title: Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis.
abstract: BACKGROUND
  Lithium is the established standard in the long-term treatment of bipolar disorder, but several new drugs have been assessed for this indication. We did a network meta-analysis to investigate the comparative efficacy and tolerability of available pharmacological treatment strategies for bipolar disorder.
  
  
  METHODS
  We systematically searched Embase, Medline, PreMedline, PsycINFO, and the Cochrane Central Register of Controlled Trials for randomised controlled trials published before June 28, 2013, that compared active treatments for bipolar disorder (or placebo), either as monotherapy or as add-on treatment, for at least 12 weeks. The primary outcomes were the number of participants with recurrence of any mood episode, and the number of participants who discontinued the trial because of adverse events. We assessed efficacy and tolerability of bipolar treatments using a random-effects network meta-analysis within a Bayesian framework.
  
  
  RESULTS
  We screened 114 potentially eligible studies and identified 33 randomised controlled trials, published between 1970 and 2012, that examined 17 treatments for bipolar disorder (or placebo) in 6846 participants. Participants assigned to all assessed treatments had a significantly lower risk of any mood relapse or recurrence compared with placebo, except for those assigned to aripiprazole (risk ratio [RR] 0·62, 95% credible interval [CrI] 0·38-1·03), carbamazepine (RR 0·68, 0·44-1·06), imipramine (RR 0·95, 0·66-1·36), and paliperidone (RR 0·84, 0·56-1·24). Lamotrigine and placebo were significantly better tolerated than carbamazepine (lamotrigine, RR 5·24, 1·07-26·32; placebo, RR 3·60, 1·04-12·94), lithium (RR 3·76, 1·13-12·66; RR 2·58, 1·33-5·39), or lithium plus valproate (RR 5·95, 1·02-33·33; RR 4·09, 1·01-16·96).
  
  
  CONCLUSIONS
  Although most of the drugs analysed were more efficacious than placebo and generally well tolerated, differences in the quality of evidence and the side-effect profiles should be taken into consideration by clinicians and patients. In view of the efficacy in prevention of both manic episode and depressive episode relapse or recurrence and the better quality of the supporting evidence, lithium should remain the first-line treatment when prescribing a relapse-prevention drug in patients with bipolar disorder, notwithstanding its tolerability profile.
  
  
  BACKGROUND
  None.
authors.affiliation: Department of Neuropsychiatry Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: tmiura@npsych.med.kyushu-u.ac.jp.
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authors.affiliation: Department of Data Science, The Institute of Statistical Mathematics, Tokyo, Japan.
authors.forename: Hisashi
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authors.lastname: Noma
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine and School of Public Health, Kyoto, Japan.
authors.forename: Toshi A
authors.initials: TA
authors.lastname: Furukawa
authors.affiliation: Department of Neuropsychiatry Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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authors.lastname: Mitsuyasu
authors.affiliation: Department of Pharmacoepidemiology, Kyoto University School of Public Health, Kyoto, Japan.
authors.forename: Shiro
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authors.lastname: Tanaka
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK.
authors.forename: Sarah
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authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
authors.forename: Georgia
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authors.affiliation: Department of Neuropsychiatry Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Keisuke
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authors.affiliation: Department of Neuropsychiatry Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Satomi
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authors.lastname: Shimano-Katsuki
authors.affiliation: Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
authors.forename: Stefan
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authors.lastname: Leucht
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK; Department of Public Health and Community Medicine, Section of Psychiatry and Clinical Psychology, University of Verona, Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cipriani
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Geddes
authors.affiliation: Department of Neuropsychiatry Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Kanba