safetyriskБезопасность и риск фармакотерапииSafety and Risk of Pharmacotherapy2312-78212619-1164Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/2312-7821-2025-517safetyrisk-517Research ArticleГЛАВНАЯ ТЕМА: ТОНКОЕ ИСКУССТВО ВРАЧЕВАНИЯ ДУШИ: КАМО ГРЯДЕШИ?MAIN TOPIC: THE SUBTLE ART OF SOUL HEALING: QUO VADIS?Фармакогенетические биомаркеры сиалореи, вызванной приемом клозапина: систематический обзорPharmacogenetic Biomarkers of Clozapine-Induced Sialorrhoea: A Systematic Reviewhttps://orcid.org/0000-0003-4263-6640КироваА. Г.KirovaA. G.

Кирова Анастасия Григорьевна

ул. Баррикадная, д. 2/1, стр. 1, Москва, 125993

Anastasia G. Kirova

2/1/1 Barrikadnaya St., Moscow 125993

https://orcid.org/0009-0000-5996-8575БеллевичЮ. С.BellevichYu. S.

Беллевич Юрий Сергеевич

ул. Баррикадная, д. 2/1, стр. 1, Москва, 125993

Yuri S. Bellevich

2/1/1 Barrikadnaya St., Moscow 125993

https://orcid.org/0000-0002-2314-7174СосинД. Н.SosinD. N.

Сосин Дмитрий Николаевич, канд. мед. наук, доцент

ул. Баррикадная, д. 2/1, стр. 1, Москва, 125993; Абрикосовский пер., д. 2 корп. 1, Москва, 119435

Dmitriy N. Sosin, Cand. Sci. (Med.), Associate Professor

2/1/1 Barrikadnaya St., Moscow 125993; 2/1 Abrikosovsky Lane, Moscow 119435

sosin.dmitriy@gmail.comhttps://orcid.org/0000-0002-5749-3964МосоловС. Н.MosolovS. N.

Мосолов Сергей Николаевич, д-р мед. наук, профессор

ул. Баррикадная, д. 2/1, стр. 1, Москва, 125993; ул. Потешная, д. 3, Москва, 107076

Sergey N. Mosolov, Dr. Sci. (Med.), Professor

2/1/1 Barrikadnaya St., Moscow 125993; 3 Poteshnaya St., Moscow 107076

https://orcid.org/0000-0002-4496-3680СычевД. А.SychevD. A.

Сычев Дмитрий Алексеевич, академик РАН, д-р мед. наук, профессор

ул. Баррикадная, д. 2/1, стр. 1, Москва, 125993; Абрикосовский пер., д. 2 корп. 1, Москва, 119435

Dmitry A. Sychev, Academician of the Russian Academy of Sciences, Dr. Sci. (Med.), Professor

2/1/1 Barrikadnaya St., Moscow 125993; 2/1 Abrikosovsky Lane, Moscow 119435

dimasychev@mail.ruФедеральное государственное бюджетное образовательное учреждение дополнительного профессионального образования «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения Российской ФедерацииРоссияRussian Medical Academy of Continuous Professional EducationRussian FederationФедеральное государственное бюджетное образовательное учреждение дополнительного профессионального образования «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения Российской Федерации; Государственный научный центр Российской Федерации Федеральное государственное бюджетное учреждение науки «Российский научный центр хирургии имени академика Б.В. Петровского»РоссияRussian Medical Academy of Continuous Professional Education; Russain Research Center of Surgery Named after Academician B.V. PetrovskyRussian FederationФедеральное государственное бюджетное образовательное учреждение дополнительного профессионального образования «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения Российской Федерации; Московский научно-исследовательский институт психиатрии — филиал Национального медицинского исследовательского центра психиатрии и наркологии имени В.П. СербскогоРоссияRussian Medical Academy of Continuous Professional Education; Moscow Research Institute of Psychiatry — branch of the Serbsky National Medical Research Centre for Psychiatry and NarcologyRussian Federation202518122025134382393Copyright © Кирова А.Г., Беллевич Ю.С., Сосин Д.Н., Мосолов С.Н., Сычев Д.А., 20252025Кирова А.Г., Беллевич Ю.С., Сосин Д.Н., Мосолов С.Н., Сычев Д.А.Kirova A.G., Bellevich Y.S., Sosin D.N., Mosolov S.N., Sychev D.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.risksafety.ru/jour/article/view/517ВВЕДЕНИЕ

