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8/10/2019 Schizophr Bull 2012 Kishimoto Schbul Sbs150
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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: journals.permissions@oup.com
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: ccorrell@lij.edu
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:ccorrell@lij.edumailto:ccorrell@lij.edu8/10/2019 Schizophr Bull 2012 Kishimoto Schbul Sbs150
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8/10/2019 Schizophr Bull 2012 Kishimoto Schbul Sbs150
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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)
8/10/2019 Schizophr Bull 2012 Kishimoto Schbul Sbs150
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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
8/10/2019 Schizophr Bull 2012 Kishimoto Schbul Sbs150
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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
8/10/2019 Schizophr Bull 2012 Kishimoto Schbul Sbs150
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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
8/10/2019 Schizophr Bull 2012 Kishimoto Schbul Sbs150
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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
Recommended