Pharmacotherapy for Cocaine Dependence: d-cycloserine with Contingency Management

描述（由申请人提供）：可卡因依赖是一个发病率很高的公共卫生问题，但FDA尚未批准有效的药物治疗可卡因依赖。与以往寻求从药理学上减少可卡因强化、寻求或渴望的药物研究不同，这项探索性临床试验将测试d-环丝氨酸（DCS）改善基于学习的可卡因依赖行为治疗的能力。DCS是一种NMDA部分激动剂，在临床前模型中已被证明可以显著改善学习，包括消除可卡因条件下的位置偏好和阻断可卡因再获取，并改善基于消失学习的暴露治疗多种焦虑症。这项II期临床试验将探讨结合应急管理（CM）和新型家庭环境暴露疗法的行为治疗对可卡因依赖的药理学（DCS）增强作用。在以家庭为基础的接触过程中，高强度的CM激励将用于促进可卡因戒断。参与者将被随机分为两组：CM与安慰剂（CM+PL）， 2。CM带DCS （CM+DCS）。在小组分配后的19天内，参与者将每周3次（周一、三、五）到实验室报到，提供尿样，领取临时代金券，并完成药物使用、渴望、情绪、戒断和戒烟自我效能的评估。DCS（50毫克）或安慰剂将在周一和周五的研究访问中使用（在实验室访问结束后，在DCS行动期间返回家庭环境进行暴露会话）。随访时间分别为cm完成后1周、1个月和3个月，随访期间测量药物使用情况（自我报告和尿检）、渴望、情绪和戒断。两组间cm术后持续戒断的比较将是主要的结局指标。在最初的实验阶段，一系列学习/认知任务将测试DCS增强的学习/认知形式，这些形式可能有助于治疗效果。该项目将测试一种针对可卡因依赖的新型干预措施的有效性，该干预措施是基于一种已知的有效可卡因依赖治疗（CM）、消退学习理论原理和一种被证明可以改善临床前学习的药物，包括消退可卡因条件反射和基于临床学习的焦虑症暴露治疗。该研究可能表明，在消除突发事件后，增加成本效益（家庭暴露会议和DCS）以扩大CM的效益，因此可能会增加CM在社区环境中的传播。

DESCRIPTION (provided by applicant): Cocaine dependence is a public health problem with substantial morbidity, however no effective pharmacotherapy for cocaine dependence has been approved by the FDA. Unlike previous medication studies that have sought to pharmacologically reduce cocaine reinforcement, seeking or craving, this exploratory clinical trial will test d-cycloserine (DCS) for its ability to improve learning-based behavioral treatment of cocaine dependence. DCS is an NMDA partial agonist that has been shown to robustly improve learning in preclinical models, including extinction of cocaine conditioned place preference and blockade of cocaine reacquisition, and to improve extinction-learning based exposure therapy for multiple anxiety disorders. This Phase II clinical trial will investigate the pharmacological (DCS) enhancement of a behavioral treatment combining contingency management (CM) and novel home-environment exposure therapy sessions for cocaine dependence. High magnitude CM incentives will be used to promote the cocaine abstinence necessary for extinction in home-based exposure sessions. Participants will be randomized into 2 groups: 1. CM with placebo (CM+PL), and 2. CM with DCS (CM+DCS). For 19 days after group assignment, participants will report to the laboratory 3 times per week (Mon, Wed, Fri) to provide urine samples, receive contingent vouchers, and complete assessments of drug use, craving, mood, withdrawal, and quit self-efficacy. DCS (50 mg) or placebo will be administered on Mon and Fri study visits (at the end of the lab visit before returning to the home environment for exposure sessions during the time of DCS action). Follow-up visits will be conducted at 1 week, 1 month, and 3 months post-CM completion, during which time measures of drug use (self-reported and urinalysis), craving, mood, and withdrawal will be obtained. Comparison of continuous abstinence post-CM between the groups will be the primary outcome measure. During an initial laboratory session, a battery of learning/cognitive tasks will test for forms of learning/cognition enhanced by DCS that might contribute to the treatment effect. This project will test the efficacy of a novel intervention for cocaine dependence that was developed based on a known efficacious cocaine dependence treatment (CM), principles of extinction learning theory, and a medication shown to improve preclinical learning in general, including extinction of cocaine conditioning, and clinical learning-based exposure treatment of anxiety disorders. The study may indicate cost effective additions (home exposure sessions and DCS) to extend CM benefit after the removal of contingencies, and therefore may increase the dissemination of CM in community settings. PUBLIC HEALTH RELEVANCE: No medication has been approved by the FDA for the treatment of cocaine dependence. The proposed study will test a novel approach to cocaine medications development that differs from other attempts at cocaine medications development, which have sought to pharmacologically alter the effects of cocaine. This study will test the ability of d-cycloserine (DCS), which has improved behavioral treatment of anxiety disorders, to improve behavioral treatment of cocaine dependence. This trial may ultimately translate into significant advancement in the medical treatment of cocaine dependence.