Aripiprazole and Topiramate on Free-Choice Alcohol Use

描述（由申请人提供）：由于目前药物治疗的效果有限，必须开发更有效的治疗方法以最佳治疗酒精依赖患者。将药物疗法与不同的作用机制相结合的治疗方法可能会更好地解决酒精的神经生物学多样性和酗酒者的异质性。阿立哌唑（APZ）是一种部分多巴胺激动剂，作用于多巴胺和5-羟色胺受体，而没有其他非典型抗精神病药的限制性副作用。多巴胺抑制基于饮酒和渴望的奖励。托吡酯（TPMT）是一种抗癫痫药，影响谷氨酸和GABA-A受体，并有望减少大量饮酒。谷氨酸和GABA可能介导基于缓解的饮酒和长期戒断。尽管有强有力的证据表明多种神经递质导致酒精中毒，但很少有研究使用两种具有如此多样化的作用组合的药物来研究减少酒精消费的潜在协同作用。主要目的是：（1）确定APZ和TPMT是否各自 在酒精自我给药实验（ASAE）中，APZ和TPMT的组合在减少非寻求治疗的酒精依赖受试者的酒精使用方面比安慰剂更有效，并且APZ和TPMT的组合比单独药物或安慰剂更有效;（2）检查两种剂量的APZ的假设剂量反应（3）探讨APZ、TPMT单独及联合应用对饮酒后的渴求、主观刺激、候选基因影响及其他行为效应的作用机制;（4）建立APZ与TPMT联合用药的安全性。我们将使用3 × 2药物（20 mg、30 mg APZ vs.安慰剂）-药物（500 mg TPMT vs.安慰剂）受试者间析因设计。将从社区招募非禁欲、非寻求治疗、酒精依赖者（N=216），并随机分配到6个牢房之一。在5周内滴定至其目标剂量，监测受试者的饮酒和安全性，导致实验室内酒精自我给药阶段，在此期间，在获得酒精期间评估临床和行为影响。1个月的随访评估不良事件和饮酒情况。这项研究的长期目标是改善可用于酒精中毒治疗的药物，并为此类药物作用机制的研究和理论提供信息。

DESCRIPTION (provided by applicant): Due to the modest effect of current pharmacotherapies, more effective treatments must be developed to optimally treat alcohol dependent patients. Treatments combining pharmacotherapies with different mechanisms of action may better address the diverse neurobiology of alcohol and the heterogeneity of alcoholics. Aripiprazole (APZ), a partial dopamine agonist, effects dopamine and serotonin receptors without the limiting side effects seen with other atypical antipsychotics. Dopamine medicate reward based drinking and craving. Topi ram ate (TPMT), an antiepileptic, affects glutamate and GABA-A receptors and shows promise in reducing heavy drinking. Glutamate and GABA may mediate relief-based drinking and protracted withdrawal. Despite strong evidence that multiple neurotransmitters contribute to alcoholism, few studies have used two medications with such a diverse combination of actions to examine a potential synergistic effect on reducing alcohol consumption. The primary aims are to: (1) determine if APZ and TPMT are each more effective than placebo, and the combination of APZ and TPMT is more effective than either drug alone or placebo, in reducing alcohol use in non-treatment seeking alcohol dependent subjects in an alcohol selfadministration experiment (ASAE); (2) examine a hypothesized dose-response for two doses of APZ (20mg/d and 30 mg/d) and an established dose TPMT (300mg/d); (3) examine the putative mechanisms of action of APZ, TPMT alone and together on craving, subjective stimulation, candidate gene influences and other behavioral effects associated with alcohol consumption; and (4) establish the safety of giving APZ and TPMT together. We will use of a 3 X 2 drug (20mg, 30mg APZ vs. placebo) by drug (SOOmg TPMT vs. placebo) between-subjects factorial design. Nonabstinent, non-treatment seeking, alcohol dependent persons (N=216) will be recruited from the community and randomly assigned to one of 6 cells. Subjects drinking and safety is monitored over a 5-week titration to their target dose, leading to an in-laboratory alcohol self administration session, during which clinical and behavioral effects are assessed during access to alcohol. A 1 month follow-up assesses adverse events and drinking. The long term objectives of this research are to improve medications available for alcoholism treatment and inform research and theory on the mechanisms of action of such medications.