Genotype-Specific Treatment Outcomes in Alcohol Dependence: DRD4 for Cyanamide effect and DRD2 for Placebo Response

Background: Pharmacogenetic markers are a promising tool for a personalized approach to treating alcohol dependence (AD). Previous studies using dominant models have identified several associations between polymorphisms in dopamine system genes and the efficacy of disulfiram and cyanamide therapy, but they did not allow for an evaluation of the influence of individual genotypes. Objective: To study the associations of specific genotypes from a pathogenetic panel of pharmacogenetic markers with the efficacy of disulfiram and cyanamide for stabilizing remission in patients with AD. Methods: The pharmacogenetic study was based on a 12-week, double-blind, 3 randomized, comparative, placebo-controlled clinical trial on the efficacy and tolerability of disulfiram and cyanamide in AD therapy. The study included 150 detoxified patients with AD (mean age 40.65±1.09 years, 19.3% women) who were randomized into three treatment groups: disulfiram, cyanamide, and placebo. The genetic panel included 15 polymorphic loci in 9 genes related to the dopamine and opioid systems, as well as the aldehyde dehydrogenase enzyme cluster. Results: The homozygous CC genotype of rs1800955 in the dopamine receptor type 4 (DRD4) gene was associated with longer retention in the treatment program for patients receiving cyanamide (tendency at the border of significance, p=0.052). At the same time, the homozygous AA genotype of rs6275 in the dopamine receptor type 2 (DRD2) gene was associated with a higher risk of rapid dropout from therapy in the placebo group (p=0.015). Conclusion: Preliminary pharmacogenetic markers for the efficacy of alcohol dependence treatment have been identified at the level of specific genotypes. This approach is optimal for the practical application of pharmacogenetic research in clinical medicine. After validation, these markers can be used for patient stratification and the optimization of personalized therapy.

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