META-ANALYSIS
`
`Second-Generation Antipsychotic Agents
`in the Treatment of Acute Mania
`
`A Systematic Review and Meta-analysis of Randomized Controlled Trials
`
`Harald Scherk, MD; Frank Gerald Pajonk, MD, PhD; Stefan Leucht, MD, PhD
`
`Context: Recommendations of treatment guidelines con-
`cerning the use of second-generation antipsychotic (SGA)
`agents for acute mania vary substantially across commit-
`tees or working groups. Meta-analyses addressing the use
`of SGAs in the treatment of acute mania are lacking.
`
`Objective: To conduct a meta-analysis of the efficacy
`and safety of SGAs in the treatment of acute mania.
`
`Data Sources: Randomized controlled trials compar-
`ing SGAs with placebo, first-generation antipsychotic
`drugs, or mood stabilizers (MSs) in the treatment of acute
`mania were searched for in the PsiTri and MEDLINE da-
`tabases (last search: May 2006).
`
`Study Selection: The abstracts, titles, and index terms
`of studies were searched using the following key words:
`aripiprazole, amisulpride, clozapine, olanzapine, quetiap-
`ine, risperidone, ziprasidone, and zotepine in conjunc-
`tion with mania, manic, and bipolar.
`
`Data Extraction: Data on efficacy, global dropout, drop-
`out due to adverse events, dropout due to inefficacy, weight
`gain, rate of somnolence, and extrapyramidal symptoms
`were extracted and combined in a meta-analysis.
`
`Data Synthesis: A total of 24 studies with 6187 pa-
`tients were included. The SGAs were significantly more
`efficacious than placebo. The analysis demonstrated that
`adding antipsychotic agents to MS treatment was signifi-
`cantly more effective than treatment with MSs alone. The
`SGAs displayed efficacy comparable with that of MSs.
`Some SGAs seemed to induce more extrapyramidal symp-
`toms than placebo. The SGAs were also associated with
`higher rates of somnolence than placebo.
`
`Conclusion: Currently available data suggest that com-
`bining SGAs and MSs is the most efficacious treatment
`of acute mania.
`
`Arch Gen Psychiatry. 2007;64:442-455
`
`M OOD STABILIZERS (MSS)
`
`and first-generation an-
`tipsychotic agents have
`long been the main-
`stay of treatment of
`acute mania with and without psychotic fea-
`tures. However, there are reports of first-
`generation antipsychotics inducing or wors-
`ening depressive symptoms in patients with
`bipolar disorder.1 Furthermore, patients
`with bipolar disorder are more suscep-
`tible to extrapyramidal symptoms (EPSs)
`than those with schizophrenia.2,3 There-
`fore, first-generation antipsychotics are of
`limited applicability in the treatment of bi-
`polar disorders.
`In recent years, second-generation an-
`tipsychotic (SGA) agents have been devel-
`oped and have proved to be effective in the
`treatment of bipolar mania. The SGAs do
`not seem to induce depressive episodes, and
`recent studies4,5 revealed that some SGAs
`may have antidepressant effects.
`Fountoulakis et al6 recently reviewed
`treatment guidelines for bipolar disor-
`
`der. Their investigation revealed that
`guidelines for the treatment of bipolar dis-
`order vary significantly across commit-
`tees or specialist groups. In particular for
`the treatment of acute mania, some guide-
`lines recommend monotherapy with an MS
`or an SGA drug as first-line treatment,
`whereas others recommend a combina-
`tion of an MS and an antipsychotic agent.
`However, meta-analyses addressing the ef-
`ficacy and effectiveness of SGAs in the
`treatment of acute mania are lacking.7-9
`Thus, the aim of this study is to com-
`pare the efficacy and safety of (1) SGAs
`vs placebo, (2) SGAs vs MSs, (3) combi-
`nation therapy with SGAs plus MSs vs
`MSs alone, and (4) SGAs vs haloperidol.
`
`METHODS
`
`SEARCH
`
`All published and unpublished randomized con-
`trolled trials that assessed the efficacy of SGAs
`(aripiprazole, amisulpride, clozapine, olanza-
`
`Author Affiliations:
`Department of Psychiatry and
`Psychotherapy, Georg-August
`University Goettingen,
`Goettingen (Dr Scherk), Center
`for Psychiatric and
`Psychotherapeutic Care and
`Rehabilitation,
`Dr K. Fontheim’s Hospital for
`Mental Health, Liebenburg
`(Dr Pajonk), and Department of
`Psychiatry and Psychotherapy,
`Klinikum rechts der Isar der
`Technischen Universita¨t
`Mu¨ nchen, Munich (Dr Leucht),
`Germany.
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 64, APR 2007
`442
`
`WWW.ARCHGENPSYCHIATRY.COM
`
`©2007 American Medical Association. All rights reserved.
