clinvestКачественная клиническая практикаKachestvennaya Klinicheskaya Praktika = Good Clinical Practice2588-05192618-8473ООО «Издательство ОКИ10.37489/2588-0519-2021-2-78-88clinvest-577Research ArticleФАРМАКОГЕНЕТИКАPHARMACOGENETICSАнализ ассоциаций фармакодинамических генетических факторов с эффективностью и безопасностью антипсихотиков у подростков с острым психотическим эпизодом в течение 28 днейAnalysis of associations between pharmacodynamic genetic factors and antipsychotics’ effectiveness and safety in adolescents with acute psychotic episodes taking antipsychotics during a 28-day follow-uphttps://orcid.org/0000-0002-2295-7167ИващенкоД. В.IvaschenkoD. V.

Иващенко Дмитрий Владимирович, к. м. н., с. н. с. отдела персонализированной медицины НИИ молекулярной и персонализированной медицины. SPIN-код: 9435-7794

МоскваПенза

Ivashchenko Dmitriy V., Cand. Sci. (Med.), senior research fellow of the Department of personalized medicine of the research Institute of molecular and personalized medicine. SPIN code: 9435-7794

MoscowPenza

dvi1991@yandex.ruhttps://orcid.org/0000-0002-6417-9535ФединаЛ. В.FedinaL. V.

Федина Людмила Владимировна, ординатор кафедры клинической фармакологии и терапии

Москва

Fedina Lyudmila V., Resident, Department of Clinical Pharmacology and Therapy

Moscow

fedina201368@gmail.comhttps://orcid.org/0000-0003-0991-4960БуромскаяН. И.BuromskayaN. I.

Буромская Нина Ивановна, заведующий отделением №1

Москва

Buromskaya Nina I., Head of Department #1

Moscow

ogirra@mail.ruhttps://orcid.org/0000-0002-9050-4776ШимановП. В.ShimanovP. V.

Шиманов Павел Викторович, заведующий отделением №12

Москва

Shimanov Pavel V., Head of Department #12

Moscow

meroving83@mail.ruДейчР. В.DeitschR. V.

Дейч Роман Витальевич, зав. отделением №14

Москва

Deitch Roman V., Cand. Sci. (Med.), Head of Department #14

Moscow

rdeitch@yandex.ruhttps://orcid.org/0000-0002-7727-7839НастовичМ. И.NastovichM. I.

Настович Марина Игоревна, врач-психиатр

Москва

Nastovich Marina I., Psychiatrist

Moscow

marinka0505@mail.ruhttps://orcid.org/0000-0003-3505-8520АкмаловаК. А.AkmalovaK. A.

Акмалова Кристина Анатольевна, н. с. отдела молекулярной медицины НИИ Молекулярной и персонализированной медицины

Москва

Akmalova Kristina A., Research fellow, Department of Molecular medicine

Moscow

kriistinkaa@mail.ruhttps://orcid.org/0000-0003-3194-4410КачановаА. А.KachanovaA. A.

Качанова Анастасия Алексеевна, м. н. с. отдела молекулярной медицины НИИ Молекулярной и персонализированной медицины

Москва

Kachanova Anastasia A., Research fellow, Department of Molecular medicine

Moscow

aakachanova@yandex.ruhttps://orcid.org/0000-0002-5621-8266ГришинаЕ. А.GrishinaE. A.

Гришина Елена Анатольевна, д.б.н., доцент, директор НИИ Молекулярной и персонализированной медицины

Москва

Grishina Elena A., Dr. Sci. (Biol.), Head, Department of Molecular medicine

Moscow

gelana2010@yandex.ruhttps://orcid.org/0000-0002-2411-3494СавченкоЛ. М.SavchenkoL. M.

Савченко Людмила Михайловна, к. м. н., доцент, профессор кафедры наркологии

Москва

Savchenko Lyudmila M., Cand. Sci. (Med.)

Moscow

uch_sovet@rmanpo.ruhttps://orcid.org/0000-0001-7790-9595ШевченкоЮ. С.ShevchenkoY. S.

Шевченко Юрий Степанович, д. м. н., профессор, зав. кафедрой детской психиатрии и психотерапии

Москва

Shevchenko Yuriy S., Dr. Sci. (Med.), Professor

Moscow

shevchenko2010@mail.ruhttps://orcid.org/0000-0002-4496-3680СычёвД. А.SychevD. A.

