psychiatryПСИХИАТРИЯPsychiatry (Moscow) (Psikhiatriya)1683-83192618-6667FSBSI “The Mental Health Research Centre”; LLC «Publisher «MIA»10.30629/2618-6667-2024-22-5-75-86psychiatry-1251Research ArticleНАУЧНЫЕ ОБЗОРЫSCIENTIFIC REVIEWSПерсонализированный подход к прогнозированию и профилактике клозапин-индуцированного удлинения интервала QTPersonalized Approach to Prediction and Prevention Clozapine-Induced QT Prolongationhttps://orcid.org/0000-0003-1874-9434НасыроваР. Ф.NasyrovaR. F.

Регина Фаритовна Насырова, доктор медицинских наук, невролог, психиатр, клинический фармаколог, главный научный сотрудник, научный руководитель; профессор

Санкт-Петербург

Тула

Regina F. Nasyrova, Dr. Sci. (Med.), neurologist, psychiatrist, clinical pharmacologist, Сhief Researcher, Scientific Director; Professor, Department of Psychiatry, General and Clinical Psychology

St. Petersburg

Tula

regina_nmrcpn@mail.ruhttps://orcid.org/0009-0006-8999-9296КидяеваА. В.KidyaevaA. V.

Алла Викторовна Кидяева, младший научный сотрудник; заведующая психиатрическим отделением

Санкт-Петербург

Alla V. Kidyaeva, Junior Researcher; Head of the Psychiatric Unit

St. Petersburg

alla.kid@mail.ruhttps://orcid.org/0000-0001-8279-4198ГречкинаВ. В.GrechkinaV. V.

Виолетта Владимировна Гречкина, младший научный сотрудник; врач-стажер

Санкт-Петербург

Violetta V. Grechkina, Junior Researcher; trainee physician

St. Petersburg

grechkina.vv@mail.ruhttps://orcid.org/0000-0002-8493-0058ПетроваМ. М.PetrovaM. M.

Марина Михайловна Петрова, доктор медицинских наук, профессор, заведующая кафедрой поликлинической терапии и семейной медицины с курсом последипломного образования

Красноярск

Мarina М. Petrova, Dr. Sci. (Med.), Professor, Head of Department, Department of outpatient therapy and general practice with a PE-course

Krasnoyarsk

Stk99@yandex.ruhttps://orcid.org/0000-0002-2840-837XШнайдерН. А.ShnayderN. A.

Наталья Алексеевна Шнайдер, доктор медицинских наук, профессор, главный научный сотрудник; ведущий научный сотрудник

Санкт-Петербург

Красноярск

Natalia A. Shnayder, Dr. Sci. (Med.), Professor, Chief Researcher; Leading Researcher

St. Petersburg

Krasnoyarsk

naschnaider@yandex.ruИнститут персонализированной психиатрии и неврологии, Центр общего пользования, Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева Министерства здравоохранения Российской Федерации; СПб ГКУЗ «Психиатрическая больница Святого Николая Чудотворца»; Кафедра психиатрии, общей и клинической психологии, Тульский государственный университетРоссияV.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Institute of Personalized Psychiatry and Neurology, Shared Use Center; St. Petersburg State Psychiatric Hospital of Nicholas the Wonderworker; Department of Psychiatry, General and Clinical Psychology, Tula State UniversityRussian FederationИнститут персонализированной психиатрии и неврологии, Центр общего пользования, Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева Министерства здравоохранения Российской Федерации; СПб ГКУЗ «Психиатрическая больница Святого Николая Чудотворца»РоссияV.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Institute of Personalized Psychiatry and Neurology, Shared Use Center; St. Petersburg State Psychiatric Hospital of Nicholas the WonderworkerRussian FederationИнститут персонализированной психиатрии и неврологии, Центр общего пользования, Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева Министерства здравоохранения Российской Федерации; Городской эпилептологический центр, СПб ГКУЗ Городская психиатрическая больница № 6РоссияV.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Institute of Personalized Psychiatry and Neurology, Shared Use Center; City Epileptology Centre, St. Petersburg State Clinical Institution, Municipal Psychiatric Hospital No. 6Russian FederationКрасноярский государственный медицинский университет им. проф. В.Ф. Войно-Ясенецкого, Центр коллективного пользования «Молекулярные и клеточные технологии»РоссияV.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Shared Use Center “Molecular and Cellular Technologies”Russian FederationИнститут персонализированной психиатрии и неврологии, Центр общего пользования, Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева Министерства здравоохранения Российской Федерации; Красноярский государственный медицинский университет им. проф. В.Ф. Войно-Ясенецкого, Центр коллективного пользования «Молекулярные и клеточные технологии»РоссияV.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Institute of Personalized Psychiatry and Neurology, Shared Use Center; V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Shared Use Center “Molecular and Cellular Technologies”Russian Federation2024090120252257586Copyright © Насырова Р.Ф., Кидяева А.В., Гречкина В.В., Петрова М.М., Шнайдер Н.А., 20252025Насырова Р.Ф., Кидяева А.В., Гречкина В.В., Петрова М.М., Шнайдер Н.А.Nasyrova R.F., Kidyaeva A.V., Grechkina V.V., Petrova M.M., Shnayder N.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.journalpsychiatry.com/jour/article/view/1251

