Optimizing Pharmacotherapy for Bipolar Alcoholics

这是应用程序1 R01 AA015385-01的修订版，其重点是评估一个有前景的 酒精中毒合并双相情感障碍患者的药物干预 未得到满足的主要治疗需求。我们提出了双盲、安慰剂对照、随机、平行的 测试阿片类拮抗剂纳曲酮和抗点燃药联合的疗效的团体试验 心境稳定剂丙戊酸盐与单用丙戊酸盐治疗合并症的疗效比较 酗酒和躁郁症。在美国有近200万受影响的个人，共同患有酒精中毒 而双相情感障碍是一个重大的公共卫生挑战。这种共病与 严重的残疾、发病率和高自杀风险。令人惊讶的是，几乎没有研究，而且有限 对于这一高危人群，存在循证治疗选择。我们最近出版的随机化 丙戊酸盐对双相酒精患者疗效的对照试验仍然是迄今为止唯一完成的此类研究(ARCH 《普通精神病学》2005；62：37-45)。这项研究的结果表明丙戊酸盐比丙戊酸盐有优势 安慰剂在减少大量酒精使用中的作用。然而，丙戊酸盐治疗的受试者中有相当大比例 继续以滥用的水平饮酒。有令人信服的理论和不断积累的临床 有证据表明，丙戊酸纳曲酮联合用药可能对降低 酗酒。丙戊酸盐，可以通过稳定病理情绪状态来减少酒精使用，并通过 抑制急性和长期戒酒的负面强化作用。相反， 纳曲酮可以通过降低饮酒欲望来减少酒精的积极强化作用 酒精。我们的开放、随机、先导研究的结果表明，丙戊酸纳曲酮强效 促进戒酒，减少饥饿感，改善情绪和功能。都是 在患有严重精神病的患者中尤其令人满意的结果。这些结果提供了 在随机对照试验中测试这种方法的令人信服的证据。我们提出以下建议 目的：1)比较纳曲酮联合丙戊酸盐与丙戊酸盐和安慰剂治疗慢性前列腺炎的疗效。 DSM-IV酒精依赖和共病双相I型障碍患者的治疗；2)评估 原发与继发性酒精中毒、双相亚型(抑郁与躁狂/混合亚型)的影响，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因素；3)评估 服药依从性、情绪症状的持续性和社会支持作为中介的影响 酒精使用结果。104名病情严重且经常饮酒的成年受试者 在为期3个月的双盲研究和3个月的随访中，进行了随机和前瞻性的随访 相位。所有受试者都将接受旨在提高治疗依从性的个别咨询。

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.