`
`Downloaded From: http://archpsyc.jamanetwork.com/ by a Infotrieve Inc User on 09/28/2016
`
`1 of 16
`
`Alkermes, Ex. 1054
`
`

`
`pine, quetiapine, risperidone, ziprasidone, and zotepine) in the
`treatment of mania were searched for in the PsiTri database (http:
`//psitri.stakes.fi) (last search: May 2006). PsiTri is a register of
`controlled trials that compiles the registers of all Cochrane re-
`view groups in the field of mental health. The registers of the
`single Cochrane review groups are compiled by means of regu-
`lar searches of numerous electronic databases and conference ab-
`stract books and hand searches of major journals (the exact search
`strategies of the individual review groups are listed in The Coch-
`rane Library10). We also searched MEDLINE. The abstracts, titles,
`and index terms of studies were searched using the following
`key words: aripiprazole, amisulpride, clozapine, olanzapine, queti-
`apine, risperidone, ziprasidone, and zotepine in conjunction with
`mania, manic, and bipolar. In addition, the reference sections of
`included articles and key reviews were screened, and the first
`and last authors (Michael Berk, Charles Bowden, William Carson,
`Marielle Erdekens, Robert Hirschfeld, Paul Keck, Sumant Khanna,
`Roger McIntyre, Steven Potkin, Gary Sachs, Mauricio Tohen,
`Lakshmi Yatham, and John Zajecka) of the included studies and
`the pharmaceutical companies (AstraZeneca, Eli Lilly, Janssen-
`Cilag, Bristol-Myers Squibb, and Pfizer) were asked by e-mail be-
`tween October 1, 2005, and March 31, 2006, whether they were
`aware of further trials. They were also contacted for the provi-
`sion of missing data necessary for the meta-analysis. We thank
`Tohen et al, Yatham et al, McIntyre et al, Smulevich et al, and
`Bowden et al for sending us additional data. A rating based on
`the 3 quality categories described in The Cochrane Collabora-
`tion Handbook11 was given for each trial: A indicates low risk of
`bias (adequate allocation concealment); B, moderate risk of bias
`(some doubt about the results, mainly studies said to be ran-
`domized but without an explanation of the method); and C, high
`risk of bias (clearly inadequate allocation concealment, eg, al-
`ternate randomization). Only trials belonging to categories A and
`B were included. Two of us (H.S. and S.L.) independently ex-
`tracted data from the trials. Any disagreement was discussed, and
`the decisions were documented.
`
`OUTCOME PARAMETERS
`
`The primary outcome of interest was the mean change in the
`Young Mania Rating Scale (YMRS) score or similar scale scores
`from baseline to the end point. Further outcome parameters
`were the rate of response and effectiveness criteria, such as the
`number of participants leaving the study early (dropouts) for
`any reason, dropouts due to adverse events, dropouts due to
`inefficacy, mean weight gain, rate of somnolence, and EPSs. For
`response, the definition used by the authors of the original stud-
`ies was adopted by the reviewers. This was generally a reduc-
`tion of at least 50% on an efficacy scale such as the YMRS.12
`In a once randomized–analyzed approach (last observation car-
`ried forward method) we assumed in the case of dichotomous
`data that participants who dropped out before completion had
`no change in their condition unless otherwise stated. Continu-
`ous data had to be reported as presented in the original studies
`without any assumptions about those lost to follow-up.
`
`META-ANALYTIC CALCULATIONS
`
`The outcome data were combined in a meta-analysis. For con-
`tinuous data the standardized mean difference based on the Hedges
`adjusted g (a slightly modified version of the Cohen D for cor-
`rection in the case of small participant numbers below 10)13 and
`its 95% confidence interval (CI) were calculated. When stan-
`dard deviations were not indicated we either derived them from
`P values or used the mean standard deviations of the other stud-
`ies. For dichotomous data, the relative risk (RR), which is de-
`fined as the ratio of the risk of an unfavorable outcome among
`
`treatment-allocated participants to the corresponding risk of an
`unfavorable outcome among those in the control group, was es-
`timated again along with its 95% CI. Whereas many meta-
`analysts preferred to use odds ratios some years ago, it has been
`shown that the RR is more intuitive14 and that odds ratios tend
`to be interpreted as RRs by physicians.15 This misinterpretation
`then leads to an overestimated impression of the effect. The ran-
`dom-effects model of DerSimonian and Laird16 was used in all
`cases. Random-effects models are, in general, more conservative
`than fixed-effects models because they take heterogeneity among
`studies into account, even if this heterogeneity is not statistically
`significant. Study heterogeneity was sought for by visual inspec-
`tion of the forest plots and by using a ␹2 test, which contrasts the
`RRs of the individual trials with the pooled RR. Significance lev-
`els of P⬍.1 were set a priori to assume the presence of heteroge-
`neity. Results of the pooled analyses, which were statistically sig-
`nificantly heterogeneous, were noted in the results. In the case
`of significant differences between groups, the number of partici-
`pants needed to treat (NNT) and the number of participants needed
`to harm (NNH) were calculated. For this purpose we calculated
`risk differences (RDs) in addition to RRs. Then, NNT/NNH was
`derived from the RD by the formula NNT/NNH=1/RD, with the
`95% CIs of NNT/NNH being the inverse of the upper and lower
`limits of the 95% CI of the RD. Studies with negative results are
`less likely to be published than studies with significant results.
`The possibility of such publication bias was examined using the
`funnel plot method described by Egger and colleagues.11 Owing
`to the small number of studies, we also tentatively analyzed the
`antipsychotics as a single group compared with placebo or MSs
`in the secondary analyses. All the calculations were performed
`using MetaView, meta-analytic standard software used by The
`Cochrane Collaboration (Review Manager Version 4.2.8, The
`Cochrane Collaboration, Oxford, England). The exact formulas
`were reported there. A P⬍.05 was considered significant. We con-
`ducted 4 comparisons: (1) SGAs vs placebo, (2) SGAs vs MSs,
`(3) SGAs vs placebo as add-on medication to MSs, and (4) SGAs
`vs haloperidol. In addition, in each comparison SGAs were en-
`tered in an exploratory pooled analysis. The latter results are de-
`tailed only in cases in which they were not heterogeneous.
`
`RESULTS
`
`INCLUDED STUDIES
`
`A total of 24 studies dealing with all the SGAs except zo-
`tepine and amisulpride were included (eTables; avail-
`able at: http://www.archgenpsychiatry.com). These stud-
`ies could be classified according to 4 different comparisons
`(Table 1): (1) SGAs vs placebo,17-28 (2) SGAs vs MSs,22,29-32
`(3) SGAs vs placebo as add-on to MSs,33-38 and (4) SGAs
`vs haloperidol.23,26,32,39,40 Four studies22,23,26,32 conducted
`3-branch examinations and could be used in 2 compari-
`sons each. Assessment of manic symptoms was per-
`formed using the YMRS (18 trials), the Mania Rating Scale
`(3 trials), and the Mania Scale (1 trial).
