Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study

J Clin Psychiatry. 2007 Dec;68(12):1840-4. doi: 10.4088/jcp.v68n1203.


Objective: To determine the efficacy of divalproex (extended release) in the treatment of acute nonrefractory bipolar depression.

Method: In a stratified, double-blind, randomized, placebo-controlled trial, 18 acutely depressed bipolar outpatients (DSM-IV criteria) received either divalproex monotherapy (target dose level, 70-90 ng/dL) (N = 9) or placebo (N = 9) for 6 weeks. Patients were recruited between January 2004 and May 2005. Clinical assessment on the Montgomery-Asberg Depression Rating Scale (MADRS) determined primary efficacy.

Results: The divalproex treatment group showed significantly greater reduction in MADRS scores compared to placebo (group x time interaction, p = .0078). Absolute effect size of estimated MADRS total score reduction over time was 13.6 points with divalproex versus 1.4 points with placebo (p = .003, linear growth curve model). Standardized effect size was large (Cohen d = 0.81). MADRS item analyses demonstrated improvement in core mood symptoms more than in anxiety or insomnia symptoms. There was also a modest but significant association between MADRS and Mania Rating Scale scores in the divalproex group (r = 0.29, df = 51, p = .03), but not in the placebo group (r = -0.15, df = 35, p = .36).

Conclusions: Divalproex appeared to be an effective treatment for acute nonrefractory bipolar depression, which is consistent with previous small randomized studies. Some evidence of benefit in the depressive mixed state was observed. Confirmation or refutation with larger randomized clinical trials is warranted.

Clinical trial registration: ClinicalTrials.gov identifier NCT00226343.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adult
  • Antimanic Agents / administration & dosage
  • Antimanic Agents / therapeutic use*
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / psychology
  • Delayed-Action Preparations
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pilot Projects
  • Treatment Outcome
  • Valproic Acid / administration & dosage
  • Valproic Acid / therapeutic use*


  • Antimanic Agents
  • Delayed-Action Preparations
  • Valproic Acid

Associated data

  • ClinicalTrials.gov/NCT00226343