The Influence of Concentration of micro-RNA hsa-miR-370-3p and CYP2D6*4 on Equilibrium Concentration of Sertraline in Patients Diagnosed with Depressive Disorders Comorbid with Alcohol Use Disroder

Introduction: Sertralineis commonly administered topatients with depressive disorders comorbid with alcohol use disroder. Some part of such patients do not respond adequately to treatment regimen containing sertraline, whereas many of them experience type A adverse drug reactions (type A ADRs). Previous studies have shown that CYP2D6 is involved in the metabolism of sertraline, the activity of which is considerablydependent on the polymorphism of the gene encoding it. Objective: The objective of the study was to investigate the impact of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of sertralinepatients diagnosed with depressive disorders comorbid with alcoholism, using findings on activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma concentration levels patients suffering from depressive disorders comorbid with alcoholism. Material and Methods: The study included 120 patients with depressive disorders comorbid with alcoholism (age - 40.5±14.7 years). Therapy included sertraline in an average daily dose of 88.8±35.6 mg per day. Treatment efficacy was assessed using the validated psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels we performed the real-time polymerase chain reaction (PCR Real-time). The activity of CYP2D6 was assessed with HPLC-MS/MS method by the content of the endogenous substrate of given isoenzyme and its metabolite in urine (6M-THBC/pinoline). Theraputic drug monitoring (TDM) has been performed using HPLC-MS/MS. Results: Our study revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMD scores at the end of the treatment course): (GG) 1.0 [1.0; 2.0] and (GA) 4.0 [3.0; 5.0], p < 0.001; at the same time, the statistical significance in the safety profile was obtained (the UKU scores): (GG) 3.0 [2.0; 3.0] and (GA) 3.0 [3.0; 3.0], p = 0.018. We didn't reveal a statistical significance for concentration/dose indicator of sertraline in patients with different genotypes: (GG) 0.749 [0.593; 1.277] and (GA) 1.030 [0.829; 1.257], p = 0.052). Analysis of the results of the pharmacotranscriptomic part of the study didn’t show the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 23.4 [16.3; 29.3], (GA) 26.1 [16.5; 28.9], p = 0.945. At the same time, correlation analysis didn't reveal a statistically significant relationship between the sertraline efficacy profile evaluated by changes in HAMD scale scores and the hsa-miR-370-3p plasma concentration: rs = -0.05, p = 0.592. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.07, p = 0.421. Also we revealed the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs = -0.25, p = 0.005. At the same time, correlation analysis revealed a statistically significant relationship between the sertraline concentration and the hsa-miR-370-3p plasma concentration: rs = 0.30, p < 0.001. Conclusion: Thus, the effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of sertraline was demonstrated in a group of 120 patients with depressive disorders comorbid with alcoholism. At the same time, hsa-miR-370-3p remains a promising biomarker for assessing the level of CYP2D6 expression, because it correlates with encoded isoenzyme activity. Funding Statement: This work was supported by the grant of the Russian Science Foundation (project No. 18- 75-10073). This work was financially supported by the project 16-15-00227 entitled “Fundamental research and exploratory research in priority areas of research” of the Russian Science Foundation. Declaration of Interests: The authors declare that there is no conflict of interest regarding the publication of this article. Ethics Approval Statement: The local ethical committee of the Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation approved the research (The protocol No. 6 from 5/16/2017).