`The baseline mania scores were similar in all the trials
`except 2 studies with more25 or less33 severely manic pa-
`tients. The duration of most studies was 3 weeks; how-
`ever, 3 studies investigated a 4-week period21,31,32 and 2 a
`6-week period.33,40 Four trials23,26,30,37 investigated a 12-
`week period but also evaluated treatment outcomes after
`3 weeks. The 3-week data were used for the analysis.
`Four trials22-24,35 investigated purely manic patients,
`4 studies26,31,32,34 did not report the types of manic epi-
`sodes, and all the other trials examined patients with
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 64, APR 2007
`443
`
`WWW.ARCHGENPSYCHIATRY.COM
`
`©2007 American Medical Association. All rights reserved.
`
`Downloaded From: http://archpsyc.jamanetwork.com/ by a Infotrieve Inc User on 09/28/2016
`
`2 of 16
`
`Alkermes, Ex. 1054
`
`

`
`Table 1. Characteristics of the 24 Included Studies
`
`Dose, Mean (SD),
`Range, mg/d, or
`[Blood Level,
`Mean (SD)]
`
`MS
`Blood
`Level,
`Mean
`(SD)
`
`Intervention
`
`Aripiprazole
`
`27.9 (NA), 15-30
`
`Placebo
`Aripiprazole
`
`Placebo
`Aripiprazole
`
`Placebo
`Olanzapine
`
`Placebo
`Olanzapine
`
`Placebo
`Quetiapine
`
`YMRS
`Score,
`Age, Mean
`LOCF,
`Randomized,
`Duration,
`Mean (SD)
`(SD), y
`No.
`No.
`wk
`Comparison 1: Second-Generation Antipsychotics vs Placebo
`3
`130
`123
`40.5 (12.7)
`28.2
`
`3
`
`3
`
`3
`
`4
`
`3
`
`3
`
`132
`NA
`
`NA
`137
`
`135
`70
`
`69
`55
`
`60
`107
`
`122
`256
`
`40.5 (11.8)
`NA
`
`29.7
`27.9
`
`130
`136
`
`NA
`37.3 (0.9)
`
`28.3
`NA
`
`132
`70
`
`40.4 (0.9)
`39.5 (11.0)
`
`NA
`28.7 (6.7)
`
`66
`54
`
`27.6 (6.5)
`39.5 (11.0)
`38.3 (10.7) 28.76 (6.7)
`
`56
`107
`
`39.0 (10.1)
`38.0
`
`29.4 (6.8)
`32.7
`
`38.8
`41.3
`42.8
`
`33.3
`34.0
`34.0
`
`Episode
`Type, %
`
`Manic Mixed
`
`Completers,
`%
`
`Source
`
`72
`
`63
`61
`
`61
`60
`
`57
`83
`
`83
`56
`
`58
`100
`
`100
`100
`100
`
`28
`
`37
`39
`
`39
`40
`
`43
`17
`
`17
`44
`
`42
`0
`
`0
`0
`0
`
`Keck
`et al,17
`2003
`
`McQuade
`et al,18
`2003
`
`Sachs
`et al,19
`2006
`
`Tohen
`et al,20
`1999
`
`Tohen
`et al,21
`2000
`
`Bowden et
`al,22
`2005
`
`42
`
`21
`NA
`
`NA
`16
`
`26
`61
`
`35
`62
`
`42
`91
`
`86
`69
`65
`
`NA
`
`NA
`NA
`
`NA
`NA
`
`NA, 15-30
`
`27.7 (NA), 15-30
`
`14.9 (5.0), 5-20
`
`NA
`
`16.4 (4.2), 5-20
`
`NA
`
`586 (NA), 400-800
`
`NA
`
`0.8 (NA), 0.6-1.4*
`
`NA, 400-800
`
`NA
`
`NA
`
`Lithium
`Placebo
`Quetiapine
`
`Haloperidol
`Placebo
`Risperidone
`
`NA, 2-8
`
`4.1 (1.4), 1-6
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`98
`97
`102
`
`99
`101
`127
`
`119
`146
`
`144
`154
`
`144
`140
`140
`
`70
`140
`
`66
`
`98
`95
`101
`
`98
`100
`127
`
`45.1
`40.6
`38.1 (11.9)
`
`32.3
`33.1
`29.1 (5.1)
`
`119
`144
`
`39.5 (12.2)
`34.7 (12.0)
`
`29.2 (5.5)
`36.9 (8.0)
`
`142
`153
`
`35.5 (12.3)
`41.3 (13.1)
`
`37.4 (7.9)
`32.1 (6.9)
`
`144
`138
`131
`
`38.5 (12.2)
`39.4 (13.0)
`39 (10.6)
`
`31.3 (6.5)
`31.5 (6.7)
`27.0 (3.8)†
`
`66
`137
`
`37 (10.3)
`38.9 (11.6)
`
`26.7 (7.0)†
`26.2 (7.2)†
`
`100
`100
`100
`
`100
`97
`
`94
`NA
`
`NA
`NA
`65
`
`63
`59
`
`65
`
`39.0 (11.5)
`
`26.4 (7.5)†
`
`61
`
`0
`0
`0
`
`0
`3
`
`6
`NA
`
`NA
`NA
`35
`
`37
`41
`
`39
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`78
`60
`59
`
`44
`89
`
`71
`89
`
`90
`85
`54
`
`44
`61
`
`55
`
`McIntyre
`et al,23
`2005
`
`Hirschfeld
`et al,24
`2004
`
`Khanna
`et al,25
`2005
`
`Smulevich
`et al,26
`2005
`
`Keck
`et al,27
`2003
`
`Potkin
`et al,28
`2005
`
`(continued)
`
`5.6 (NA), 1-6
`
`4.2 (1.7), 1-6
`
`8.0 (3.6), 2-12
`
`130.1 (34.5), 80-160
`
`112.0 (NA), 80-160
`
`NA
`
`Placebo
`Risperidone
`
`Placebo
`Risperidone
`
`Haloperidol
`Placebo
`Ziprasidone
`
`Placebo
`Ziprasidone
`
`Placebo
`
`purely manic symptoms (45%-97%) and patients with
`mixed symptoms (3%-55%). Each of these trials was
`matched for episode type. Seven studies22,23,25,26,34,35,39
`excluded patients with rapid cycling, 12 studies* did
`not report data on this aspect, and 5 trials19-21,29,30
`
`*References 17, 18, 24, 27, 28, 31-33, 36-38, 40.