Обоснование: антипсихотики широко используются в психиатрии. Клозапин остается незаменимым антипсихотиком в силу своей эффективности. Однако он обладает достаточно широким спектром нежелательных эффектов, в том числе повышает риск развития удлинения интервала QT — потенциально фатального осложнения, которое может привести к развитию пируэтной желудочковой тахикардии Тorsade de Рointes (TdP) и внезапной сердечной смерти. Цель: систематизировать информацию для практикующих психиатров о персонализированном подходе к профилактике удлинения интервала QT у пациентов с психическими расстройствами при приеме клозапина. Методы: поиск полнотекстовых статей, опубликованных с 01.02.2014 по 01.02.2024, проведен в PubMed, eLIBRARY.RU, Google Scholar. Результаты: в обзоре проанализированы и обобщены результаты исследований, посвященных влиянию клозапина на интервал QT, роли факторов риска и наследственной предрасположенности в развитии клозапин-индуцированного удлинения интервала QT и тахикардии Тorsade de Рointes у пациентов с психическими расстройствами. Основной механизм кардиотоксического действия клозапина заключается в дозозависимом ингибировании калиевых каналов мембраны кардиомиоцитов. Клозапин активно метаболизируется в печени, что может вызывать значительную индивидуальную вариабельность его фармакокинетики. Снижение скорости метаболизма клозапина может привести к росту его концентрации в крови и тем самым повысить риск развития кардиотоксических эффектов. Для снижения риска развития клозапин-индуцированного удлинения интервала QT целесообразно использовать предиктивное фармакогенетическое тестирование. Заключение: обобщенные данные о влиянии клозапина на длительность интервала QT, риск развития TdP у пациентов с психическими расстройствами могут быть востребованы психиатрами при подборе дозы и длительности приема клозапина. Предиктивное фармакогенетическое тестирование может способствовать снижению вероятности возникновения потенциально фатальных желудочковых нарушений ритма.

Background: antipsychotics are widely used in psychiatry. Clozapine remains an indispensable antipsychotic due to its effectiveness. However, it has a wide range of undesirable effect, including an increased risk of QT prolongation, a potentially fatal complication that can lead to Torsade de Pointes (TdP) and sudden cardiac death. Objective: to systematize information for practicing psychiatrists about a personalized approach to the prevention of QT interval prolongation in patients with mental disorders when taking clozapine. Methods: a search for full-text articles published from 02/01/2014 to 02/01/2024 was carried out in PubMed, eLIBRARY.RU, Google Scholar. Results: this review analyzed and summarized the results of studies on the effect of clozapine on the QT interval, the role of risk factors and hereditary predisposition in the development of clozapine-induced prolongation of the QT interval and Torsade de Pointes in patients with mental disorders. The main mechanism of clozapine’s cardiotoxic effect is dose-dependent inhibition of potassium channels in the cardiomyocyte membrane. Clozapine is extensively metabolized in the liver, which may cause significant interindividual variability in its pharmacokinetics. A decrease in the rate of metabolism of clozapine may lead to an increase in its concentration in the blood, and thereby increase the risk of developing cardiotoxic adverse reactions. To reduce the risk of clozapine-induced QT prolongation, it is advisable to use predictive pharmacogenetic testing. Conclusion: Generalized data on the effect of clozapine on the duration of the QT interval and the risk of developing TdP in patients with mental disorders may be needed by psychiatrists when selecting the dose and duration of clozapine. Predictive pharmacogenetic testing can help reduce the incidence of potentially fatal ventricular arrhythmias.

