An Exploratory Study of Naltrexone Plus Aripiprazole for Alcohol Dependence

描述(由申请人提供)：我们的团队在酒精依赖患者使用纳曲酮和其他药物进行复杂的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方面找到了实用的方法，但仍有相当大的改进空间，因为它并不适用于所有人。一种可能提高纳曲酮疗效的方法是将其与另一种具有独特药理学特征的药物相结合。类似的联合治疗方法已被发现在许多医学疾病(如高血压、糖尿病、抑郁症)中有效。与纳曲酮不同，阿立哌唑是FDA批准的治疗精神障碍的药物，它通过稳定多巴胺系统发挥作用，多巴胺系统是已知在强化和成瘾方面发挥重要作用的神经化学系统。我们在对酗酒者的临床试验中使用阿立哌唑的经验，在亚急性剂量和对未寻求治疗的酗酒者进行神经成像的酒吧实验室研究中，以及从动物数据中的经验表明，对于寻求治疗的酒精依赖者来说，与纳曲酮联合使用将是一种很好的药物。阿立哌唑在经常饮酒的人中耐受性和安全性很好，而且也没有作用于大脑多巴胺的药物所显示的许多更严重的不良反应(例如，锥体外系效应和技能障碍)。作为这一建议的前奏，我们在一项小型先导性研究中发现，阿立哌唑与纳曲酮联合使用时耐受性良好。虽然到目前为止收集的数据表明这种联合用药的耐受性，但还需要进一步的数据来探索阿立哌唑和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，我们建议随机选择60名酒精依赖者，分别接受纳曲酮、纳曲酮和阿立哌唑治疗，或在16周的治疗期间服用与其相匹配的安慰剂。所有个人都将接受为联合学习而开发的9个医疗管理课程。主要结果变量将是每天饮酒的饮酒量。还将评估大量饮酒天数、临床总体结果、渴望、依从性、不良事件、情绪和其他变量，以评估联合用药比单用纳曲酮的效果。如果这种药物组合在这项探索性研究中被发现有效，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.