`
`included 16% to 61% of patients with a rapid cycling
`course.
`Given the small number of studies, the use of fun-
`nel plots (a method based on symmetry) was appropri-
`ate only for SGAs vs placebo. The plots on the primary
`efficacy outcomes did not suggest publication bias.
`The plot on dropouts regardless of reason was the only
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 64, APR 2007
`444
`
`WWW.ARCHGENPSYCHIATRY.COM
`
`©2007 American Medical Association. All rights reserved.
`
`Downloaded From: http://archpsyc.jamanetwork.com/ by a Infotrieve Inc User on 09/28/2016
`
`3 of 16
`
`Alkermes, Ex. 1054
`
`

`
`Table 1. Characteristics of the 24 Included Studies (cont)
`
`Dose, Mean (SD),
`Range, mg/d, or
`[Blood Level,
`Mean (SD)]
`
`Intervention
`
`Olanzapine
`
`17.4 (NA), 5-20
`
`Valproate
`Olanzapine
`
`[83.9 (32.1)]‡
`14.7 (NA), 5-25
`
`Valproate
`Olanzapine
`
`[84.6 (36.8)]‡
`10 (NA)
`
`Lithium
`Risperidone
`
`[0.74 (NA)]*
`6 (NA)
`
`YMRS
`MS
`Score,
`Age, Mean
`LOCF,
`Randomized,
`Duration,
`Blood Level,
`Mean (SD)
`(SD), y
`No.
`No.
`wk
`Mean (SD)
`Comparison 2: Second-Generation Antipsychotics vs Mood Stabilizers
`NA
`3
`125
`125 40.0 (12.1) 27.4 (5.2)
`
`NA
`NA
`
`NA
`NA
`
`NA
`NA
`
`3
`
`4
`
`4
`
`126
`57
`
`123 41.1 (12.3) 27.9 (6.6)
`57 38.1 (12.2) 32.3
`
`63
`15
`
`15
`15
`
`63 38.9 (12.1) 30.8
`15 29.4
`31.7§
`
`15 31.9
`15 34.3
`
`31.6§
`28.6†
`
`Episode
`Type, %
`
`Manic Mixed
`
`56
`
`45
`
`59
`54
`
`51
`NA
`
`NA
`NA
`
`41
`46
`
`49
`NA
`
`NA
`NA
`
`Haloperidol
`Lithium
`
`Olanzapine
`
`Placebo
`
`Quetiapine
`
`Placebo
`
`Quetiapine
`
`NA
`NA
`
`15
`15
`
`15 29.5
`15 37.1
`
`24.8†
`28.4†
`
`NA
`NA
`
`NA
`NA
`
`10 (NA)
`[0.72 (NA)]*
`Comparison 3: Second-Generation Antipsychotics vs Placebo as Add-on Medication to Mood Stabilizers
`10.4 (4.9), 5-20
`Lithium: 0.76 (0.16)*
`6
`229
`220 40.7 (11.2) 22.3 (5.4)
`45
`55
`valproate sodium:
`63.6 (18.4)‡
`Lithium: 0.82 (0.19)*
`valproate:
`74.7 (18.6)‡
`504 (NA), 200-800 Lithium: 0.78 (NA)*
`valproate: 65 (NA)‡
`
`115
`
`114 40.4 (10.8) 22.7 (9.4)
`
`53
`
`47
`
`3
`
`91
`
`81 39.6
`
`31.5
`
`NA
`
`NA
`
`100
`
`197
`
`89 41.3
`
`185 39.2
`
`31.1
`
`32.0
`
`NA
`
`NA
`
`100
`
`0
`
`3
`
`Completers,
`%
`
`Source
`
`Tohen
`et al,29
`2002
`
`Zajecka
`et al,30
`2002
`
`Berk
`et al,31
`1999
`
`Segal
`et al,32
`1998
`
`Tohen
`et al,33
`2002
`
`Sachs
`et al,34
`2004
`
`69
`
`64
`68
`
`62
`93
`
`87
`87
`
`80
`93
`
`70
`
`71
`
`62
`
`49
`
`68
`
`Lithium: 0.71 (NA)*
`valproate: 65 (NA)‡
`492 (204), 400-800 Lithium: 0.76 (0.22)*
`valproate:
`69.5 (20.2)‡
`Lithium: 0.73 (0.2)*
`valproate:
`73.6 (18.8)‡
`Lithium: 0.7 (0.3)*
`valproate:
`65.4 (27.1)‡
`Lithium: 0.8 (0.3)*
`valproate:
`77.3 (27.3)‡
`Lithium/valproate/
`carbamazepine: NA
`
`3.8 (1.8), 1-6
`
`4.0 (NA), 1-6
`
`NA, 80-160
`
`NA
`
`NA
`
`Placebo
`
`Risperidone
`
`Placebo
`
`Risperidone
`
`Placebo
`Ziprasidone
`
`Placebo
`
`3
`
`3
`
`3
`
`205
`
`185 40.7
`
`31.9
`
`100
`
`0
`
`52
`
`51
`
`75
`
`51 41
`
`28.0 (5.5)
`
`81
`
`19
`
`47 43
`
`28.0 (6.1)
`
`78
`
`22
`
`68 37
`
`29.3 (0.7)
`
`93
`
`7
`
`75
`102
`
`72 42
`101 36.5 (11.5)
`
`28.3 (0.7)
`NA
`
`103
`
`103 36.6 (12.4)
`
`NA
`
`Aripiprazole
`
`22.6 (NA), 15-30
`
`Comparison 4: Second-Generation Antipsychotics vs Haloperidol
`NA
`3
`175
`174 42.6
`31.1
`
`Haloperidol
`Olanzapine
`
`11.6 (NA), 10-15
`15.0 (5.1), 5-20
`
`Haloperidol
`
`7.1 (4.3), 3-15
`
`NA
`NA
`
`NA
`
`6
`
`172
`234
`
`162 41.0
`231 41.0 (13)
`
`31.5
`31.1 (7.6)
`
`219
`
`213 40.0 (13)
`
`30.6 (7.7)
`
`95
`
`5
`
`Abbreviations: LOCF, last observation carried forward; MS, mood stabilizer; NA, not available; YMRS, Young Mania Rating Scale.
