Investigators: Thomas R. Kosten, M.D. (Baylor College of Medicine), Eugene Somoza, M.D., Ph.D., Thomas P. Beresford, M.D., Ph.D. (Cincinnati VA Medical Center), Thomas P. Beresford, M.D. (University of Pennsylvania), Marc Fishman, M.D. (Mountain Manor Treatment Center), Sandra C. Lapham, M.D. (Pacific Institute for Research & Education), Daniel George, MPH (Matrix Institute on Addictions), Frances Levin, M.D. (Columbia University), Christopher J. Stock, PharmD. (Salt Lake City VAMC), Robert Anthenelli, M.D. (VA San Diego Healthcare System)
Release Date: TBA
Abstract: Drug addictions are common polygenic, chronic, relapsing brain diseases whose pharmacotherapy would benefit from becoming more optimally defined through molecular-genetic approaches. Mutations in genetic code may be responsible for differences in the subjective effects of drugs of abuse making them either more rewarding or aversive depending on the individual’s genotype. The goal of genetic testing relates to the prediction and matching of patients to the best individual therapy for patients.
From the previous clinical studies involving cocaine dependent patients, we have already identified that the medication, disulfiram, is very effective in reducing cocaine abuse, but its efficacy occurs primarily in patients who have normal levels of the enzyme dopamine beta-hydroxylase (DBH). This enzyme is normal in 60% of the population, but 40% have a genetic polymorphism in the promoter region of this gene that leads to 10 to 1000 fold lower levels of DBH. When disulfiram is used in patients with the gene polymorphism leading to normal DBH levels, their treatment response is twice as large as giving this medication to an unselected group of cocaine dependent patients. One of the examples is C-1021T SNP, which is a functional polymorphism that gives rise to altered transcription and decreased plasma levels of DBH. Studies link the C-1021T (-1021C>T) SNP to differences in circulating DBH levels. Decreased DBH attributed to C-1021T is found in diverse populations (European Americans, African Americans, Eastern Indian and Japanese) accounting for up to 52% of overall variation. Differences in DBH enzyme levels or activity is linked with a number of psychiatric disorders. SNP mapping profiles aimed at detecting DBH genotype may help predict whether an individual will respond well to treatment with DBH inhibitor for cocaine dependence.
In this study, during the screening period an additional blood sample will be taken from subjects who consent to provide blood for genetic analyses. Blood specimens will be studied for the genetic polymorphism in both treatment responders and non-responders and will be analyzed for trend towards the efficacy of nepicastat vs. placebo. Samples will be obtained and processed at each clinic site and shipped to the NIH Central Data Repository at Rutgers University (RUCDR) for processing, storage and analysis. Samples will be kept at RUCDR until they are deemed no longer of scientific value, or will be destroyed if the subject revokes his or her permission to participate in the genetics analyses and to sample storage/retention.
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