антипсихотикклозапинудлинение интервала QTкардиотоксичностьфармакогенетическое тестированиеизоферменты цитохрома Р450метаболизмпсихическое расстройствоantipsychoticclozapineprolongation of the QT intervalcardiotoxicitypharmacogenetic testingcytochrome P450 isoenzymesmetabolismmental disorderReferencesKhasanova AK. Pharmacogenetic factors of clozapine-induced metabolic syndrome. Personalized Psychiatry and Neurology. 2023;3(2):38-47. doi: 10.52667/2712-9179-2023-3-2-38-47Khasanova AK. Pharmacogenetic factors of clozapine-induced metabolic syndrome. Personalized Psychiatry and Neurology. 2023;3(2):38-47. doi: 10.52667/2712-9179-2023-3-2-38-47Gorobets LN, Semenova ND, Litvinov AV. Application of antipsychotic medication: gender differences in tolerance and medication response. Personalized Psychiatry and Neurology. 2022;2(2):57-66. doi: 10.52667/2712-9179-2022-2-2-57-66Gorobets LN, Semenova ND, Litvinov AV. Application of antipsychotic medication: gender differences in tolerance and medication response. Personalized Psychiatry and Neurology. 2022;2(2):57-66. doi: 10.52667/2712-9179-2022-2-2-57-66Lambiase PD, de Bono JP, Schilling RJ, Lowe M, Turley A, Slade A, Collinson J, Rajappan K, Harris S, Collison J, Carpenter V, Daw H, Hall A, Roberts E, Holding S, Paisey J, Sopher M, Wright I, Wiles B, Murgatroyd F, Taylor D. British heart rhythm society clinical practice guidelines on the management of patients developing QT prolongation on antipsychotic medication. Arrhythm Electrophysiol Rev. 2019;8(3):161-165. doi: 10.15420/aer.2019.8.3.G1Lambiase PD, de Bono JP, Schilling RJ, Lowe M, Turley A, Slade A, Collinson J, Rajappan K, Harris S, Collison J, Carpenter V, Daw H, Hall A, Roberts E, Holding S, Paisey J, Sopher M, Wright I, Wiles B, Murgatroyd F, Taylor D. British heart rhythm society clinical practice guidelines on the management of patients developing QT prolongation on antipsychotic medication. Arrhythm Electrophysiol Rev. 2019;8(3):161-165. doi: 10.15420/aer.2019.8.3.G1Wunderink L. Personalizing antipsychotic treatment: evidence and thoughts on individualized tailoring of antipsychotic dosage in the treatment of psychotic disorders. Ther Adv Psychopharmacol. 2019;9:2045125319836566. doi: 10.1177/2045125319836566Wunderink L. Personalizing antipsychotic treatment: evidence and thoughts on individualized tailoring of antipsychotic dosage in the treatment of psychotic disorders. Ther Adv Psychopharmacol. 2019;9:2045125319836566. doi: 10.1177/2045125319836566Vaiman EE, Linova LP. Antipsychotic-induced parkinsonism and dyskinesia in a 43-years old male with schizophrenia: clinical case. Personalized Psychiatry and Neurology. 2023;3(1):48-52. doi: 10.52667/2712-9179-2023-3-1-48-52Vaiman EE, Linova LP. Antipsychotic-induced parkinsonism and dyskinesia in a 43-years old male with schizophrenia: clinical case. Personalized Psychiatry and Neurology. 2023;3(1):48-52. doi: 10.52667/2712-9179-2023-3-1-48-52Kaar SJ, Natesan S, McCutcheon R, Howes OD. Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology. 2020;172:107704. doi: 10.1016/j.neuropharm.2019.107704Kaar SJ, Natesan S, McCutcheon R, Howes OD. Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology. 2020;172:107704. doi: 10.1016/j.neuropharm.2019.107704Остроумова ОД, Голобородова ИВ. Лекарственно-индуцированное удлинение интервала QT: распространенность, факторы риска, лечение и профилактика. Consilium Medicum. 2019;21(5):62-67. doi: 10.26442/20751753.2019.5.190415.Ostroumova OD, Goloborodova IV. Drug-induced long QT interval: prevalence, risk factors, treatment and prevention. Consilium Medicum. 2019;21(5):62-67. (In Russ.). doi: 10.26442/20751753.2019.5.190415.Friedrich ME, Winkler D, Konstantinidis A, Huf W, Engel R, Toto S, Grohmann R, Kasper S. Cardiovascular adverse reactions during antipsychotic treatment: results of AMSP, a drug surveillance program between 1993 and 2013. Int J Neuropsychopharmacol. 2020;23(2):67-75. doi: 10.1093/ijnp/pyz046Friedrich ME, Winkler D, Konstantinidis A, Huf W, Engel R, Toto S, Grohmann R, Kasper S. Cardiovascular adverse reactions during antipsychotic treatment: results of AMSP, a drug surveillance program between 1993 and 2013. Int J Neuropsychopharmacol. 2020;23(2):67-75. doi: 10.1093/ijnp/pyz046Shnayder NA, Kidyaeva AV, Vaiman EE, Asadullin AR, Petrova MM, Kaskaeva DS, Matyushin GV, Evsyukov AA, Galko EV, Garganeeva NP, Chumakova GA, Lareva NV, Neznanov NG, Nasyrova RF. Role of pharmacokinetics and pharmacogenetics of antidepressant-induced prolongation of the QT interval and Torsade de Pointes in patients with mental disorders. Personalized Psychiatry and Neurology. 