Charles R. Schuster - US grants

DESCRIPTION: (Applicant's Abstract) The proposed study is designed to develop a more effective treatment program for heroin-dependent poly-drug abusers. We will determine whether Voucher-Based Reinforcement Therapy (VBRT) enhances outcome when combined with a pharmacotherapy/psychosocial treatment program. Previous studies demonstrated that both the pharmacotherapy (buprenorphine) and VBRT are moderately effective for decreasing heroin abuse when used independently. VBRT involves contingent reinforcement for drug-free urines; it is designed to reinforce continuous abstinence and the development of a drug-free lifestyle. Previous studies have used VBRT to target a specific drug; however, the approach can be easily extended to target use of several illicit drugs concurrently, as is proposed in this study. In contrast, buprenorphine alone is often not effective in helping patients achieve abstinence from the other drugs often abused by heroin dependent individuals since buprenorphine's effects are pharmacologically specific. The aim of this proposal is to determine whether VBRT can enhance a standard buprenorphine program's effectiveness in achieving abstinence from several drugs. Other specific aims include evaluation of (a) the relative efficacy of a reduced-value VBRT program; (b) a less costly urine testing regimen; and (c) the role of gender, race, and psychiatric comorbidity, including Antisocial Personality Disorder, in treatment outcome. Heroin dependent poly-drug abusers will receive buprenorphine in the context of our standard psychosocial clinic program (29 Weeks). They will be inducted onto buprenorphine during Weeks 1-2 and maintained on a fixed dose for Weeks 3 through 25. At Week 6. all participants who continue to show evidence of illicit drug use will be randomly assigned to one of three treatment groups for a twelve week VBRT phase (Weeks 6-17). The three treatment groups are standard VBRT, a VBRT condition in which voucher values are reduced, and a yoked control condition. Yoked control participants are linked to an active VBRT participant and receive vouchers of the same value and frequency as that individual, but independent of their urinalysis results. After the VBRT intervention phase, participants will be maintained on buprenorphine with weekly individual counseling and medical monitoring for 8 more weeks (Weeks 18-25), followed by a 4-week phase of gradual withdrawal from buprenorphine (Weeks 26-29). All participants will be asked to return to the clinic for a 12-month follow-up visit.

DESCRIPTION: (Applicant's Abstract) As smoking prevalence in the United States has declined, the proportion of current smokers with concomitant psychiatric disorders has increased. Depression, anxiety disorders, and other forms of drug abuse or dependence occur in approximately 33% of cigarette smokers (Breslau, Kilbey & Andreski, 1991). This proportion is even higher in treatment populations (Hall et al, 1993; Glassman et al, 1990; Glassman, 1993). Because these individuals may have greater difficulty quitting smoking, more attention must be given to how to help them achieve smoking abstinence. The proposed study will examine the effect of pretreating smokers with the antidepressant fluoxetine before a standard, state-of-the-art smoking cessation program including cognitive-behavioral therapy and transdermal nicotine patches. [Fluoxetine was selected based on its use in prior research in smokers, its low side effect profile, and its potential to attenuate weight gain associated with cessation.] Participants will be 225 normal, healthy cigarette smokers with or without a history of Major Depressive Disorder (MDD) or current dysphoric symptoms. Participants will be randomly assigned to a treatment group: (1) placebo; (2) 20 mg fluoxetine; and (3) 40 mg fluoxetine. This randomized, placebo-controlled trial involves 14 weeks of fluoxetine (or placebo), 10 weeks of standard transdermal nicotine replacement therapy (6 weeks on 15 mg, 2 weeks on 10 mg, and 2 weeks on 5 mg nicotine patch), and 6 weeks of cognitive-behavioral group therapy with follow up visits at six weeks, eight weeks, ten weeks, three months, six months and one year after the quit date. Fluoxetine will be started four weeks before, the group therapy two weeks before, and nicotine patch on the quit date. The study will examine whether fluoxetine dose dependently improves quit rates and latency to relapse in these participants. It is expected that fluoxetine will be most efficacious in those with a history of MDD or current depressive symptoms. [Two proposed mechanism[s] for fluoxetine's effect [will] be examined: reduction of negative affect experienced [prior to and] during smoking cessation [and/or reduction of nicotine craving]. If fluoxetine safely and effectively suppresses negative affect associated with smoking cessation, a new tool will be developed to help those least likely to initiate or maintain abstinence. This could potentially save hundreds of thousands of lives each year in the United States.