Сычёв Дмитрий Алексеевич, д. м. н., профессор, член-корр. РАН, ректор, зав. кафедрой клинической фармакологии и терапии. SPIN-код: 4525-7556

Москва

Sychev Dmitry A., Dr. Sci. (Med.), Professor, Corresponding Member RAS, Rector, Head Department of Clinical Pharmacology and Therapy. SPIN code: 4525-7556

Moscow

dmitriy.alex.sychev@gmail.comФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения РФ; Пензенский институт усовершенствования врачей — филиал ФГБОУ ДПО РМАНПО Минздрава РоссииРоссияRussian Medical Academy of Continuous Professional Education; PIFTPh — Branch Campus of the FSBEI FPE «Russian Medical Academy of Continuous Professional Education» MOHRussian FederationФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения РФРоссияRussian Medical Academy of Continuous Professional EducationRussian FederationГБУЗ «Научно-практический центр психического здоровья детей и подростков им. Г. Е. Сухаревой» Департамента здравоохранения г. МосквыРоссияMoscow State Budgetary Health Care Institution «Scientific and Practical Center for Mental Health of Children and Adolescents named G.E. Sukhareva of Moscow Health Department»Russian Federation202112082021027888Copyright © Иващенко Д.В., Федина Л.В., Буромская Н.И., Шиманов П.В., Дейч Р.В., Настович М.И., Акмалова К.А., Качанова А.А., Гришина Е.А., Савченко Л.М., Шевченко Ю.С., Сычёв Д.А., 20212021Иващенко Д.В., Федина Л.В., Буромская Н.И., Шиманов П.В., Дейч Р.В., Настович М.И., Акмалова К.А., Качанова А.А., Гришина Е.А., Савченко Л.М., Шевченко Ю.С., Сычёв Д.А.Ivaschenko D.V., Fedina L.V., Buromskaya N.I., Shimanov P.V., Deitsch R.V., Nastovich M.I., Akmalova K.A., Kachanova A.A., Grishina E.A., Savchenko L.M., Shevchenko Y.S., 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.clinvest.ru/jour/article/view/577

Введение. Антипсихотики являются основными препаратами для лечения расстройств шизофренического спектра. Фармакодинамические генетические факторы активно изучаются для повышения точности подбора антипсихотиков на основе фармакогенетического тестирования. Цель настоящего исследования: установить ассоциации полиморфных вариантов генов DRD2, DRD3, DRD4, HTR2A, COMT, ZNF804A и ANKS1B с эффективностью и безопасностью антипсихотиков у подростков с острым психотическим эпизодом в течение 28 дней наблюдения. Материалы и методы. В исследование были включены 68 подростков с установленным диагнозом острое полиморфное психотическое расстройство на момент поступления (F23.0-9 по МКБ-10). Все пациенты получали антипсихотик в качестве основной терапии. Наблюдение за пациентами проводилось в течение 28 дней. Эффективность антипсихотиков оценивалась при помощи шкал Children’s Global Assessment Scale (CGAS), Positive and Negative Symptoms Scale (PANSS), Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I). Безопасность фармакотерапии оценивалась по шкалам UKU Side Effects Rating Scale (UKU SERS), Sympson-Angus Scale (SAS), Barnes Akathisia rating scale (BARS). Определение полиморфных вариантов генов DRD2 rs1800497 (C>T), DRD3 rs6280 (C>T), DRD3 rs324026 (C>T), DRD4 rs1800955 (C>T), HTR2A rs6313 (T>C), COMT rs4680 (Val158Met, G>A), ZNF804A rs1344706 (A>C), ANKS1B rs7968606 (C>T) осуществлялось методом полимеразной цепной реакции (ПЦР) в реальном времени. Результаты. У носителей аллели T DRD2 rs1800497 подшкала PANSS «Продуктивная симптоматика» сильнее редуцировалась на 14-й (Me=-7,0 [-9,0;-5,0] vs. Me=-7,0 [-8,0; -2,0]; p=0,018) и 28-й день наблюдения (Me=-11,0 [-9,0;-5,5] vs. Me=-8,0 [-8,0; -2,0]; p=0,019). Также более выраженное улучшение состояния по шкале CGAS на 14-й день наблюдения было отмечено у носителей TC+CC HTR2A rs6313 (Me=2,0 [1,0; 3,0] vs. Me=2,0 [1,0; 2,0]; p=0,029). У гомозиготных носителей DRD3 rs324026 (TT) на 28-е сутки терапии был значимо ниже балл шкалы SAS (Me=0,5 [0,0; 1,0] vs. Me=1,0 [0,0; 5,0]; p=0,016) и подшкалы UKU «Неврологические нарушения» на 28-е сутки приёма антипсихотиков (Me=0,0 [0,0; 0,0] vs. Me=1,0 [0,0; 3,8]; p=0,005). Также у носителей DRD3 rs324026 (TT) была ниже выраженность акатизии по шкале BARS. У носителей аллели T DRD4 rs1800955 балл шкалы SAS на 28-е сутки терапии был выше по сравнению с гомозиготами CC (Me=1,0 [0,0;4,0] vs. Me=0,0 [0,0; 1,0]; p=0,036). Заключение. Полиморфный вариант DRD2 rs1800497 был предиктором лучшей редукции продуктивной симптоматики, аналогичную связь продемонстрировал HTR2A rs6313. DRD3 rs324026 и HTR2A rs6313 были ассоциированы с меньшей частотой неврологических нежелательных реакций и акатизии. Напротив, носители полиморфного варианта DRD4 rs1800955 были более склонны к нежелательным реакциям на фоне фармакотерапии.

