Genotype significantly predicted topiramate response, the researchers found. Patients who had two of the major C alleles at rs2832407 showed a significantly greater reduction in heavy drinking with topiramate versus placebo. Interestingly, the C allele is also the risk allele for alcohol dependence.
Using an innovative method, Kranzler and colleagues obtained daily reports of patients’ subjective states during the clinical trial, which allowed within-day analyses of the mechanism underlying the pharmacogenetic treatment effect. Topiramate’s pharmacogenetic effect was mediated by its ability to enhance self-efficacy in avoiding heavy drinking among patients with alcohol dependence, the findings indicated.
Disulfiram is an investigational treatment posited to reduce cocaine use via dopamine beta-hydroxylase inhibition and reduction of the reinforcing properties of cocaine.
Thomas Kosten, MD, director of Alcohol and Addiction Psychiatry at Baylor College of Medicine discussed the pharmacogenetics of disulfiram as a cocaine-dependence treatment at AAAP 2014.
He and colleagues randomly assigned 74 patients with cocaine- and heroin-dependence, who were on methadone maintenance to disulfiram or placebo. To examine the effects of a the rs1611115 functional genetic variant in the dopamine beta-hydroxylase gene (DBH).5 The variant T allele results in substantially less available enzyme in vivo.
Overall, disulfiram outperformed placebo with a small effect size reducing cocaine-positive urines from 80% to 62%. The response was much better in subjects with the CC genotype, and was essentially ineffective in carriers of the T allele, the researchers found.
However, this finding was not replicated in an independent sample of 155 patients with cocaine and opioid dependence on buprenorphine maintenance and were treated with disulfiram or placebo to reduce cocaine use.6
In another study of 71 subjects receiving cocaine vaccine or placebo, rs1611115 in the DBH gene was again found to have a moderate treatment response. Carriers of the T allele (low enzyme levels) were found to have a much better response to treatment than CC individuals.7
These findings suggest that the variant T allele may be associated with a translational phenotype of altered reward and reinforcement of cocaine and other drugs, and that the vaccine (which reduces exposure to the drug of abuse as its mechanism of action), is more effective in those subjects.
More clinical and translational work is needed to identify and characterize important pharmacogenetic treatment interactions to use these properties to guide treatment for addictive disorders.
Some of the discrepant findings to date may be due to fact that analyses have focused largely on single-candidate genes and only a single variant, ignoring the effects of variation in other genes that may also affect treatment response.
Methods designed to capture daily subjective effects during treatment trials may help shed light on how pharmacogenetic interactions translate into clinically significant changes in behavior. Despite these needs, a pharmacogenetic approach to addiction treatment is foreseeable in the future, perhaps within the next 10 years.
Albert Arias, MD, is an assistant professor of psychiatry at Yale School of Medicine. His research focuses on new treatments for alcohol addiction and personalized medicine by applying genetics to treatment research.
- Oslin DW, Berrettini W, Kranzler HR, et al. A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology. 2003;28(8):1546-1552.
- Oslin DW, O’Brien C, Berrettini W, Gordon A. Prospective Study Of Asn40asp As A Moderator Of Naltrexone Treatment Of Alcohol Dependence. Alcoholism: Clinical and Experimental Research. 2014;38(s1):327A.
- Kranzler HR, Covault J, Feinn R, et al. Topiramate Treatment for Heavy Drinkers: Moderation by a GRIK1 Polymorphism. Am J Psychiatry. 2014; 171(4):445-52.
- Kranzler HR, Gelernter J, Anton RF, et al. Association of markers in the 3′ region of the GluR5 kainate receptor subunit gene to alcohol dependence. Alcohol Clin Exp Res. 2009;33(5):925-930.
- Kosten TR, Wu G, Huang W, et al. Pharmacogenetic Randomized Trial for Cocaine Abuse: Disulfiram and Dopamine beta-Hydroxylase. Biol Psychiatry. 2013;73(3):219-224.
- Schottenfeld RS, Chawarski MC, Cubells JF, George TP, Lappalainen J, Kosten TR. Randomized clinical trial of disulfiram for cocaine dependence or abuse during buprenorphine treatment. Drug Alcohol Depend. 2014;136:36-42.
- Kosten TR, Domingo CB, Hamon SC, Nielsen DA. DBH gene as predictor of response in a cocaine vaccine clinical trial. Neurosci Lett. 2013;541:29-33.