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Acute Efficacy of Divalproex Sodium Versus Placebo in Mood Stabilizer–Naive Bipolar I or II Depression: A Double-Blind, Randomized, Placebo-Controlled Trial
Objective: To conduct an exploratory evaluation of the acute efficacy of extended-release divalproex sodium compared to placebo in patients with bipolar I or II depression.
Method: Outpatients aged 18–70 years with mood stabilizer–naive bipolar I or II disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 6 weeks of divalproex sodium monotherapy or placebo. The primary outcome measure was mean change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary outcomes included rates of response and remission, changes in the Clinical Global Impressions-Bipolar (CGI-BP) Severity of Illness scores, and changes in anxiety symptoms as measured by the Hamilton Anxiety Rating Scale. The study was conducted between 2003 and 2007.
Results: Fifty-four subjects with bipolar I (n = 20) or bipolar II (n = 34) disorder were randomly assigned to divalproex or placebo; 67% (36 of 54) met DSM-IV criteria for rapid cycling. Divalproex treatment produced statistically significant improvement in MADRS scores compared with placebo from week 3 onward. The proportions of patients meeting response criteria were 38.5% (10 of 26) in the divalproex group versus 10.7% (3 of 28) for the placebo group (P = .017). The proportions of patients meeting remission criteria were 23.1% (6 of 26) for divalproex versus 10.7% (3 of 28) for placebo (P = .208). Subgroup analysis revealed no separation between divalproex and placebo for those with bipolar II diagnoses. Nausea, increased appetite, diarrhea, dry mouth, and cramps were the most common side effects.
Conclusions: These data suggest that divalproex sodium is efficacious and reasonably well tolerated in the acute treatment of mood stabilizer–naive patients with bipolar depression, particularly for those with rapid-cycling type I presentations, and that confirmatory large-scale studies are indicated.
Trial Registration: clinicaltrials.gov Identifier:
J Clin Psychiatry
Submitted: July 30, 2009; accepted November 10, 2009.
Online ahead of print: August 24, 2010 (doi:10.4088/JCP.09m05570gre).
Corresponding author: Joseph R. Calabrese, MD, 10524 Euclid Ave, Cleveland, OH 44106 (Joseph.Calabrese@uhhospitals.org).