Полиморфные варианты DRD2 rs1800497 и ABCB1 3435C>T ассоциированы с параметрами безопасности антипсихотиков у подростков с острым психотическим эпизодом: результаты пилотного исследования

Дети и подростки чаще, чем взрослые, испытывают неблагоприятные побочные эффекты при приеме антипсихотиков. Фармакогенетическое тестирование позволяет более точно подбирать начальную дозу препарата. Показано, что гены фармакокинетических факторов имеют высокую прогностическую значимость в отношении безопасности антипсихотиков у взрослых.

Пациенты и методы. В исследование было включено 36 подростков (средний возраст – 14,83±1,84 года, 58,3% – мужского пола). Все пациенты принимали антипсихотик. Наблюдение продолжалось 28 дней. Эффективность и безопасность терапии оценивались на 14-е и 28-е сутки при помощи шкал CGAS, PANSS, UKU SERS, SAS, BARS. Пациенты были генотипированы на CYP3A4*22, CYP3A5*3, CYP2D6*4, *9, *10, ABCB1 1236C>T, 2677G>T/A, 3435C>T, DRD2 rs1800497, DRD4 rs1800955, HTR2A rs6313.

Результаты и обсуждение. Снижение среднего балла подшкалы PANSS «Продуктивная симптоматика» было более выраженным у носителей полиморфного варианта DRD2 rs1800497 на 14-й день (-6,5 [-10,25; -3,75] vs -3 [-6,5; -2]; p=0,028) и на 28-й день (-11 [-13; -9,5] vs -5 [-9; -3,5]; p=0,001) по сравнению с изначальным состоянием. Носительство ABCB1 3435CT+TT ассоциировалось с худшей переносимостью фармакотерапии на 14-е сутки (общий балл шкалы UKU SERS M – 8 [3; 11,75] vs M – 2 [1; 6]; p=0,034). Носители DRD2 rs1800497 отмечали большую выраженность индуцированных антипсихотиком неврологических нарушений (балл подшкалы UKU SERS M – 1 [0; 2,25] vs M – 0 [0; 1]; p=0,029).

Заключение. Установлено, что полиморфные варианты DRD2 rs1800497 и ABCB1 3435C>T значимо ассоциированы с эффективностью и безопасностью антипсихотиков у подростков с острым психотическим эпизодом.

1. Haddad PM, Correll CU. The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses. Ther Adv Psychopharmacol. 2018 Oct 8;8(11):303-18. doi: 10.1177/2045125318781475. eCollection 2018 Nov.

2. Balijepalli C, Druyts E, Zoratti MJ, et al. Change in Prolactin Levels in Pediatric Patients Given Antipsychotics for Schizophrenia and Schizophrenia Spectrum Disorders: A Network Meta-Analysis. Schizophr Res Treatment. 2018 Apr 1;2018:1543034. doi: 10.1155/2018/1543034. eCollection 2018.

3. Zhai D, Lang Y, Feng Y, et al. Early onset of cardiometabolic risk factor profiles in drug naive adolescents and young adults with firstepisode schizophrenia. Schizophr Res. 2017 Dec;190:60-2. doi: 10.1016/j.schres.2017.03.004. Epub 2017 Mar 18.

4. Eum S, Lee AM, Bishop JR. Pharmacogenetic tests for antipsychotic medications: clinical implications and considerations. Dialogues Clin Neurosci. 2016 Sep;18(3):323-37.

5. Xiang Q, Zhao X, Zhou Y, et al. Effect of CYP2D6, CYP3A5, and MDR1 Genetic Polymorphisms on the Pharmacokinetics of Risperidone and Its Active Moiety. J Clin Pharmacol. 2010 Jun;50(6):659-66. doi: 10.1177/0091270009347867. Epub 2010 Mar 23.

