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No. 4 (2024)

GENERAL THERAPY QUESTIONS AND REVIEWS

Pharmacogenetic Predictors of Clozapine Metabolic Disturbances

https://doi.org/10.21265/PSYPH.2024.88.88.004

Published 2024-12-30

  • D.N. Sosin
    • ,
  • A.K. Khasanova
    • ,
  • S.U. Moshevitin
    • ,
  • S.N. Mosolov

D.N. Sosin
Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation; State budgetary institution of health care “Psychiatric Clinical Hospital No 4 of Department of health care of Moscow named after P.B. Gannushkin”

A.K. Khasanova
Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation; State budgetary institution of health care “Psychiatric Clinical Hospital No 4 of Department of health care of Moscow named after P.B. Gannushkin”

S.U. Moshevitin
State budgetary institution of health care “Psychiatric Clinical Hospital No 4 of Department of health care of Moscow named after P.B. Gannushkin”

S.N. Mosolov
Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation; Moscow Research Institute of Psychiatry — branch of the Federal State Budgetary Institution V.P. Serbsky National Medical Research Centre for Psychiatry and Narcology of the Ministry of Heath of the Russian Federation

Abstract

About one-third of patients with schizophrenia have treatment resistance. The gold standard of treatment for such patients is the prescription of clozapine. The most common adverse effect of clozapine are metabolic disorders, which occur in more than half of patients. This review article summarizes the results of clinical studies investigating pharmacogenetic pharmacokinetic predictors of metabolic abnormalities in patients taking clozapine. PRISMA recommendations were used in writing the review. To date, the following gene polymorphisms have been studied for their influence on metabolic disorders during clozapine administration: CYP1A2, CYP2C19, CYP2D6, ABCB1, ABCC1, and UGT1A4. The most studied variants include rs762551 CYP1A2, rs1045642 ABCB1 and rs4244285 CYP2C19. Results for other polymorphisms are few and inconsistent. All studies included in this review have significant limitations. New studies with a more rigorous, prospective design as well as a comprehensive evaluation of genetic, epigenetic, and environmental factors are needed. This approach will allow not only to predict metabolic side effects but also will shed light on the pathogenetic mechanisms of their development.

Keywords

clozapine, metabolic disturbance, metabolic syndrome, genes polymorphisms, antipsychotics, treatment resistant schizophrenia

PDF (Русский)

