spain

46

RM

52

PtswithSCZ

(DSM-IV)who

hadaviolent

episodeinthe

previousyear,with

ascoreofatleast

3onthephysical

aggressionsubscale

ofthemodified

OvertAggression

Scale

Hpb

34.0(NR)83

0

N

R

Zuclopen-

thixoldepot

26

26

233mg/2

wks(NR)

Zuclopen-

thixol

20

20

35mg/d

(NR)

Second-generationantipsychotic-LA

Is

Olanzapine-LAI

Kaneetal.1

310/

International

1065lDBDD24

Clinicallystable

PtswithSCZ

(DSM-IV)defined

ashavingOP

statusfor4wks,

withaBPRS-P4

onthefollowing

items:conceptual

disorganization,

suspiciousness,hal-

lucinatorybehav-

ior,andunusual

thoughtcontent

Psychotic

exac-

erbationb

:(1)

anincreaseof

anyBPRS-Pto

ascoreof>4,

withanabso-

luteincre

ase

2forthe

specificit

em,

(2)increa

seof

anyBPRS-Pto

ascore>4,with

anabsolu

te

increase4on

thepositive

subscale,

(3)

Hpastheresult

ofworsening

ofpositiv

e

psychotic

Sx

38.9(1875)

65

0

M

ean

d

uration

o

fillness:

1

3.3years.

3

6.9%had

2psychotic

e

pisodesor

e

xacerba-

t

ionsinlast

2

4months

OLA-LAI

599

599

150mg/2

wks,

405mg/4

wks,

300mg/2

wks(fixed)

OLA

322

322

14.3mg/d

(10,15,

20mg/d)

Table1.Continued


6/22

Page 6 of 22

Study/Country

na

Study

Design

D

uration

(wks)

InclusionCriteria

Definition

ofRelapse-

Related

Outcome

Mean

Age(Range)

(y.o.)

%Male

%Hpat

BaselineI

nformation

R

egarding

C

hronicity

(

#Hp,

D

urationof

illnessetc.)

Medication

Randomized#

Safety/

Efficacy#

MeanDose

(Range)

Detkeetal.5

0

11/International

524

OL

104

OPswithSCZ

(DSM-IV)who

hadnoacuteHpin

the8wkspriorto

visit1,PANSS-T

25%

increasein

PANSS-T

,

including

25%increase

including

10

pointsincrease

(3)1inc

rease

inCGI-S

CGI-Sof

4,

(4)delibe

rate

self-injuryor

injurytoothers,

(5)discon

tinua-

tionfrom

study

becauseo

f

worseningofSx

40.9(1865)

67

0

M

ean

d

uration

o

fillness:

1

4.7years.

M

ean#of

p

sychoticepi-

s

odeinlast

2

4months:

2

.7

OLALAI

264

264

386.6mg/4

wks(15

405mg/4

wks)

OLA

260

260

12.7mg/d

(520mg/d)

Risperidone-LAI

Keksetal.5

1

07/International

629mOL

53

IP/OPswith

SCZorSzADn

(DSM-IV)who

hadacuteexac-

erbation(Hpor

requiringmedical

intervention)inthe

past2months,and

hadanadditional

acuteexacerbation

inthepast2years,

PANSS-T50,

BMI40

Significan

t

deterioration

b):1)HpforSx

exacerbation,

2)needfo

ran

increased

level

ofcareand2

pointsincrease

inCGI-S

over

2wks,3)

self-

injury,suicidal/

homicida

lide-

ationorv

iolent

behavior

35.2(18)

57

44

M

ean

d

uration

o

fillness:

8

.6years

RIS-LAI

253

247

40.7mg/2

wks(25,

50mg/2

wks)

OLA

310

300

14.6mg/d

(520mg/d)

Table1.Continued


7/22

Page 7 of 22

Study/Country

na

Study

Design

D

uration

(wks)

InclusionCriteria

Definition

ofRelapse-

Related

Outcome

Mean

Age(Range)

(y.o.)

%Male

%Hpat

BaselineI

nformation

R

egarding

C

hronicity

(

#Hp,

D

urationof

illnessetc.)

Medication

Randomized#

Safety/

Efficacy#

MeanDose

(Range)

Baietal.2

3

07/Taiwan

50

RM

48

Symptomatically

stableSCZ

(DSM-IV)andhave

beenonoralRIS

for3months,

PANSS-T

schizophr bull 2012 kishimoto schbul sbs150

Documents