Effect of Genetic Polymorphism of the CYP2D6 Gene on the Efficacy and Safety of Fluvoxamine in Major Depressive Disorder

Abstract

Background: Previous studies have shown that cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of fluvoxamine, the activity of which is highly dependent, inter alia, on the polymorphism of the gene encoding it. The objective of our study was to investigate the effect of 1846G.A polymorphism of the CYP2D6 gene on the efficacy and safety of fluvoxamine, using findings on CYP2D6 enzymatic activity and on CYP2D6 expression level in patients with depressive disorders comorbid with alcohol use disorder.Study question: Efficacy and safety of fluvoxamine depend on the polymorphism of CYP2D6 gene in patients with major depressive disorder.Study design: Our study enrolled 96 male patients with depressive disorders comorbid with alcohol use disorder. Patients were examined on days 1, 9, and 16 of fluvoxamine therapy.Measures and Outcomes: Treatment efficacy was evaluated 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. 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 (6-hydroxy-1,2,3,4tetrahydro-b-carboline/pinoline ratio).Results: Our study revealed the statistically significant results for the treatment efficacy evaluation [the Hamilton Depression Rating Scale scores at the end of the treatment course: (GG) 2.0 (1.0-4.0) and (GA) 5.0 (4.0-7.0), P , 0.001]. Analysis of the results of the pharmacotranscriptomic part of the study did not show the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 26.9 (15.0-32.2), (GA) 31.8 (22.7-33.7), P 5 0.247. In addition, we evaluated the relationship between the CYP2D6 enzymatic activity (as evaluated by 6-hydroxy-1,2,3,4-tetrahydro-b-carboline/ pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs 5 20.243, P 5 0.017.

Serum Concentration–Dose Relationship and Modulation Factors in Children and Adolescents Treated with Fluvoxamine

“…Studies in adult patients showed conflicting results, too [ 24 , 25 , 26 , 27 , 28 ]. The result of nonlinearity in smaller studies might be modulated by CYP2D6 gene variants, which were not considered in any study and can remarkably affect plasma exposure to fluvoxamine [ 29 , 30 , 31 , 32 ]. Unfortunately, no data on metabolizer status were available in the present sample.…”

Update on Pharmacological Treatment for Comorbid Major Depressive and Alcohol Use Disorders: The Role of Extended-release Trazodone

“…Recent clinical studies have shown as well that SSRIs improved both depressive symptoms and craving measures [ 19 ] and confirmed the efficacy of fluoxetine, fluvoxamine, and citalopram in treating depression in MDD + AUD patients, with statistically significant differences related to the presence of CYP polymorphisms [ 20 - 22 ]. However, these findings were limited by the small sample size, the heterogeneity of inclusion criteria, and the lack of a control group.…”

CYP2D6 gene polymorphism and apatinib affect the metabolic profile of fluvoxamine

“…Drug efficacy stratification may be the result of individual differences in blood concentrations which caused by genetic polymorphisms of metabolic enzymes and drug interactions. Cytochrome P450 family member 2D6 (CYP2D6) is a major enzyme involved in catalyzing metabolism of fluvoxamine, which produced desmethyl fluvoxamine (Hicks et al, 2015;Zastrozhin et al, 2021). However, there are genetic polymorphism of CYP2D6 resulting in large inter-individual variability in enzyme activity, further leading to subtherapeutic phenomena or severe adverse effects (Zastrozhin et al, 2021).…”

“…Cytochrome P450 family member 2D6 (CYP2D6) is a major enzyme involved in catalyzing metabolism of fluvoxamine, which produced desmethyl fluvoxamine (Hicks et al, 2015;Zastrozhin et al, 2021). However, there are genetic polymorphism of CYP2D6 resulting in large inter-individual variability in enzyme activity, further leading to subtherapeutic phenomena or severe adverse effects (Zastrozhin et al, 2021). Moreover, interactions between fluvoxamine and other drugs are frequently being reported.…”