Divalproex in the Treatment of Acute Bipolar Depression: A Preliminary Double-Blind, Randomized, Placebo-Controlled Pilot Study

S. Nassir Ghaemi, M.D., M.P.H.; William S. Gilmer, M.D.; Joseph F. Goldberg, M.D.; Benjamin Zablotsky, B.A.; David E. Kemp, M.D.; Mary E. Kelley, Ph.D.; Amber D. Bauer, M.A.; Jenelle Fleck, M.N., R.N., A.P.N.; Megan M. Filkowski, B.A.; Vanessa A. Stan, A.B.; and Robert T. Dunn, M.D.

Objective: To determine the efficacy of divalproex (extended release) in the treatment of acute nonrefractory bipolar depression.

Method: In a stratified, double-blind, randomized, placebo-controlled trial, 18 acutely depressed bipolar outpatients (DSM-IV criteria) received either divalproex monotherapy (target dose level, 70-90 ng/dL) (N = 9) or placebo (N = 9) for 6 weeks. Patients were recruited between January 2004 and May 2005. Clinical assessment on the Montgomery-Asberg Depression Rating Scale (MADRS) determined primary efficacy.

Results: The divalproex treatment group showed significantly greater reduction in MADRS scores compared to placebo (group x time interaction, p = .0078). Absolute effect size of estimated MADRS total score reduction over time was 13.6 points with divalproex versus 1.4 points with placebo (p = .003, linear growth curve model). Standardized effect size was large (Cohen d = 0.81). MADRS item analyses demonstrated improvement in core mood symptoms more than in anxiety or insomnia symptoms. There was also a modest but significant association between MADRS and Mania Rating Scale scores in the divalproex group (r = 0.29, df = 51, p = .03), but not in the placebo group (r = -0.15, df = 35, p = .36).

Conclusions: Divalproex appeared to be an effective treatment for acute nonrefractory bipolar depression, which is consistent with previous small randomized studies. Some evidence of benefit in the depressive mixed state was observed. Confirmation or refutation with larger randomized clinical trials is warranted.

Clinical trial registration: ClinicalTrials.gov identifier NCT00226343.

(J Clin Psychiatry 2007;68:1840-1844)

Received Jan. 25, 2007; accepted March 19, 2007. From the Bipolar Disorder Research Program, Department of Psychiatry and Behavioral Sciences (Dr. Ghaemi and Ms. Filkowski) and Rollins School of Public Health, (Drs. Ghaemi and Kelley), Emory University, Atlanta, Ga.; the Asher Center for the Study and Treatment of Depressive Disorders, Northwestern University, Chicago, Ill. (Drs. Gilmer and Kemp and Mss. Bauer and Fleck); the Affective Disorders Program, Silver Hill Hospital, New Canaan, Conn. (Dr. Goldberg); the Zucker Hillside Hospital, North Shore Long Island Jewish Health System, Glen Oaks, N.Y. (Dr. Goldberg); and the Cambridge Bipolar Disorder Research Program, Cambridge Health Alliance, Harvard Medical School, Cambridge, Mass. (Dr. Dunn, Mr. Zablotsky, and Ms. Stan). Dr. Goldberg is now with the Department of Psychiatry, Mt. Sinai School of Medicine, New York, N.Y.

Supported by a grant from Abbott Laboratories, Chicago, Ill. All data collection, analysis, and writing were conducted solely by the authors.

Financial disclosure appears at the end of this article.

Corresponding author and reprints: S. Nassir Ghaemi, M.D., 1841 Clifton Rd., N.E., Atlanta, GA 30322 (e-mail: nghaemi@emory.edu).