Impact of the Omics-Based Biomarkers on the Fluvoxamine’s Steady-State Concentration, Efficacy and Safety in Patients with Affective Disorders Comorbid with Alcohol Use Disorder
Zastrozhin M.S. Skryabin V. Smirnov V. Zastrozhina A.K. Kaverina E.V. Klepikov D.A. Grishina E.A. Ryzhikova K.A. Bure I.V. Bryun E.A. Sychev D.A.
2021MedWorks Media LLC
Psychopharmacology Bulletin
2021#51Issue 169 - 80 pp.
~ Introduction: 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. 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 fluvoxamine 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 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. 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 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: rs = −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: rs = −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. 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 fluvoxamine was not demonstrated in a group of 105 patients with depressive disorder and alcohol use disorder.
alcohol use disorder , biotransformation , depressive spectrum disorders , fluvoxamine , personalized medicine , pharmacogenetics
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Laboratory of Genetics and Fundamental Studies, Addiction Psychiatry Department, Moscow, Russian Federation
Clinical Department, Addiction Psychiatry Department, Moscow, Russian Federation
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, Russian Federation
Pharmaceutical Toxicology Department, 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
Biomolecular Researchers Department of the Research Center, Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russian Federation
Academy of Sciences of Russia, Clinical Pharmacology and Therapy Department, Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russian Federation
Department of Public Health, Healthcare and Hygiene, Peoples Friendship University of Russia, Moscow, Russian Federation
Clinical Pharmacology, Kazakh National Medical University, Almaty, Kazakhstan
Laboratory of Genetics and Fundamental Studies
Clinical Department
Addiction Psychiatry Department
Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare
Pharmaceutical Toxicology Department
NRC Institute of Immunology FMBA of Russia
Biomolecular Researchers Department of the Research Center
Academy of Sciences of Russia
Department of Public Health
Clinical Pharmacology
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