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Published online August 17, 2011 DOI:10.1016/S0140-6736(11)60873-8
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Published
Online
August 17, 2011DOI:10.1016/S0140-6736(11)60873-8See
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DOI:10.1016/S0140-6736(11)61060-X
Department of Public Healthand Community Medicine,Section of Psychiatry andClinical Psychology, Universityof Verona, Verona, Italy
 (A Cipriani PhD,Prof C Barbui MD,M Purgato PsyD)
; Departmentof Hygiene and EpidemiologyUniversity of Ioannina Schoolof Medicine, Ioannina, Greece
(Prof G Salanti PhD,L M Spineli MSc)
; andDepartment of Psychiatry,University of Oxford, Oxford,UK
(J Rendell PhD,S Stockton BA(Hons),R Brown BPharm,Prof G M Goodwin FMedSci,Prof J R Geddes MD)Correspondence to:Dr Andrea Cipriani,WHO Collaborating Centre forResearch and Training in MentalHealth and Service Evaluation
 ,
Department of Public Healthand Community Medicine,Department of Medicineand Public Health, Section of Psychiatry and ClinicalPsychology, University of Verona,Policlinico “G.B. Rossi”, PiazzaleLA Scuro, 10, 37134 Verona, Italy
andrea.cipriani@univr.it
Comparative effi cacy and acceptability of antimanic drugsin acute mania: a multiple-treatments meta-analysis
 Andrea Cipriani, Corrado Barbui, Georgia Salanti, Jennifer Rendell, Rachel Brown, Sarah Stockton, Marianna Purgato, Loukia M Spineli,Guy M Goodwin, John R Geddes
Summary
Background
Conventional meta-analyses have shown inconsistent results for effi cacy of pharmacological treatmentsfor acute mania. We did a multiple-treatments meta-analysis, which accounted for both direct and indirectcomparisons, to assess the effects of all antimanic drugs.
Methods
We systematically reviewed 68 randomised controlled trials (16 073 participants) from Jan 1, 1980, to Nov 25,2010, which compared any of the following pharmacological drugs at therapeutic dose range for the treatment of acute mania in adults: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine,lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. The main outcomes were the meanchange on mania rating scales and the number of patients who dropped out of the allocated treatment at 3 weeks.Analysis was done by intention to treat.
Findings
Haloperidol (standardised mean difference [SMD] –0·56 [95% CI –0·69 to –0·43]), risperidone (–0·50[–0·63 to –0·38), olanzapine (–0·43 [–0·54 to –0·32], lithium (–0·37 [–0·63 to –0·11]), quetiapine (–0·37 [–0·51 to–0·23]), aripiprazole (–0·37 [–0·51 to –0·23]), carbamazepine (–0·36 [–0·60 to –0·11], asenapine (–0·30 [–0·53 to–0·07]), valproate (–0·20 [–0·37 to –0·04]), and ziprasidone (–0·20 [–0·37 to –0·03]) were significantly more effectivethan placebo, whereas gabapentin, lamotrigine, and topiramate were not. Haloperidol had the highest number of significant differences and was significantly more effective than lithium (SMD –0·19 [95% CI –0·36 to –0·01]),quetiapine (–0·19 [–0·37 to 0·01]), aripiprazole (–0·19 [–0·36 to –0·02]), carbamazepine (–0·20 [–0·36 to –0·01]),asenapine (–0·26 [–0·52 to 0·01]), valproate (–0·36 [–0·56 to –0·15]), ziprasidone –0·36 [–0·56 to –0·15]), lamotrigine(–0·48 [–0·77 to –0·19]), topiramate (–0·63 [–0·84 to –0·43]), and gabapentin (–0·88 [ –1·40 to –0·36]). Risperidoneand olanzapine had a very similar profile of comparative effi cacy, being more effective than valproate, ziprasidone,lamotrigine, topiramate, and gabapentin. Olanzapine, risperidone, and quetiapine led to significantly fewer discontinuations than did lithium, lamotrigine, placebo, topiramate, and gabapentin.
