An Exploratory Study of Naltrexone Plus Aripiprazole for Alcohol Dependence

描述（由申请人提供）：我们的团队在使用纳曲酮和其他药物进行酒精依赖个体的复杂药物治疗试验方面获得了相当多的经验。虽然纳曲酮在治疗这种疾病中已经发现了效用，但仍有相当大的改进空间，因为它并不是对每个人都有效。一种潜在提高纳曲酮疗效的方法是将其与另一种具有独特药理特征的药物联合使用。类似的联合治疗方法已被发现对许多疾病（如高血压、糖尿病、抑郁症）有用。与纳曲酮不同，阿立哌唑是FDA批准的一种治疗精神疾病的药物，通过稳定多巴胺系统起作用，多巴胺系统是一种神经化学系统，在强化和成瘾中起着重要作用。我们在嗜酒者临床试验中使用阿立哌唑的经验，在亚急性剂量和酒吧实验室研究中对非寻求治疗的酗酒者进行神经影像学研究，并从动物数据中表明，对于寻求治疗的酒精依赖个体，阿立哌唑与纳曲酮联合使用是一种很好的药物。阿立哌唑对经常饮酒的人具有良好的耐受性和安全性，而且也没有许多对脑多巴胺起作用的药物所显示的更严重的副作用（例如，锥体外系效应和运动障碍）。作为该建议的前奏，我们在一项小型试点研究中发现阿立哌唑与纳曲酮联合使用时耐受性良好。虽然目前收集的数据表明这种组合的耐受性，但需要进一步的数据来探索阿立哌唑与纳曲酮联合使用的潜在安全性和有效性。因此，在这项探索性/先导性研究中，我们建议随机选取60名酒精依赖者，在16周的治疗期内接受纳曲酮、纳曲酮加阿立哌唑或与其相匹配的安慰剂。所有个体都将接受为COMBINE研究开发的9次医疗管理课程。主要的结果变量将是每天的饮酒量。还将评估重度饮酒天数、临床总体结果、渴望、依从性、不良事件、情绪和其他变量，以评估联合用药比纳曲酮单独用药的效果。如果在探索性研究中发现这种药物组合有效，将计划进行更大规模的临床试验。

DESCRIPTION (provided by applicant): Our group has gained considerable experience in the conduct of sophisticated pharmacotherapy trials with naltrexone, and other medications, in alcohol dependent individuals. While naltrexone has found utility in the treatment of this condition, there is considerable room for improvement, since it does not work for everyone. One way to potentially enhance naltrexone's efficacy is to combine it with another medication having a unique pharmacological profile. Similar combination therapy approaches have been found useful in a number of medical conditions (e.g. hypertension, diabetes, depression). Differing from naltrexone, aripiprazole is an FDA approved medication for the treatment of psychotic disorders which works by stabilizing the dopamine system, a neurochemical system known to play a large role in reinforcement and addiction. Our experience with the use of aripiprazole in a clinical trial with alcoholics, during a sub-acute dosing and bar-lab study with neuroimaging in non-treatment seeking alcoholics, and from animal data, suggests that it would be a good medication to combine with naltrexone for treatment-seeking alcohol dependent individuals. Aripiprazole is well-tolerated and safe in actively drinking individuals, and also lacks many of the more serious adverse effects shown by medications working on brain dopamine (e.g., extrapyramidal effects and dyskinisias). As a prelude to this proposal, we have found aripiprazole to be well tolerated when combined with naltrexone in a small pilot study. While data collected so far indicate tolerability of this combination, further data are needed to explore the potential safety and efficacy of combining aripiprazole with naltrexone. Therefore, in this exploratory/pilot study, we propose to randomize 60 alcohol dependent individuals to receive either naltrexone, naltrexone plus aripiprazole, or their matching placebos over a 16-week treatment period. All individuals will receive 9 sessions of Medical Management as developed for the COMBINE Study. The primary outcome variable will be drinks per drinking day. Heavy drinking days, clinical global outcome, craving, compliance, adverse events, mood and other variables will also be assessed to evaluate the effects of the medication combination over naltrexone alone. If this medication combination is found effective in this exploratory study, a larger clinical trial will be planned.