`*Given in milliequivalents per liter.
`†Mania Rating Scale.
`‡Given in micrograms per liter.
`§Mania Scale.
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 64, APR 2007
`445
`
`WWW.ARCHGENPSYCHIATRY.COM
`
`©2007 American Medical Association. All rights reserved.
`
`Yatham
`et al,35
`2004
`
`Sachs
`et al,36
`2002
`
`Yatham
`et al,37
`2003
`
`Weisler
`et al,38
`2003
`
`Vieta
`et al,39
`2005
`
`Tohen
`et al,40
`2003
`
`56
`
`73
`
`49
`
`64
`
`48
`69
`
`72
`
`50
`
`29
`71
`
`64
`
`91
`61
`
`68
`
`92
`
`86
`94
`
`9
`39
`
`32
`
`8
`
`14
`6
`
`Downloaded From: http://archpsyc.jamanetwork.com/ by a Infotrieve Inc User on 09/28/2016
`
`4 of 16
`
`Alkermes, Ex. 1054
`
`

`
`outcome (YMRS score changes), and Table 2 gives the
`pooled results of the secondary outcome parameters.
`
`Reduction in Manic Symptoms and Response Rates
`
`Each individual SGA agent was significantly superior to
`placebo in treating acute manic symptoms (Figure 1). Re-
`sponse rates were significantly higher in the aripipra-
`zole, olanzapine, risperidone, and ziprasidone trials but
`not in the quetiapine trials.
`
`Dropout Rates
`
`The analysis revealed a significantly lower global drop-
`out rate in patients treated with olanzapine and risperi-
`done but not with aripiprazole, quetiapine, and ziprasi-
`done. Dropout due to adverse events did not differ
`between treatments.
`Except for aripiprazole, the dropout rate due to inef-
`ficacy was lower for SGAs and for the pooled data com-
`pared with placebo.
`
`Weight Change and Somnolence
`
`Weight gain was significantly greater in patients treated
`with olanzapine and quetiapine but not with the other
`SGAs.
`All the SGAs exhibited significantly higher rates of som-
`nolence (Figure 2).
`
`Extrapyramidal Symptoms
`
`The incidence of EPSs was significantly higher in the arip-
`iprazole (NNH, 13; 95% CI, 9-20) and risperidone trials
`and in the pooled analysis of all SGAs (Figure 3). In
`addition, increased EPS rates were found for ziprasi-
`done. Although this difference was not significant (P=.06),
`the RD was (NNH, 11; 95% CI, 7-33). The results were
`heterogeneous in the risperidone trials and in the pooled
`analysis (␹2=4.98; P=.03).
`There were no overall differences in the symptom se-
`verity of EPS measures using the Simpson Angus Scale
`or the Extrapyramidal Symptom Rating Scale in the arip-
`iprazole, olanzapine, risperidone, and ziprasidone trials.
`Akathisia, however, assessed using the Barnes Akathisia
`Scale, proved to be significantly more pronounced in pa-
`tients treated with aripiprazole and ziprasidone.
`
`COMPARISON 2: SGAs vs MSs
`
`Five studies investigated olanzapine, quetiapine, and ris-
`peridone vs the MSs valproate sodium29,30 or lithium22,31,32
`(Table 1). Figure 4 displays the results of the primary
`outcome (YMRS score changes), and Table 3 gives the
`pooled results of the secondary outcome parameters.
`
`Reduction in Manic Symptoms
`and Response and Dropout Rates
`
`Olanzapine compared with valproate showed greater
`symptom improvement (Figure 4). In no other trials were
`differences between the comparative treatments found.
