Modafinil and Escitalopram for Cocaine Addiction

描述(由申请人提供)：本申请涉及广泛的NIH挑战领域04：临床研究和特定挑战主题04-DA-101：评价针对药物滥用的新的、合理化的多药物治疗策略。可卡因依赖问题仍然是一个重大的医疗、社会和法律问题，迫切需要一种广泛有效的治疗方法。数十种药物已经在临床试验中进行了评估，尽管做出了这些努力，但没有一种被证明是有效的治疗方法。到目前为止，被评估的最有希望的药物是莫达非尼，在一项双盲、安慰剂对照的临床试验中，它已被证明可以减少静脉注射可卡因产生的愉悦效应，减少吸烟可卡因的自我给药和相关的积极主观影响，并减少可卡因的使用。然而，随后，一项大型、多地点、门诊临床试验的结果表明，莫达非尼治疗在改善可卡因戒断或减少可卡因阳性尿量方面并不比安慰剂好。最近的数据表明，在慢性治疗期间，莫达非尼会产生实质性的多巴胺转运体(DAT)抑制。鉴于可卡因抑制DA、去甲肾上腺素(NE)和5-羟色胺(5-HT)的再摄取，很可能需要针对多个神经递质系统才能使药物有效。假设这一说法属实，我们假设同时调节多个神经递质系统的联合药物治疗方法可能比使用单一药物的试验显示出显著的临床疗效水平。提出的方法是基于临床前数据，表明提高大脑5-羟色胺水平的药物减少了刺激剂的影响。我们假设，将莫达非尼与选择性5-羟色胺再摄取抑制剂(SSRI)相结合，将增加5-羟色胺的突触水平，将进一步提高莫达非尼减少可卡因产生的影响的疗效。我们提出了以下具体目标：在实验室内确定莫达非尼(0或200 mg)与SSRI西妥普兰(0或20 mg)联合治疗对吸烟可卡因(0和25 mg)产生的主观和增强效应的影响。我们将采用安慰剂对照、双盲、平行分组研究设计。所有参与者都将符合目前可卡因依赖的DSM标准，不会寻求治疗。主观效果将使用视觉模拟标尺来衡量，强化效果将使用选择程序来衡量。这项建议代表了一项具有相当大公共卫生意义的重要研究努力，因为它将建立一个评估药物合理组合的计划，这些药物针对的是可卡因(即DA和5-羟色胺)对可卡因依赖者产生影响的补充神经生物学机制。 公共卫生相关性：在这项应用中，我们将评估莫达非尼与艾司匹兰联合使用对实验室中吸烟的可卡因产生的主观和强化效果的影响。

DESCRIPTION (provided by applicant): This application addresses broad NIH Challenge Area 04: Clinical Research and specific Challenge Topic 04-DA-101: Evaluation of novel, rationalized poly-pharmacotherapeutic treatment strategies for substance abuse. The problem of cocaine dependence remains a major medical, social, and legal concern, and there is a pressing need for a broadly effective treatment approach. Dozens of medications have been evaluated in clinical trials, and despite these efforts not one has proved effective as a treatment. The most promising medication evaluated to date is modafinil, which has been shown to reduce the euphoric effects produced by intravenous cocaine, to reduce smoked cocaine self-administration and associated positive subjective effects, and to reduce cocaine use in a double-blind, placebo-controlled clinical trial. Subsequently, however, findings from a large, multi-site, outpatient clinical trial indicated that modafinil treatment was no better than placebo for improving abstinence from cocaine or for reducing cocaine-positive urines. Recent data indicates that during chronic treatment modafinil produces substantial dopamine transporter (DAT) inhibition. Given that cocaine inhibits DA, norepenepherine (NE) and serotonin (5-HT) reuptake, it is highly likely that targeting more than one neurotransmitter system will be necessary for a medication to be effective. Assuming that this statement is true, we hypothesize that a combination pharmacotherapeutic approach that concurrently modulates multiple neurotransmitter systems will likely demonstrate a clinically significant level of efficacy above trials in which a single medication is used. The proposed approach is based on preclinical data indicating that medications that increase brain 5-HT levels reduce the effects of stimulants. We hypothesize that combining modafinil with a selective serotonin reuptake inhibitor (SSRI), which will increase synaptic levels of 5-HT, will further improve the efficacy of modafinil for reducing the effects produced by cocaine. We propose the following Specific Aim: To determine the effects of treatment with modafinil (0 or 200 mg) plus the SSRI escitalopram (0 or 20 mg) on the subjective and reinforcing effects produced by smoked cocaine (0 and 25 mg) in the laboratory. We will use a placebo-controlled, double-blind, parallel-groups study design. All participants will meet DSM criteria for current cocaine dependence and will not be seeking treatment. Subjective effects will be measured using visual-analogue scales and reinforcing effects will be measured using choice procedures. This proposal represents an important research effort with considerable public health significance since it will establish a program for evaluating rational combinations of drugs that target complementary neurobiological mechanisms that underlie the effects produced by cocaine (i.e., DA and 5-HT) in cocaine-dependent individuals. PUBLIC HEALTH RELEVANCE: In this application, we will evaluate the effects of modafinil combined with escitalopram on the subjective and reinforcing effects produced by smoked cocaine in the laboratory.