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.
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