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Charles L. Bowden, MD; Joseph R. Calabrese, MD; Susan L. McElroy, MD; Laszlo Gyulai, MD; Adel Wassef, MD; Frederick Petty, MD, PhD; Harrison G. Pope, Jr, MD; James C.-Y. Chou, MD; Paul E. Keck, Jr, MD; Linda J. Rhodes, MD; Alan C. Swann, MD; Robert M. A. Hirschfeld, MD; Patricia J. Wozniak, PhD; for the Divalproex Maintenance Study Group

Arch Gen Psychiatry. 2000;57:481-489.

Background  Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy.

Methods  A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n=372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia–Change Version subscale scores for depression and mania, and Global Assessment of Function scores.

Results  The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores.

Conclusions  The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.

From the Departments of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Tex (Drs Bowden and Rhodes), Case Western Reserve University School of Medicine, Cleveland, Ohio (Drs Calabrese), University of Cincinnati College of Medicine, Cincinnati, Ohio (Drs McElroy and Keck), University of Pennsylvania Medical Center, Philadelphia (Dr Gyulai), and the University of Texas Health Science Center (Dr Wassef) and Medical School (Dr Swann), Houston; Psychiatry Service, Veterans Affairs Medical Center, Dallas, Tex (Dr Petty); Biological Psychiatry Laboratory, McLean Hospital, Belmont, Mass, and the Department of Psychiatry, Harvard Medical School, Boston, Mass (Dr Pope); Nathan S. Kline Institute, Orangeburg, NY (Dr Chou); Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston (Dr Hirschfeld); and Clinical Statistics, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Ill (Dr Wozniak).

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