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Olanzapine Versus Divalproex Versus Placebo in the Treatment of Mild to Moderate Mania: A Randomized, 12-Week, Double-Blind Study
Mauricio Tohen, M.D., Dr.P.H.; Eduard Vieta, M.D.; Guy M. Goodwin, M.D.; Bin Sun, Ph.D.; Jay D. Amsterdam, M.D.; Michael Banov, M.D.; Anantha Shekhar, M.D.; Scott T. Aaronson, M.D.; Leonid Bardenstein, M.D.; Iosif Grecu-Gaboş, M.D.; Vladimir Tochilov, M.D.; Dan Prelipceanu, M.D.; Heather S. Oliff, Ph.D.; Ludmila Kryzhanovskaya, M.D., Dr.Sc.; and Charles Bowden, M.D.
Objective: To evaluate the efficacy and safety of olanzapine, divalproex, and placebo in a randomized, double-blind trial in mild to moderate mania (DSM-IV-TR criteria).
Method: The study was conducted from October 2004 to December 2006. A total of 521 patients from private practices, hospitals, and university clinics were randomly assigned to olanzapine (5-20 mg/day), divalproex (500-2500 mg/day), or placebo for 3 weeks; those completing continued with a 9-week double-blind extension. Efficacy (mean change in Young Mania Rating Scale [YMRS] total score was the primary outcome) and safety were assessed.
Results: After 3 weeks of treatment, olanzapine-treated (N = 215) and placebo-treated (N = 105) patients significantly differed in YMRS baseline-to-endpoint total score change (p = .034; least squares [LS] mean: -9.4 and -7.4, respectively). Such changes were not significantly different between olanzapine vs. divalproex (N = 201) or divalproex vs. placebo. After 12 weeks of treatment, olanzapine- and divalproex-treated patients significantly differed in YMRS baseline-to-endpoint changes (p = .004; LS mean: -13.3 and -10.7, respectively). Of observed cases, 35.4% (35/99; 3 weeks) to 57.1% (28/49; 12 weeks) had valproate plasma concentrations lower than the recommended valproate therapeutic range, but these patients' YMRS scores were lower than those of patients with valproate concentrations above/within range. Compared with divalproex, after 12 weeks, olanzapine-treated patients had significant increases in weight (p < .001) and in glucose (p < .001), triglyceride (p = .003), cholesterol (p = .024), uric acid (p = .027), and prolactin (p < .001) levels. Divalproex-treated patients had significant decreases in leukocytes (p = .044) and platelets (p < .001) compared with olanzapine after 12 weeks of treatment. The incidence of potentially clinically significant weight gain (>= 7% from baseline) was higher with olanzapine than with divalproex (3-week: p = .064, 6.4% vs. 2.7%; 12-week: p = .002, 18.8% vs. 8.5%; respectively).
Conclusion: Olanzapine was significantly more efficacious than placebo but not divalproex at 3 weeks and significantly more efficacious than divalproex at 12 weeks. Olanzapine-treated patients had significantly greater increases in weight and in glucose, cholesterol, triglyceride, uric acid, and prolactin levels than divalproex-treated patients.
Trial Registration: clinicaltrials.gov Identifier: NCT00094549
(J Clin Psychiatry 2008;69:1776-1789. Online Ahead of Print October 7, 2008.)
Received Sept. 27, 2007; accepted Feb. 29, 2008. From Lilly Research Laboratories, Indianapolis, Ind. (Drs. Tohen, Sun, and Kryzhanovskaya); McLean Hospital, Harvard Medical School, Belmont, Mass. (Drs. Tohen and Vieta); Bipolar Disorders Program, University of Barcelona Hospital Clinic, IDIBAPS, CIBER-SAM, Barcelona, Spain (Dr. Vieta); the University Department of Psychiatry, Warneford Hospital, Oxford, United Kingdom (Dr. Goodwin); Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia (Dr. Amsterdam); Northwest Behavioral Medicine, Marietta, Ga. (Dr. Banov); the Department of Psychiatry, Indiana University School of Medicine, Indianapolis (Dr. Shekhar); Clinical Research Programs, Sheppard Pratt Health System, Baltimore, Md. (Dr. Aaronson); Moscow Medical University, Russia (Dr. Bardenstein); the Psychiatry Department I, County Emergency Hospital, Tg. Mures, Romania (Dr. Grecu-Gaboş; Saint Petersburg Medical Academy, Russia (Dr. Tochilov); Clinical Psychiatric Hospital "Al.Obregia," Bucharest, Romania (Dr. Prelipceanu); Science Consulting Group, North Tustin, Calif. (Dr. Oliff); and the Department of Psychiatry, University of Texas Health Science Center, San Antonio (Dr. Bowden).
This study was supported by Eli Lilly and Co., Indianapolis, Ind.
Financial disclosure appears at the end of this article.
Corresponding author and reprints: Mauricio Tohen, M.D., Lilly Research Laboratories, 450 South Madison Ave., Indianapolis, IN 46225 (e-mail: firstname.lastname@example.org).