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.
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View Article and Find Full Text PDFInfluence of Plasma Concentration of Hsa-Mir-370-3p and Cyp2d6*4 On Equilibrium Concentration of Phenazepam in Patients with Recurrent Depressive Disorder.
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Introduction: Phenazepam is commonly administered to patients diagnosed with major depressive disorder. Some proportion of such patients do not show adequate response to treatment regimen containing phenazepam, whereas many of them experience type A adverse drug reactions. Previous studies showed that CYP2D6 IS involved in the biotransformation of phenazepam, the activity of which is highly dependent on the polymorphism of the gene encoding it.
View Article and Find Full Text PDFEffect of Genetic Polymorphism of the CYP2D6 Gene on the Efficacy and Safety of Fluvoxamine in Major Depressive Disorder.
Am J Ther
June 2021
Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation.
Background: Previous studies have shown that cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of fluvoxamine, the activity of which is highly dependent, inter alia, on the polymorphism of the gene encoding it. The objective of our study was to investigate the effect of 1846G>A polymorphism of the CYP2D6 gene on the efficacy and safety of fluvoxamine, using findings on CYP2D6 enzymatic activity and on CYP2D6 expression level in patients with depressive disorders comorbid with alcohol use disorder.
Study Question: Efficacy and safety of fluvoxamine depend on the polymorphism of CYP2D6 gene in patients with major depressive disorder.
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.
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MS Zastrozhin, M.D., PhD, head of laboratory of genetics and fundamental studies, AE Petukhov, M.D., PhD, clinical laboratory diagnostician of the analytical toxicology lab of the Reference center for psychoactive substances use monitoring, EP Pankratenko, paramedic-laboratory assistant of the analytical toxicology lab of the Reference center for psychoactive substances use monitoring, VYu Skryabin, M.D., head of clinical department, RV Vlasovskih, PhD, vice-director, EA Bryun, M.D., PhD, professor, president, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. MS Zastrozhin, associate professor of addiction psychiatry department, AK Zastrozhina, assistant of the Department, EA Grishina, PhD, head of biomolecular researchers department of the Research center, KA Ryzhikova, research fellow of the biomolecular researchers department of the Research center, IV Bure, PhD, research fellow of the biomolecular researchers department of the Research center, EA Bryun, head of addiction psychiatry department, DA Sychev, corresponding member of the Academy of Sciences of Russia, M.D., PhD, professor, rector, head of clinical pharmacology and therapy department, Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia. VV Smirnov, PhD, associate professor of pharmaceutical toxicology department, AE Petukhov, associate professor of pharmaceutical and toxicological chemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation. VV Smirnov, head of laboratory of pharmacokinetics, NRC Institute of Immunology FMBA of Russia, Moscow, Russian Federation.
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.
View Article and Find Full Text PDFImpact of Polymorphism of CYP2D6 on Equilibrium Concentration of Duloxetine in Patients Suffering from Major Depressive Disorder.
Psychopharmacol Bull
July 2020
MS Zastrozhin, M.D., PhD, head of laboratory of genetics and fundamental studies, AE Petukhov, M.D., PhD, clinical laboratory diagnostician of the analytical toxicology lab of the Reference center for psychoactive substances use monitoring, EP Pankratenko, paramedic-laboratory assistant of the analytical toxicology lab of the Reference center for psychoactive substances use monitoring, VYu Skryabin, M.D., head of clinical department, SG Koporov, M.D., PhD, director, EA Bryun, M.D., PhD, professor, president, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. MS Zastrozhin, associate professor of addiction psychiatry department, EA Grishina, PhD, head of biomolecular researchers department of the Research center, KA Ryzhikova, research fellow of the biomolecular researchers department of the Research center, EA Bryun, M.D., PhD, professor, president, DA Sychev, corresponding member of the Academy of Sciences of Russia, M.D., PhD, professor, rector, head of clinical pharmacology and therapy department, Moscow Research and Practical Centre on Addictions of the Moscow Department of Moscow, Russia. AE Petukhov, associate professor of pharmaceutical and toxicological chemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation.
Introduction: Duloxetine is commonly prescribed to patients with recurrent depressive disorder. Some part of patients in this group do not respond adequately to treatment regimen containing duloxetine, while many of them experience dose-dependent adverse drug reactions. Previous research investigated that CYP2D6 is involved in the biotransformation of duloxetine, the activity of which is highly dependent on the polymorphism of the gene encoding it.
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