MS Zastrozhin, M.D., PhD, Head of Laboratory of Genetics and Fundamental Studies, Associate Professor of the Addiction Psychiatry Department; VYu Skryabin, M.D., Head of Clinical Department, Teaching Assistant of the Addiction Psychiatry Department; EA 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. VV 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. 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; 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. EV Kaverina, M.D., PhD, Associate Professor of the Department of Public Health, Healthcare and Hygiene, Peoples Friendship University of Russia, Moscow, Russian Federation. DA Klepikov, M.D., Assistant Professor of Clinical Pharmacology, Kazakh National Medical University, Almaty, Kazakhstan.
Psychopharmacol Bull. 2021 Jan 12;51(1):69-80.
Fluvoxamine is commonly administered to patients with recurrent depressive disorder. Some of these patients do not show adequate response to the therapy with fluvoxamine, whereas many of them experience dose-dependent adverse drug reactions. Previous research revealed that CYP2D6 is involved in the metabolism of fluvoxamine, the activity of which is highly dependent on the polymorphism of the gene encoding it.
The objective of this study was to investigate the effect of polymorphisms of the CYP3A4, CYP2C9, CYP3A5, ABCB1, CYP2C19, SCL6A4, and 5-HTR2A genes on the concentration/dose indicator of fluvoxamine and on the CYP3A expression level obtained by measuring the miR-27b plasma concentration levels in patients suffering from a recurrent depressive disorder.
Our study included 105 patients with recurrent depressive disorder (average age - 37.5 ± 13.2 years). The treatment regimen included fluvoxamine in an average daily dose of 117.6 ± 44.3 mg per week. Therapy efficacy was assessed 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 CYP3A was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of the given isoenzyme and its metabolite in urine (6b-HC/cortisol). Therapeutic drug monitoring has been performed using HPLC-MS/MS.
Our study didn't reveal any statistically significant results in terms of the treatment efficacy and safety of the therapy. We also didn't reveal a statistical significance for the concentration/dose indicator of fluvoxamine in patients with different genotypes. Analysis of the results of the pharmacotranscriptomic part of the study didn't demonstrate the statistically significant difference in the miR-27b plasma levels in patients with different genotypes. At the same time, correlation analysis didn't reveal a statistically significant relationship between the fluvoxamine efficacy profile evaluated by changes in HAMD scale scores and the miR-27b plasma concentration: r = -0.012, p = 0.63. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = -0.175, p = 0.30. In addition, we didn't reveal the relationship between the CYP3A enzymatic activity and the miR-27b plasma concentration: r = -0.197, p < 0.32. However, the difference in the CYP3A enzymatic activity in carriers of AG and GG genotypes of the 6986A > G polymorphism of CYP3A5 gene has been revealed: (AG) 4.72 [1.18; 8.45] vs (GG) 9.23 [5.12; 15.53], p-value = 0.23.
Thus, the effect of genetic polymorphism of the CYP3A4, CYP2C9, CYP2C9, CYP3A5, ABCB1, CYP2C19, CYP2C19, CYP2C19, SCL6A4, 5-HTR2A gene on the efficacy and safety profiles of fluvoxamine was not demonstrated in a group of 105 patients with depressive disorder and alcohol use disorder.
氟伏沙明常用于治疗复发性抑郁障碍患者。有些患者对氟伏沙明治疗反应不佳，而许多患者则出现剂量依赖性药物不良反应。先前的研究表明，CYP2D6 参与氟伏沙明的代谢，其活性高度依赖于编码该基因的多态性。
本研究旨在探讨 CYP3A4、CYP2C9、CYP3A5、ABCB1、CYP2C19、SCL6A4 和 5-HTR2A 基因的多态性对复发性抑郁障碍患者氟伏沙明浓度/剂量指标的影响，以及通过测量 miR-27b 血浆浓度来评估 CYP3A 表达水平。
我们的研究纳入了 105 例复发性抑郁障碍患者（平均年龄 37.5±13.2 岁）。治疗方案包括氟伏沙明，每周平均剂量为 117.6±44.3mg。采用国际心理计量学量表评估治疗效果，采用 UKU 副作用评定量表评估治疗安全性。采用实时聚合酶链反应进行基因分型和 miRNA 血浆水平检测。采用 HPLC-MS/MS 法评估 CYP3A 活性，通过内源性底物及其代谢物在尿液中的含量（6b-HC/皮质醇）进行评估。采用 HPLC-MS/MS 进行治疗药物监测。
本研究未发现治疗效果和安全性方面有统计学意义的结果。我们也没有发现不同基因型患者氟伏沙明浓度/剂量指标有统计学意义。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 miR-27b 血浆水平无统计学差异。同时，相关性分析也未显示出 HAMD 评分变化评估的氟伏沙明疗效与 miR-27b 血浆浓度之间存在统计学意义的关系：r=-0.012，p=0.63。此外，我们也未发现 miRNA 浓度与安全性之间的相关性：rs=-0.175，p=0.30。此外，我们还未发现 CYP3A 酶活性与 miR-27b 血浆浓度之间存在相关性：r=-0.197，p<0.32。然而，我们发现了 CYP3A5 基因 6986A>G 多态性的 AG 和 GG 基因型携带者的 CYP3A 酶活性存在差异：（AG）4.72[1.18；8.45]与（GG）9.23[5.12；15.53]，p 值=0.23。
因此，在 105 例伴有酒精使用障碍的抑郁障碍患者中，并未显示 CYP3A4、CYP2C9、CYP2C9、CYP3A5、ABCB1、CYP2C19、CYP2C19、CYP2C19、SCL6A4、5-HTR2A 基因的遗传多态性对氟伏沙明的疗效和安全性有影响。
