Optimizing Pharmacotherapy for Bipolar Alcoholics

Project: Research project

Project Details


This is a revision of application 1 R01 AA015385-01 that focuses on the evaluation of a promising
pharmacological intervention for patients with alcoholism complicated by comorbid bipolar disorder, an area
of major unmet treatment needs. We propose a double-blind, placebo-controlled, randomized, parallel
group trial to test the efficacy of the combination of the opioid antagonist, naltrexone, and the antikindling
mood stabilizing agent valproate, versus valproate alone, in the treatment of patients with comorbid
alcoholism and bipolar disorder. With nearly two million affected individuals in the U.S., comorbid alcoholism
and bipolar disorder represents a significant public health challenge. This comorbidity is associated with
severe disability, morbidity, and heightened risk for suicide. Surprisingly, little research and limited
evidence-based treatment options exist for this high-risk population. Our recently published randomized
controlled trial of valproate efficacy in bipolar alcoholics remains the only such study completed to date (Arch
Gen Psychiatry 2005;62:37-45). The results of that study suggested an advantage of valproate over
placebo in reducing heavy alcohol use. However, a significant proportion of valproate treated subjects
continued to consume alcohol at abusive levels. There are compelling theoretical, and accruing clinical
evidence suggesting that combined valproate + naltrexone may have synergistic effects on decreasing
alcohol use. Valproate, may decrease alcohol use by stabilizing pathological mood states, and by
dampening the negative reinforcing effects of acute and protracted alcohol withdrawal. Conversely,
naltrexone would decrease the positive reinforcing effects of alcohol by decreasing the desire to drink
alcohol. The results of our open-label, randomized, pilot study suggests that valproate + naltrexone robustly
enhances abstinence from alcohol, decreases craving, and improves mood and functioning. All are
particularly desirable outcomes in patients suffering from severe psychopathology. These results provide
compelling evidence for testing this approach in a randomized, controlled trial. We propose the following
aims: 1) Examine the efficacy of naltrexone plus valproate compared to valproate and placebo in the
treatment of patients with DSM-IV alcohol dependence and comorbid bipolar I disorder;2) Assess the
effects of primary vs. secondary alcoholism, bipolar subtype (depressed vs. manic/mixed subtype), and the
presence of another substance use disorder (SUD) as moderators of alcohol use outcome;3) Assess the
effects of medication compliance, persistence of mood symptoms or SUD, and social support as mediators
of alcohol use outcome. One hundred and four acutely ill and actively drinking adult subjects will be
randomized and prospectively followed during a 3-month double-blind study, and a 3-month follow-up
phase. All subjects will receive individual counseling designed to enhance treatment adherence.
Effective start/end date3/1/064/30/13


  • National Institute on Alcohol Abuse and Alcoholism: $500,478.00
  • National Institute on Alcohol Abuse and Alcoholism: $513,607.00
  • National Institute on Alcohol Abuse and Alcoholism: $76,895.00
  • National Institute on Alcohol Abuse and Alcoholism: $455,369.00
  • National Institute on Alcohol Abuse and Alcoholism: $482,253.00
  • National Institute on Alcohol Abuse and Alcoholism: $404,533.00


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