2023;3(2):72-119. doi: 10.52667/2712-9179-2023-3-2-72-119Shnayder NA, Kidyaeva AV, Vaiman EE, Asadullin AR, Petrova MM, Kaskaeva DS, Matyushin GV, Evsyukov AA, Galko EV, Garganeeva NP, Chumakova GA, Lareva NV, Neznanov NG, Nasyrova RF. Role of pharmacokinetics and pharmacogenetics of antidepressant-induced prolongation of the QT interval and Torsade de Pointes in patients with mental disorders. Personalized Psychiatry and Neurology. 2023;3(2):72-119. doi: 10.52667/2712-9179-2023-3-2-72-119Nasyrova RF, Shnayder NA, Osipova SM, Khasanova AK, Efremov IS, Al-Zamil M, Petrova MM, Narodova EA, Garganeeva NP, Shipulin GA. Genetic predictors of antipsychotic efflux impairment via blood-brain barrier: role of transport proteins. Genes. 2023;14(5):1085. doi: 10.3390/genes14051085Nasyrova RF, Shnayder NA, Osipova SM, Khasanova AK, Efremov IS, Al-Zamil M, Petrova MM, Narodova EA, Garganeeva NP, Shipulin GA. Genetic predictors of antipsychotic efflux impairment via blood-brain barrier: role of transport proteins. Genes. 2023;14(5):1085. doi: 10.3390/genes14051085Клиническая психофармакогенетика / под ред. Р.Ф. Насыровой, Н.Г. Незнанова. СПб.: Издательство ДЕАН, 2019. 405 с.Clinical psychopharmacogenetics, ed. R.F. Nasyrova, N.G. Neznanova. SPb.: DEAN Publishing House, 2019. 405 p. (In Russ.). ISBN 978-5-6043573-7-8.Zhuravlev NM, Otmachov AP, Bartasinskaya AE. Clinical case of a 36-year-old patient with paranoid schizophrenia and drug-induced QT prolongation. Personalized Psychiatry and Neurology. 2022;2(2):78-83. doi: 10.52667/2712-9179-2022-2-2-78-833Zhuravlev NM, Otmachov AP, Bartasinskaya AE. Clinical case of a 36-year-old patient with paranoid schizophrenia and drug-induced QT prolongation. Personalized Psychiatry and Neurology. 2022;2(2):78-83. doi: 10.52667/2712-9179-2022-2-2-78-833Клинические рекомендации «Желудочковые нарушения ритма. Желудочковые тахикардии и внезапная сердечная смерть». Министерство здравоохранения Российской Федерации, 2020.Clinical recommendations “Ventricular arrhythmias. Ventricular tachycardia and sudden cardiac death”. Ministry of Health of the Russian Federation, 2020. (Accessed on February 4, 2024). Available from: https://cr.minzdrav.gov.ru/schema/569_1#doc_a2.Khatib R, Sabir FRN, Omari C, Pepper C, Tayebjee MH. Managing drug-induced QT prolongation in clinical practice. Postgrad Med J. 2021;97(1149):452-458. doi: 10.1136/postgradmedj-2020-138661Khatib R, Sabir FRN, Omari C, Pepper C, Tayebjee MH. Managing drug-induced QT prolongation in clinical practice. Postgrad Med J. 2021;97(1149):452-458. doi: 10.1136/postgradmedj-2020-138661Rochester MP, Kane AM, Linnebur SA, Fixen DR. Evaluating the risk of QTc prolongation associated with antidepressant use in older adults: a review of the evidence. Ther Adv Drug Saf. 2018;9(6):297-308. doi: 10.1177/2042098618772979Rochester MP, Kane AM, Linnebur SA, Fixen DR. Evaluating the risk of QTc prolongation associated with antidepressant use in older adults: a review of the evidence. Ther Adv Drug Saf. 2018;9(6):297-308. doi: 10.1177/2042098618772979Salvati B, Miola A, Toffanin T, Pigato G, Pavan C, Favaro A, Sambataro F, Solmi M. Prevalence and risk factors for QTc prolongation in acute psychiatric hospitalization. Prim Care Companion CNS Disord. 2022; 24(1):21m02915. doi: 10.4088/PCC.21m02915Salvati B, Miola A, Toffanin T, Pigato G, Pavan C, Favaro A, Sambataro F, Solmi M. Prevalence and risk factors for QTc prolongation in acute psychiatric hospitalization. Prim Care Companion CNS Disord. 2022; 24(1):21m02915. doi: 10.4088/PCC.21m02915Christensen L, Turner JR, Peterson GM, Naunton M, Thomas J, Yee KC, Kosari S. Identification of risk of QT prolongation by pharmacists when conducting medication reviews in residential aged care settings: a missed opportunity? J Clin Med. 2019;8(11):1866. doi: 10.3390/jcm8111866Christensen L, Turner JR, Peterson GM, Naunton M, Thomas J, Yee KC, Kosari S. Identification of risk of QT prolongation by pharmacists when conducting medication reviews in residential aged care settings: a missed opportunity? J Clin Med. 2019;8(11):1866. doi: 10.3390/jcm8111866Danielsson B, Collin J, Nyman A, Bergendal A, Borg N, State M, Bergfeldt L, Fastbom J. Drug use and torsades de pointes cardiac arrhythmias in Sweden: a nationwide register-based cohort study. BMJ Open. 2020;10(3):e034560. doi: 10.1136/bmjopen-2019-034560Danielsson B, Collin J, Nyman A, Bergendal A, Borg N, State M, Bergfeldt L, Fastbom J. Drug use and torsades de pointes cardiac arrhythmias in Sweden: a nationwide register-based cohort study. BMJ Open. 2020;10(3):e034560. doi: 10.1136/bmjopen-2019-034560Salem JE, Dureau P, Bachelot A, Germain M, Voiriot P, Lebourgeois B, Trégouët DA, Hulot JS, Funck-Brentano C. Association of oral contraceptives with drug-induced QT interval prolongation in healthy nonmenopausal women. JAMA Cardiol. 