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：药物滥用的新型，合理化的多药治疗策略的评估。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办法。数十种药物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，莫达非尼已被证明可以减少静脉注射可卡因产生的欣快效果，减少吸食可卡因的自我给药和相关的积极主观效应，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对可卡因的戒断或减少可卡因阳性尿方面并不比安慰剂更好。最近的数据表明，在慢性治疗期间，莫达非尼产生大量的多巴胺转运体（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，很可能需要针对不止一种神经递质系统才能使药物有效。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比使用单一药物的试验显示出临床显著的疗效水平。提出的方法是基于临床前数据，表明增加大脑5-羟色胺水平的药物可以减少兴奋剂的作用。我们假设莫达非尼与选择性5-羟色胺再摄取抑制剂（SSRI）联合使用将增加突触的5-羟色胺水平，将进一步提高莫达非尼减少可卡因产生的影响的功效。我们提出以下具体目标：在实验室中确定莫达非尼（0或200毫克）加SSRI艾司西酞普兰（0或20毫克）治疗对吸烟可卡因（0和25毫克）产生的主观和强化效应的影响。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对当前可卡因依赖的标准，并且不会寻求治疗。主观效应将使用视觉模拟量表来测量，强化效应将使用选择程序来测量。该提案代表了一项重要的研究工作，具有相当大的公共卫生意义，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）对可卡因依赖个体产生影响的互补神经生物学机制。

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.