`
`Keck et al,17 2003
`
`SMD (95% CI)
`
`–0.35 (–0.61 to –0.10)
`
`McQuade et al,18 2003
`
`–0.02 (–0.23 to 0.19)
`
`–0.41 (–0.65 to –0.16)
`
`–0.25 (–0.50 to –0.01)
`
`–0.43 (–0.76 to –0.09)
`
`–0.52 (–0.90 to –0.14)
`
`–0.47 (–0.72 to –0.22)
`
`–0.44 (–0.72 to –0.16)
`
`–0.37 (–0.64 to –0.09)
`
`–0.40 (–0.60 to –0.20)
`
`–0.61 (–0.86 to –0.35)
`
`–0.84 (–1.08 to –0.60)
`
`–0.53 (–0.77 to –0.30)
`
`–0.66 (–0.84 to –0.48)
`
`–0.37 (–0.67 to –0.07)
`
`–0.50 (–0.80 to –0.20)
`
`–0.44 (–0.65 to –0.23)
`
`–0.45 (–0.57 to –0.32)
`
`Sachs et al,19 2006
`
`Aripiprazol Pooled
`Heterogeneity: χ2 = 6.64; P = .04
`Overall: z = 2.01; P = .04; n = 899
`
`Tohen et al,20 1999
`
`Tohen et al,21 2000
`
`Olanzapine Pooled
`Heterogeneity: χ2 = 0.14; P = .70
`Overall: z = 3.65; P< .001; n = 249
`
`Bowden et al,22 2005
`
`McIntyre et al,23 2005
`
`Quetiapine Pooled
`Heterogeneity: χ2 = 0.13; P = .72
`Overall: z = 3.98; P< .001; n = 403
`
`Hirschfeld et al,24 2004
`
`Khanna et al,25 2005
`
`Smulevich et al,26 2005
`
`Risperidone Pooled
`Heterogeneity: χ2 = 3.39; P = .18
`Overall: z = 7.07; P< .001; n = 823
`
`Keck et al,27 2003
`
`Potkin et al,28 2005
`
`Ziprasidone Pooled
`Heterogeneity: χ2 = 0.36; P = .55
`Overall: z = 4.05; P< .001; n = 399
`
`All SGAs Pooled
`Heterogeneity: χ2 = 29.18; P = .002
`Overall: z = 6.89; P< .001; n = 2773
`
`Aripiprazol
`
`Olanzapine
`
`Quetiapine
`
`Risperidone
`
`Ziprasidone
`
`–0.8 –0.6 –0.4 –0.2
`–1
`(SMD)
`Favors SGA
`
`0
`
`0.4
`0.2
`Favors Placebo
`
`Figure 1. Mean Young Mania Rating Scale score changes:
`second-generation antipsychotics (SGAs) vs placebo. CI indicates confidence
`interval; SMD, standardized mean difference.
`
`asymmetrical one, but it remains unclear whether a
`study was unpublished in case an SGA failed to prove
`superiority in terms of dropout rate.
`
`COMPARISON 1: SGAs vs PLACEBO
`
`Twelve trials compared the effects of aripiprazole,17-19
`olanzapine,20,21 quetiapine,22,23 risperidone,24-26 and zipra-
`sidone27,28 vs placebo in the treatment of acute mania
`(Table 1). Figure 1 displays the results of the primary
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 64, APR 2007
`446
`
`WWW.ARCHGENPSYCHIATRY.COM
`
`©2007 American Medical Association. All rights reserved.
`
`Downloaded From: http://archpsyc.jamanetwork.com/ by a Infotrieve Inc User on 09/28/2016
`
`5 of 16
`
`Alkermes, Ex. 1054
`
`

`
`Table 2. Comparison 1: SGAs vs Placebo
`
`Trials, No.
`
`Participants, No.
`
`RR or SMD (95% CI)
`
`P Value
`
`NNT (95% CI)
`
`Response
`Aripiprazole
`Olanzapine
`Quetiapine
`Risperidone
`Ziprasidone
`Combined
`Global dropout
`Aripiprazole
`Olanzapine
`Quetiapine
`Risperidone
`Ziprasidone
`Combined
`Dropout due to adverse event
`Aripiprazole
`Olanzapine
`Quetiapine
`Risperidone
`Ziprasidone
`Combined
`Dropout due to inefficacy
`Aripiprazole
`Olanzapine
`Quetiapine
`Risperidone
`Ziprasidone
`Combined
`Weight gain
`Aripiprazole
`Olanzapine
`Quetiapine
`Risperidone
`Ziprasidone
`Combined
`SAS/ESRS
`Aripiprazole
`Olanzapine
`Quetiapine
`Risperidone
`Ziprasidone
`Combined
`BAS
`Aripiprazole
`Olanzapine
`Quetiapine
`Risperidone
`Ziprasidone
`Combined
`
`2
`2
`2
`3
`2
`11
`
`2
`2
`2
`3
`2
`11
`
`2
`2
`2
`3
`2
`11
`
`2
`2
`2
`3
`2
`11
`
`2
`2
`1
`3
`1
`9
`
`2
`2
`NA
`1
`2
`7
`
`2
`2
`NA
`NA
`2
`6
`
`534
`254
`407
`844
`416
`2455
`
`534
`254
`407
`844
`416
`2455
`
`534
`254
`407
`844
`416
`2455
`
`534
`254
`407
`844
`416
`2455
`
`514
`246
`203
`824
`203
`1990
`
`507
`246
`NA
`247
`395
`1395
`
`507
`251
`NA
`NA
`395
`1595
`
`1.82 (1.43 to 2.32)*
`1.76 (1.31 to 2.36)*
`1.46 (0.81 to 2.64)*
`1.75 (1.41 to 2.18)*
`1.49 (1.13 to 1.98)*
`1.67 (1.48 to 1.89)*
`
`0.82 (0.65 to 1.04)†
`0.62 (0.48 to 0.80)†
`0.54 (0.18 to 1.59)†
`0.61 (0.38 to 0.95)†
`0.85 (0.68 to 1.05)†
`0.72 (0.62 to 0.83)†
`
`1.13 (0.66 to 1.93)†
`0.79 (0.08 to 8.27)†
`1.13 (0.49 to 2.60)†