2018;3(9):877-882. doi: 10.1001/jamacardio.2018.2251Salem JE, Dureau P, Bachelot A, Germain M, Voiriot P, Lebourgeois B, Trégouët DA, Hulot JS, Funck-Brentano C. Association of oral contraceptives with drug-induced QT interval prolongation in healthy nonmenopausal women. JAMA Cardiol. 2018;3(9):877-882. doi: 10.1001/jamacardio.2018.2251Li M, Ramos LG. Drug-induced QT prolongation and Torsades de Pointes. P T. 2017; 42(7):473-477. PMID: 28674475Li M, Ramos LG. Drug-induced QT prolongation and Torsades de Pointes. P T. 2017; 42(7):473-477. PMID: 28674475de Leon J, Schoretsanitis G, Smith RL, Molden E, Solismaa A, Seppälä N, Kopeček M, Švancer P, Olmos I, Ricciardi C, Iglesias-Garcia C, Iglesias-Alonso A, Spina E, Ruan CJ, Wang CY, Wang G, Tang YL, Lin SK, Lane HY, Kim YS, Kim SH, Rajkumar AP, González-Esquivel DF, Jung-Cook H, Baptista T, Rohde C, Nielsen J, Verdoux H, Quiles C, Sanz EJ, De Las Cuevas C, Cohen D, Schulte PFJ, Ertuğrul A, Anıl Yağcıoğlu AE, Chopra N, McCollum B, Shelton C, Cotes RO, Kaithi AR, Kane JM, Farooq S, Ng CH, Bilbily J, Hiemke C, López-Jaramillo C, McGrane I, Lana F, Eap CB, Arrojo-Romero M, Rădulescu FŞ, Seifritz E, Every-Palmer S, Bousman CA, Bebawi E, Bhattacharya R, Kelly DL, Otsuka Y, Lazary J, Torres R, Yecora A, Motuca M, Chan SKW, Zolezzi M, Ouanes S, De Berardis D, Grover S, Procyshyn RM, Adebayo RA, Kirilochev OO, Soloviev A, Fountoulakis KN, Wilkowska A, Cubała WJ, Ayub M, Silva A, Bonelli RM, Villagrán-Moreno JM, Crespo-Facorro B, Temmingh H, Decloedt E, Pedro MR, Takeuchi H, Tsukahara M, Gründer G, Sagud M, Celofiga A, Ignjatovic Ristic D, Ortiz BB, Elkis H, Pacheco Palha AJ, LLerena A, Fernandez-Egea E, Siskind D, Weizman A, Masmoudi R, Mohd Saffian S, Leung JG, Buckley PF, Marder SR, Citrome L, Freudenreich O, Correll CU, Müller DJ. An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry. 2022;55(2):73-86. doi: 10.1055/a-1625-6388de Leon J, Schoretsanitis G, Smith RL, Molden E, Solismaa A, Seppälä N, Kopeček M, Švancer P, Olmos I, Ricciardi C, Iglesias-Garcia C, Iglesias-Alonso A, Spina E, Ruan CJ, Wang CY, Wang G, Tang YL, Lin SK, Lane HY, Kim YS, Kim SH, Rajkumar AP, González-Esquivel DF, Jung-Cook H, Baptista T, Rohde C, Nielsen J, Verdoux H, Quiles C, Sanz EJ, De Las Cuevas C, Cohen D, Schulte PFJ, Ertuğrul A, Anıl Yağcıoğlu AE, Chopra N, McCollum B, Shelton C, Cotes RO, Kaithi AR, Kane JM, Farooq S, Ng CH, Bilbily J, Hiemke C, López-Jaramillo C, McGrane I, Lana F, Eap CB, Arrojo-Romero M, Rădulescu FŞ, Seifritz E, Every-Palmer S, Bousman CA, Bebawi E, Bhattacharya R, Kelly DL, Otsuka Y, Lazary J, Torres R, Yecora A, Motuca M, Chan SKW, Zolezzi M, Ouanes S, De Berardis D, Grover S, Procyshyn RM, Adebayo RA, Kirilochev OO, Soloviev A, Fountoulakis KN, Wilkowska A, Cubała WJ, Ayub M, Silva A, Bonelli RM, Villagrán-Moreno JM, Crespo-Facorro B, Temmingh H, Decloedt E, Pedro MR, Takeuchi H, Tsukahara M, Gründer G, Sagud M, Celofiga A, Ignjatovic Ristic D, Ortiz BB, Elkis H, Pacheco Palha AJ, LLerena A, Fernandez-Egea E, Siskind D, Weizman A, Masmoudi R, Mohd Saffian S, Leung JG, Buckley PF, Marder SR, Citrome L, Freudenreich O, Correll CU, Müller DJ. An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry. 2022;55(2):73-86. doi: 10.1055/a-1625-6388Yin J, Barr AM, Ramos-Miguel A, Procyshyn RM. Antipsychotic induced dopamine supersensitivity psychosis: a comprehensive review. Curr Neuropharmacol. 2017;15(1):174-183. doi: 10.2174/1570159x14666160606093602Yin J, Barr AM, Ramos-Miguel A, Procyshyn RM. Antipsychotic induced dopamine supersensitivity psychosis: a comprehensive review. Curr Neuropharmacol. 2017;15(1):174-183. doi: 10.2174/1570159x14666160606093602Adetiloye AO, Abdelmottaleb W, Ahmed MF, Victoria AM, Ozbay MB, Valencia Manrique JC, Alaameri R, Badero O, Mushiyev S. Clozapine-induced myocarditis in a young man with refractory schizophrenia: case report of a rare adverse event and review of the literature. Am J Case Rep. 2022; 23:e936306. doi: 10.12659/AJCR.936306Adetiloye AO, Abdelmottaleb W, Ahmed MF, Victoria AM, Ozbay MB, Valencia Manrique JC, Alaameri R, Badero O, Mushiyev S. Clozapine-induced myocarditis in a young man with refractory schizophrenia: case report of a rare adverse event and review of the literature. Am J Case Rep. 2022; 23:e936306. doi: 10.12659/AJCR.936306Mijovic A, MacCabe JH. Clozapine-induced agranulocytosis. Ann Hematol. 2020;99(11):2477-2482. doi: 10.1007/s00277-020-04215-yMijovic A, MacCabe JH. Clozapine-induced agranulocytosis. Ann Hematol. 