Optimizing Pharmacotherapy for Bipolar Alcoholics

描述（由申请人提供）： 这是申请1 R 01 AA 015385 -01的修订版，重点是评价一种有前景的药物干预治疗酒精中毒合并双相情感障碍共病患者的效果，这是一个主要未满足的治疗需求领域。我们提出了一项双盲、安慰剂对照、随机、平行组试验，以检测阿片类拮抗剂纳洛酮和抗点燃情绪稳定剂丙戊酸盐联合治疗与丙戊酸盐单药治疗酒精中毒和双相情感障碍共病患者的疗效。美国有近两百万人受影响，酒精中毒和躁郁症共病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，对于这一高危人群，几乎没有研究和有限的循证治疗方案。我们最近发表的关于丙戊酸盐在双相性酗酒者中疗效的随机对照试验仍然是迄今为止唯一完成的此类研究。该研究的结果表明，丙戊酸盐在减少重度酒精使用方面优于安慰剂。然而，相当比例的丙戊酸盐治疗受试者继续滥用酒精。有令人信服的理论和不断积累的临床证据表明，丙戊酸盐+纳曲酮联合使用可能对降低血压具有协同作用。 饮酒丙戊酸盐可能通过稳定病理性情绪状态和通过 抑制急性和长期酒精戒断的负面强化作用。相反地， 纳洛酮通过降低饮酒欲望， 酒精我们的开放标签、随机化、初步研究结果表明，丙戊酸盐+纳曲酮可显著增强戒酒能力、减少渴求、改善情绪和功能。所有这些都是患有严重精神病理学的患者特别期望的结果。这些结果为在随机对照试验中测试这种方法提供了令人信服的证据。我们提出以下目标：1）检查纳洛酮+丙戊酸盐与丙戊酸盐和安慰剂相比在治疗DSM-IV酒精依赖和共病双相I型障碍患者中的疗效; 2）评估原发性与继发性酒精中毒，双相亚型（抑郁与躁狂/混合亚型），以及存在另一种物质使用障碍（SUD）作为酒精使用结果的调节剂; 3）评估药物依从性，情绪症状或SUD的持续性和社会支持作为酒精使用结果的中介的影响。在为期3个月的双盲研究和为期3个月的随访期内，将对104例急性疾病和主动饮酒的成年受试者进行随机化和前瞻性随访。所有受试者将接受旨在提高治疗依从性的个体化咨询。

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.