Pharmacotherapy for Cocaine Dependence: d-cycloserine with Contingency Management

描述（由申请人提供）：可卡因依赖是一种具有大量发病率的公共卫生问题，但FDA尚未批准用于可卡因依赖的有效药物治疗。与以前试图减少可卡因强化、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）改善可卡因依赖的学习型行为治疗的能力。DCS是一种NMDA部分激动剂，已被证明可以在临床前模型中稳健地改善学习，包括消除可卡因条件性位置偏好和阻断可卡因重新获得，并改善基于预防学习的暴露疗法用于多种焦虑症。这项II期临床试验将研究结合应急管理（CM）和新的家庭环境暴露治疗可卡因依赖的行为治疗的药理学（DCS）增强。高强度的CM激励措施将用于促进可卡因戒断必要的灭绝在家庭为基础的暴露会议。受试者将被随机分为2组：1. CM+安慰剂（CM+PL），和2. CM + DCS（CM+DCS）在分组后的19天内，受试者将每周3次（周一、周三、周五）到实验室报告，以提供尿液样本，接收应急凭证，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 mg）或安慰剂将在周一和周五研究访视时给药（在实验室访视结束时，然后在DCS行动期间返回家庭环境进行暴露阶段）。将在CM完成后1周、1个月和3个月进行随访访视，在此期间将获得药物使用（自我报告和尿液分析）、渴望、情绪和戒断的指标。两组间CM后持续禁欲的比较将是主要结局指标。在初始实验室会话期间，一组学习/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。该项目将测试一种新的可卡因依赖干预措施的有效性，该干预措施是基于已知有效的可卡因依赖治疗（CM），消退学习理论的原则，以及一种药物，该药物可改善临床前学习，包括可卡因条件反射的消退，以及基于临床学习的焦虑症暴露治疗。这项研究可能表明，成本效益的增加（家庭接触会议和DCS），以扩大CM的好处后，删除意外事件，因此可能会增加CM在社区设置的传播。 公共卫生相关性：FDA尚未批准任何药物用于治疗可卡因依赖。这项拟议的研究将测试一种新的可卡因药物开发方法，该方法不同于其他试图改变可卡因效果的可卡因药物开发方法。这项研究将测试d-环丝氨酸（DCS）的能力，它已经改善了焦虑症的行为治疗，以改善可卡因依赖的行为治疗。这项试验可能最终转化为可卡因依赖性药物治疗的重大进展。

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.