2020;99(11):2477-2482. doi: 10.1007/s00277-020-04215-yKhokhar JY, Henricks AM, Sullivan EDK, Green AI. Unique effects of clozapine: a pharmacological perspective. Adv Pharmacol. 2018;82:137-162. doi: 10.1016/bs.apha.2017.09.009Khokhar JY, Henricks AM, Sullivan EDK, Green AI. Unique effects of clozapine: a pharmacological perspective. Adv Pharmacol. 2018;82:137-162. doi: 10.1016/bs.apha.2017.09.009Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789-796. doi: 10.1001/archpsyc.1988.01800330013001Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789-796. doi: 10.1001/archpsyc.1988.01800330013001Keepers GA, Fochtmann LJ, Anzia JM, Benjamin S, Lyness JM, Mojtabai R, Servis M, Walaszek A, Buckley P, Lenzenweger MF, Young AS, Degenhardt A, Hong SH. The American psychiatric association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868-872. doi: 10.1176/appi.ajp.2020.177901Keepers GA, Fochtmann LJ, Anzia JM, Benjamin S, Lyness JM, Mojtabai R, Servis M, Walaszek A, Buckley P, Lenzenweger MF, Young AS, Degenhardt A, Hong SH. The American psychiatric association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868-872. doi: 10.1176/appi.ajp.2020.177901Государственный регистр лекарственных средств. Клозапин [State register of medicines. Clozapine]. (Accessed on March 1, 2024). Available from: https://grls.rosminzdrav.ru/grls.aspx?s=%D0%BA%D0%BB%D0%BE%D0%B7%D0%B0%D0%BF%D0%B8%D0%BD&m=INNГосударственный регистр лекарственных средств. Клозапин [State register of medicines. Clozapine]. (Accessed on March 1, 2024). Available from: https:// grls.rosminzdrav.ru/grls.aspx?s=%D0%BA%D0%BB%D0%BE%D0%B7%D0%B0%D0%BF%D0%B8%D0%BD&m=INNYuen JWY, Kim DD, Procyshyn RM, Panenka WJ, Honer WG, Barr AM. A focused review of the metabolic side-effects of clozapine. Front Endocrinol (Lausanne). 2021;12:609240. doi: 10.3389/fendo.2021.609240Yuen JWY, Kim DD, Procyshyn RM, Panenka WJ, Honer WG, Barr AM. A focused review of the metabolic side-effects of clozapine. Front Endocrinol (Lausanne). 2021;12:609240. doi: 10.3389/fendo.2021.609240Beach SR, Celano CM, Sugrue AM, Adams C, Ackerman MJ, Noseworthy PA, Huffman JC. QT prolongation, Torsades de Pointes, and psychotropic medications: a 5-year update. Psychosomatics. 2018; 59(2):105-122. doi: 10.1016/j.psym.2017.10.009Beach SR, Celano CM, Sugrue AM, Adams C, Ackerman MJ, Noseworthy PA, Huffman JC. QT prolongation, Torsades de Pointes, and psychotropic medications: a 5-year update. Psychosomatics. 2018; 59(2):105-122. doi: 10.1016/j.psym.2017.10.009Xiang YT, Chiu HF, Ungvari GS, Correll CU, Lai KY, Wang CY, Si TM, Lee EH, He YL, Yang SY, Chong MY, Kua EH, Fujii S, Sim K, Yong MK, Trivedi JK, Chung EK, Udomratn P, Chee KY, Sartorius N, Tan CH, Shinfuku N. QTc prolongation in schizophrenia patients in Asia: clinical correlates and trends between 2004 and 2008/2009. Hum Psychopharmacol. 2015;30(2):94-99. doi: 10.1002/hup.2458Xiang YT, Chiu HF, Ungvari GS, Correll CU, Lai KY, Wang CY, Si TM, Lee EH, He YL, Yang SY, Chong MY, Kua EH, Fujii S, Sim K, Yong MK, Trivedi JK, Chung EK, Udomratn P, Chee KY, Sartorius N, Tan CH, Shinfuku N. QTc prolongation in schizophrenia patients in Asia: clinical correlates and trends between 2004 and 2008/2009. Hum Psychopharmacol. 2015;30(2):94-99. doi: 10.1002/hup.2458Raschi E, Poluzzi E, Salvo F, Koci A, Suling M, Antoniazzi S, Perina L, Hazell L, Moretti U, Sturkenboom M, Garbe E, Pariente A, De Ponti F. The contribution of national spontaneous reporting systems to detect signals of torsadogenicity: issues emerging from the ARITMO project. Drug Saf. 2016;39(1):59-68. doi: 10.1007/s40264-015-0353-1Raschi E, Poluzzi E, Salvo F, Koci A, Suling M, Antoniazzi S, Perina L, Hazell L, Moretti U, Sturkenboom M, Garbe E, Pariente A, De Ponti F. The contribution of national spontaneous reporting systems to detect signals of torsadogenicity: issues emerging from the ARITMO project. Drug Saf. 2016;39(1):59-68. doi: 10.1007/s40264-015-0353-1CredibleMeds [Internet]. (Accessed February 18, 2024). Available from: www.CredibleMeds.orgCredibleMeds [Internet]. (Accessed February 18, 2024). Available from: www.CredibleMeds.orgSicouri S, Antzelevitch C. Mechanisms underlying the actions of antidepressant and antipsychotic drugs that cause sudden cardiac arrest. Arrhythm Electrophysiol Rev. 2018;7(3):199-209. doi: 10.15420/aer.2018.29.2Sicouri S, Antzelevitch C. Mechanisms underlying the actions of antidepressant and antipsychotic drugs that cause sudden cardiac arrest. Arrhythm Electrophysiol Rev. 2018;7(3):199-209. doi: 10.15420/aer.2018.29.2Волков ВП. Кардиотоксичность антипсихотических препаратов. Тверь: ООО «Издательство “Триада”», 2018. 