Adjunctive Topiramate Therapy in Patients Receiving a Mood Stabilizer for Bipolar I Disorder: A Randomized, Placebo-Controlled Trial

K. N. Roy Chengappa, M.D.; Lesley K. Schwarzman, M.B.A.; Joseph F. Hulihan, M.D.; Jim Xiang, Ph.D.; and Norman R. Rosenthal, M.D., for the Clinical Affairs Product Support Study-168 Investigators

Objective: To investigate the efficacy and safety of topiramate versus placebo as adjunctive therapy for the outpatient management of bipolar I disorder.

Method: In this 12-week, randomized, double-blind, placebo-controlled trial, adults with bipolar I disorder (DSM-IV criteria) experiencing a manic or mixed episode with a Young Mania Rating Scale (YMRS) score of >= 18 while taking therapeutic levels of valproate or lithium received adjunctive topiramate or placebo. Topiramate was titrated from 25 to 400 mg/day over 8 weeks and was continued for 4 additional weeks. The study was conducted from October 2001 through October 2003. The primary outcome measure was the change in YMRS score from baseline to last study visit during the double-blind phase.

Results: The mean ± SD change in YMRS score from baseline was -10.1 ± 8.7 (-40.1%) in the topiramate group (N = 143) and -9.6 ± 8.2 (-40.2%) in the placebo group (N = 144, p = .797). Greater than 50% reduction in YMRS was achieved by 39% of the topiramate group and 38% of the placebo group (p = .914). No significant treatment differences were observed for secondary efficacy measures. Compared with adjunctive placebo, adjunctive topiramate did not worsen mania or induce depression. Paresthesia, diarrhea, and anorexia were more common in the topiramate group. The topiramate group achieved greater reductions than the placebo group in body weight (-2.5 vs. 0.2 kg, p < .001) and body mass index (-0.84 vs. 0.07 kg/m², p < .001).

Conclusion: In patients treated with lithium or valproate, there was no difference in the reduction of YMRS score in the topiramate and placebo groups. Both groups showed declines of 40%. Topiramate reduced body weight significantly relative to placebo without worsening depressive or manic symptoms.

(J Clin Psychiatry 2006;67:1698-1706)

Received Oct. 24, 2005; accepted April 10, 2006. From the Department of Psychiatry, University of Pittsburgh Medical Center and Mayview State Hospital, Pittsburgh, Pa. (Dr. Chengappa); the Department of Medical Affairs, Ortho-McNeil Neurologics, Inc., Titusville, N.J. (Ms. Schwarzman and Dr. Hulihan); the Department of Quantitative Methodology, Ortho-McNeil Janssen Scientific Affairs, LLC, Raritan, N.J. (Dr. Xiang); and the Department of Medical Affairs, PriCara, Unit of Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J. (Dr. Rosenthal).

This study was supported by Ortho-McNeil Neurologics, Inc., Titusville, N.J.

Dr. Chengappa has received grant/research support from, is a consultant for, and has received honoraria from Ortho-McNeil Neurologics. Ms. Schwarzman and Dr. Hulihan are employees of Ortho-McNeil Neurologics and major stock shareholders in Johnson & Johnson. Dr. Xiang is an employee of Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Rosenthal is an employee of Ortho-McNeil Pharmaceutical, Inc.

Participating investigators are listed at the end of this article.

Corresponding author and reprints: K. N. Roy Chengappa, M.D., Western Psychiatric Institute and Clinic, 3811 O'Hara St., Pittsburgh, PA 15213-2593 (e-mail: chengappakn@upmc.edu).