Evaluation of CYP2C19*3 effectiveness and safety of fluvoxamine in patients with depressive disorders, comorbide with alcoholism

Alcohol dependence is often combined with affective disorders, in particular, depressive disorder (DD), which worsens the prognosis of the course of both diseases and their outcomes. For the treatment of DD, drugs from the group of selective serotonin reuptake inhibitors (SSRIs), whose representative is fluvoxamine, are used. The fluvoxamine therapy is often ineffective, and some patients develop dose-related adverse drug reactions: dizziness, headache, dyspepsia, xerostomia, increased anxiety, etc., which reduces the effectiveness of therapy for patients with DD, comorbid with alcoholism. In the biotransformation of fluvoxamine, isozymes CYP2D6 and CYP2C19 take part. In this case, the genes encoding the synthesis of these isoenzymes have a high level of polymorphism, which can influence the synthesis of the amount of protein. The presence of some polymorphic markers increases the amount of synthesized isoenzyme, or increases its activity, which leads to an acceleration of biotransformation of the drug and a decrease in its effectiveness. Some polymorphisms, on the contrary, reduce the activity of the isoenzyme encoded by the gene, which leads to a slowing of biotransformation and elimination of drugs, which increases the risk of developing dose-dependent adverse drug reactions. The purpose of our study was to study the effect of the polymorphism of the CYP2C19 gene on the efficacy and safety of fluvoxamine in patients with DD, comorbid with alcoholism, in order to develop algorithms for optimizing fluvoxamine therapy to reduce the risk of pharmacological resistance and the development of dose-dependent adverse drug reactions. The study was conducted on 45 Russian patients suffering from alcohol dependence. To correct the subdepressive disorder within the framework of cyclothymia, fluvoxamine was prepared in tableted form at a dosage of 100.0 [50.0; 150.0] mg/day. Genotyping was performed by real-time polymerase chain reaction with allelespecific hybridization. The effectiveness and safety assessment was carried out using psychometric scales and scales for assessing the severity of ADR. Based on the results of the study, there were no statistically significant differences in the efficacy and safety of Fluvoxamine in patients with depressive disorder and comorbid alcohol dependence. On the scale HADS on the first day of therapy the scores were calculated: (GG) 21.00 [19.00; 24.00], (GA) 19.00 [18.75; 19.75], р=0.18. On the 9th day of therapy: (GG) 10.00 [7.00; 34.00], (GA) 20,50 [7.25; 33.25], р=0.86. On the 16th day of the therapy: (GG) 32.00 [15.00; 33.00], (GA) 28.50 [19.75; 33.00], р=0.95. Scores on the UKU scale on the first day of therapy Fluvoxamine: (GG) 3.00 [3.00; 10.00], (GA) 11.00 [8.75; 11.00], p=0.12. On the 9th day: (GG) 15.00 [12.00; 15.00], (GA) 14.00 [13.50; 14.25], p=0.65. On the 16th day therapy: (GG) 6.00 [5.00; 7.00], (GA) 10.50 [5.50; 15.50], p=0.50. In a study of a group of 45 patients with depressive disorders comorbid alcohol dependence, it was show that the polymorphism of the CYP2C19*3 gene does not affect the efficacy and safety of therapy Fluvoxamine. Thus, it seems possible to formulate a recommendation on the possible non-inclusion of CYP2C19*3 in a pharmacogenetic panel, that can be used to select a therapeutic dose of fluvoxamine, in patients with depressive disorders comorbid with alcoholism. It is possible that the absence of a statistically significant difference in the rates was not revealed, due to the insufficient sample size. It is necessary to continue the study, including more patients, to address this issue. © 2018, UE Professional Editions. All rights reserved.

Zastrozhin M.1, 2 , Antonenko A.2 , Grishina E.1 , Ryzhikova K.1 , Sorokin A. 2 , Ivanov A. 2 , Kubarev D.2 , Romanov A.2 , Pirogova A.2 , Fedorova T. 2 , Anisimova A.2 , Efimova A.3 , Savchenko L.1 , Brun E.1, 2 , Sychev D.1
UE Professional Editions
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  • 1 Russian Medical Academy of Continuous Professional Education, Moscow, Russian Federation
  • 2 Moscow Research and Practical Centre on Addictions, Moscow, Russian Federation
  • 3 Peoples friendship unversity of Russia, Moscow, Russian Federation
Alcohol dependence; Biotransformation; CYP2C19; Depressive disorders; Fluvoxamine; Personalized medicine; Pharmacogenetics; SSRIs
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