622с.Volkov VP. Cardiotoxicity of antipsychotic drugs. Tver: Triada Publishing House LLC, 2018. 622 p. (In Russ.) ISBN 978-5-94789-855-2Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int. 2011; 108(41):687-693. doi: 10.3238/arztebl.2011.0687Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int. 2011; 108(41):687-693. doi: 10.3238/arztebl.2011.0687Kim K, Kim YS, Joo EJ, Kim EJ, Bhang SY, Choi JW, Jeong JH, Lee KY. Clozapine blood concentration predicts corrected QT-interval prolongation in patients with psychoses. J Clin Psychopharmacol. 2022;42(6):536-543. doi: 10.1097/JCP.0000000000001605Kim K, Kim YS, Joo EJ, Kim EJ, Bhang SY, Choi JW, Jeong JH, Lee KY. Clozapine blood concentration predicts corrected QT-interval prolongation in patients with psychoses. J Clin Psychopharmacol. 2022;42(6):536-543. doi: 10.1097/JCP.0000000000001605Olmos I, Ibarra M, Vázquez M, Maldonado C, Fagiolino P, Giachetto G. Population pharmacokinetics of clozapine and norclozapine and switchability assessment between brands in Uruguayan patients with schizophrenia. Biomed Res Int. 2019;2019:3163502. doi: 10.1155/2019/3163502Olmos I, Ibarra M, Vázquez M, Maldonado C, Fagiolino P, Giachetto G. Population pharmacokinetics of clozapine and norclozapine and switchability assessment between brands in Uruguayan patients with schizophrenia. Biomed Res Int. 2019;2019:3163502. doi: 10.1155/2019/3163502Clozapine. DrugBank [Internet]. (Accessed on February 20, 2024). Available from: https://go.drugbank.com/drugs/DB00363Clozapine. DrugBank [Internet]. (Accessed on February 20, 2024). Available from: https://go.drugbank.com/drugs/DB00363Thorn CF, Müller DJ, Altman RB, Klein TE. PharmGKB summary: clozapine pathway, pharmacokinetics. Pharmacogenet Genomics. 2018;28(9):214-222. doi: 10.1097/FPC.0000000000000347Thorn CF, Müller DJ, Altman RB, Klein TE. PharmGKB summary: clozapine pathway, pharmacokinetics. Pharmacogenet Genomics. 2018;28(9):214-222. doi: 10.1097/FPC.0000000000000347Akamine Y, Sugawara-Kikuchi Y, Uno T, Shimizu T, Miura M. Quantification of the steady-state plasma concentrations of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia using a novel HPLC method and the effects of CYPs and ABC transporters polymorphisms. Ann Clin Biochem. 2017;54(6):677-685. doi: 10.1177/0004563216686377Akamine Y, Sugawara-Kikuchi Y, Uno T, Shimizu T, Miura M. Quantification of the steady-state plasma concentrations of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia using a novel HPLC method and the effects of CYPs and ABC transporters polymorphisms. Ann Clin Biochem. 2017;54(6):677-685. doi: 10.1177/0004563216686377Okon-Rocha E, Ramudo-Cela L, Taylor D. Genetic analysis of clozapine metabolism in a patient with subtherapeutic clozapine plasma concentrations-the importance of CYP3A5: a case report. J Clin Psychopharmacol. 2022;42(6):604-606. doi: 10.1097/JCP.0000000000001615Okon-Rocha E, Ramudo-Cela L, Taylor D. Genetic analysis of clozapine metabolism in a patient with subtherapeutic clozapine plasma concentrations-the importance of CYP3A5: a case report. J Clin Psychopharmacol. 2022;42(6):604-606. doi: 10.1097/JCP.0000000000001615Molins C, Carceller-Sindreu M, Navarro H, Carmona C, Piñeiro M, Martínez E, Álvarez E, Portella MJ. Plasma ratio of clozapine to N-desmethylclozapine can predict cognitive performance in treatment-resistant psychotic patients. Psychiatry Res. 2017;258:153-157. doi: 10.1016/j.psychres.2017.10.010Molins C, Carceller-Sindreu M, Navarro H, Carmona C, Piñeiro M, Martínez E, Álvarez E, Portella MJ. Plasma ratio of clozapine to N-desmethylclozapine can predict cognitive performance in treatment-resistant psychotic patients. Psychiatry Res. 2017;258:153-157. doi: 10.1016/j.psychres.2017.10.010Piatkov I, Caetano D, Assur Y, Lau SL, Coelho M, Jones T, Nguyen T, Boyages S, McLean M. CYP2C19*17 protects against metabolic complications of clozapine treatment. World J Biol Psychiatry. 2017;18(7):521-527. doi: 10.1080/15622975.2017.1347712Piatkov I, Caetano D, Assur Y, Lau SL, Coelho M, Jones T, Nguyen T, Boyages S, McLean M. CYP2C19*17 protects against metabolic complications of clozapine treatment. World J Biol Psychiatry. 2017;18(7):521-527. doi: 10.1080/15622975.2017.1347712Azmanova M, Pitto-Barry A, Barry NPE. Schizophrenia: synthetic strategies and recent advances in drug design. Medchemcomm. 2018;9(5):759-782. doi: 10.1039/c7md00448fAzmanova M, Pitto-Barry A, Barry NPE. Schizophrenia: synthetic strategies and recent advances in drug design. Medchemcomm. 2018;9(5):759-782. doi: 10.1039/c7md00448fKhasanova AK, Nasyrova RF. Pharmacogenetic testing of cytochrome P450 system enzymes in the therapy of bipolar affective disorder. Personalized Psychiatry and Neurology. 