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

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  • Authors: Zastrozhin M.S.1,2, Smirnov V.V.3,4, Sorokin A.S.2, Grishina E.A.1, Ryzhikova K.A.1, Bedina I.A.2, Shipitsyn V.V.2, Savchenko L.M.1, Buzik O.Z.1,2, Koporov S.S.2, Bryun E.А.1,2, Sychev D.A.1
  • Affiliations:
    1. Russian Medical Academy of Continuous Professional Education
    2. Moscow Research and Practical Centre on Addictions
    3. National Research Center Institute of Immunology of Federal Medical-Biological Agency of Russia
    4. I.M. Sechenov First Moscow State Medical University (Sechenov University)
  • Issue: Vol 73, No 6 (2018)
  • Pages: 411-419
  • Section: PSYCHOLOGY AND PSYCHIATRY: CURRENT ISSUES
  • URL: https://vestnikramn.spr-journal.ru/jour/article/view/1035
  • DOI: https://doi.org/10.15690/vramn1035
  • Cite item
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Abstract


Background: Alcohol dependence is often combined with affective disorders, in particular, depressive disorder (DD), which worsens adversely affects 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, whose representative is fluvoxamine, are used. Fluvoxamine therapy is often associated with a risk of development is shown to be ineffective, and a part of patients develop dose-dependent adverse drug reactions (ADR) and pharmacoresistance.

Objective: To study the effects of CYPD6 isoenzyme activity on the efficacy and safety of fluvoxamine therapy in patients with depressive disorders, comorbid with alcoholism.

Methods: The study was conducted on 117 Russian patients with DD, alcohol-dependent comorbid. For the purpose of correction of depressive disorders within the framework of cyclothymia, fluvoxamine (Fevarin) was administered to patients at a dosage of 50−150 mg/day. Genotyping was carried out by the method of polymerase chain reaction in Real-time mode with allele-specific hybridization. Efficacy and safety were assessed using validated psychometric scales and an assessment of the severity of ADR. To evaluate the activity of CYP2D6, the method of high performance liquid chromatography with mass spectrometry was used to measure the urinary content of the endogenous substrate of this isoenzyme and its metabolite, the ratio of 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline.

Results: By the 9th day of the study, the severity of depressive symptoms on the HAMD scale was statistically significantly different in patients with different genotypes: (GG) 7.0 [6.0; 8.0], (GA) 4.0 [3.0; 5.0] (p<0.001); safety indicator, estimated on a UKU scale: 3.0 [2.0; 4.0], (GA) 4.0 [4.0; 4.2] (p<0.001). The presence of differences persisted on the 16th day: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.0] (p<0.001); safety indicator, estimated on a UKU scale: (GG) 9.0 [9.0; 10.0], (GA) 6.0 [6.0; 7.0] (p<0.001). The calculation of the correlation coefficients between the difference in the number of scores on psychometric scales and the metabolic ratio showed a statistically significant inverse correlation of the average power degree between the efficiency index estimated by the HAMD scale (r=-0.467, p<0.05). There was no connection with the difference on the UKU scale (r=0.173, p>0.05).

Conclusion: In a study of a group of 117 patients with DD, comorbid with alcohol dependence, the effect of CYP2D6 activity, estimated by the ratio of the endogenous substrate concentrations of pinolin and its metabolite 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline, on the efficacy of fluvoxamine therapy. This effect was also shown using the results of genotyping. The results of genotyping also showed the existence of a difference in the safety index in patients with different genotypes from the polymorphic marker CYP2D6 1846G>A.


Mikhail S. Zastrozhin

Russian Medical Academy of Continuous Professional Education; Moscow Research and Practical Centre on Addictions

Author for correspondence.
Email: rudnmed@yandex.ru
ORCID iD: 0000-0003-0607-4812

Russian Federation

MD, PhD

37/1, Lyublinskaya street, 109390 Moscow

Valery V. Smirnov

National Research Center Institute of Immunology of Federal Medical-Biological Agency of Russia; I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: valsmirnov@gmail.com
ORCID iD: 0000-0002-8232-6682

Russian Federation PhD

Alexander S. Sorokin

Moscow Research and Practical Centre on Addictions

Email: assorokin@gmail.com
ORCID iD: 0000-0002-0053-8252

Russian Federation

SPIN-код: 5874-3924

Elena A. Grishina

Russian Medical Academy of Continuous Professional Education

Email: eagrishina@gmail.com
ORCID iD: 0000-0002-5621-8266

Russian Federation PhD, Assistant professor

Kristina A. Ryzhikova

Russian Medical Academy of Continuous Professional Education

Email: karyzhikova@gmail.com
ORCID iD: 0000-0003-3505-8520

Russian Federation

SPIN-код: 2604-1922

Inessa A. Bedina

Moscow Research and Practical Centre on Addictions

Email: iabedina@gmail.com

Russian Federation

MD, PhD, Assistant professor

Valery V. Shipitsyn

Moscow Research and Practical Centre on Addictions

Email: vvshipitsyn@gmail.com

Russian Federation

SPIN-код: 2261-1516

Ludmila M. Savchenko

Russian Medical Academy of Continuous Professional Education

Email: lmsavchenko@gmail.com
ORCID iD: 0000-0002-2411-3494

Russian Federation

MD, PhD, Professor

Oleg Zh. Buzik

Russian Medical Academy of Continuous Professional Education; Moscow Research and Practical Centre on Addictions

Email: ozhbuzik@gmail.com

Russian Federation

MD, PhD, Professor

Sergey S. Koporov

Moscow Research and Practical Centre on Addictions

Email: sergeykoporov@gmail.com

Russian Federation

MD, PhD

Evgeny А. Bryun

Russian Medical Academy of Continuous Professional Education; Moscow Research and Practical Centre on Addictions

Email: evgenybryunrmapo@gmail.com
ORCID iD: 0000-0002-8366-9732

Russian Federation

Доктор медицинских наук, профессор

SPIN-код: 6736-7656

Dmitry A. Sychev

Russian Medical Academy of Continuous Professional Education

Email: dmitrysychevrmapo@gmail.com
ORCID iD: 0000-0002-4496-3680

Russian Federation

MD, PhD, Professor

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