Novel Pharmacotherapy for Dual Dependence

双重依赖的新型药物疗法

• 批准号: 6825159
• 负责人: Bankole A Johnson
• 金额: $ 52.49万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6825159
• 关键词: alcoholism /alcohol abuse; alcoholism /alcohol abuse chemotherapy; anticonvulsants; behavioral /social science research tag; clinical research; clinical trials; cocaine; cognitive behavior therapy; combination therapy; comorbidity; craving; drug /alcohol abstinence; drug abuse chemotherapy; drug addiction; drug detection; drug screening /evaluation; glutamyltransferase; human subject; human therapy evaluation; patient oriented research; psychological adaptation; quality of life; questionnaires; substance abuse related behavior; substance abuse related disorder; transferrin

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.

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上瘾，但很少有药物治疗研究来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）途径介导的，并通过从伏核投射到皮质的γ-氨基丁酸（GABA）传出神经表达。这些 GABA 传出神经本身受到谷氨酰胺能兴奋性氨基酸 (EAA) 途径的强直抑制。最近，我们假设托吡酯（一种氨基磺酸盐取代的吡喃果糖衍生物）通过促进中皮质 GABA 能功能和抑制 EAA，应该更可靠地减少物质诱导的大脑奖赏，因为 DA 释放及其中脑表达都会减少。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治疗酒精依赖的有效方法。将这一概念扩展到其他药物滥用疾病，我们预测，就像酒精依赖一样，正如临床前研究所表明的那样，托吡酯也将有效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共病的安全性和有效性。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) 以戒除可卡因和酒精使用。受试者将被随机分配接受抗渴药托吡酯（300 毫克/天）或安慰剂的辅助治疗。治疗期为 12 周，随访将在试验停止后 2 周以及 1、2 和 3 个月进行。本研究的主要具体目的是检验我们假设的两个预测：1) 托吡酯组在以下结果指标上将优于安慰剂组：a) 增加每周不吸可卡因天数的平均比例（由自我评估） - 苯甲酰爱康宁（可卡因的主要代谢物）的使用和尿液检测报告，以及 b) 减少自我报告的饮酒量（通过饮酒/天、饮酒/饮酒日来衡量）禁欲天数）和饮酒生化标志物、血浆碳水化合物缺乏的转铁蛋白和γ-谷氨酰转移酶。 2) 托吡酯组在降低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），并且渴望减少的量将与减少每种滥用物质的摄入量。我们还将测试额外的次要预测：3）与安慰剂相比，托吡酯将与心理社会功能的改善相关，例如改善：a）总体幸福感； b) 社会功能，以及 c) 生活质量提高。我们的目标支持 NIH 的使命，即了解物质依赖的基本机制，并为可卡因和酒精依赖共病的个体开发有效的治疗方法。