Impact of the Omics-Based Biomarkers on the Mirtazapine's Steady-State Concentration, Efficacy and Safety in Patients with Affective Disorders Comorbid with Alcohol Use Disorder.

Q3 Medicine
Psychopharmacology bulletin Pub Date : 2021-03-16
M S Zastrozhin, VYu Skryabin, VYu Smirnov, A K Zastrozhina, E V Kaverina, D A Klepikov, E A Grishina, K A Ryzhikova, I V Bure, E A Bryun, D A Sychev
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引用次数: 0

Abstract

Introduction: Mirtazapine is commonly administered to patients with recurrent depressive disorder. Some of these patients do not show adequate response to the therapy with mirtazapine, whereas many of them experience dose-dependent adverse drug reactions. Previous research revealed that CYP2D6 is involved in the metabolism of mirtazapine, the activity of which is highly dependent on the polymorphism of the gene encoding it.

Objective: 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 mirtazapine and on the CYP3A expression level obtained by measuring the miR-27b plasma concentration levels in patients suffering from a recurrent depressive disorder.

Material and methods: Our study included 108 patients with recurrent depressive disorder (average age - 35.2 ± 15.1 years). The treatment regimen included mirtazapine in an average daily dose of 45.0 [30.0; 60.0] 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.

Results: 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 mirtazapine 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 mirtazapine efficacy profile evaluated by changes in HAMD scale scores and the miR-27b plasma concentration: rs = -0.2, p = 0.46. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.029, p = 0.93. In addition, we didn't reveal the relationship between the CYP3A enzymatic activity and the miR-27b plasma concentration: rs = -0,188, p = 0.85. 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) 4.75 [1.28; 7.34] vs (GG) 8.83 [4.73; 13.62], p-value = 0.023.

Conclusion: 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 mirtazapine was not demonstrated in a group of 108 patients with depressive disorder and alcohol use disorder.

基于 Omics 的生物标记物对米氮平在合并酒精使用障碍的情感障碍患者中的稳态浓度、疗效和安全性的影响。
简介米氮平通常用于复发性抑郁症患者。其中一些患者对米氮平的治疗没有足够的反应,而许多患者则出现剂量依赖性的药物不良反应。以往的研究表明,CYP2D6参与了米氮平的代谢,其活性与编码该基因的多态性有很大关系:本研究旨在探讨CYP3A4、CYP2C9、CYP3A5、ABCB1、CYP2C19、SCL6A4和5-HTR2A基因的多态性对米氮平浓度/剂量指标的影响,以及对通过测量miR-27b血浆浓度水平获得的复发性抑郁症患者CYP3A表达水平的影响:研究对象包括108名复发性抑郁障碍患者(平均年龄为35.2 ± 15.1岁)。治疗方案包括米氮平,平均日剂量为每周 45.0 [30.0; 60.0] 毫克。疗效采用国际心理测量量表进行评估。治疗安全性采用UKU副作用评定量表进行评估。为了进行基因分型和估计血浆中的微RNA (miRNA)水平,我们进行了实时聚合酶链反应。我们采用 HPLC-MS/MS 方法,通过给定同工酶的内源性底物及其代谢物(6b-HC/皮质醇)在尿液中的含量来评估 CYP3A 的活性。使用 HPLC-MS/MS 进行了治疗药物监测:我们的研究在疗效和安全性方面没有发现任何有统计学意义的结果。我们也没有发现米氮平在不同基因型患者中的浓度/剂量指标有统计学意义。对药物转录组学部分研究结果的分析表明,不同基因型患者的 miR-27b 血浆水平差异没有统计学意义。同时,相关性分析也没有发现米氮平的疗效特征(根据 HAMD 量表评分的变化进行评估)与 miR-27b 血浆浓度之间存在统计学意义上的显著关系:rs = -0.2,p = 0.46。同时,我们也没有发现 miRNA 浓度与安全性之间的相关性:rs = 0.029,p = 0.93。此外,我们没有发现 CYP3A 酶活性与 miR-27b 血浆浓度之间的关系:rs = -0,188,p = 0.85。然而,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) 4.75 [1.28; 7.34] vs (GG) 8.83 [4.73; 13.62],P 值 = 0.023:因此,在一组 108 例抑郁障碍和酒精使用障碍患者中,CYP3A4、CYP2C9、CYP2C9、CYP3A5、ABCB1、CYP2C19、CYP2C19、CYP2C19、SCL6A4、5-HTR2A 基因多态性对米氮平疗效和安全性的影响未得到证实。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Psychopharmacology bulletin
Psychopharmacology bulletin PHARMACOLOGY & PHARMACY-PSYCHIATRY
CiteScore
2.70
自引率
0.00%
发文量
32
期刊介绍: Information not localized
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