References

  1. Мосолов С.Н. Полвека нейролептической терапии: основные итоги и новые рубежи // Новые достижения в терапии психических заболеваний. – М.: БИНОМ. Лаборатория знаний, 2002. – С. 47–81.
  2. Howes O.D. McCutcheon R., Agid O. et al. Treatment-resistant schizophrenia: Treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology // American Journal of Psychiatry. – 2017. – Vol. 174 (3). – Pр. 216–229. – https://doi.org/10.1176/appi.ajp.2016.16050503
  3. Correll C.U., Agid O., Crespo-Facorro B. et al. A Guideline and checklist for initiating and managing clozapine treatment in patients with treatment-resistant schizophrenia // CNS Drugs. – 2022. Vol. 36 (7). – Pр. 659–679. – https://doi.org/10.1007/s40263-022-00932-2
  4. Mizuno Y., McCutcheon R., Brugger S.P., Howes O.D. Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: A meta-analysis // Neuropsychopharmacology. 2020. – Vol. 45 (4). – Pр. 622–631. – https://doi.org/10.1038/s41386-019-0577-3
  5. Хасанова А.К., Коврижных И.В., Мосолов С.Н. Антисуицидальный эффект клозапина (алгоритм применения и клинического мониторинга) // Современная терапия психиче расстройств. – 2023. – № 4. – С. 48–63. https://doi.org/10.21265/PSYPH.2023.31.74.005
  6. Agid O., Arenovich T., Sajeev G. et al. An Algorithm-based approach to first-episode schizophrenia // J Clin Psychiatry. – 2011. – Vol. 72 (11). – Pр. 1439–1444. – https://doi.org/10.4088/jcp.09m05785yel
  7. Correll C.U., Howes O.D. Treatment-resistant schizophrenia: definition, predictors, and therapy options // J Clin Psychiatry. – 2021. – Vol. 82 (5). – https://doi.org/10.4088/jcp.my20096ah1c
  8. Schoretsanitis G., Kuzin M., Kane J.M. et al. Elevated clozapine concentrations in clozapine-treated patients with hypersalivation // Clin Pharmacokinet. – 2021. – Vol. 60 (3). – Pр. 329–335. – https://doi.org/10.1007/s40262-020-00944-5
  9. Tanzer T.D., Brouard T., Pra S.D. et al. Treatment strategies for clozapine-induced hypotension: A systematic review // Ther Adv Psychopharmacol. – 2022. – Vol. 12. – https://doi.org/10.1177/20451253221092931
  10. Deepak M.B., Deeksha K., Pallavi R. et al. Clozapine induced hypertension and its association with autonomic dysfunction // Psychopharmacol Bull. – 2021. – Vol. 51 (4). – Pр. 122–127.
  11. Vickers M., Ramineni V., Malacova E. et al. Risk factors for clozapine-induced myocarditis and cardiomyopathy: A systematic review and meta-analysis // Acta Psychiatr Scand. – 2022. – Vol. 145 (5). – Pр. 442–455. – https://doi.org/10.1111/acps.13398
  12. Osborne I.J., McIvor R.J. Clozapine-induced myoclonus: A case report and review of the literature // Ther Adv Psychopharmacol. – 2015. – Vol. 5 (6). – Pр. 351–356. – https://doi.org/10.1177/2045125315612015
  13. Shirazi A., Stubbs B., Gomez L. et al. Prevalence and predictors of clozapine-associated constipation: A systematic review and meta-analysis // Int J Mol Sci. – 2016. – Vol. 17 (6). – Art. 863. – https://doi.org/10.3390/ijms17060863
  14. Verdoux H., Quiles C., Bachmann C.J., Siskind D. Prescriber and institutional barriers and facilitators of clozapine use: A systematic review // Schizophr Res. – 2018. – Vol. 201. – Pр. 10–19. – https://doi.org/10.1016/j.schres.2018.05.046
  15. Lappin J.M., Wijaya M., Watkins A., et al. Cardio-metabolic risk and its management in a cohort of clozapine-treated outpatients // Schizophr Res. – 2018. – Vol. 199. – Pр. 367– 373. – https://doi.org/10.1016/j.schres.2018.02.035
  16. Henderson D.C. Weight gain with atypical antipsychotics: evidence and insights // J Clin Psychiatry. – 2007. – Vol. 68, suppl. 1. – Pр. 18–26.
  17. De Hert M., Detraux J., Winkel R. et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs // Nat Rev Endocrinol. – 2012. – Vol. 8 (2). – Pр. 114–126. – https://doi.org/10.1038/nrendo.2011.156