ВВЕДЕНИЕ. Клозапин эффективен при лечении пациентов с терапевтической резистентностью при шизо­френии, но его применение может сопровождаться развитием нежелательных реакций, в частности клозапин-индуцированной сиалореей (КИС). Данные о механизме развития КИС ограниченны. Выделение фармакогенетических предикторов КИС позволит оценить вероятность возникновения осложнений до назначения терапии, а также уточнить отдельные звенья патогенетического механизма данной нежелательной реакции.

ЦЕЛЬ

ЦЕЛЬ. Выявление фармакогенетических предикторов клозапин-индуцированной сиалореи при помощи систематического анализа данных литературы.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Поиск исследований проводили независимо два соавтора по базам PubMed, Google Scholar, GeneCads, PharmGKB. В общей сложности было найдено 6 исследований, в которых рассматривалось 17 генов-кандидатов. Ассоциация с КИС была выявлена для генов ADRA2A, DRD4. Полиморфизм rs1800544 гена ADRA2A регулирует экспрессию адренорецептора альфа 2А типа (ADRA2A). При этом α2-адренорецепторы участвуют в регуляции секреции слюны, а антагонистическое действие клозапина на них приводит к возникновению КИС. Носительство полиморфизма 120-bp DRD4 приводит к снижению уровня экспрессии дофаминового рецептора 4-го типа (DRD4). Это, в свою очередь, может вызвать развитие КИС за счет повышения степени блокады рецептора клозапином. Однако полученные данные противоречат результатам ряда других исследований. Возможным объяснением данного несоответствия является анализ различных полиморфизмов в указанных работах. Кроме того, проанализированные исследования имели ряд методологических ограничений.

ВЫВОДЫ

ВЫВОДЫ. Проведенный систематический обзор литературы позволил определить фармакогенетические предикторы КИС. Но для уточнения полученных ассоциаций и разработки фармакогенетической панели с высокой прогностической точностью в отношении КИС необходимо проведение крупных мультицентровых исследований, использующих строгий проспективный дизайн с учетом выявленных ограничений.

INTRODUCTION

INTRODUCTION. Despite the proven clozapine effectiveness in patients with treatment-resistant schizophrenia, its use can cause adverse drug reactions, including clozapine-induced sialorrhea (CIS). Data on CIS pathogenesis are limited. Identifying CIS pharmacogenetic predictors will make it possible to both predict adverse drug reactions prior to therapy and specify individual pathogenetic elements.

AIM

AIM. This review aimed to identify CIS predictors using systematic analysis of literature data.

DISCUSSION

DISCUSSION. Research was conducted independently by two co-authors using PubMed, Google Scholar, GeneCads, and PharmGKB databases. A total of six (6) studies were selected that examined 17 candidate genes. The ADRA2A and DRD4 genes were associated with CIS. Polymorphism rs1800544 of ADRA2A gene regulates the expression of alpha-2A adrenoreceptor (ADRA2A). Alpha-2-adrenoreceptors regulate salivation, thus clozapine antagonistic effect causes CIS. Polymorphism of 120-bp DRD4 will reduce expression of type 4 dopamine receptor (DRD4). In turn, this may result in CIS as clozapine increases the receptor blockade. However, the results contradicted other studies, presumably due to assessment of different polymorphisms in the above studies. Moreover, the analysed studies had a number of methodological limitations.

CONCLUSIONS

CONCLUSIONS. The performed systematic review made it possible to identify CIS pharmacogenetic predictors. However, large multicenter studies using a strong prospective design and considering these limitations are required in order to develop a pharmacogenetic panel with high predictive accuracy for CIS.

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The authors declare that there are no conflicts of interest present.