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 protected]).