CYP2D6 phenotype and ABCB1 haplotypes are associated with antipsychotic safety in adolescents experiencing acute psychotic episodes

Dmitriy V. Ivashchenko; Daria A. Yudelevich; Nina I. Buromskaya; Pavel V. Shimanov; Roman V. Deitch; Kristina A. Akmalova; Anastasia A. Kachanova; Irina V. Dorina; Marina I. Nastovich; Elena A. Grishina; Lyudmila M. Savchenko; Yuriy S. Shevchenko; Dmitriy A. Sychev

doi:10.1515/dmpt-2021-0124

Article

CYP2D6 phenotype and ABCB1 haplotypes are associated with antipsychotic safety in adolescents experiencing acute psychotic episodes

Dmitriy V. Ivashchenko , Daria A. Yudelevich , Nina I. Buromskaya , Pavel V. Shimanov , Roman V. Deitch , Kristina A. Akmalova , Anastasia A. Kachanova , Irina V. Dorina , Marina I. Nastovich , Elena A. Grishina , Lyudmila M. Savchenko , Yuriy S. Shevchenko and Dmitriy A. Sychev

Published/Copyright: August 12, 2021

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From the journal Drug Metabolism and Personalized Therapy Volume 37 Issue 1

Abstract

Objectives

To identify possible associations of CYP2D6, CYP3A4/5, and ABCB1 gene polymorphisms with the efficacy and safety of antipsychotics in adolescents with acute psychotic episodes.

Methods

We examined the associations of pharmacogenetic factors with the efficacy and safety of antipsychotics in 101 adolescents with acute psychotic episodes. The diagnosis on admission was “Brief psychotic disorder” (F23.0–23.9 by ICD-10). All patients were administered antipsychotics for 14 days. Treatment efficacy and safety were assessed using the PANSS, CGAS, CGI-S(I), UKU SERS, BARS, and SAS scales. Pharmacokinetic genotyping was performed for the CYP2D6*4, *10, ABCB1 1236C>T, 2677G>T, and 3435C>T genes.

Results

CYP2D6 intermediate metabolisers had “Micturition disturbances” more often than extensive metabolisers (24.2 vs. 7.4%; p=0.026). “Wild” homozygote ABCB1 3435C>T CC was associated with more prominent akathisia. Haplotype analysis of three ABCB1 polymorphisms revealed that the “wild” alleles “C-G-C” (ABCB1 1236-2677-3435) were associated with higher risk of “Reduced salivation” (OR=2.95; 95% CI=1.35–6.45; p=0.0078).

Conclusions

CYP2D6 intermediate metabolism was associated with the risk of urinary difficulties under treatment with antipsychotics. We found that “wild” homozygotes ABCB1 1236C>T, 2677G>T, and 3435C>T were predictors of adverse drug effects caused by treatment with antipsychotics.

Keywords: ABCB1; adolescents; antipsychotic; CYP2D6; pharmacogenetic

Corresponding author: Dmitriy V. Ivashchenko, MD, PhD, Molecular and Personalized Medicine Research Institute, Russian Medical Academy of Continuous Professional Education, Moscow, Russia; and Department of Psychiatry, PIUV – Branch of Russian Medical Academy of Continuous Professional Education, Penza, Russia, E-mail: dvi1991@yandex.com

Funding source: Russian Science Foundation 10.13039/501100006769

Award Identifier / Grant number: 18-75-00046

Research funding: Research was supported by the grant No 18-75-00046 of Russian Science Foundation.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The study was approved by the local Ethics Committees of the Russian Medical Academy of Continuous Professional Education (Minutes No. 3 of 06 June 2018) and Scientific-Practical Children’s and Adolescents Mental Health Center n.a. G.E. Sukhareva (Minutes No. 2 of 14 June 2018). This study complied with the World Medical Association Declaration of Helsinki.