Recognizing the need for and value in bridging the gap between clinical research and treatment, this initiative shall establish a consortium of academic substance abuse researchers and community treatment programs to serve as the Great Lakes Regional Node (GLRN) for the NIDA National Drug Abuse Treatment Clinical Trials Network (CTN). This consortium involves substance abuse clinical researchers from the three major research universities in the State of Michigan (Wayne State University; University of Michigan; and Michigan State University) in collaboration with a variety of substance abuse Community Treatment Programs (CTPs). The CTPs have been selected to assure diversity in therapeutic modalities employed, demographic and psychiatric characteristics of patients served, and the nature of the drug problems being treated. The CTN has two principal goals: first, to determine whether treatment interventions with demonstrated efficacy in rigorously controlled clinical trials are both useful and effective in CTPs. Because the CTN will have access to large samples of patients to participate in controlled clinical trials of treatment interventions, the process of evaluation can be rapid. Such large scale testing also will allow secondary analyses of outcome data to identify predictors for matching patients to effective treatment. The second goal of the CTN is to improve the quality of care available in CTPs by facilitating the adoption of research-based treatment interventions. The proposed GLRN assembles a group of academic researchers with long standing expertise in the evaluation of the efficacy and usefulness of behavioral, pharmacologic, and combined treatments for a variety of substance abuse problems, and with parallel expertise in the data management of large scale clinical trials. In many instances, the CTPs and these academic centers already have established research collaborations that will facilitate the rapid implementation of new research protocols. The inclusion of other CTPs without this background will allow us to investigate the process of introducing research and collaboration into a CTP to determine the problems encountered and their solutions. To this end we have enlisted the aid of researchers with a history of process evaluation for technology transfer. We also document the Node's capability to implement currently approved CTN concept proposals, as well as to implement new proposals in areas relating to behavioral therapy, pharmacotherapy and health services delivery research. In summary we believe that the GLRN has a very strong research team, the administrative infrastructure to manage the program, and enthusiastic CTPs anxious to participate in the NIDA CTN.

neurotoxicology; methamphetamine; neurophysiology; brain imaging /visualization /scanning; levodopa; cognition; psychotropic drugs; dopamine; clinical research; positron emission tomography; human subject; neuropsychological tests;

Cocaine abuse/dependence remains a major and public health problem and for a significant number of cocaine dependent individuals, current treatment interventions are ineffective. Finding a pharmacological treatment for cocaine abuse is an important elusive goal. The primary purpose of this grant is to developed safety data on a slow onset, long- active selective dopamine (DA) reuptake inhibitor being developed through the SPIRCAP mechanism for the treatment of cocaine dependence. Prior to the initiation of this research project, toxicity and pharmacokinetic studies will have been carried out with the test medication (Project 5). Because it is likely that individuals receiving a medication for the treatment of cocaine dependence may continue to use cocaine, particularly early in treatment, it is essential to determine whether this drug combination produces any adverse reactions. In this project, cocaine's physiological and psychological effects will be assessed after both acute and chronic administration of the test medication in cocaine abusing volunteers. Vital signs (heart rate, blood pressure, temperature, respiratory rate, oxygenation levels and ECG) will be monitored during each test session. Trained nurse observers will monitor participants and an adverse event symptom questionnaire will be administered at regular intervals. Complete physical exams and laboratory tests will be done before and after the study. In addition to providing safety data, this research will yield information about the efficacy of the test medication. We are hypothesizing that the dysphoria and craving associated with cocaine abstinence will be diminished by the test medication's DA reuptake blocking properties. It is also hypothesized that the test medication will produce positive mood changes as measured by the Profile of Mood States and the Addiction Research Center Inventory. This is a positive attribute for a treatment medication since it will enhance patient compliance with medication regimens. Finally, it is hypothesized that the test medication since it will enhance patient compliance with medication regimens. Finally, it is hypothesized that the test medication will attenuate the effects of cocaine that are mediated by DA through activation of autoreceptors. Activation of autoreceptors would be expected to decrease DNA synthesis rates and rates of DA neuronal firing. Because cocaine's effects are impulse-dependent, decreases in rate of firing of DA neurons should decrease cocaine's ability to elevate synaptic levels of DA. If no significant adverse events are found in these safety studies the test compound will be considered for a clinical trial in cocaine dependent research volunteers.