6. Kim K-A, Joo H-J, Lee H-M, et al. Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers. Pharmacogenet Genomics. 2014 Jan;24(1):35-42. doi: 10.1097/FPC.0000000000000020

7. Wolking S, Schaeffeler E, Lerche H, et al. Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature. Clin Pharmacokinet. 2015 Jul;54(7):709-35. doi: 10.1007/s40262-015-0267-1

8. Rafaniello C, Sessa M, Bernardi FF, et al. The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions. Pharmacogenomics J. 2018 May 22;18(3):422-30. doi: 10.1038/tpj.2017.38. Epub 2017 Jul 18.

9. Mi W, Liu F, Liu Y, et al. Association of ABCB1 Gene Polymorphisms with Efficacy and Adverse Reaction to Risperidone or Paliperidone in Han Chinese Schizophrenic Patients. Neurosci Bull. 2016 Dec;32(6):547-9. doi: 10.1007/s12264-016-0050-9. Epub 2016 Jul 25.

10. Zhang J-P, Lencz T, Malhotra AK. D2 Receptor Genetic Variation and Clinical Response to Antipsychotic Drug Treatment: A Meta-Analysis. Am J Psychiatry. 2010 Jul;167(7):763-72. doi: 10.1176/appi.ajp.2009.09040598. Epub 2010 Mar 1.

11. Ma L, Zhang X, Xiang Q, et al. Association between dopamine receptor gene polymorphisms and effects of risperidone treatment: A systematic review and meta-analysis. Basic Clin Pharmacol Toxicol. 2019 Jan;124(1):94-104. doi: 10.1111/bcpt.13111. Epub 2018 Sep 11.

12. Wehry AM, Ramsey L, Dulemba SE, et al. Pharmacogenomic Testing in Child and Adolescent Psychiatry: An Evidence-Based Review. Curr Probl Pediatr Adolesc Health Care. 2018 Feb;48(2):40-9. doi: 10.1016/j.cppeds.2017.12.003. Epub 2018 Jan 8.

13. Ivanova SA, Filipenko ML, Vyalova NM, et al. CYP1A2 and CYP2D6 Gene Polymorphisms in Schizophrenic Patients with Neuroleptic Drug-Induced Side Effects. Bull Exp Biol Med. 2016 Mar;160(5):687-90. doi: 10.1007/s10517-016-3250-4. Epub 2016 Mar 29.

14. Ito T, Yamamoto K, Ohsawa F, et al. Association of CYP2D6 polymorphisms and extrapyramidal symptoms in schizophrenia patients receiving risperidone: a retrospective study. J Pharm Heal Care Sci. 2018 Nov 19;4:28. doi: 10.1186/s40780-018-0126-y. eCollection 2018.

15. Gardner DM, Murphy AL, O’Donnell H, et al. International Consensus Study of Antipsychotic Dosing. Am J Psychiatry. 2010 Jun;167(6):686-93. doi: 10.1176/appi.ajp.2009.09060802. Epub 2010 Apr 1.

16. Shaffer D, Gould MS, Brasic J, et al. A Children’s Global Assessment Scale (CGAS). Arch Gen Psychiatry. 1983 Nov;40(11):1228-31. doi: 10.1001/archpsyc.1983.01790100074010

17. Kay SR, Opler LA, Spitzer RL, et al. SCID-PANSS: two-tier diagnostic system for psychotic disorders. Compr Psychiatry. Jul-Aug 1991;32(4):355-61. doi: 10.1016/0010-440x(91)90085-q

18. Lingjaerde O, Ahlfors UG, Bech P, et al. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1-100. doi: 10.1111/j.1600-0447.1987.tb10566.x

19. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11-9. doi: 10.1111/j.1600-0447.1970.tb02066.x

20. Barnes TRE. The Barnes Akathisia Rating Scale-Revisited. J Psychopharmacol. 2003 Dec;17(4):365-70. doi: 10.1177/0269881103174013

21. Gasso P, Mas S, Alvarez S, et al. Xenobiotic metabolizing and transporter genes: gene-gene interactions in schizophrenia and related disorders. Pharmacogenomics. 2010 Dec;11(12):1725-31. doi: 10.2217/pgs.10.158

22. Noble EP. D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am J Med Genet. 2003 Jan 1;116B(1):103-25. doi: 10.1002/ajmg.b.10005

