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Efficacy of Divalproex vs Lithium and Placebo in the Treatment of Mania

Charles L. Bowden, MD; Andrew M. Brugger, MD; Alan C. Swann, MD; Joseph R. Calabrese, MD; Philip G. Janicak, MD; Frederick Petty, MD, PhD; Steven C. Dilsaver, MD; John M. Davis, MD; A. John Rush, MD; Joyce G. Small, MD; Enrique S. Garza-Treviño, MD; S. Craig Risch, MD; Paul J. Goodnick, MD; David D. Morris, PhD; V. Shu, PhD; P. Johnson, MBA; M. Blake, MS; M. Javors, PhD; L. Ereshefsky, PharmD; T. McLeod; A. Shoaib, MBBA; M. Johnson, RN; S. Kimmel, MD; A. Wesley; R. Qualtiere, RN; C. Trivedi; J. Javaid, PhD; J. Peterson; M. Lambert, MD; M. Zielinski, MD; P. Orsulak, PhD; L. Sharp, RN; L. Akers, MS; M. Miller, MD; J. Kellams, MD; G. Woodham, MD; A. Frazer, RN
JAMA. 1994;271(12):918-924. doi:10.1001/jama.1994.03510360044034.
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Objective.  —To compare the effectiveness of divalproex sodium with that of lithium and placebo in patients with acute mania.

Design.  —Randomized, double-blind, parallel-group study of treatment outcomes in patients with manic-depressive illness.

Patients.  —A total of 179 hospitalized, acutely manic patients meeting the Research Diagnostic Criteria for manic disorder, approximately half of whom had been nonresponsive to lithium previously, were studied at nine university-affiliated hospitals.

Interventions.  —After a minimum 3-day washout period, random assignment for 21 days to divalproex, lithium, or placebo in a 2:1:2 ratio. Dosage of divalproex and lithium was increased if tolerated to a target concentration of 1041 μmol/L (150 μg/ mL) or 1.5 mmol/L (conventionally expressed as milliequivalents per liter), respectively.

Main Outcome Measures.  —Primary outcome measures were changes in the Mania Rating scale derived from the Schedule for Affective Disorders and Schizophrenia.

Results.  —Intent-to-treat analysis for efficacy was based on data from 68, 35, and 73 patients in the divalproex, lithium, and placebo groups, respectively. Groups were initially comparable except that all eight patients with four or more manic episodes in the previous year were in the divalproex group. In 30%, 33%, and 51% of the above groups, treatment was prematurely terminated due to lack of efficacy, with fewer premature terminations from divalproex than placebo (P=.017). The proportions of patients improving at least 50% were higher for divalproex and lithium groups than for the placebo group: 48% for divalproex (P=.004) and 49% for lithium (P=.025) vs 25% for placebo. Divalproex was as effective in rapid-cycling manic patients as in other patients.

Conclusions.  —Both divalproex and lithium were significantly more effective than placebo in reducing the symptoms of acute mania. The efficacy of divalproex appears to be independent of prior responsiveness to lithium.(JAMA. 1994;271:918-924)


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