Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study

Arch Gen Psychiatry. 2005 Jan;62(1):37-45. doi: 10.1001/archpsyc.62.1.37.


Background: More than half of all individuals with bipolar disorder have a substance abuse problem at some point in their lifetime. Patients with comorbid substance abuse disorders often are excluded from clinical trials. Thus, treatments targeting this high-risk clinical population are lacking.

Objective: To evaluate the efficacy of divalproex sodium (hereafter referred to as valproate) in decreasing alcohol use and stabilizing mood symptoms in acutely ill patients with bipolar disorder and alcoholism.

Design: A 24-week, double-blind, placebo-controlled, randomized parallel-group trial.

Setting: A university hospital serving as a primary catchment-area hospital and tertiary-care facility.

Participants: Fifty-nine subjects with diagnoses of bipolar I disorder and alcohol dependence. Intervention All study subjects received treatment as usual, including lithium carbonate and psychosocial interventions, and were randomized to receive valproate or placebo.

Main outcome measures: Primary alcohol use outcomes included changes in alcohol use as indicated by changes in proportion of heavy drinking days and number of drinks per heavy drinking day. Other alcohol use outcomes included proportion of any drinking days, number of drinks per drinking day, and relapse to sustained heavy drinking. Mood outcomes included changes in depressive and manic symptoms. We used the mixed model to analyze longitudinal data. The first model used time of assessment, bipolar subtype (mixed, manic, or depressed), and treatment group (placebo or valproate) as covariates. The second nested model included the additional covariate of medication adherence.

Results: The valproate group had a significantly lower proportion of heavy drinking days (P = .02) and a trend toward fewer drinks per heavy drinking day (P = .055) than the placebo group. When medication adherence was added as covariate, the valproate group had significantly fewer drinks per heavy drinking day (P = .02) and fewer drinks per drinking day (P = .02). Higher valproate serum concentration significantly correlated with improved alcohol use outcomes. Manic and depressive symptoms improved equally in both groups. Level of gamma-glutamyl transpeptidase was significantly higher in the placebo group compared with the valproate group.

Conclusions: Valproate therapy decreases heavy drinking in patients with comorbid bipolar disorder and alcohol dependence. The results of this study indicate the potential clinical utility of the anticonvulsant mood stabilizer, valproate, in bipolar disorder with co-occurring alcohol dependence.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alcohol Drinking / drug therapy
  • Alcohol Drinking / prevention & control
  • Alcoholism / drug therapy
  • Alcoholism / epidemiology
  • Alcoholism / prevention & control*
  • Anticonvulsants / therapeutic use*
  • Bipolar Disorder / drug therapy
  • Bipolar Disorder / epidemiology
  • Bipolar Disorder / prevention & control*
  • Comorbidity
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Patient Compliance
  • Placebos
  • Psychiatric Status Rating Scales
  • Treatment Outcome
  • Valproic Acid / therapeutic use*


  • Anticonvulsants
  • Placebos
  • Valproic Acid