23. Kurylev AA, Brodyansky VM, Andreev BV, et al. The combined effect of CYP2D6 and DRD2 Taq1A polymorphisms on the antipsychotics daily doses and hospital stay duration in schizophrenia inpatients (observational naturalistic study). Psychiatr Danub. 2018;30(2):157-63. doi: 10.24869/psyd.2018.157

24. Ikeda M, Yamanouchi Y, Kinoshita Y, et al. Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. Pharmacogenomics. 2008 Oct;9(10):1437-43. doi: 10.2217/14622416.9.10.1437

25. Escamilla R, Camarena B, Saracco R, et al. Association study between COMT, DRD2, and DRD3 gene variants and antipsychotic treatment response in Mexican patients with schizophrenia. Neuropsychiatr Dis Treat. 2018 Nov 5;14:2981-7. doi: 10.2147/NDT.S176455. eCollection 2018.

26. Kang S-G, Na K-S, Lee H-J, et al. DRD2 Genotypic and Haplotype Variation Is Associated With Improvements in Negative Symptoms After 6 Weeks’ Amisulpride Treatment. J Clin Psychopharmacol. 2015 Apr;35(2):158-62. doi: 10.1097/JCP.0000000000000294

27. Vehof J, Burger H, Wilffert B, et al. Clinical response to antipsychotic drug treatment: Association study of polymorphisms in six candidate genes. Eur Neuropsychopharmacol. 2012 Sep;22(9):625-31. doi: 10.1016/j.euroneuro.2012.01.006. Epub 2012 Mar 3.

28. Hattori S, Suda A, Kishida I, et al. Effects of ABCB1 gene polymorphisms on autonomic nervous system activity during atypical antipsychotic treatment in schizophrenia. BMC Psychiatry. 2018 Jul 17;18(1):231. doi: 10.1186/s12888-018-1817-5

29. Consoli G, Lastella M, Ciapparelli A, et al. ABCB1 polymorphisms are associated with clozapine plasma levels in psychotic patients. Pharmacogenomics. 2009 Aug;10(8):1267-76. doi: 10.2217/pgs.09.51

30. Saiz-Rodriguez M, Belmonte C, Roman M, et al. Effect of ABCB1 C3435T Polymorphism on Pharmacokinetics of Antipsychotics and Antidepressants. Basic Clin Pharmacol Toxicol. 2018 Oct;123(4):474-85. doi: 10.1111/bcpt.13031. Epub 2018 Jun 13.

31. Suzuki Y, Tsuneyama N, Fukui N, et al. Impact of the ABCB1 Gene Polymorphism on Plasma 9-Hydroxyrisperidone and Active Moiety Levels in Japanese Patients With Schizophrenia. J Clin Psychopharmacol. 2013 Jun;33(3):411-4. doi: 10.1097/JCP.0b013e31828ecd52

32. Gasso P, Mas S, Bioque M, et al. Impact of NTRK2, DRD2 and ACE polymorphisms on prolactin levels in antipsychotic-treated patients with first-episode psychosis. J Psychopharmacol. 2018 Jun;32(6):702-10. doi: 10.1177/0269881118773026. Epub 2018 May 16.

33. Miura I, Zhang J-P, Hagi K, et al. Variants in the DRD2 locus and antipsychotic-related prolactin levels: A meta-analysis. Psychoneuroendocrinology. 2016 Oct;72:1-10. doi: 10.1016/j.psyneuen.2016.06.002. Epub 2016 Jun 6.

34. Mas S, Gasso P, Torra M, et al. Intuitive pharmacogenetic dosing of risperidone according to CYP2D6 phenotype extrapolated from genotype in a cohort of first episode psychosis patients. Eur Neuropsychopharmacol. 2017 Jul;27(7):647-56. doi: 10.1016/j.euroneuro.2017.03.012. Epub 2017 Apr 5.

35. Jovanovic N, Bozina N, Lovric M, et al. The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naive patients with first-episode schizophrenia treated with risperidone. Eur J Clin Pharmacol. 2010 Nov;66(11):1109-17. doi: 10.1007/s00228-010-0850-1. Epub 2010 Jun 19.