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.
Psychopharmacol Bull. 2020 Jul 23;50(3):47-57.
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.
The objective of this study was to evaluate the influence of 1846G > A polymorphism of the CYP2D6 gene on the concentration/dose indicator of duloxetine, 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 recurrent depressive disorder.
This study enrolled 118 patients with recurrent depressive disorder (average age - 40.6±17.1 years). Therapy included duloxetine in an average daily dose of 103.7±37.1 mg per day. Treatment efficacy was assessed using the international psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping we performed the real-time polymerase chain reaction (PCR Real-time). Therapeutic drug monitoring has been performed using HPLC-MS/MS.
Our findings revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMD scores at the end of the treatment course): (GG) 9.0 [7.0; 10.0] and (GA) 11.0 [8.5; 14.0], p < 0.001; at the same time, the statistical significance in the safety profile was obtained (the UKU scores): (GG) 3.0 [3.0; 4.0] and (GA) 4.0 [3.0; 4.0], p = 0.007. We revealed a statistical significance for concentration/dose indicator of duloxetine in patients with different genotypes: (GG) 0.776 [0.529; 1.067] and (GA) 1.388 [0.942; 1.732], p < 0.001.
Thus, the effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of duloxetine was demonstrated in a group of 118 patients with recurrent depressive disorder.
度洛西汀常用于治疗复发性抑郁障碍患者。该组患者中部分人对包含度洛西汀的治疗方案反应不足，而许多人则出现剂量依赖性不良反应。先前的研究表明，CYP2D6 参与度洛西汀的生物转化，其活性高度依赖于编码该基因的多态性。
本研究旨在通过测量复发性抑郁障碍患者的 CYP2D6 酶活性（通过 6M-THBC/ 胡椒碱比值测量）和 hsa-miR-370-3p 血浆浓度水平来评估 CYP2D6 基因 1846G > A 多态性对度洛西汀的浓度/剂量指标的影响。
本研究纳入了 118 例复发性抑郁障碍患者（平均年龄 40.6±17.1 岁）。治疗方案包括度洛西汀，平均日剂量为 103.7±37.1mg/天。采用国际心理计量量表评估治疗效果，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（PCR 实时）进行基因分型。采用高效液相色谱-串联质谱法（HPLC-MS/MS）进行治疗药物监测。
我们的研究结果表明，在治疗效果评估（治疗结束时 HAMD 评分）方面存在统计学显著差异：（GG）9.0[7.0;10.0]和（GA）11.0[8.5;14.0]，p<0.001；同时，在安全性方面也获得了统计学显著差异（UKU 评分）：（GG）3.0[3.0;4.0]和（GA）4.0[3.0;4.0]，p=0.007。我们发现不同基因型患者的度洛西汀浓度/剂量指标存在统计学显著差异：（GG）0.776[0.529;1.067]和（GA）1.388[0.942;1.732]，p<0.001。
因此，本研究在 118 例复发性抑郁障碍患者中证明了 CYP2D6 基因遗传多态性对度洛西汀疗效和安全性的影响。
