Sertraline Augmentation for Cocaine Dependence

在我们之前的中心，研究了SSRI舍曲林单独使用以及与多巴胺再摄取抑制剂安非他酮联合使用对抑郁的、最近戒断的可卡因滥用者的疗效。初步结果是，与安慰剂相比，舍曲林单独使用组和舍曲林-安非他酮组出现可卡因阳性尿液的可能性显著降低，这种效果在整个试验中没有得到单独使用舍曲林的患者的持续。在这项建议中，将使用具有GABA能活性的药物进一步探索舍曲林单独的疗效和舍曲林的增强作用，根据证据表明，GABA能活性，除了多巴胺和5-羟色胺能活性，可能在治疗可卡因依赖患者中发挥作用， 尤其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，一种GABA能药在促进可卡因滥用美沙酮稳定患者戒断可卡因方面的有效性。因此，该项目将检验舍曲林单独以及与GABA转运体抑制剂替加宾或GABA能药加巴喷丁联合治疗抑郁症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五年内为140名抑郁的可卡因依赖者(18-65岁)提供治疗。参与者首先将住在VA CT Healthcare System的住院病房中开始最初的可卡因戒断，根据抑郁症状严重程度和舍曲林转运体基因多态性进行随机分配，并被分配接受以下一种药物：安慰剂、舍曲林(200毫克/天)、舍曲林+替加宾(12毫克/天)或舍曲林+加巴喷丁(1200毫克/天)。然后，参与者转入门诊治疗研究计划，并继续接受为期3-12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，并获得遵守研究要求的金钱奖励。在12周结束时，患者将逐渐停止研究药物治疗，并转介到适当的治疗计划。疗效将取决于治疗时间的长短、复发的时间长短、自我报告和尿毒学、抑郁症状的严重性和心理社会功能。我们将研究抑郁症状严重程度、性别、催乳素水平、舍曲林、多巴胺和GABA转运体基因多态性以及经颅磁刺激反应等因素与预后的相关性。

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.