Interpretation
Overall, antipsychotic drugs were significantly more effective than mood stabilisers. Risperidone,olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes. These results should be considered in the development of clinical practice guidelines.
Funding
None.
Introduction
Mania is a condition of excessively raised mood thataffects about 1% of the population, usually occurs inassociation with episodes of depression, and defines thediagnosis of bipolar disorder. Bipolar disorder is arecurring illness, and one of the leading causes of worldwide disability, especially in those aged 15–44 years.
1
 Mood stabilisers and antipsychotic drugs have long beenthe mainstay of treatment of acute mania with andwithout psychotic features.
2
These medicines have beenshown to be individually more effective than placebo, butguidelines have not usually attempted to rank theeffectiveness of these drugs.
3–7
We report a systematic review of randomised controlledtrials that compared effi cacy and acceptability of antimanic drugs, either against placebo or against oneanother, in the treatment of acute mania. We used themethod of multiple-treatments meta-analysis, to allowthe integration of data from direct and indirectcomparisons.
8,9
We had previously compared theeffectiveness of antidepressants in unipolar depressionin this way.
10
This method comprehensively synthesisesdata to provide a clinically useful summary that can guidetreatment decisions.
Methods
Study protocol
At the beginning of this project, we drafted a studyprotocol and subsequently made it freely available to thepublic on our institutional website before doing the finalanalyses (webappendix p
 
1). Furthermore, with thepublication of this Article, the overall dataset will be inthe public domain for anyone who would be interestedto use it.
Search strategy and selection criteria
We searched Medline, Embase, Cumulative Index toNursing and Allied Health (CINAHL), PsycINFO, the
For the
trial protocol
see http://cebmh.warne.ox.ac.uk/cebmh/downloads/MTM%20acute%20mania_protocol_To%20be%20published_1.pdf See
Online
for webappendixFor the
overall dataset
seehttp://www.psychiatry.ox.ac.uk/research/researchunits/octumi/downloads/MTMacutemania
 
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Published online August 17, 2011 DOI:10.1016/S0140-6736(11)60873-8
Cochrane Central Register of Controlled Trials, and thetrial databases of the main regulatory agencies toidentify relevant studies published between Jan 1
,
1980,and Nov 25, 2010. The webappendix (p 7) shows fulldetails of the review methods and the search strategy.All relevant authors and principal manufacturers werecontacted to supplement incomplete reports of theoriginal papers or to provide new data for unpublishedstudies. The Cochrane risk-of-bias method was used toassess study quality.
11,12
We included all randomised, double-blind trialscomparing one active antimanic drug at a therapeuticdose with another active antimanic drug or with placeboas oral therapy for adults with acute mania. Combinationand augmentation studies were also included. Theparticipants were both men and women, aged 18 yearsor older, and with a primary diagnosis of bipolar Idisorder (manic or mixed episode) according tostandardised diagnostic criteria. Both fixed-dose andflexible-dose designs were allowed.
Outcome measures
Acute treatment was defined as a 3-week treatment inboth the effi cacy and acceptability analyses.
 
Meanchange scores on the Young Mania Rating Scale(YMRS)
13
and dropout rates (treatment discontinuation)were chosen as primary outcomes to represent,respectively, the most sensible and sensitive estimatesof acute treatment effi cacy and acceptability. Treatmentdiscontinuation (acceptability) was defined as thenumber of patients who left the study early for anyreason during the first 3 weeks of treatment of the totalnumber of patients randomly assigned to each treatmentgroup. As a secondary analysis, we also estimated theproportion of patients who responded to treatment.We did sensitivity analyses according to the followingvariables: (1) exclusion of studies adopting combinationor augmentation treatment strategies and (2) splittingof risperidone and paliperidone. Furthermore, Toinvestigate the effect of sponsorship on outcomeestimate, we did a meta-regression analysis.
