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.
Psychopharmacol Bull. 2020 Jul 23;50(3):58-75.
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.
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.
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.
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.
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.
米氮平常用于治疗被诊断患有重度抑郁症的患者。一些患者对包含米氮平的治疗方案没有显示出足够的反应，而许多患者则经历了剂量依赖性的药物不良反应。先前的研究结果表明，CYP2D6 参与了米氮平的生物转化，其活性高度依赖于编码它的基因的多态性。
我们的研究目的是通过评估复发性抑郁障碍患者的 CYP2D6 酶活性（通过 6M-THBC/哌啶比值测量评估）和 hsa-miR-370-3p 血浆水平测量来研究 CYP2D6 基因 1846G>A 多态性对米氮平的浓度/剂量指标的影响。
我们的研究包括 192 名患有重度抑郁症的患者（年龄 41.4±15.6 岁）。治疗方案包括米氮平，平均每周剂量为 37.4±13.5mg。使用国际心理计量学量表评估治疗效果，使用 UKU 副作用评定量表评估治疗安全性。通过实时聚合酶链反应进行基因分型和 miRNA（微 RNA）血浆水平的估计。通过高效液相色谱-串联质谱法（HPLC-MS/MS）测定内源性底物及其代谢物在尿液中的含量，评估 CYP2D6 的活性（6M-THBC/哌啶）。使用 HPLC-MS/MS 进行治疗药物监测（TDM）。
我们的研究在治疗效果评估方面揭示了具有统计学意义的结果（治疗过程结束时的 HAMD 评分）：（GG）10.0[9.0;11.0]和（GA）12.0[11.0;12.0]，p<0.001；同时，在安全性方面也获得了统计学意义（UKU 评分）：（GG）3.0[2.0;4.0]和（GA）4.0[3.0;5.0]，p<0.001。我们没有发现不同基因型患者的米氮平浓度/剂量指标具有统计学意义：（GG）0.229[0.158;0.468]和（GA）0.290[0.174;0.526]，p=0.196。对研究中药物转录组学部分的结果分析表明，不同基因型患者的 hsa-miR-370-3p 血浆水平没有统计学差异：（GG）23.6[17.6;28.0]，（GA）21.8[17.2;27.0]，p=0.663。同时，相关性分析表明，HAMD 评分变化评估的米氮平疗效与 hsa-miR-370-3p 血浆浓度之间没有统计学意义：rs=0.05，p=0.460。此外，我们也没有发现 miRNA 浓度与安全性之间的相关性：rs=0.11，p=0.124。另外，我们发现了 CYP2D6 酶活性（通过 6M-THBC/哌啶比值测量评估）与 hsa-miR-370-3p 血浆浓度之间的关系：rs=-0.32，p<0.001。同时，相关性分析表明，米氮平浓度与 hsa-miR-370-3p 血浆浓度之间存在统计学意义：rs=0.31，p<0.001。
因此，在一组 192 名复发性抑郁障碍患者中，证明了 CYP2D6 基因的遗传多态性对米氮平的疗效和安全性的影响。同时，hsa-miR-370-3p 仍然是评估 CYP2D6 表达水平的有前途的生物标志物，因为它与编码同工酶的活性相关。