  18. Rojas E., Ana Castro A., Manzano A. et al. Diagnostic criteria and management of metabolic syndrome: Evolution overtime // Gac Med Caracas. – 2020. – Vol. 128 (4). – Pр. 480–504. – http://dx.doi.org/10.47307/GMC.2020.128.4.5
  19. Gurcan G., Şenol S.H., A Yağcıoğlu E.A. et al. Common side effects and metabolic syndrome due to clozapine: Relationship with the clinical variables and disability // Turkish Journal of Psychiatry. – 2020. – https://doi.org/10.5080/u25737
  20. Jae S.Y., Kunutsor S., Sudhir Kurl S., Laukkanen J.A. Impact of diabetes and hypertension on the heightened risk of sudden cardiac death associated with metabolic syndrome: Interrelationship with cardiorespiratory fitness // CardioMetabolic Syndrome Journal. – 2024. – Vol. 4 (2). – Art. 106. – http://dx.doi.org/10.51789/cmsj.2024.4.e12
  21. Dickerson F., Khan S., Origoni A. et al. Risk factors for natural cause mortality in schizophrenia // JAMA Netw Open. – 2024. – Vol. 7 (9). – e2432401. – https://doi.org/10.1001/jamanetworkopen.2024.32401
  22. Vasudev K., Choi Y.H., Norman R. et al. Genetic determinants of clozapine-induced metabolic side effects // The Canadian Journal of Psychiatry. – 2017. – Vol. 62 (2). – Pр. 138–149. – https://doi.org/10.1177/0706743716670128.
  23. Brennan M.D. Pharmacogenetics of second-generation antipsychotics // Pharmacogenomics. 2014. – Vol. 15 (6). – Pр. 869–884. – https://doi.org/10.2217/pgs.14.50
  24. Jin H., Meyer J.M., Mudaliar S., Jeste D.V. Impact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin // Schizophr Res. – 2008. – Vol. 100 (1–3). – Pр. 70–85. – https://doi.org/10.1016/j.schres.2007.11.026
  25. De Luca V., Mueller D.J., de Bartolomeis A., Kennedy J.L. Association of the HTR2C gene and antipsychotic induced weight gain: A meta-analysis // Int J Neuropsychopharmacol. – 2007. – Vol. 10 (05). – https://doi.org/10.1017/s1461145707007547
  26. Sicard M.N., Zai C.C., Tiwari A.K. et al. Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: An update and meta-analysis // Pharmacogenomics. – 2010. – Vol. 11 (11). – Pр. 1561–1571. – https://doi.org/10.2217/pgs.10.123
  27. Miller D.D., Ellingrod V.L., Holman T.L. et al. Clozapine-induced weight gain associated with the 5HT2C receptor −759C/T polymorphism // American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. – 2005. – Vol. 133B (1). – Pр. 97–100. – https://doi.org/10.1002/ajmg.b.30115
  28. Arranz M.J., Rivera M., Munro J.C. Pharmacogenetics of response to antipsychotics in patients with schizophrenia // CNS Drugs. – 2011. – Vol. 25 (11). – Pр. 933–969. – https://doi.org/10.2165/11595380-000000000-00000
  29. Basile V.S., Masellis M., McIntyre R. S. et al. Genetic dissection of atypical antipsychotic-induced weight gain: Novel preliminary data on the pharmacogenetic puzzle // J Clin Psychiatry. – 2001. – Vol. 62, suppl. 2. – Pр. 45–66.
  30. Piatkov I., Caetano D., Assur Y. et al. ABCB1 and ABCC1 single-nucleotide polymorphisms in patients treated with clozapine // Pharmgenomics Pers Med. – 2017. – Vol. 10. – Pр. 235–242. – https://doi.org/10.2147/pgpm.s142314
  31. Melkersson K.I., Scordo M.G., Gunes A., Dahl M.-L. Impact of CYP1A2 and CYP2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients // J Clin Psychiatry. – 2007. – Vol. 68 (05). – Pр. 697–704. – https://doi.org/10.4088/jcp.v68n0506
  32. Landi M.T., Sinha R., Lang N.P., Kadlubar F.F. Human cytochrome P4501A2 // IARC Sci Publ. – 1999. – No. 148. – Pр. 173–195.
  33. Guengerich F.P., Distlerath L.M., Reilly P.E. et al. Human-liver cytochromes P-450 involved in polymorphisms of drug oxidation // Xenobiotica. – 1986. – Vol. 16 (5). – Pр. 367– 378. – https://doi.org/10.3109/00498258609050245
