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A Double-blind Placebo-Controlled Study

Ihsan M. Salloum, MD, MPH; Jack R. Cornelius, MD, MPH; Dennis C. Daley, PhD; Levent Kirisci, PhD; Jonathan M. Himmelhoch, MD; Michael E. Thase, MD

Arch Gen Psychiatry. 2005;62:37-45.

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 -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.

Author Affiliations: Western Psychiatric Institute and Clinic of the University of Pittsburgh Medical Center (Drs Salloum, Cornelius, Daley, Himmelhoch, and Thase) and School of Pharmacy, University of Pittsburgh (Dr Kirisci), Pittsburgh, Pa.

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