Aripiprazole and Topiramate on Free-Choice Alcohol Use

描述（由申请人提供）：由于目前的药物治疗效果一般，必须开发更有效的治疗方法来最佳地治疗酒精依赖患者。结合不同作用机制的药物治疗可以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，作用于多巴胺和血清素受体，没有其他非典型抗精神病药物的限制性副作用。多巴胺治疗基于饮酒和渴望的奖励。Topi ram （TPMT）是一种抗癫痫药，影响谷氨酸和GABA-A受体，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会导致酒精中毒，但很少有研究使用两种药物结合如此多样化的作用来检验减少酒精消耗的潜在协同效应。主要目的是：(1)确定APZ和TPMT是否各自存在

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.