Introduction. Antipsychotics are the main drugs for treatment of schizophrenia spectrum disorders. Pharmacodynamic genetic factors are being actively studied to improve the accuracy of antipsychotic selection based on pharmacogenetic testing. Purpose of this study: to establish associations of genetic polymorphisms of the DRD2, DRD3, DRD4, HTR2A, COMT, ZNF804A, and ANKS1B genes with the efficacy and safety of antipsychotics in adolescents with an acute psychotic episode during a 28-day follow-up. Materials and methods. The study included 68 adolescents with an established diagnosis of acute polymorphic psychotic disorder at the time of admission (F23.0-9 according to ICD-10). All patients received an antipsychotic as their main therapy. Patients were monitored for 28 days. The effectiveness of antipsychotics was assessed using the Children’s Global Assessment Scale (CGAS), Positive and Negative Symptoms Scale (PANSS), Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I). The safety of pharmacotherapy was assessed using the UKU Side Effects Rating Scale (UKU SERS), Sympson-Angus Scale (SAS), Barnes Akathisia rating scale (BARS). From each patient we obtained a buccal scraped epithelium, extracted DNA from it by sorbent method and detected carriage of genetic polymorphisms DRD2 rs1800497 (C>T), DRD3 rs6280 (C>T), DRD3 rs324026 (C>T), DRD4 rs1800955 (C>T), HTR2A rs6313 (T>C), COMT rs4680 (Val158Met, G>A), ZNF804A rs1344706 (A>C), ANKS1B rs7968606 (C>T) by real-time PCR. Results. DRD2 rs1800497 T allele carriers had a stronger reduction in the PANSS subscore «Productive Symptomatics» on day 14 (Me=-7.0 [-9.0;-5.0] vs Me=-7.0 [-8.0;-2.0]; p=0.018) and day 28 of follow-up (Me=-11.0 [-9.0;-5.5] vs Me=-8.0 [-8.0;-2.0]; p=0.019). Also, greater improvement on the CGAS scale on day 14 of follow-up was seen in TC+CC HTR2A rs6313 carriers (Me=2.0 [1.0;3.0] vs. Me=2.0 [1.0;2.0]; p=0.029). DRD3 rs324026 homozygous carriers (TT) had a significantly lower SAS score (Me=0.5 [0.0; 1.0] vs. Me=1.0 [0.0; 5.0]; p=0.016) and UKU subscore «Neurological Disorders» on 28 days of antipsychotic therapy (Me=0.0 [0.0; 0.0] vs. Me=1.0 [0.0; 3.8]; p=0.005). DRD3 rs324026 TT carriers also had lower severity of akathisia according to the BARS scale. Carriers of the T DRD4 rs1800955 allele had a higher SAS scale score on day 28 of therapy compared with CC homozygotes (Me=1.0 [0.0;4.0] vs Me=0.0 [0.0;1.0]; p=0.036). Conclusion. The DRD2 rs1800497 was a predictor of better reduction of productive symptoms; HTR2A rs6313 demonstrated a similar association. The DRD2 rs1800497 polymorphic variant was a predictor of better reduction of productive symptomatology; HTR2A rs6313 demonstrated a similar association. DRD3 rs324026 and HTR2A rs6313 were associated with a lower frequency of neurological adverse reactions and akathisia. In contrast, carriers of the DRD4 rs1800955 were more prone to adverse reactions on pharmacotherapy.

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