`1.15 (0.62 to 2.17)†
`3.09 (0.70 to 13.57)†
`1.19 (0.84 to 1.69)†
`
`0.58 (0.30 to 1.12)†
`0.64 (0.46 to 0.90)†
`0.50 (0.31 to 0.81)†
`0.39 (0.27 to 0.58)†
`0.50 (0.35 to 0.72)†
`0.52 (0.44 to 0.61)†
`
`0.16 (−0.02 to 0.33)‡
`0.75 (0.49 to 1.01)‡
`0.44 (0.17 to 0.72)‡
`0.29 (−0.19 to 0.78)‡
`0.0 (−0.29 to 0.29)‡
`0.33 (0.12 to 0.55)‡
`
`0.17 (0.0 to 0.35)‡
`−0.18 (−0.43 to 0.07)‡
`NA
`0.24 (−0.01 to 0.49)‡
`0.13 (−0.08 to 0.34)‡
`0.10 (−0.03 to 0.23)‡
`
`0.34 (0.12 to 0.56)‡
`−0.18 (−0.43 to 0.07)‡
`NA
`NA
`0.22 (0.01 to 0.43)‡
`0.15 (−0.06 to 0.35)‡
`
`⬍.001
`⬍.001
`.20
`⬍.001
`.005
`⬍.001
`
`.10
`⬍.001
`.26
`.03
`.12
`⬍.001
`
`.65
`.84
`.77
`.66
`.13
`.32
`
`.11
`.01
`.005
`⬍.001
`⬍.001
`⬍.001
`
`.06
`⬍.001
`.002
`.23
`⬎.99
`.002
`
`.05
`.15
`NA
`.06
`.24
`.13
`
`.002
`.15
`NA
`NA
`.04
`.16
`
`5 (3-8)
`4 (3-8)
`NA
`4 (3-11)
`7 (4-17)
`5 (4-7)
`
`NA
`4 (3-8)
`NA
`8 (5-50)
`NA
`8 (6-13)
`
`NA
`NA
`NA
`NA
`NA
`NA
`
`NA
`7 (4-25)
`5 (3-8)
`7 (4-33)
`6 (4-14)
`8 (8-13)
`
`NA
`NA
`NA
`NA
`NA
`NA
`
`NA
`NA
`NA
`NA
`NA
`NA
`
`NA
`NA
`NA
`NA
`NA
`NA
`
`Abbreviations: BAS, Barnes Akathisia Scale; CI, confidence interval; ESRS, Extrapyramidal Symptom Rating Scale; NA, not available; NNT, number of
`participants needed to treat; RR, relative risk; SAS, Simpson Angus Scale; SGAs, second-generation antipsychotics; SMD, standardized mean difference.
`*RR⬎1 favors SGA; RR⬍1 favors placebo.
`†RR⬍1 favors SGA; RR⬎1 favors placebo.
`‡Negative SMD values favor SGA; positive SMD values favor placebo.
`
`All the trials together indicated a trend for superiority
`of SGAs compared with MSs. Response rates were re-
`ported in 2 trials only.22,24 In the olanzapine vs valproate
`comparison, patients treated with olanzapine showed a
`higher response rate. In the quetiapine vs lithium com-
`parison, no difference was observed. As to the global drop-
`out rate and the dropout rates due to adverse events or
`
`inefficacy, no differences between SGAs and MSs could
`be discerned.
`
`Weight Change, Somnolence, and EPSs
`
`Patients treated with olanzapine and quetiapine had
`greater weight gain and a greater rate of somnolence than
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 64, APR 2007
`447
`
`WWW.ARCHGENPSYCHIATRY.COM
`
`©2007 American Medical Association. All rights reserved.
`
`Downloaded From: http://archpsyc.jamanetwork.com/ by a Infotrieve Inc User on 09/28/2016
`
`6 of 16
`
`Alkermes, Ex. 1054
`
`

`
`Relative Risk (95% CI)
`
`4.95 (2.38 to 10.28)
`
`1.41 (0.64 to 3.11)
`
`0.99 (0.33 to 2.97)
`
`1.25 (0.66 to 2.37)
`
`5.63 (2.88 to 11.00)
`
`1.97 (1.03 to 3.75)
`
`3.32 (1.17 to 9.36)
`
`7.07 (0.95 to 52.41)
`
`2.71 (1.47 to 5.00)
`
`Aripiprazol
`McQuade et al,18 2003
`Heterogeneity: Not Applicable
`Overall: z = 4.29; P< .001; n = 977
`
`Bowden et al,22 2005
`
`McIntyre et al,23 2005
`
`Quetiapine Pooled
`Heterogeneity: χ2 = 0.26; P = .61
`Overall: z = 0.68; P = .50; n = 407
`
`Khanna et al,25 2005
`
`Smulevich et al,26 2005
`
`Risperidone Pooled
`Heterogeneity: χ2 = 4.98; P = .03
`Overall: z = 2.26; P = .02; n = 585
`
`Ziprasidone
`Potkin et al,28 2005
`Heterogeneity: Not Applicable
`Overall: z = 1.91; P = .06; n = 206
`
`All SGAs Pooled
`Heterogeneity: χ2 = 15.27; P = .009
`Overall: z = 3.18; P = .001; n = 2175
`
`Aripiprazol
`
`Quetiapine
`
`Risperidone
`
`Ziprasidone
`
`0.1
`Favors SGA
`
`1
`
`100
`10
`Favors Placebo (Relative
`Risk)
`
`Figure 3. Mean rates of extrapyramidal adverse effects: second-generation
`antipsychotics (SGAs) vs placebo. CI indicates confidence interval.
`
`Reduction in Manic Symptoms and Response Rates
`
`Compared with placebo as add-on medication to MSs,
`statistically significant superiority in improving manic
`symptoms was found for olanzapine, quetiapine,
`and risperidone but not for ziprasidone (Figure 5).
`Considered as a group, the SGAs were significantly
`superior.
