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

加巴喷丁预防复发：Alc。

• 批准号: 9315600
• 负责人: RAYMOND F ANTON
• 金额: $ 51.24万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315600
• 关键词: Abstinence; Acute; Aftercare; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Alleles; Anticonvulsants; Attention; Basic Science; Biological; Biology; Brain; Characteristics; Clinical; Clinical Trials; Code; Conduct Clinical Trials; DSM-IV; DSM-V; Data; Development; Evaluation; FDA approved; Future; GABA Receptor; Generic Drugs; Genes; Genetic; Genotype; Glutamate Receptor; Glutamates; Goals; Heavy Drinking; Imaging technology; Individual; Investigation; Lead; Literature; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Mediator of activation protein; Medical; Medicine; Naltrexone; Neurotransmitters; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Placebos; Population; Prevention; Prevention approach; Publishing; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Recording of previous events; Relapse; Reporting; Risk; Signs and Symptoms; Single Nucleotide Polymorphism; Subgroup; System; Testing; Translational Research; Treatment outcome; Variant; Withdrawal; Withdrawal Symptom; Work; acamprosate; alcohol abuse therapy; alcohol relapse; alcohol use disorder; alcoholism therapy; base; control trial; disorder later incidence prevention; drinking; effective therapy; experience; gabapentin; gamma-Aminobutyric Acid; genetic variant; improved; interest; meetings; neurochemistry; novel; personalized approach; personalized medicine; prevent; problem drinker; prospective; prospective test; public health relevance; receptor; relapse prediction; relapse risk; response; sound; topiramate; treatment response; week trial

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.

描述（由申请人提供）：酒精依赖的药物治疗是有限的，并且已被证明有效的药物显然并不适合所有人。在医学领域，人们非常渴望和需要更加个性化的治疗方法。为了实现这一值得称赞的目标，需要更好地匹配安全、负担得起且对酗酒者的临床和/或生物学亚组有效的新型药物。一个未被充分研究的酒精使用障碍亚组是那些经历酒精戒断（AW）综合症的人，这是一组明确的体征和症状，出现在许多突然停止饮酒的人身上。我们在两项已完成并已发表的临床试验中发现，加巴喷丁（一种经过充分研究且普遍使用的仿制药）此前已显示出治疗急性 AW 的功效，也可能在较长时间内有效预防患有 AW 的患者复发。一部“AW的历史”。由于这些研究中加巴喷丁与其他药物联合使用且给药时间相对较短（六周），因此需要进行更长的前瞻性对照试验来证明其单独给药时对有 AW 病史的患者的疗效。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，并且可能被加巴喷丁修饰。通过使用先进的磁共振成像技术 (1H-MRS) 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和治疗中的作用。加巴喷丁作用机制 - 为良好进行的临床试验提供重要的转化科学组成部分。 为此，将对 190 名酒精使用障碍患者进行筛查，并在戒酒 3-7 天后，符合 DSM-5 AW 病史标准的 90 名患者将被随机分配接受为期 16 周的加巴喷丁或安慰剂试验。所有受试者将在治疗随机化之前以及治疗第17-24天之间再次接受1H-MRS，并且所有受试者将针对谷氨酸8受体和GABA2A基因的特定变异进行基因分型。将在 16 周（以及治疗后第 20 周和 28 周）内对受试者的饮酒情况和其他显着结果变量进行评估。主要结果变量是“再次酗酒的受试者百分比”。大脑谷氨酸和/或 GABA 水平的变化以及遗传变异将分别作为治疗反应的调节因子或调节因子进行评估。积极的结果将提供另一种药物选择，同时推进酒精使用障碍药物治疗的更加个性化的方法。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，对酒精依赖个体的生物学和治疗的理解将大大加强。