EFFICACY OF DIVALPROEX VS LITHIUM AND PLACEBO IN THE TREATMENT OF MANIA

Objective.-To compare the effectiveness of divalproex sodium with that of lithium and placebo in patients with acute mania. Design.-Randomiz ed, double-blind, parallel-group study of treatment outcomes in patien ts with manic-depressive illness. Patients.-A total of 179 hospitalize d, 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-affiliate hospital s. Interventions.-After a minimum 3-day washout period, random assignm ent for 21 days to divalproex, lithium, or placebo in a 2:1:2 ratio. D osage of divalproex and lithium was increased if tolerated to a target concentration of 1041 mu mol/L (150 mu g/ mL) or 1.5 mmol/L (conventi onally expressed as milliequivalents per liter), respectively. Main Ou tcome Measures.-Primary outcome measures were changes in the Mania Rat ing scale derived from the Schedule for Affective Disorders and Schizo phrenia. Results.-lntent-to-treat analysis for efficacy was based on d ata from 68, 35, and 73 patients in the divalproex, lithium, and place bo groups, respectively. Groups were initially comparable except that all eight patients with four or more manic episodes in the previous ye ar were in the divalproex group. In 30%, 33%, and 51% of the above gro ups, treatment was prematurely terminated due to lack of efficacy, wit h fewer premature terminations from divalproex than placebo (P=.017). The proportions of patients improving at least 50% were higher for div alproex and lithium groups than for the placebo group: 48% for divalpr oex (P=.004) and 49% for lithium (P=.025) vs 25% for placebo. Divalpro ex was as effective in rapid-cycling manic patients as in other patien ts. Conclusions.-Both divalproex and lithium were significantly more e ffective than placebo in reducing the symptoms of acute mania. The eff icacy of divalproex appears to be independent of prior responsiveness to lithium.