Efficacy and safety of antipsychotics in adolescents with an acute psychotic episode in relation to the activity of CYP3A and CYP2D6 isoenzymes

Antipsychotics are a first-line treatment for psychotic disorders. The cytochrome P450 isoenzymes CYP3A4/5 and CYP2D6 metabolize most antipsychotics. The activity of these isoenzymes in children changes with maturation, so it is different from that in adults. Objective: to study the associations of CYP3A and CYP2D6 isoenzyme activity parameters with the efficacy and safety of antipsychotics in adolescents with an acute psychotic episode. Patients and methods. The investigation enrolled 53 adolescents with an acute psychotic episode who took antipsychotics. The observation period lasted 14 days. The CGAS, PANSS, UKU SERS, SAS, and BARS scales were used to evaluate the efficiency and safety of the therapy on day 14. The activity of CYP3A and CYP2D6 isoenzymes was measured by determining the metabolic ratios of the concentrations of endogenous substrates of the isoenzymes and their metabolites in a morning urine sample on days 1 and 14 of the study. The activity of CYP3A was assessed by the 6-beta hydroxycortisol/cortisol ratio; that of CYP2D6 was measured by the 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline/pinoline ratio. The influence of carriage of polymorphic variants CYP2D6*4,*9,*10, CYP3A4*22, CYP3A5*3 on the activity of isoenzymes was excluded by removing their carriers from the analysis. Results and discussion. The investigators revealed an association of certain antipsychotic-induced undesirable symptoms with CYP3A and CYP2D6 activity parameters. On day 1, a lower CYP2D6 activity was initially observed in patients with tremor (0.54 [0.34; 1.34] vs 1.25 [0.91; 1.75]; p=0.023). Also, patients with any documented adverse reaction (ARs) to therapy had initially a decreased CYP3A activity (1.2 [0.85; 2.29] vs 2.55 [1.44; 4.83]; p=0.047) and an enhanced CYP3A activity during therapy (the activity difference between day 14 and day 1 was 0.28 [-0.28; 2.32] vs -1.3 [-3.47; 0.66]; p=0.042). Conclusion. The initially reduced activity of CYP2D6 and CYP3A isoenzymes is a significant predictor of antipsychotic-induced ARs in adolescents with an acute psychotic episode. The predictive role of CYP2D6 and CYP3A activity levels in the efficacy of antipsychotics has not been confirmed.

1. Zhu Y, Li C, Huhn M, et al. How well do patients with a first episode of schizophrenia respond to antipsychotics: A systematic review and meta-analysis. Eur Neuropsychopharmacol. 2017 Sep;27(9):835-44. doi: 10.1016/j.euroneuro.2017.06.011. Epub 2017 Jun 29.

2. Minjon L, van den Ban E, de Jong E, et al. Reported Adverse Drug Reactions in Children and Adolescents Treated with Antipsychotics. J Child Adolesc Psychopharmacol. 2019 Mar;29(2):124-32. doi: 10.1089/cap.2018.0139. Epub 2019 Jan 24.

3. Stafford MR, Mayo-Wilson E, Loucas CE, et al. Efficacy and Safety of Pharmacological and Psychological Interventions for the Treatment of Psychosis and Schizophrenia in Children, Adolescents and Young Adults: A Systematic Review and Meta-Analysis. PLoS One. 2015 Feb 11;10(2):e0117166. doi: 10.1371/journal.pone.0117166. eCollection 2015.

4. 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;48(2):40-9. doi: 10.1016/j.cppeds.2017.12.003

5. Eum S, Lee AM, Bishop JR. Pharmacogenetic tests for antipsychotic medications: clinical implications and considerations. Dialogues Clin Neurosci. 2016 Sep;18(3):323-37. doi: 10.31887/DCNS.2016.18.3/jbishop

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

7. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-41. doi: 10.1016/j.pharmthera.2012.12.007

8. T'jollyn H, Vermeulen A, van Bocxlaer J. PBPK and its Virtual Populations: the Impact of Physiology on Pediatric Pharmacokinetic Predictions of Tramadol. AAPS J. 2018 Nov 29;21(1):8. doi: 10.1208/s12248-018-0277-7

9. T'jollyn H, Snoeys J, Vermeulen A, et al. Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation. AAPS J. 2015;17(6):1376-87. doi: 10.1208/s12248-015-9803-z

10. Ince I, de Wildt SN, Wang C, et al. A Novel Maturation Function for Clearance of the Cytochrome P450 3A Substrate Midazolam from Preterm Neonates to Adults. Clin Pharmacokinet. 2013 Jul;52(7):555-65. doi: 10.1007/s40262-013-0050-0

11. 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.

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

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

14. 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

15. 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

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

17. Smirnov VV, Savchenko AYu, Ramenskaya GV. Development and validation quantity method for determination of endogenous cortisole and 6-β-hydroxycortisole in human urine for activity determination of isoensim CYP 3A4. Biomeditsina. 2010;(4):56-60 (In Russ.).

18. Galteau MM, Shamsa F. Urinary 6betahydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur J Clin Pharmacol. 2003;59(10):713-33. doi: 10.1007/s00228-003-0690-3

19. Kim AH, Yoon S, Lee Y, et al. Assessment of Hepatic Cytochrome P450 3A Activity Using Metabolic Markers in Patients with Renal Impairment. J Korean Med Sci. 2018;33(53):e298. doi: 10.3346/jkms.2018.33.e298

20. Jiang XL, Shen HW, Yu AM. Pinoline may be used as a probe for CYP2D6 activity. Drug Metab Dispos. 2009 Mar;37(3):443-6. doi: 10.1124/dmd.108.025056

21. Zastrozhin MS, Skryabin VY, Smirnov VV, et al. Effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder. Can J Physiol Pharmacol. 2019;97(8):781-5. doi: 10.1139/cjpp-2019-0177

22. 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;18(3):422-30. doi: 10.1038/tpj.2017.38

23. Vandenberghe F, Najar-Giroud A, Holzer L, et al. Second-Generation Antipsychotics in Adolescent Psychiatric Patients: Metabolic Effects and Impact of an Early Weight Change to Predict Longer Term Weight Gain. J Child Adolesc Psychopharmacol. 2018;28(4):258-65. doi: 10.1089/cap.2017.0038

24. Dodsworth T, Kim DD, Procyshyn RM, et al. A systematic review of the effects of CYP2D6 phenotypes on risperidone treatment in children and adolescents. Child Adolesc Psychiatry Ment Health. 2018 Jul 16;12:37. doi: 10.1186/s13034-018-0243-2. eCollection 2018.

25. Gradinaru R, Andreescu N, Nussbaum L, et al. Impact of the CYP2D6 phenotype on hyperprolactinemia development as an adverse event of treatment with atypical antipsychotic agents in pediatric patients. Irish J Med Sci. 2019;188(4):1417-22. doi: 10.1007/s11845-019-01985-x

26. 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;50(6):659-66. doi: 10.1177/0091270009347867

27. Kim K-A, Joo H-J, Lee H-M, Park J-Y. 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