Gabapentin for Relapse Prevention: Alc. Withdrawal-Brain GABA/Glutamate Effects

描述(申请人提供)：酒精依赖的药物治疗是有限的，被证明有效的药物显然不适用于所有人。在医学领域，人们非常希望和需要更个性化的治疗方法。为了实现这一值得称赞的目标，需要更好地匹配对临床和/或生物亚组酗酒者安全、负担得起和有效的新药。一个研究较少的酒精使用障碍亚群是那些经历酒精戒断(AW)综合征的人，这是一系列明确的体征和症状，在相当数量的突然停止饮酒的人中出现。我们在两个已完成并已发表的临床试验中发现，加巴喷丁(一种经过充分研究并普遍开出的仿制药)，以前曾显示出对急性AW的治疗效果，在那些有AW病史的人中，也可能在更长的一段时间内防止复发。由于在这些研究中加巴喷丁与其他药物联合服用，持续时间相对较短(6周)，因此有必要进行更长时间的前瞻性对照试验，以证明在有AW病史的患者中单独服用加巴喷丁的有效性。基础科学研究假设，谷氨酸和GABA系统这两个重要的神经化学系统的失调是AW表达的基础，并可能被加巴喷丁改变。通过使用先进的磁共振成像技术(1H-MRS)来测量大脑中谷氨酸和GABA的水平，并通过对某些谷氨酸和GABA受体中的功能变异进行基因分型，我们有机会探索这些系统在预测复发方面的参与以及加巴喷丁的作用机制-为进行良好的临床试验提供重要的翻译科学成分。 为此，将对190名酒精使用障碍患者进行筛查，在戒酒3-7天后，90名符合DSM-5 AW病史标准的患者将被随机分配到加巴喷丁或安慰剂进行为期16周的试验。所有受试者都将在随机治疗前接受1H-MRS检查，并在治疗第17-24天之间再次接受1H-MRS检查，所有受试者都将接受谷氨酸8受体和GABA2A基因的特定变异的基因分型。受试者将在16周内(以及在治疗后20周和28周)接受饮酒和其他显著结果变量的评估。主要的结果变量将是“受试者再次大量饮酒的百分比”。大脑谷氨酸和/或GABA水平的变化和遗传变异将分别被评估为治疗反应的中介或调节因素。积极的结果将提供另一种药物选择，同时推进一种更个性化的酒精使用障碍药物治疗方法。此外，提供有关AW风险和治疗背后的大脑和遗传机制的新信息也增加了科学价值。因此，在了解酒精依赖患者的生物学和治疗方面的进步将大大增强。

DESCRIPTION (provided by applicant): Pharmacotherapy of alcohol dependence is limited and the medications with proven efficacy clearly do not work for everyone. In the field of medicine, there is a great desire, and need, for more personalized treatment approaches. To achieve this laudable goal, there needs to be better matching of novel medications that are safe, affordable, and efficacious to clinical and/or biological subgroups of alcoholics. One understudied alcohol use disorder subgroup are those that experience alcohol withdrawal (AW) syndrome, a well-defined constellation of signs and symptoms present in a significant number of those who abruptly stop drinking. We have found in two completed and published clinical trials that gabapentin (a well-studied and ubiquitously prescribed generic medication), that had previously shown efficacy in treatment of acute AW, might also be efficacious in preventing relapse over a more prolonged period in those with a "history of AW". Since gabapentin was combined with other medications in those studies and given for a relatively short duration (six weeks), a longer prospective controlled trial is necessary to prove its efficacy when given alone, in those with an AW history. Basic science investigation postulates that dysregulation in two prominent neurochemical systems, the glutamate and GABA systems, underlies the expression of AW and may be modified by gabapentin. By using advanced magnetic resonance imaging technology (1H-MRS) to measure brain levels of glutamate and GABA, and by genotyping functional variants in certain glutamate and GABA receptors, we have the opportunity to explore the involvement of these systems in predicting relapse and in the mechanism of gabapentin action - providing an important translational science component to a well-conducted clinical trial. To that end, 190 individuals with alcohol use disorder will be screened, and after 3-7 days of abstinence 90 individuals, who meet DSM-5 criteria for a history of AW, will be randomized to a 16-week trial of gabapentin or placebo. All subjects will undergo 1H-MRS prior to treatment randomization and again between days 17-24 of treatment and all subjects will be genotyped for specific variation in glutamate 8 receptor and GABA2A genes. Subjects will be evaluated over 16 weeks (and post-treatment at weeks 20 and 28) for drinking and other salient outcome variables. The main outcome variable will be "percent of subjects relapsing to a heavy drinking day". Change in brain glutamate and/or GABA levels and genetic variants will be evaluated as mediators or moderators respectively of treatment-response. Positive results would provide another medication option, while advancing a more personalized approach to pharmacotherapy of alcohol use disorder. Also, providing new information on brain and genetic mechanisms underlying AW risk and treatment adds scientific value. As such, advancement in understanding the biology and treatment of individuals with alcohol dependence would be greatly enhanced.