A Randomized, Placebo-Controlled, Multicenter Study of Divalproex Sodium Extended Release in the Treatment of Acute Mania

Charles L. Bowden, M.D.; Alan C. Swann, M.D.; Joseph R. Calabrese, M.D.; Leon M. Rubenfaer, M.D.; Patricia J. Wozniak, Ph.D.; Michelle A. Collins, Ph.D.; Walid Abi-Saab, M.D.; and Mario Saltarelli, M.D., Ph.D.; for the Depakote ER Mania Study Group

Objective: The efficacy and safety of divalproex sodium extended release (divalproex ER) were evaluated in patients hospitalized for acute mania associated with bipolar I disorder, manic or mixed type (DSM-IV-TR criteria).

Method: Following screening and washout of psychotropic medications, 377 patients were randomly assigned in a 1:1 ratio to 21 days of double-blind treatment with divalproex ER (N = 192) or placebo (N = 185). Daily dosage was initiated at 25 mg/kg, increased 500 mg on day 3, and adjusted to serum valproate concentrations of 85 to 125 mg/mL. The Mania Rating Scale (MRS) was used to assess efficacy. Patients remained hospitalized at least 15 days during blinded treatment. The study was conducted from April 2003 to May 2004.

Results: Improvement from baseline on the MRS was significantly greater among patients who received divalproex ER compared with placebo at the first on-treatment rating assessment, day 5, and all subsequent ratings through day 21 (p = .013). Furthermore, the proportion of patients achieving at least 50% improvement from baseline in MRS was significantly higher in patients receiving divalproex ER (48%) than in patients receiving placebo (34%) (p = .012). Five of the 11 MRS items improved significantly more in patients receiving divalproex ER than placebo: less need for sleep (p <= .01), more energetic (p <= .05), increased activity (p <= .05), generalized motor hyperactivity (p <= .05), and racing thoughts (p <= .001). Side effects associated with divalproex ER included somnolence, dizziness, and gastrointestinal complaints.

Conclusion: The results indicate that divalproex ER is effective and safe for the treatment of mania episodes in bipolar I patients.

Clinical Trials Registration: ClinicalTrials.gov identifier NCT00060905.

(J Clin Psychiatry 2006;67:1501-1510)

Received Feb. 21, 2006; accepted July 13, 2006. From the Department of Psychiatry, University of Texas Health Science Center, San Antonio (Dr. Bowden); the Department of Psychiatry and Behavioral Sciences, University of Texas-Mental Sciences Institute, Houston (Dr. Swann); the Mood Disorders Program, Case Western Reserve University School of Medicine, Cleveland, Ohio (Dr. Calabrese); Neuroscience Research Associates, Southfield, Mich. (Dr. Rubenfaer); and Abbott Laboratories, Abbott Park, Ill. (Drs. Wozniak, Collins, Abi-Saab, and Saltarelli).

This study was supported by Abbott Laboratories, Abbott Park, Ill.

Financial disclosure appears at the end of this article.

A list of participating study group members appears at the end of the article.

Corresponding author and reprints: Charles L. Bowden, M.D., The University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78284-7792 (e-mail: bowdenc@uthscsa.edu).