Extended-Release Carbamazepine Capsules as Monotherapy for Acute Mania in Bipolar Disorder: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Richard H. Weisler, M.D.; Paul E. Keck, Jr., M.D.; Alan C. Swann, M.D.; Andrew J. Cutler, M.D.; Terence A. Ketter, M.D.; and Amir H. Kalali, M.D.; for the SPD417 Study Group

Background: Although carbamazepine has long been used for the treatment of acute mania, only recently was its efficacy confirmed in a large, multicenter, parallel-group, placebo-controlled, randomized trial. In the present study, we further evaluated the efficacy and safety of monotherapy with beaded, extended-release carbamazepine capsules (ERC-CBZ) in patients with bipolar I disorder experiencing manic or mixed episodes.

Method: Hospitalized bipolar I disorder (DSM-IV criteria) patients (N = 239) with manic or mixed episodes were randomly assigned on a double-blind basis to receive ERC-CBZ or placebo for 3 weeks, following a single-blind placebo lead-in. Treatment with ERC-CBZ was initiated at 200 mg twice daily, and investigators were encouraged to increase doses, as necessary and tolerated, by 200 mg/day up to 1600 mg/day. Efficacy was assessed weekly with the Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression. The study was conducted from July 23, 2002, to April 1, 2003.

Results: 144 patients (60.3%) completed the study, with a significant number of placebo patients discontinuing due to lack of efficacy (p < .001). Extended-release carbamazepine treatment was associated with significant improvements in mean YMRS total and CGI total scores, using last-observation-carried-forward analyses, beginning at day 7 (p < .05). Adverse events occurring more frequently in the ERC-CBZ-treated group included dizziness (39.3%), somnolence (30.3%), and nausea (23.8%). Patients taking ERC-CBZ experienced a significant increase in total cholesterol, composed of increases in both high-density and low-density lipoproteins.

Conclusion: Extended-release carbamazepine monotherapy had significantly greater efficacy compared with placebo in the treatment of acute mania in this large, randomized, double-blind, placebo-controlled trial.

(J Clin Psychiatry 2005;66:323-330)

Received Sept. 9, 2004; accepted Dec. 27, 2004. From Duke University, Raleigh, N.C. (Dr. Weisler); the University of North Carolina, Chapel Hill (Dr. Weisler); University of Cincinnati College of Medicine, Cincinnati, Ohio (Dr. Keck); the Mental Health Care Line and General Clinical Research Center, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (Dr. Keck); the University of Texas-Houston Medical School, Houston (Dr. Swann); University of South Florida, Winter Park (Dr. Cutler); Stanford University School of Medicine, Stanford, Calif. (Dr. Ketter); University of California, Irvine (Dr. Kalali); and Quintiles, San Diego, Calif. (Dr. Kalali).

The SPD417 Study Group is supported by a grant from Shire, Wayne, Pa.

Financial disclosure is listed at the end of the article.

A complete list of the members of the SPD417 Study Group is given at the end of the article.

Corresponding author and reprints: Richard H. Weisler, M.D., Department of Psychiatry and Behavioral Sciences, Duke University, 700 Spring Forest, Suite 125, Raleigh, NC 27609 (e-mail: rweisler@aol.com).