  34. Ruan C.-J., de Leon J. Is there a future for CYP1A2 Pharmacogenetics in the optimal dosing of clozapine? // Pharmacogenomics. – 2020. – Vol. 21 (6). – Pр. 369–373. – https://doi.org/10.2217/pgs-2020-0015
  35. Bertilsson L., Carrillo J.A., Dahl M.L. et al. Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test // Br J Clin Pharmacol. – 1994. – Vol. 38 (5). – Pр. 471–473. – https://doi.org/10.1111/j.1365-2125.1994.tb04385.x
  36. Devonshire H., Kong I., Cooper M. et al. The contribution of genetically determined oxidation status to inter- individual variation in phenacetin disposition // Br J Clin Pharmacol. – 1983. – Vol. 16 (2). – Pр. 157–166. – https://doi.org/10.1111/j.1365-2125.1983.tb04980.x
  37. Barrangou-Poueys-Darlas M., Guerlais M., Laforgue E.-J. et al. CYP1A2 and tobacco interaction: a major pharmacokinetic challenge during smoking cessation // Drug Metab Rev. – 2021. – Vol. 53 (1). – Pр. 30–44. – https://doi.org/10.1080/03602532.2020.1859528
  38. Olsson E., Edman G., Bertilsson L. et al. Genetic and clinical factors affecting plasma clozapine concentration // Prim Care Companion CNS Disord. – 2015. – https://doi.org/10.4088/pcc.14m01704
  39. Browning S.L., Tarekegn A., Bekele E. et al. CYP1A2 is more variable than previously thought: A genomic biography of the gene behind the human drug-metabolizing enzyme // Pharmacogenet Genomics. – 2010. – Vol. 20 (11). – Pр. 647–664. – https://doi.org/10.1097/fpc.0b013e32833e90eb
  40. Waring R.H. Cytochrome P450: Genotype to phenotype // Xenobiotica. – 2020. – Vol. 50 (1). – Pр. 9–18. – https://doi.org/10.1080/00498254.2019.1648911
  41. Blaisdell J., Mohrenweiser H., Jackson J. et al. Identification and functional characterization of new potentially defective alleles of human CYP2C19 // Pharmacogenetics. – 2002. – Vol. 12 (9). – Pр. 703–711. – https://doi.org/10.1097/00008571-200212000-00004
  42. Botton M.R., Whirl-Carrillo M., Del Tredici A. L. et al. PharmVar GeneFocus: CYP2C19 // Clin Pharmacol Ther. – 2021. – Vol. 109 (2). – Pр. 352–366. – https://doi.org/10.1002/cpt.1973
  43. Rao S. Uppugunduri C., Daali Y., Desmeules J. et al. Transcriptional regulation of CYP2C19 and its role in altered enzyme activity // Curr Drug Metab. – 2012. – Vol. 13 (8). – Pр. 1196–1204. – https://doi.org/10.2174/138920012802850146
  44. Taylor C., Crosby I., Yip V. et al. A Review of the important role of CYP2D6 in pharmacogenomics // Genes (Basel). – 2020. – Vol. 11 (11). – Art. 1295. – ttps://doi.org/10.3390/genes11111295
  45. Pan X., Ning M., Jeong H. Transcriptional regulation of CYP2D6 expression // Drug Metabolism and Disposition. – 2017. – Vol. 45 (1). – Pр. 42–48. – https://doi.org/10.1124/dmd.116.072249
  46. Seo J., Lee C.R., Paeng J.C. et al. Biallelic mutations in ABCB1 display recurrent reversible encephalopathy // Ann Clin Transl Neurol. – 2020. – Vol. 7 (8). – Pр. 1443–1449. – https://doi.org/10.1002/acn3.51125
  47. Moons T., de Roo M., Claes S., Dom G. Relationship between P-glycoprotein and second-generation antipsychotics // Pharmacogenomics. – 2011. – Vol. 12 (8). – Pр. 1193– 1211. – https://doi.org/10.2217/pgs.11.55
  48. Lee S.-T., Ryu S., Kim S.R. et al. Association study of 27 annotated genes for clozapine pharmacogenetics // J Clin Psychopharmacol. – 2012. – Vol. 32 (4). – Pр. 441–448. – https://doi.org/10.1097/jcp.0b013e31825ac35c
  49. Breitenstein B., Brückl T.M., Ising M. et al. ABCB1 gene variants and antidepressant treatment outcome: A meta-analysis // American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. – 2015. – Vol. 168 (4). – Pр. 274–283. –https://doi.org/10.1002/ajmg.b.32309
  50. Brückl T.M., Uhr M. ABCB1 genotyping in the treatment of depression // