Clinical Efficacy of Atomoxetine for Methamphetamine Dependence

描述(由申请人提供)：本申请是对PA-10-069的重新提交，标题为“探索性发展研究资助计划”。对甲基苯丙胺(冰毒)的依赖具有深远的医疗、社会和社会不良后果。很少有研究审查治疗这种疾病的潜在药物，包括缓解冰毒戒断症状的药物的疗效。药物开发也受到了阻碍，因为通常采用研究禁欲启动的研究设计，而不是防止复发。最近的证据表明，去甲肾上腺素在成瘾过程中发挥着比以前认为的更重要的作用，特别是在复发和精神刺激性戒断的表达方面。一种有前景的治疗方法包括使用间接激动剂药物疗法治疗冰毒依赖；然而，研究数量有限，方法学上有相当大的变异性。尽管激动剂治疗对其他药物的依赖取得了成功，但由于几个原因，人们一直不愿更仔细地研究兴奋剂依赖的激动剂治疗方法。因此，鉴于最近的证据表明，改变去甲肾上腺素活性的药物在治疗药物依赖方面可能是有效的，这一应用将检验选择性去甲肾上腺素再摄取抑制剂托莫西汀在1)延迟复发时间和2)缓解最近戒断的冰毒依赖者的戒断症状方面的有效性。这项为期11周的随机、双盲、安慰剂对照临床试验将在两年内为40名冰毒依赖者(18-65岁)提供治疗。参与者首先将居住在一个居住设施(阿肯色州康复中心)，开始最初的药物戒断，并接受研究药物的引导。他们将根据性别、依赖的严重程度和儿童时期被诊断为ADHD的情况随机接受安慰剂(N=20)或托莫西汀(80毫克/天；N=20)。然后，参与者转入门诊治疗研究计划，继续接受为期3-10周的研究药物治疗。在试验的门诊部分，受试者每周参加个人认知行为治疗。在试验期间，参与者将获得遵守研究要求的金钱奖励。在10周结束时，患者将被停用研究药物，在第11周期间进行监测，并转介到适当的治疗计划。疗效将取决于治疗时间的长短、戒断症状的缓解、尿毒学确定的失效/复发时间长短以及心理社会功能。这项试验的结果，如果呈阳性，将支持R01应用，在更大的样本中检查托莫西汀的疗效和各种因素的预后相关性。因此，这些发现可能会改变临床实践，开发一种治疗冰毒依赖的有效药物疗法。

DESCRIPTION (provided by applicant): This application is a resubmission in response to PA-10-069, entitled "Exploratory Developmental Research Grant Program." Methamphetamine (METH) dependence has profound adverse medical, social and societal consequences. A paucity of studies has examined potential medications for treating this disorder, including the efficacy of medications to alleviate METH withdrawal symptoms. Medications development has also been hampered by generally employing study designs that examine the initiation of abstinence, rather preventing relapse. Recent evidence suggests that norepinephrine plays a more important role in the addiction process than previously thought, particularly in relapse as well as the expression of psychostimulant withdrawal. A promising therapeutic approach involves the use of indirect agonist pharmacotherapy for METH dependence; however, there are a limited number of studies and considerable variability in methodology. Despite successful agonist treatments for dependence on other drugs, there has been a reluctance to examine more closely agonist treatment for stimulant dependence for several reasons. Thus, given that recent evidence suggests agents that alter noradrenergic activity may be effective in treating drug dependence, this application will examine the efficacy of the selective noradrenergic reuptake inhibiter atomoxetine in 1) delaying time to relapse and 2) alleviating withdrawal symptoms in recently abstinent METH-dependent individuals. This 11-wk, randomized, double blind, placebo-controlled clinical trial will provide treatment for 40 METH-dependent (18-65 yrs) individuals over a two-year period. Participants first will reside at a residential facility (Recovery Centers of Arkansas) to initiate initial drug abstinence and be inducted on the study medication. They will be randomized by sex, severity of dependence and childhood diagnosis of ADHD to receive either placebo (N=20) or atomoxetine (80 mg/day; N=20). Then participants transfer to the Outpatient Treatment Research Program and continue to receive study medication for weeks 3-10. During the outpatient portion of the trial, subjects participate in weekly individual cognitive behavioral therapy. During the trial, participants are given monetary incentives for complying with study requirements. At the end of 10 weeks, patients will be taken off the study medication, monitored during week 11, and referred to an appropriate treatment program. Efficacy will be determined by length of time in treatment, alleviation of withdrawal symptoms, length of time to lapse/relapse as determined by urine toxicology, and psychosocial functioning. The findings of this trial, if positive, will support an R01 application to examine the efficacy of atomoxetine and prognostic relevance of various factors in a larger sample. As such, these findings may shift clinical practice with the development of an efficacious pharmacotherapy for METH dependence.