Zastrozhin, M.D., PhD, Head of Laboratory of Genetics and Fundamental Studies, Associate Professor of Addiction Psychiatry Department, Bryun, M.D., PhD, Professor, President, Head of Addiction Psychiatry Department, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation; Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia. Efimova, M.D., Physician of Clinical Department, Balashikha Regional Hospital. Skryabin, M.D., Head of Clinical Department, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. Smirnov, PhD, Associate Professor of Pharmaceutical Toxicology Department, Head of Laboratory of Pharmacokinetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation; NRC Institute of Immunology FMBA of Russia, Moscow, Russian Federation. Petukhov, M.D., PhD, Clinical Laboratory Diagnostician of the Analytical Toxicology lab of the Reference Center for Psychoactive Substances use Monitoring, Associate Professor of Pharmaceutical and Toxicological Chemistry, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation; I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation. Pankratenko, Paramedic-Laboratory Assistant of the Analytical Toxicology Lab of the Reference Center for Psychoactive Substances use Monitoring, Pozdniakov, Researcher of the Laboratory of Genetics and Fundamental Studies, M.D., the Researcher of the Department of Dermatovenerology and Cosmetology, M.D., PhD, Associate Professor of Addiction Psychiatry Department, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. Kaverina, M.D., PhD, Associate Professor of the Department of Public Health, Healthcare and Hygiene, Peoples Friendship University of Russia, Moscow, Russian Federation, Peoples Friendship University of Russia. Klepikov, M.D., Assistant Professor of Clinical Pharmacology, Kazakh National Medical University, Almaty, Kazakhstan. Grishina, PhD, Head of Biomolecular Researchers Department of the Research Center, Ryzhikova, Research Fellow of the Biomolecular Researchers Department of the Research Center, Bure, PhD, Research Fellow of the Biomolecular Researchers Department of the Research Center, 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.
Psychopharmacol Bull. 2021 Nov 3;51(4):87-104.
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. Objective. The objective of the study was to evaluate the impact of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of phenazepam, 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 concentration levels in patients suffering from major depressive disorder. MATERIAL AND METHODS: The study enrolled 191 patients with recurrent depressive disorder (age -40.0 ± 16.3 years). Treatment regimen included phenazepam in an average daily dose of 6.0 ± 2.3 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 evaluated using the 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 has been performed using HPLC-MS/MS. RESULTS: Our findings didn't reveal the statistically significant results in terms of the treatment efficacy evaluation (HAMA scores at the end of the treatment course): (GG) 6.0 [4.0; 8.0] and (GA) 6.0 [5.0; 7.8], p > 0.999; the statistical significance in the safety profile was not obtained (the UKU scores): (GG) 3.0 [2.0; 4.0] and (GA) 3.0 [3.0; 3.0], p > 0.999. We didn't reveal a statistical significance for concentration/dose indicator of phenazepam in patients with different genotypes: (GG) 0.812 [0.558; 1.348] and (GA) 0.931 [0.630; 1.271], p = 0.645). 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) 22.5 [16.9; 29.8], (GA) 22.7 [15.7; 31.5], p = 0.695. At the same time, correlation analysis didn't reveal a statistically significant relationship between the phenazepam efficacy profile evaluated by changes in HAMA scale scores and the hsa-miR-370-3p plasma concentration: rs = -0.01, p = 0.866. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.07, p = 0.348. Also we did not reveal the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs = -0.14, p = 0.056. At the same time, correlation analysis did not reveal a statistically significant relationship between the phenazepam concentration and the hsa-miR-370-3p plasma concentration: rs = -0.05, p = 0.468. CONCLUSION: The effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of phenazepam was not demonstrated in a group of 191 patients with recurrent depressive disorder. At the same time, hsa-miR-370-3p does not remain a promising biomarker for assessing the level of CYP2D6 expression, because it does not correlate with encoded isoenzyme activity.
介绍：苯甲噁唑常用于治疗重度抑郁症患者。一些此类患者对含苯甲噁唑的治疗方案没有足够的反应，而许多患者则经历 A 型药物不良反应。先前的研究表明，CYP2D6 参与苯甲噁唑的生物转化，其活性高度依赖于编码该基因的多态性。目的：本研究旨在评估 CYP2D6 基因 1846G>A 多态性对苯甲噁唑浓度/剂量指标的影响，方法是评估 CYP2D6 酶活性（通过 6M-THBC/哌啶比值测量）和重度抑郁症患者血浆 hsa-miR-370-3p 浓度水平来测量 CYP2D6 表达水平。
材料和方法：研究纳入 191 例复发性抑郁症患者（年龄 40.0±16.3 岁）。治疗方案包括苯甲噁唑，平均日剂量为 6.0±2.3mg/天。使用经过验证的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。进行实时聚合酶链反应（PCR Real-time）进行基因分型和 miRNA（microRNA）血浆水平的估计。使用高效液相色谱-串联质谱法（HPLC-MS/MS）通过内源性底物的含量及其尿液中的代谢物（6M-THBC/哌啶）评估 CYP2D6 的活性。使用 HPLC-MS/MS 进行治疗药物监测。
结果：我们的研究结果并未显示治疗效果评估（治疗过程结束时的 HAMA 评分）方面有统计学意义的结果：（GG）6.0[4.0；8.0]和（GA）6.0[5.0；7.8]，p>0.999；安全性方面未获得统计学意义（UKU 评分）：（GG）3.0[2.0；4.0]和（GA）3.0[3.0；3.0]，p>0.999。我们在不同基因型患者的苯甲噁唑浓度/剂量指标中未发现统计学意义：（GG）0.812[0.558；1.348]和（GA）0.931[0.630；1.271]，p=0.645。对研究中药物转录组学部分的结果进行分析，发现不同基因型患者的 hsa-miR-370-3p 血浆水平无统计学差异：（GG）22.5[16.9；29.8]，（GA）22.7[15.7；31.5]，p=0.695。同时，相关性分析未显示苯甲噁唑疗效评估（通过 HAMA 评分变化）与 hsa-miR-370-3p 血浆浓度之间存在统计学意义的关系：rs=-0.01，p=0.866。此外，我们也没有发现 miRNA 浓度与安全性之间的相关性：rs=0.07，p=0.348。同时，我们也没有发现 CYP2D6 酶活性（通过 6M-THBC/哌啶比值测量）与 hsa-miR-370-3p 血浆浓度之间的关系：rs=-0.14，p=0.056。同时，相关性分析也未显示苯甲噁唑浓度与 hsa-miR-370-3p 血浆浓度之间存在统计学意义的关系：rs=-0.05，p=0.468。
结论：在 191 例复发性抑郁症患者中，未发现 CYP2D6 基因多态性对苯甲噁唑疗效和安全性的影响。同时，hsa-miR-370-3p 不能成为评估 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无关。
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