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Randomized, Double-Blind, Placebo-Controlled Study of Divalproex Extended Release Loading Monotherapy in Ambulatory Bipolar Spectrum Disorder Patients With Moderate-to-Severe Hypomania or Mild Mania
Objective: To determine whether divalproex extended release (ER) would be effective in outpatients with DSM-IV-TR–diagnosed ambulatory bipolar spectrum disorder (BSD) and moderate-to-severe hypomanic or mild manic symptoms (hypomania/mild mania).
Method: An 8-week, randomized, double-blind, placebo-controlled trial of divalproex ER oral loading (begun at 15 mg/kg/d and titrated to a maximum of 30 mg/kg/d) in ambulatory BSD with hypomania/mild mania patients, operationally defined as a Young Mania Rating Scale (YMRS) score ≥ 10 but < 21 at baseline and at 1 other study visit at least 3 days apart over the 2 weeks before baseline, was conducted. Patients were enrolled from October 2003 through November 2007.
Results: Sixty patients (n = 30 in the divalproex ER group) had at least 1 postbaseline assessment. The divalproex ER group showed a significantly greater rate of reduction in mean total YMRS score than the placebo group (longitudinal analysis, P = .024). The divalproex ER group also showed more improvement in depressive symptoms the greater the severity of baseline depression (P = .11 for analysis of covariance treatment-by-baseline interaction). Baseline-to-endpoint change scores using last-observation-carried-forward showed that divalproex ER was associated with a marginally significant change in mean total YMRS score (P = .080). Comparable numbers of patients discontinued divalproex ER (n = 17) and placebo (n = 15), including those that discontinued use because of adverse events (n = 4 and 3, respectively).
Conclusions: Divalproex ER begun at 15 mg/kg/d was superior to placebo in reducing hypomanic/mild manic symptoms in ambulatory BSD. It was associated with fairly good tolerability but a high discontinuation rate. Controlled trials of divalproex ER and other mood stabilizers in larger groups of ambulatory BSD patients with hypomanic/mild manic symptoms appear warranted.
Trial Registration: clinicaltrials.gov Identifier: NCT00278772
J Clin Psychiatry
Submitted: November 5, 2008; accepted January 9, 2009.
Online ahead of print: February 23, 2010 (doi:10.4088/JCP.08m04854yel).
Corresponding author: Susan L. McElroy, MD, 4075 Old Western Row Road, Mason, OH 45040 (email@example.com).