Sertraline Augmentation for Cocaine Dependence

在我们以前的中心，SSRI舍曲林单独和增加与多巴胺再摄取抑制剂安非他酮在抑郁症，最近戒断可卡因滥用者的疗效进行了检查。初步结果是，与安慰剂组相比，单独舍曲林组和舍曲林-安非他酮组可卡因阳性尿液的可能性显著降低，在整个试验中，单独舍曲林组的效果并不持续。在该提议中，将使用具有GABA能活性的药剂进一步探索舍曲林单独和舍曲林增强的功效，基于表明除了多巴胺能和多巴胺能活性之外，GABA能活性可能在治疗可卡因依赖患者中起作用的证据， 特别是那些同时患有抑郁症的人。例如，GABA的增加与抑郁症状的减少有关，我们有初步数据显示GABA能药物在可卡因滥用美沙酮稳定患者中促进可卡因戒断的疗效。因此，本项目将检查舍曲林单独使用以及与GABA转运蛋白抑制剂噻加宾或GABA能药物加巴喷丁联合使用对抑郁的可卡因滥用者的临床疗效。这项为期12周的双盲随机临床试验将在5年内为140名抑郁的可卡因依赖者（18-65岁）提供治疗。参与者首先将居住在VA CT医疗保健系统的住宅病房，以开始初始可卡因戒断，根据抑郁症状严重程度和舍曲林转运蛋白的遗传多态性进行随机分配，并被分配接受以下药物之一：安慰剂，舍曲林（200 mg/天），舍曲林加噻加滨（12 mg/天）或舍曲林加巴喷丁（1200 mg/天）。然后，参与者转入门诊治疗研究项目，并继续接受研究药物治疗3-12周。在试验的门诊部分，受试者参加每周一次的个体认知行为治疗，并因遵守研究要求而获得金钱奖励。在12周结束时，患者将逐渐停用研究药物，并接受适当的治疗方案。疗效将通过治疗时间长度、复发时间长度、自我报告和尿液毒理学、抑郁症状严重程度和心理社会功能来确定。抑郁症状严重程度、性别、催乳素水平、遗传多态性等因素的预后相关性，将检查舍曲林、多巴胺和GABA转运蛋白以及对经颅磁刺激的反应。

In our previous center, the efficacy of the SSRI sertraline alone and augmented with the dopamine-reuptake inhibitor bupropion in depressed, recently-abstinent cocaine abusers was examined. Preliminary findings are that the likelihood of cocaine-positive urines was significantly decreased relative to placebo in the sertraline alone and sertraline-bupropion groups, an effect that was not sustained for the entire trial in the sertraline alone group. In this proposal, the efficacy of sertraline alone and sertraline augmentation will be explored further using agents with GABAergic activity, based on evidence suggesting that GABAergic activity, in addition to dopaminergic and serotonergic activity, may play a role in treating cocaine dependent patients, particularly those with concurrent depression. For instance, increases in GABA are associated with decreases in depressive symptoms and we have preliminary data showing efficacy of a GABAergic agent in facilitating cocaine abstinence in cocaine-abusing methadone-stabilized patients. Thus, this project will examine the clinical efficacy of sertraline alone and in combination with either the GABA transporter inhibitor tiagabine or the GABAergic agent gabapentin in depressed cocaine abusers. This 12-wk, double-blind, randomized clinical trial will provide treatment for 140 depressed, cocaine-dependent individuals (18-65 yrs) over a five-year period. Participants first will reside in a residential ward at the VA CT Healthcare System to initiate initial cocaine abstinence, be randomized by depressive symptom severity and genetic polymorphism at the sertraline transporter, and be assigned to receive one of the following: placebo, sertraline (200 mg/day), sertraline plus tiagabine (12 mg/day), or sertraline plus gabapentin (1200 mg/day). Then participants transfer to the Outpatient Treatment Research Program and continue to receive study medication for weeks 3-12. During the outpatient portion of the trial, subjects participate in weekly individual cognitive behavioral therapy and are given monetary incentives for complying with study requirements. At the end of 12 weeks, patients will be tapered off the study medication and referred to an appropriate treatment program. Efficacy will be determined by length of time in treatment, length of time to relapse, by self-report and urine toxicology, depressive symptom severity and psychosocial functioning. Prognostic relevance of factors such as depressive symptom severity, sex, prolactin levels, genetic polymorphisms at the, e.g., sertraline, dopamine, and GABA transporters, and response to transcranial magnetic stimulation will be examined.