References

1. Krause, M, Zhu, Y, Huhn, M, Schneider-Thoma, J, Bighelli, I, Nikolakopoulou, A, et al.. Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur Arch Psychiatr Clin Neurosci 2018;268:625–39. https://doi.org/10.1007/s00406-018-0869-3.Search in Google Scholar PubMed

2. Minjon, L, van den Ban, E, de Jong, E, Souverein, PC, Egberts, TCG, Heerdink, ER. Reported adverse drug reactions in children and adolescents treated with antipsychotics. J. Child Adolesc. Psychopharmacol. 2019;29:124–32. https://doi.org/10.1089/cap.2018.0139.Search in Google Scholar PubMed

3. Stafford, MR, Mayo-Wilson, E, Loucas, CE, James, A, Hollis, C, Birchwood, M, 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. Myin-Germeys I, ed. PLoS One 2015;10:e0117166. https://doi.org/10.1371/journal.pone.0117166.Search in Google Scholar PubMed PubMed Central

4. van Westrhenen, R, Aitchison, KJ, Ingelman-Sundberg, M, Jukić, MM. Pharmacogenomics of antidepressant and antipsychotic treatment: how far have we got and where are we going? Front Psychiatr 2020;11:94. https://doi.org/10.3389/fpsyt.2020.00094.Search in Google Scholar PubMed PubMed Central

5. van Schaik, RHN, Müller, DJ, Serretti, A, Ingelman-Sundberg, M. Pharmacogenetics in psychiatry: an update on clinical usability. Front Pharmacol 2020;11:575540. https://doi.org/10.3389/fphar.2020.575540.Search in Google Scholar PubMed PubMed Central

6. Hiemke, C, Bergemann, N, Clement, HW, Conca, A, Deckert, J, Domschke, K, et al.. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry 2018;51:9–62. https://doi.org/10.1055/s-0043-116492.Search in Google Scholar PubMed

7. Moons, T, de Roo, M, Claes, S, Dom, G. Relationship between P-glycoprotein and second-generation antipsychotics. Pharmacogenomics 2011;12:1193–211. https://doi.org/10.2217/pgs.11.55.Search in Google Scholar PubMed

8. Wehry, AM, Ramsey, L, Dulemba, SE, Mossman, SA, Strawn, JR. Pharmacogenomic testing in child and adolescent psychiatry: an evidence-based review. Curr Probl Pediatr Adolesc Health Care 2018;48:40–9. https://doi.org/10.1016/j.cppeds.2017.12.003.Search in Google Scholar PubMed PubMed Central

9. Maruf, AA, Stein, K, Arnold, PD, Aitchison, KJ, Müller, DJ, Bousman, C. CYP2D6 and antipsychotic treatment outcomes in children and youth: a systematic review. J Child Adolesc Psychopharmacol 2021;31:33–45. https://doi.org/10.1089/cap.2020.0093.Search in Google Scholar PubMed

10. Oshikoya, KA, Neely, KM, Carroll, RJ, Aka, IT, Maxwell-Horn, AC, Roden, DM, et al.. CYP2D6 genotype and adverse events to risperidone in children and adolescents. Pediatr Res 2019;85:602–6. https://doi.org/10.1038/s41390-019-0305-z.Search in Google Scholar PubMed PubMed Central

11. Grădinaru, R, Andreescu, N, Nussbaum, L, Suciu, L, Puiu, M. Impact of the CYP2D6 phenotype on hyperprolactinemia development as an adverse event of treatment with atypical antipsychotic agents in pediatric patients. Ir J Med Sci (1971 -) 2019;188:1417–22. https://doi.org/10.1007/s11845-019-01985-x.Search in Google Scholar

12. Sukasem, C, Vanwong, N, Srisawasdi, P, Ngamsamut, N, Nuntamool, N, Hongkaew, Y, et al.. Pharmacogenetics of risperidone-induced insulin resistance in children and adolescents with autism spectrum disorder. Basic Clin Pharmacol Toxicol 2018;123:42–50. https://doi.org/10.1111/bcpt.12970.Search in Google Scholar

13. Sukasem, C, Hongkaew, Y, Ngamsamut, N, Puangpetch, A, Vanwong, N, Chamnanphon, M, et al.. Impact of pharmacogenetic markers of CYP2D6 and DRD2 on prolactin response in risperidone-treated Thai children and adolescents with autism spectrum disorders. J Clin Psychopharmacol 2016;36:141–6. https://doi.org/10.1097/JCP.0000000000000474.Search in Google Scholar

14. Thümmler, S, Dor, E, David, R, Leali, G, Battista, M, David, A, et al.. Pharmacoresistant severe mental health disorders in children and adolescents: functional abnormalities of cytochrome P450 2D6. Front Psychiatr 2018;9:2. https://doi.org/10.3389/fpsyt.2018.00002.Search in Google Scholar

