Atypical Antipsychotics in the Treatment of Mania: A Meta-Analysis of Randomized, Placebo-Controlled Trials

Roy H. Perlis, M.D.; Jeffrey A. Welge, Ph.D.; Lana A. Vornik, M.S.; Robert M. A. Hirschfeld, M.D.; and Paul E. Keck, Jr., M.D.

Background: Randomized, controlled trials have demonstrated efficacy for atypical antipsychotics in the treatment of mania in bipolar disorder, either as monotherapy or adjunctive treatment. However, there are no published comparisons of individual atypical antipsychotics for mania.

Data Sources and Study Selection: We conducted a systematic review and meta-analysis of randomized, placebo-controlled monotherapy and adjunctive therapy trials of atypical antipsychotics for acute bipolar mania. Studies published through 2004 were identified using searches of PubMed/MEDLINE with the search terms mania, placebo, and each of the atypical antipsychotics, limited to randomized, controlled clinical trials; review of abstracts from the 2003 meetings of the American College of Neuropsychiatry, American Psychiatric Association, and International Conference on Bipolar Disorder; and consultations with study investigators and representatives of pharmaceutical companies that market atypical antipsychotics.

Data Extraction: Analyses were performed on the changes in Young Mania Rating Scale or Mania Rating Scale total scores from baseline to endpoint, using last observation carried forward and computing the difference in change scores between each drug and its corresponding placebo arm. A random-effects model with fixed drug effects was used to combine the studies and make comparisons of the antipsychotics to each other and to placebo.

Data Synthesis: Data from 12 placebo-controlled monotherapy and 6 placebo-controlled adjunctive therapy trials involving a total of 4304 subjects (including 1750 placebo-treated subjects) with bipolar mania were obtained. Aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone all demonstrated significant efficacy in monotherapy (i.e., all confidence intervals exclude zero). However, after adjusting for multiple comparisons, pairwise comparisons of individual effects identified no significant differences in efficacy among antipsychotics. Magnitude of improvement was similar whether the antipsychotic was utilized as monotherapy or adjunctive therapy.

Conclusions: The 5 newer atypical antipsychotics were all superior to placebo in the treatment of bipolar mania. For monotherapy and add-on therapy, cross-trial comparisons suggest that differences in acute efficacy between the drugs, if any, are likely to be small.

(J Clin Psychiatry 2006;67:509-516)

Received April 4, 2005; accepted Aug. 30, 2005. From the Bipolar Research Program, Massachusetts General Hospital and Harvard Medical School, Boston (Dr. Perlis); Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio (Dr. Welge); the Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston (Ms. Vornik and Dr. Hirschfeld); and the Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine and the General Clinical Research Center and Mental Health Care Line, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (Dr. Keck).

Supported by grant K23MH067060 from the National Institute of Mental Health, Bethesda, Md. (Dr. Perlis).

Presented in part at the 44th annual meeting of the New Clinical Drug Evaluation Unit (NCDEU), June 1-4, 2004, Phoenix, Ariz.

Financial disclosure is listed at the end of the article.

Corresponding author and reprints: Roy H. Perlis, M.D., Massachusetts General Hospital, Harvard Bipolar Research Program, 15 Parkman St., WACC 812, Boston, MA 02114 (e-mail: rperlis@partners.org).