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IntroductionMirtazapine is commonly prescribed to patients diagnosed with major depressive disorder.Some proportion of these patients do not show adequate response to treatment regimen containing mirtazapine, whereas many of them experience dose-dependent adverse drug reactions.ObjectivesThe objective of our study was to investigate the influence of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of mirtazapine, using findings on enzymatic activity of CYP2D6 and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma levels in patients suffering from recurrent depressive disorder.MethodsOur study included 192 patients with major depressive disorder. Treatment efficacy was evaluated using the international psychometric scales. For genotyping and estimation of the microRNA plasma levels we performed the real-time polymerase chain reaction. 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. Therapeutic drug monitoring has been performed using HPLC-MS/MS.ResultsWe didn’t reveal a statistical significance for concentration/dose indicator of mirtazapine in patients with different genotypes: (GG) 0.229 [0.158; 0.468] and (GA) 0.290 [0.174; 0.526], p = 0.196). We revealed the relationship between the CYP2D6 enzymatic activity and the hsa-miR-370-3p plasma concentration: rs = -0.32, p < 0.001. At the same time, correlation analysis revealed a statistically significant relationship between the mirtazapine concentration and the hsa-miR-370-3p plasma concentration: rs = 0.31, p<0.001.ConclusionsThus, the effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of mirtazapine was demonstrated in a group of 192 patients with recurrent depressive disorder.Conflict of interestAuthors do not have any conflict of interests.

Diazepam is one of the most widely prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). However, diazepam therapy often turns out to be ineffective, and some patients experience dose-dependent adverse drug reactions. Previous studies have shown that the metabolism of diazepam involves the CYP2C19 isoenzyme, whose activity is highly dependent on polymorphism of the encoding gene. The objective of our study was to investigate the effects of CYP2C19*2 genetic polymorphisms on plasma and saliva concentrations of diazepam as well as its impact on the efficacy and safety rates of therapy in patients with AWS. The study was conducted on 100 Russian male patients with AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time polymerase chain reaction. The efficacy and safety assessment was performed using psychometric scales. We revealed differences in the efficacy and safety of therapy in patients with different CYP2C19 681G>A genotypes. Therapeutic drug monitoring (TDM) revealed the statistically significant differences in the levels of diazepam plasma concentration: (GG) 199.83 [82.92; 250.58] vs (GA+AA) 313.47 [288.99; 468.33], p=0.040, and diazepam saliva concentration: (GG) 2.80 [0.73; 3.80] vs (GA+AA) 5.33 [5.14; 6.00], p=0.003).