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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; Depakote Mania Study Group; 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.

Abstract
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)

Author Affiliations
Abbott Laboratories, North Chicago, Ill; University of Texas Health Science Center at San Antonio.; University of Texas Medical School, Houston; Harris County Psychiatric Center, Houston, Tex.; Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio.; Illinois State Psychiatric Center, Chicago.; Department of Psychiatry, University of Texas Southwestern Medical Center and the Veterans Affairs Medical Center, Dallas.; Department of Psychiatry, Indiana University School of Medicine, Indianapolis.; Larue D. Carter Memorial Hospital, Indianapolis, Ind.

From the Department of Psychiatry, University of Texas Health Science Center and Audie L. Murphy Memorial Veterans Hospital, San Antonio (Drs Bowden and Garza-Treviño); Clinical Research Section, Abbott Laboratories, North Chicago, Ill (Drs Brugger and Morris); Department of Psychiatry, University of Texas Medical School, Houston (Drs Swann and Dilsaver); Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio (Dr Calabrese); Illinois State Psychiatric Institute, Chicago, and Department of Psychiatry, University of Illinois at Chicago (Drs Janicak and Davis); Veterans Affairs Medical Center and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas (Drs Petty and Rush); Department of Psychiatry, Indiana University School of Medicine, Indianapolis (Dr Small); Department of Psychiatry, Emory University School of Medicine, Atlanta, Ga (Dr Risch); and Department of Psychiatry, University of Miami (Fla) (Dr Goodnick). Other members of the Depakote Mania Study Group are listed at the end of this article. Drs Brugger and Morris purchase Abbott Laboratories stock on a regular basis as part of their retirement plans; Drs Bowden, Swann, Calabrese, and Janicak have received honoraria from Abbott for educational programs; Dr Janicak owns equities in Abbott Laboratories through an investment plan for retirement funds. Drs Davis and Goodnick have received remuneration from Abbott as speakers. Dr Small owns stock in Abbott Laboratories and has received honoraria for participation in educational programs. Dr Garza-Treviño has received remuneration from Abbott for participation in continuing medical education activities. Dr Risch has received remuneration from Abbott as a speaker and a consultant.

Footnotes
Reprint requests to Division of Biological Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78284-7792 (Dr Bowden).

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