Optimizing Pharmacotherapy for Bipolar Alcoholics

描述（由申请人提供）：这是对申请1 R01 AA015385-01的修订，重点是评估酒精中毒合并双相情感障碍患者的有希望的药物干预，这是一个主要未满足治疗需求的领域。我们提出了一项双盲、安慰剂对照、随机、平行组试验，以测试阿片类拮抗剂、纳曲酮和抗引火情绪稳定剂丙戊酸联合使用，与丙戊酸单独使用相比，在治疗酒精中毒合并双相情感障碍患者中的疗效。在美国有近200万受影响的个体，共病的酒精中毒和双相情感障碍是一个重大的公共卫生挑战。这种合并症与严重残疾、发病率和自杀风险增加有关。令人惊讶的是，针对这一高危人群的研究和循证治疗选择很少。我们最近发表的丙戊酸盐对双相酗酒者疗效的随机对照试验是迄今为止唯一完成的此类研究。该研究的结果表明丙戊酸盐在减少大量饮酒方面优于安慰剂。然而，接受丙戊酸治疗的受试者中有很大一部分继续酗酒。有令人信服的理论和积累的临床证据表明，丙戊酸盐+纳曲酮联合使用可能具有降低血压的协同作用

DESCRIPTION (provided by applicant): 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. 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.