Novel Pharmacotherapy for Dual Dependence

描述（由申请人提供）：尽管高达90%的可卡因依赖个体也可能对酒精上瘾，但很少进行药物治疗研究，以确定联合治疗这些常见合并症的有效药物。神经科学的进展表明，物质诱导的大脑奖励是通过中脑边缘多巴胺（DA）通路介导的，并通过从伏隔核投射到皮层的γ -氨基丁酸（GABA）传出信号表达。这些GABA的传出作用本身受到谷氨酰胺能兴奋性氨基酸（EAA）通路的强直抑制。最近，我们假设托吡酯，一种磺胺酸取代的果糖吡喃糖衍生物，通过促进中脑皮质gaba能功能和抑制EAAs，应该更可靠地减少物质诱导的脑奖励，因为DA的释放和中脑表达都会减少。作为支持这一假设的证据，我们在一项随机对照临床试验中证明托吡酯是一种有效的酒精依赖治疗方法。将这一概念扩展到其他药物滥用障碍，我们预测，就像酒精依赖一样，正如临床前研究表明的那样，托吡酯也将有效地治疗可卡因依赖，以及共病障碍。因此，我们建议进行一项随机、双盲、对照临床试验，以确定托吡酯治疗可卡因和酒精依赖合并症的安全性和有效性。一个由180名可卡因和酒精依赖者组成的多种族、多性别研究小组将接受联合认知行为疗法（CBT），以停止可卡因和酒精的使用。受试者将随机接受抗渴望药物托吡酯（300毫克/天）或安慰剂的辅助治疗。治疗期为12周，随访时间为试验结束后2周、1、2、3个月。本研究的主要具体目的是验证我们假设的两个预测：1)托吡酯组在以下结果测量上优于安慰剂组：a)增加每周无可卡因天数的平均比例（通过自我报告使用和尿液苯甲酰茶碱测定，可卡因的主要代谢物），b)减少自我报告饮酒（通过饮酒/日、饮酒/饮酒日和戒断天数百分比测量）和酒精消耗、血浆碳水化合物缺乏转铁蛋白和γ -谷氨酰转移酶的生化指标。2)托吡酯组在减少对可卡因和酒精的渴望方面优于安慰剂组（使用可卡因渴望问卷- now - ccq和强迫性饮酒量表- OCDS进行测量），并且渴望减少的数量将与每一种或两种滥用物质的摄入量减少相关。我们还将测试额外的次要预测：3)与安慰剂相比，托吡酯将与社会心理功能的改善有关，例如改善：a)一般幸福感；B)社会功能，c)提高生活质量。我们的目标支持NIH的使命，即了解物质依赖的基本机制，并为同时患有可卡因和酒精依赖的个体开发有效的治疗方法。

DESCRIPTION (provided by applicant): Although up to 90% of cocaine-dependent individuals also may be addicted to alcohol, few pharmacotherapy studies have been undertaken to identify efficacious agents for the combined treatment of these commonly occurring comorbid disorders. Advances in the neurosciences show that substance-induced brain reward is mediated through mesolimbic dopamine (DA) pathways and expressed via gamma-aminobutyric acid (GABA) efferents that project from the nucleus accumbens to the cortex. These GABA efferents are themselves under the tonic inhibition of glutaminergic excitatory amino acid (EAA) pathways. Recently, we hypothesized that topiramate, a sulfamate substituted fructo-pyranose derivative, through facilitation of mesocortical GABAergic function and inhibition of EAAs, should more reliably diminish substance-induced brain reward because both DA release and its midbrain expression will be diminished. As evidence in support of this hypothesis, we have demonstrated in a randomized, controlled clinical trial that topiramate is an effective treatment for alcohol dependence. Extending this concept to other substance-abuse disorders, we predict that, like in alcohol dependence, and as suggested by preclinical studies, topiramate also will be effective as a treatment for cocaine dependence, as well as for comorbid disorder. We, therefore, propose to conduct a randomized, double-blind, controlled clinical trial to determine the safety and efficacy of topiramate in the treatment of comorbid cocaine and alcohol dependence. A multi-ethnic, multi-gender study group consisting of 180 cocaine and alcohol dependent individuals will receive combined Cognitive Behavioral Therapy (CBT) for cocaine and alcohol use cessation. Subjects will be randomized to receive either adjuvant treatment with the anti-craving medication topiramate (300 mg/day) or placebo. The treatment period will be 12 weeks, and follow-up will occur at 2 weeks and 1, 2, and 3 months post-trial cessation. The primary specific aims of this study are to test two predictions of our hypothesis: 1) The Topiramate group will be superior to the Placebo group on the following outcome measures: a) increasing the weekly mean proportion of cocaine-free days (assessed by self-report of use and urine assays for benzoylecgonine, the major metabolite of cocaine), and b) decreasing self-reported drinking (measured by Drinks/Day, Drinks/Drinking Day, and Percent Days Abstinent) and biochemical markers of alcohol consumption, plasma carbohydrate-deficient transferrin and gamma-glutamyl transferase. 2) The Topiramate group will be superior to the Placebo group at decreasing craving for cocaine and alcohol (measured using the Cocaine Craving Questionnaire-Now-CCQ, and the Obsessive Compulsive Drinking Scale - OCDS), and the amount of craving reduction will be associated with reduced intake of each and both abused substances. We also will test the additional secondary predictions that: 3) Topiramate, compared with placebo, will be associated with an improvement in psychosocial functioning as exemplified by improved: a) general well-being; b) social functioning, and c) enhanced quality of life. Our objectives support NIH's mission to understand the basic mechanisms that underpin substance dependence, and to develop efficacious treatments for individuals with comorbid cocaine and alcohol dependence.