2022;2(2):90-96. doi: 10.52667/2712-9179-2022-2-2-90-96Khasanova AK, Nasyrova RF. Pharmacogenetic testing of cytochrome P450 system enzymes in the therapy of bipolar affective disorder. Personalized Psychiatry and Neurology. 2022;2(2):90-96. doi: 10.52667/2712-9179-2022-2-2-90-96Meyer JM, Proctor G, Cummings MA, Dardashti LJ, Stahl SM. Ciprofloxacin and clozapine: a potentially fatal but underappreciated interaction. Case Rep Psychiatry. 2016;2016:5606098. doi: 10.1155/2016/5606098Meyer JM, Proctor G, Cummings MA, Dardashti LJ, Stahl SM. Ciprofloxacin and clozapine: a potentially fatal but underappreciated interaction. Case Rep Psychiatry. 2016;2016:5606098. doi: 10.1155/2016/5606098Shah RR, Smith RL. Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. Drug Metab Dispos. 2015;43(3):400-410. doi: 10.1124/dmd.114.061093Shah RR, Smith RL. Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. Drug Metab Dispos. 2015;43(3):400-410. doi: 10.1124/dmd.114.061093Hassab Errasoul A, Alarabi MA. Factors predicting serum clozapine levels in Middle Eastern patients: an observational study. BMC Psychiatry. 2022;22(1):269. doi: 10.1186/s12888-022-03910-6Hassab Errasoul A, Alarabi MA. Factors predicting serum clozapine levels in Middle Eastern patients: an observational study. BMC Psychiatry. 2022;22(1):269. doi: 10.1186/s12888-022-03910-6Westin AA, Brekke M, Molden E, Skogvoll E, Castberg I, Spigset O. Treatment with antipsychotics in pregnancy: changes in drug disposition. Clin Pharmacol Ther. 2018; 103(3):477-484. doi: 10.1002/cpt.770Westin AA, Brekke M, Molden E, Skogvoll E, Castberg I, Spigset O. Treatment with antipsychotics in pregnancy: changes in drug disposition. Clin Pharmacol Ther. 2018; 103(3):477-484. doi: 10.1002/cpt.770Park HS, Kim E, Moon BS, Lim NH, Lee BC, Kim SE. In vivo tissue pharmacokinetics of carbon-11-labeled clozapine in healthy volunteers: a positron emission tomography study. CPT Pharmacometrics Syst Pharmacol. 2015;4(5):305-311. doi: 10.1002/psp4.38Park HS, Kim E, Moon BS, Lim NH, Lee BC, Kim SE. In vivo tissue pharmacokinetics of carbon-11-labeled clozapine in healthy volunteers: a positron emission tomography study. CPT Pharmacometrics Syst Pharmacol. 2015;4(5):305-311. doi: 10.1002/psp4.38Piatkov I, Caetano D, Assur Y, Lau SL, Jones T, Boyages SC, McLean M. ABCB1 and ABCC1 single-nucleotide polymorphisms in patients treated with clozapine. Pharmgenomics Pers Med. 2017;10:235-242. doi: 10.2147/PGPM.S142314Piatkov I, Caetano D, Assur Y, Lau SL, Jones T, Boyages SC, McLean M. ABCB1 and ABCC1 single-nucleotide polymorphisms in patients treated with clozapine. Pharmgenomics Pers Med. 2017;10:235-242. doi: 10.2147/PGPM.S142314Shnayder NA, Abdyrakhmanova AK, Nasyrova RF. Phase I of antipsychotics metabolism and its pharmacogenetic testing. Personalized Psychiatry and Neurology. 2022;2(1):4-21. doi: 10.52667/2712-9179-2022-2-1-4-21Shnayder NA, Abdyrakhmanova AK, Nasyrova RF. Phase I of antipsychotics metabolism and its pharmacogenetic testing. Personalized Psychiatry and Neurology. 2022;2(1):4-21. doi: 10.52667/2712-9179-2022-2-1-4-21Приказ № 1233н Минздрава РФ от 20 декабря 2012 года «Об утверждении стандарта специализированной медицинской помощи при шизофрении, острой (подострой) фазе, с резистентностью, интолерантностью к терапии».Order # 1233n of the Ministry of Health of the Russian Federation of December 20, 2012 “On approval of the standard of specialized medical care for schizophrenia, acute (subacute) phase, with resistance, intolerance to therapy”. (Accessed on March 1, 2024). Available from: https://base.garant.ru/70338502/.Shnayder NA, Abdyrakhmanova AK, Nasyrova RF. Oxidation of antipsychotics. Encyclopedia 2022;2:974-989. doi: 10.3390/encyclopedia2020064Shnayder NA, Abdyrakhmanova AK, Nasyrova RF. Oxidation of antipsychotics. Encyclopedia 2022;2:974-989. doi: 10.3390/encyclopedia2020064Shnayder NA, Grechkina VV, Khasanova AK, Bochanova EN, Dontceva EA, Petrova MM, Asadullin AR, Shipulin GA, Altynbekov KS, Al-Zamil M, Nasyrova RF. Therapeutic and toxic effects of valproic acid metabolites. Metabolites. 2023;13:134. doi: 10.3390/metabo13010134Shnayder NA, Grechkina VV, Khasanova AK, Bochanova EN, Dontceva EA, Petrova MM, Asadullin AR, Shipulin GA, Altynbekov KS, Al-Zamil M, Nasyrova RF. Therapeutic and toxic effects of valproic acid metabolites. Metabolites. 2023;13:134. doi: 10.3390/metabo13010134OMIM [Updated February 2, 2024] (Accessed on February 4, 2024). Available from: https://www.omim.org/.OMIM [Updated February 2, 2024] (Accessed on February 4, 2024). Available from: https://www.omim.org/.

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