15. Geers, LM, Pozhidaev, IV, Ivanova, SA, Freidin, MB, Schmidt, AF, Cohen, D, et al.. Association between 8 P-glycoprotein (MDR1/ABCB1) gene polymorphisms and antipsychotic drug-induced hyperprolactinaemia. Br J Clin Pharmacol 2020;86. https://doi.org/10.1111/bcp.14288.Search in Google Scholar

16. Hattori, S, Suda, A, Kishida, I, Miyauchi, M, Shiraishi, Y, Fujibayashi, M, et al.. Effects of ABCB1 gene polymorphisms on autonomic nervous system activity during atypical antipsychotic treatment in schizophrenia. BMC Psychiatr 2018;18:231. https://doi.org/10.1186/s12888-018-1817-5.Search in Google Scholar

17. Ivashchenko, DV, Khoang, SZ, Makhmudova, BV, Buromskaya, NI, Shimanov, PV, Deitch, RV, et al.. Pharmacogenetics of antipsychotics in adolescents with acute psychotic episode during first 14 days after admission: effectiveness and safety evaluation. Drug Metab Pers Ther 2020;35:20200102. https://doi.org/10.1515/dmdi-2020-0102.Search in Google Scholar

18. Ivashchenko, DV, Khoang, SZ, Tazagulova, MK, Buromskaya, NI, Shimanov, PV, Deitch, RV, et al.. The polymorphic variants DRD2 rs1800497 and ABCB1 3435C>T are associated with antipsychotic safety parameters in adolescents with an acute psychotic episode: the results of a pilot study. Nevrol Nejropsihiatr Psihosom 2020;12:24–31. https://doi.org/10.14412/2074-2711-2020-5-24-31.Search in Google Scholar

19. Shaffer, D, Gould, MS, Brasic, J, Ambrosini, P, Fisher, P, Bird, H, et al.. A children’s global assessment scale (CGAS). Arch Gen Psychiatr 1983;40:1228. https://doi.org/10.1001/archpsyc.1983.01790100074010.Search in Google Scholar

20. Kay, SR, Opler, LA, Spitzer, RL, Williams, JB, Fiszbein, A, Gorelick, A. SCID-PANSS: two-tier diagnostic system for psychotic disorders. Compr Psychiatr 1991;32:355–61.10.1016/0010-440X(91)90085-QSearch in Google Scholar

21. Busner, J, Targum, SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont) 2007;4:28–37.Search in Google Scholar

22. Lingjaerde, O, Ahlfors, UG, Bech, P, Dencker, SJ, Elgen, K. 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;334:1–100.10.1111/j.1600-0447.1987.tb10566.xSearch in Google Scholar PubMed

23. Simpson, GM, Angus, JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:11–9. https://doi.org/10.1111/j.1600-0447.1970.tb02066.x.Search in Google Scholar PubMed

24. Barnes, TRE. The Barnes akathisia rating scale–revisited. J Psychopharmacol 2003;17:365–70. https://doi.org/10.1177/0269881103174013.Search in Google Scholar PubMed

25. Gardner, DM, Murphy, AL, O’Donnell, H, Centorrino, F, Baldessarini, RJ. International consensus study of antipsychotic dosing. Am J Psychiatr 2010;167:686–93. https://doi.org/10.1176/appi.ajp.2009.09060802.Search in Google Scholar PubMed

26. Rodriguez, S, Gaunt, TR, Day, INM. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 2009;169:505–14. https://doi.org/10.1093/aje/kwn359.Search in Google Scholar PubMed PubMed Central

27. Caudle, KE, Sangkuhl, K, Whirl-Carrillo, M, Swen, JJ, Haidar, CE, Klein, TE, et al.. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci 2020;13:116–24. https://doi.org/10.1111/cts.12692.Search in Google Scholar PubMed PubMed Central

28. Mas, S, Gassó, P, Lafuente, A, Bioque, M, Lobo, A, Gonzàlez-Pinto, A, et al.. Pharmacogenetic study of antipsychotic induced acute extrapyramidal symptoms in a first episode psychosis cohort: role of dopamine, serotonin and glutamate candidate genes. Pharmacogenomics J 2016;16:439–45. https://doi.org/10.1038/tpj.2016.44.Search in Google Scholar PubMed

Received: 2021-04-07

Accepted: 2021-05-28

Published Online: 2021-08-12

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Articles in the same Issue

https://doi.org/10.1515/dmpt-2021-0124

Keywords for this article

ABCB1; adolescents; antipsychotic; CYP2D6; pharmacogenetic