`The percentage of patients with a response was much
`higher in groups of patients who received add-on treat-
`ment with olanzapine and quetiapine but not with ris-
`peridone (data for ziprasidone were not available). Analy-
`sis of all the trials showed a significant advantage for
`combination therapy.
`
`Relative Risk (95% CI)
`
`1.75 (1.19 to 2.57)
`
`1.89 (1.02 to 3.49)
`
`4.58 (1.86 to 11.32)
`
`2.76 (1.16 to 6.58)
`
`6.35 (1.95 to 20.61)
`
`2.57 (0.95 to 6.96)
`
`3.82 (1.57 to 9.29)
`
`3.94 (1.99 to 7.81)
`
`3.18 (0.67 to 15.06)
`
`3.80 (2.03 to 7.12)
`
`2.89 (1.51 to 5.52)
`
`3.68 (1.35 to 10.00)
`
`3.10 (1.80 to 5.34)
`
`2.74 (2.03 to 3.68)
`
`Aripiprazol
`McQuade et al,17 2003
`Heterogeneity: Not Applicable
`Overall: z = 2.84; P = .005; n = 977
`
`Tohen et al,20 1999
`
`Tohen et al,21 2000
`
`Olanzapine Pooled
`Heterogeneity: χ2 = 2.58; P = .11
`Overall: z = 2.29; P = .02; n = 254
`
`Bowden et al,22 2005
`
`McIntyre et al,23 2005
`
`Quetiapine Pooled
`Heterogeneity: χ2 = 1.35; P = .25
`Overall: z = 2.96; P = .003; n = 407
`
`Hirschfeld et al,24 2004
`
`Smulevich et al,26 2005
`
`Risperidone Pooled
`Heterogeneity: χ2 = 0.06; P = .81
`Overall: z = 4.18; P< .001; n = 553
`
`Keck et al,27 2003
`
`Potkin et al,28 2005
`
`Ziprasidone Pooled
`Heterogeneity: χ2 = 0.16; P = .69
`Overall: z = 4.09; P< .001; n = 415
`
`All SGAs Pooled
`Heterogeneity: χ2 = 10.98; P = .20
`Overall: z = 6.64; P< .001; n = 2606
`
`Aripiprazol
`
`Olanzapine
`
`Quetiapine
`
`Risperidone
`
`Ziprasidone
`
`0.1
`Favors SGA
`
`1
`
`100
`10
`Favors Placebo (Relative
`Risk)
`
`Figure 2. Mean rates of somnolence: second-generation antipsychotics
`(SGAs) vs placebo. CI indicates confidence interval.
`
`those treated with lithium or valproate (data for risperi-
`done were not available). In these studies, the rates of
`EPS were not reported.
`
`COMPARISON 3: SGAs vs PLACEBO
`AS ADD-ON MEDICATION TO MSs
`
`Dropout Rates
`
`The 6 studies included in this analysis investigated olanza-
`pine,33 quetiapine,34,35 risperidone,36,37 and ziprasidone38 vs
`placebo as add-on medication to the MSs lithium,33-38
`valproate,33-37 and carbamazepine37 (Table 1). Three of these
`studies33-35 investigated patients who did not fully respond
`to MS monotherapy after 7, 14, or 28 days. Two more stud-
`ies36,37 included 43% and 64% of patients, respectively, with
`partial response to monotherapy with MSs. One trial38 did
`not report previous treatment. Figure 5 displays the results
`oftheprimaryoutcome(YMRSscorechanges),andTable 4
`givesthepooledresultsofthesecondaryoutcomeparameters.
`
`The global dropout rate was significantly lower in pa-
`tients treated with MSs plus quetiapine or risperidone than
`in those treated with MSs plus placebo. No difference was
`found for olanzapine and ziprasidone. Analysis of all the
`trials showed a significantly reduced global dropout rate
`in patients treated with combination therapy.
`In studies with quetiapine, risperidone, and ziprasi-
`done, adverse event dropout rates were not different; they
`were, however, higher for olanzapine than for placebo
`add-on treatment. There was no overall difference be-
`tween the active treatment and placebo groups.
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 64, APR 2007
`448
`
`WWW.ARCHGENPSYCHIATRY.COM
`
`©2007 American Medical Association. All rights reserved.
`
`Downloaded From: http://archpsyc.jamanetwork.com/ by a Infotrieve Inc User on 09/28/2016
`
`7 of 16
`
`Alkermes, Ex. 1054
`
`

`
`Regarding the dropout rate due to inefficacy, a sig-
`nificant advantage for combination therapy was shown
`in the olanzapine study but not for quetiapine and ris-
`peridone (data for ziprasidone were not available). The
`combined dropout rate due to inefficacy was signifi-
`cantly lower in patients treated with combination
`therapy.
`
`Weight Change, Somnolence, and EPS
`
`Mean weight change was increased in patients treated with
`olanzapine, risperidone, and quetiapine (data for zipra-
`sidone were not available). The rate of somnolence was
`significantly higher in patients treated with olanzapine,
`quetiapine, and ziprasidone but not with risperidone. The
`pooled analysis revealed a significantly higher rate of som-
`nolence in patients treated with MSs plus SGAs.
`Data on EPS rates were reported only in the risperi-
`done and ziprasidone trials. The incidence of EPSs was
`higher with ziprasidone than with placebo but not with
`risperidone vs placebo.
`
`COMPARISON 4: SGAs vs HALOPERIDOL
`
`We included 2 studies investigating aripiprazole39 and
`olanzapine40 vs haloperidol and the branches of 3 fur-
`ther studies analyzing quetiapine23 and risperidone26,32
`vs haloperidol (Table 1). Figure 6 displays the results
`of the primary outcome (YMRS score changes), and
`
`SMD (95% CI)
`
`–0.31 (–0