Effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder

Abstract

BackgroundFluvoxamine therapy is used for treatment of patients with depressive disorder, but it is often ineffective, and some patients suffer from dose-dependent undesirable side effects such as vertigo, headache, indigestion, xerostomia, increased anxiety, etc. CYP2D6 is involved in the biotransformation of fluvoxamine. Meanwhile, the genes encoding these isoenzymes have a high level of polymorphism, which may affect the protein synthesis.ObjectiveThe primary objective of our study was to investigate the effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder, in order to develop the algorithms of optimization of fluvoxamine therapy for reducing the risk of dose-dependent undesirable side effects and pharmacoresistance.MethodsThe study involved 45 male patients (average age: 36.44±9.96 years) with depressive disorder and comorbid alcohol use disorder. A series of psychometric scales was used in the research. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction.ResultsAccording to results of Mann–Whitney U-test, statistically significant differences between the efficacy and safety of fluvoxamine were obtained on 9th and 16th days of therapy in patients with GG and GA genotypes (The Hamilton Rating Scale for Depression: 10.0 [10.0; 23.0] vs 25.0 [24.0; 16.0] (P<0.001) on the 9th day and 4.0 [2.0; 5.0] vs 6.0 [6.0; 7.0] on the 16th day; The UKU Side Effect Rating Scale: 6.0 [4.0; 6.0] vs 9.0 [9.0; 10.0] (P<0.001) on the 9th day and 5.0 [1.0; 9.0] vs 19.0 [18.0; 22.0] on the 16th day).ConclusionThis study demonstrated the lower efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorders with GA genotype in CYP2D6 1846G>A polymorphic marker.

Relations of CYP2C19*2 genetic polymorphisms to plasma and saliva concentrations of diazepam in patients hospitalized for alcohol withdrawal

“…These results are consistent with the findings of our previous study focused on investigation of the CYP2C19*2 genetic polymorphism, which had a 2-times lower sample size and enrolled 50 patients [7]. Furthermore, previous studies which were conducted by our research group [14,15], confirm the importance, relevance and possibility to investigate the personalized approach to the prescription of BZDs (and specifically diazepam) in such cohort of patients.…”

Analysis of the Deleterious Single-Nucleotide Polymorphisms Associated With Antidepressant Efficacy in Major Depressive Disorder

“…For instance, Hodgson et al (56) analyzed the data from GENDEP and found there was no significant association between CYP2D6 polymorphisms and response to antidepressants. In contrast, some studies reported positive associations between CYP2D6 polymorphisms and response to antidepressants (58)(59)(60)(61). For example, Zastrozhin et al (59) found that patients with 1846G>A of CYP2D6 polymorphism (rs3892097) had significantly reduced efficacy of fluvoxamine.…”

“…In contrast, some studies reported positive associations between CYP2D6 polymorphisms and response to antidepressants (58)(59)(60)(61). For example, Zastrozhin et al (59) found that patients with 1846G>A of CYP2D6 polymorphism (rs3892097) had significantly reduced efficacy of fluvoxamine. For the P34S (rs1065852) substitution in CYP2D6.…”

Influence of CYP3A Activity on the Efficacy and Safety of Fluvoxamine in Patients Depressive Disorders and Comorbid Alcohol Use Disorder

“…Принципы расчета размера выборки Расчет размера выборки производился с использованием пакета pwr на основе данных, полученных в ранее проведенном исследовании на 45 пациентах [30]. Анализ мощности показал, что размер выборки в 117 пациентов является достаточным для минимизации ошибки 2-го рода (<0,2).…”

“…Нежелательные явления, которые могут быть потенциально связаны с изучаемым медицинским вмешательством, отсутствовали. ORIGINAL STUDY НАУЧНОЕ ИССЛЕДОВАНИЕ рекуррентными депрессивными расстройствами [31], а также с результатами нашего обсервационного исследования на небольшой выборке, не включавшего части фенотипирования [30].…”