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：评价药物滥用的新型合理化多药治疗策略。可卡因依赖问题仍然是一个主要的医疗、社会和法律的问题，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，但没有一种药物被证明是有效的治疗方法。迄今为止，最有希望的药物是莫达非尼，它已被证明可以减少静脉注射可卡因产生的欣快效应，减少吸食可卡因的自我管理和相关的积极主观影响，并减少可卡因的使用在双盲，安慰剂对照的临床试验。然而，随后，一项大型、多中心、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液方面并不比安慰剂更好。最近的数据表明，在长期治疗莫达非尼产生大量的多巴胺转运蛋白（DAT）抑制。考虑到可卡因抑制DA，去甲肾上腺素（NE）和5-羟色胺（5-HT）的再摄取，很可能靶向一种以上的神经递质系统是药物有效的必要条件。假设这一说法是正确的，我们假设同时调节多种神经递质系统的联合药物治疗方法可能会显示出高于使用单一药物的试验的临床显著疗效水平。提出的方法是基于临床前数据，表明增加大脑5-HT水平的药物可以减少兴奋剂的作用。我们假设，将莫达非尼与选择性5-羟色胺再摄取抑制剂（SSRI）结合，这将增加5-HT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的：在实验室中确定莫达非尼（0或200 mg）联合SSRI艾司西酞普兰（0或20 mg）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、平行组研究设计。所有参与者都将符合DSM当前可卡因依赖的标准，并且不会寻求治疗。将使用视觉模拟量表测量主观效应，并使用选择程序测量强化效应。该提案代表了一项具有相当大的公共卫生意义的重要研究工作，因为它将建立一个评估药物合理组合的计划，这些药物的目标是补充可卡因产生的作用的神经生物学机制（即，DA和5-HT）在可卡因依赖个体中的作用。 公共卫生相关性：在本申请中，我们将在实验室中评估莫达非尼联合艾司西酞普兰对吸烟可卡因产生的主观和增强效应的影响。

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.