Novel Pharmacotherapy for Dual Dependence

描述（由申请人提供）： 虽然高达90%的可卡因依赖者也可能对酒精成瘾，但很少有药物治疗研究已经进行，以确定有效的药物联合治疗这些常见的共病疾病。神经科学的进展表明，物质诱导的大脑奖赏是通过中脑边缘多巴胺（DA）通路介导的，并通过γ-氨基丁酸（GABA）传出神经，从丘脑核投射到皮层。这些GABA传出神经本身受到多巴胺能兴奋性氨基酸（EAA）通路的紧张性抑制。最近，我们假设托吡酯，一种氨基磺酸取代的果糖-吡喃糖衍生物，通过促进中皮层GABA能功能和抑制EAA，应该更可靠地减少物质诱导的大脑奖励，因为DA释放及其中脑表达都将减少。作为支持这一假设的证据，我们已经在一项随机对照临床试验中证明托吡酯是治疗酒精依赖的有效药物。将这一概念扩展到其他物质滥用障碍，我们预测，与酒精依赖一样，如临床前研究所示，托吡酯也将有效治疗可卡因依赖和共病障碍。因此，我们建议进行一项随机、双盲、对照的临床试验，以确定托吡酯治疗可卡因和酒精依赖共病的安全性和有效性。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可卡因和酒精使用停止的联合认知行为疗法（CBT）。受试者将随机接受抗烟瘾药物托吡酯（300 mg/天）或安慰剂的辅助治疗。治疗期为12周，将在试验停止后2周以及1、2和3个月进行随访。本研究的主要具体目的是检验我们假设的两个预测：1）托吡酯组在以下结局指标上上级安慰剂组：（a）增加每周无可卡因日的平均比例（通过自我报告的使用和可卡因的主要代谢物苯甲酰芽子碱的尿液分析进行评估），和B）减少自我报告的饮酒（通过饮酒/天、饮酒/饮酒日和戒酒天数百分比测量）和酒精消耗的生化标志物、血浆碳水化合物缺乏转铁蛋白和γ-谷氨酰转移酶。2)托吡酯组在减少对可卡因和酒精的渴望方面上级安慰剂组（使用可卡因渴望量表-现在-CCQ和强迫性饮酒量表- OCDS测量），并且渴望减少的量与每种和两种滥用物质的摄入量减少相关。我们还将检验额外的次要预测：3）托吡酯与安慰剂相比，将与心理社会功能的改善相关，如改善：a）总体幸福感; B）社会功能;和c）生活质量提高。我们的目标支持美国国立卫生研究院的使命，以了解基本机制，支持物质依赖，并制定有效的治疗与可卡因和酒精依赖共病的个人。

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.