Pharmacogenetic profile of the efficacy of agomelatine for stabilizing remission in patients with alcohol dependence and comorbid depressive disorders: results of a double-blind, randomized, placebo-controlled study

Abstract

Alcohol dependence (AD) and depressive disorders (DD) exhibit a high level of comorbidity, significantly complicating treatment and worsening the clinical prognosis. The search for drugs that target the common pathogenetic mechanisms of these comorbid conditions is relevant. One such drug is agomelatine: an MT1 and MT2 melatonin receptor agonist and a 5-HT2C serotonin receptor antagonist. The identification of pharmacogenetic markers of agomelatine efficacy is an important goal in personalized therapy for comorbid AD and DD, as individual treatment response remains difficult to predict. Objective: To identify pharmacogenetic markers of agomelatine efficacy in patients with AD and comorbid DD. Materials and Methods. The pharmacogenetic study was conducted based on a 12-week, double-blind, randomized, placebo-controlled trial (N=100) of agomelatine efficacy in outpatients with AD and comorbid depression. The primary efficacy indicator was treatment retention, defined as the time (weeks) until discontinuation for any reason. The study’s genetic panel included 10 polymorphic loci in 8 genes: pharmacological targets of agomelatine — the melatonin receptors MT1 ( MTNR1A ) and MT2 ( MTNR1B ) and the serotonin receptor 5-HT2C ( HTR2C) , the gene encoding the cytochrome P450 enzyme CYP1A2 , which controls agomelatine pharmacokinetics, and key genes of the dopamine system (DRD2, ANKK1 ) and the endogenous opioid system ( OPRM1 , OPRK1 ). An analysis of associations between individual genetic variants and their combinations with the risk of early treatment discontinuation was performed within the dominant model in the agomelatine and placebo groups using Cox regression models. Hazard ratio (HR) with confidence intervals (CI) were calculated. Results. In the group of patients receiving agomelatine, an increased risk of early discontinuation of therapy, taking into account gender and age adjustment, was associated with carriage of the minor allele T rs2119882 in the MTNR1A gene [HR=2.25; 95%CI: (1.02–5.00); p=0.045], as well as with combinations of this variant with carriage of the minor allele A rs1800497 in the ANKK1 gene [HR=2.5; 95%CI: (1.16–5.61), p=0.019], the major genotype GG rs6275 in the DRD2 gene [HR=2.13; 95%CI: (1.02–4.46), p=0.045], the major genotype GG rs 10830963 in the MTNR1B gene [HR=2.10; 95%CI: (1.04–4.23), p=0.039], minor allele A rs2069514 in the CYP1A2*1C gene [HR=2.32; 95%CI: (1.01–5.35), p=0.048]. There was also an independent marker of the risk of dropping out of the therapy program in the form of a combination of minor alleles C rs762551 in the CYP1A2*1F gene and C rs6318 in the HTR2C gene [HR=3.32; 95%CI: (1.04–6.42), p=0.042]. No associations were found in the placebo group. Conclusion. The results of this study suggest that the pharmacogenetic response to agomelatine is polygenic in nature and is determined by the interaction of genes regulating the pharmacodynamics of the drug, its pharmacokinetics, and the neurobiological mechanisms of AD (reward cascade). The results of the study also might create a possibility to develop a polygenic pharmacogenetic panel that can be used for personalized approach to treatment of the patients with AD and comorbid depression with agomelatine.