Data extraction
We used the data that have been extracted for the previousCochrane reviews carried out by the members of ourreview team (JG, JR, AC, and GG). Concerning theupdated search, three reviewers (AC, JR, RB, and CB)independently reviewed references and abstracts. If allreviewers agreed that the trial did not meet eligibilitycriteria, we excluded it. We obtained the full text of allremaining articles and used the same eligibility criteriato determine which, if any, to exclude at this stage. Anydisagreements were solved via discussion with anothermember of the reviewing team (JG or GG). The samereviewers (AC, JR, RB, and CB) independently read eacharticle, assessed the completeness of the data abstraction,and confirmed the quality rating. As for previousCochrane systematic reviews, we used a structured dataabstraction form to ensure consistency of appraisal forevery study. Information extracted included study charac-teristics (such as lead author, publication year, journal,study setting, and sponsorship), participant character-istics (such as diagnostic criteria, mean baseline score,and age), intervention details (such as dose ranges, meandoses of study drugs, and concomitant or rescuemedications, or both) and outcome measures.
Statistical analysis
According to study protocol, only randomised trialscontributing to both primary outcomes were included inthe multiple-treatments meta-analysis. A priori, becausepaliperidone is the main active metabolite of risperidone,we decided to combine data for these two drugs for theprimary analyses. Dichotomous outcomes were analysedwith the total number of randomly assigned participantsas the denominator. For the secondary analysis of effi cacymeasured as a binary outcome, outcomes for the missingparticipants were imputed, assuming that all missingparticipants did not respond to treatment. When data fordrop-outs were carried forward and included in theassessment (last observation carried forward, LOCF),they were analysed with data as they were reported in theprimary studies.We produced descriptive statistics for trial and studypopulation characteristics across all eligible trials,describing the types of comparisons and some importantvariables, either clinical or methodological (such as yearof publication, age, severity of illness, and sponsorship).For every pair-wise comparison between antimanicdrugs, the standardised mean difference Hedges’sadjusted g (SMD) was calculated as the effect size forcontinuous outcomes and the odds ratio (OR) wascalculated for dichotomous outcomes, both with a95% CI. We first did pair-wise meta-analyses bysynthesising studies that compared the sameinterventions using a random-effects model
14 
toincorporate the assumption that the different studieswere estimating different, yet related, treatment effects.
15
 We used visual inspection of the forest plots toinvestigate the possibility of statistical heterogeneity.This inspection was supplemented with, mainly, the
I 
² statistic, which provides an estimate of the percentageof variability due to heterogeneity rather than a samplingerror.
15
We calculated 95% CIs for
I 
² tests, and we used ap value from a standard test for heterogeneity to assessevidence of its presence.
16
Second, we did a random-effects multiple-treatmentsmeta-analysis within a Bayesian framework
17,18
and wesummarised the results using effect sizes and theircredible intervals (CrI). The model fitted is the group-based model as described by Salanti and colleagues.
9
Wecalculated the probability for each antimanic drug to bethe most effective (first-best) regimen, the second-best,the third-best, and so on, and presented the results
 
Articles
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Published online August 17, 2011 DOI:10.1016/S0140-6736(11)60873-8
3
graphically with rankograms.
19
To estimate inconsistency,we calculated the difference between indirect and directestimates whenever indirect estimates could beconstructed with a single common comparator.
20
 Inconsistency was defined as disagreement betweendirect and indirect evidence with a 95% CI excluding 0.We also fitted the model with and without the consistencyassumptions and we compared the two models in termsof fit and parsimony.
21
In case of significant inconsistency,we investigated the distribution of clinical and metho-dological variables that we suspected might be potentialsources of either heterogeneity or inconsistency in everycomparison-specific group of trials.Finally, we looked at comparative effi cacies betweenthe antimanic drugs and expressed these using placeboas reference. We present the results using severalnumerical and graphical methods.
