The Influence of Concentration of Micro-RNA hsa-miR-370-3p and CYP2D6*4 on Equilibrium Concentration of Mirtazapine in Patients With Major Depressive Disorder.

Introduction: Mirtazapine 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. Results of the previous studies showed that CYP2D6 is involved in the biotransformation of mirtazapine, the activity of which is highly dependent on the polymorphism of the gene encoding it.

Objective: The 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 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma levelsin patients suffering from recurrent depressive disorder.

Material and methods: Our study included 192 patients with major depressive disorder (age - 41.4 ± 15.6 years). Treatment regimen included mirtazapine in an average daily dose of 37.4 ± 13.5 mg per week. Treatment efficacy was evaluated using the international 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. 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). Therapeutic 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) 10.0 [9.0; 11.0] and (GA) 12.0 [11.0; 12.0], p < 0.001; at the same time, the statistical significance in the safety profile was obtained (the UKU scores): (GG) 3.0 [2.0; 4.0] and (GA) 4.0 [3.0; 5.0], p < 0.001. We 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. Analysis of the results of the pharmacotranscriptomic part of the study didn't demonstrate the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 23.6 [17.6; 28.0], (GA) 21.8 [17.2; 27.0], p = 0.663. At the same time, correlation analysis didn't reveal a statistically significant relationship between the mirtazapine efficacy profile evaluated by changes in HAMD scale scores and the hsa-miR-370-3p plasma concentration: rs = 0.05, p = 0.460. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.11, p = 0.124. In addition, 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 = -0.32, 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.

Conclusion: Thus, 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. 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.