19
Analyses were donein STATA 10.0 (pairwise meta-analysis and
I 
² calcula-tions), in R 2.11.1 (estimation of consistency, ranko-grams, and SUCRA graphs), and WinBUGS 1.4.3(multiple-treatments meta-analysis models).
Role of the funding source
There was no funding source for this study. Thecorresponding author had full access to all the data inthe study and had final responsibility for the decision tosubmit for publication
Results
In total, we included 68 trials in the multiple-treatmentsmeta-analysis (figure 1, webappendix pp 15–20 forreferences to included studies and study characteristics).14 treatments were analysed: aripiprazole, asenapine,carbamazepine, valproate, gabapentin, haloperidol,lamotrigine, lithium, olanzapine, paliperidone,quetiapine, risperidone, topiramate, ziprasidone, andplacebo. Most trials (54 [79%] of 68) were two-groupedstudies and the rest were three-grouped studies in whichone active comparator was usually haloperidol. 17 trialshad a combination design, in which the antimanic drugsof interest were added to lithium or valproate. Of thesetrials, only one was a three-grouped study and theremaining 16 were two-grouped. Overall, 16 073 patientswere randomly assigned to one of the 14 antimanictreatments or to placebo and were included in themultiple-treatments meta-analysis. 15 673 patientscontributed to the effi cacy analysis as continuousoutcome (63 studies) and 15 626 to the acceptability
7110 records identified through database search582 screened398 excluded after initial screening of titles and abstracts4 unpublished studies (from pharmaceutical industry websites)188 full-text articles assessed for eligibility129 excluded after detailed screening19 duplicates18 meeting abstracts (unable to extract any data)26 non-randomised design9 comparing with non-oral formulation of antimanic drugs3 full text unavailable13 unable to extract any reliable data37 reviews or pooled-analyses4 RCTs could not be included in the network (no usable data)9 additional unpublished studies after contact withpharmaceuticial industries manufacturing antimanic drugs68 randomised controlled trials included in the multipletreatment meta-analysis*7 aripiprazole
vs
other antimanic drugs or placebo48 placebo
vs
antimanic drugs18 lithium
vs
other antimanic drugs or placebo13 haloperidol
vs
other antimanic drugs or placebo7 quetiapine vs other antimanic drugs or placebo6 ziprasidone vs other antimanic drugs or placebo17 olanzapine
vs
other antimanic drugs or placebo3 lamotrigine vs other antimanic drugs or placebo10 valproate
vs
other antimanic drugs or placebo10 risperidone
vs
other antimanic drugs or placebo2 asenapine vs other antimanic drugs or placebo8 carbamazepine vs other antimanic drugs or placebo5 topiramate vs other antimanic drugs or placebo1 gabapentin vs other antimanic drugs or placebo6528 excluded because duplicates
Figure 1:
Included and excluded studies
*68 randomised trials correspond to 155 groups because three-group orfour-group studies were included in this multiple-treatments meta-analysis.
PlaceboAripiprazoleGabapentinLamotrigineOlanzapineTopiramateQuetiapineCarbamazepineAsenapineRisperidoneValproateZiprasidoneHaloperidolLithium
Figure 2:
Network of eligible comparisons for the multiple-treatments meta-analysis for effi cacy
The width of the lines is proportional to the number of trials comparing every pair of treatments, and the size of every node is proportional to the number of randomised participants (sample size). The networks of eligiblecomparisons for acceptability analysis dropout rate) and for effi cacy as binary outcome are similar(webappendix pp 26–27).
For more on the
Bayesianmodels fitted and R functions
 see http://www.mtm.uoi.gr/howtodoanmtm.htmlFor more on the
STATA software
see http://www.stata.comFor more on
R2.11.1
see http://www.r-project.orgFor more on
WinBUGS 1.4.3
seehttp://www.mrc-bsu.cam.ac.uk/bugs
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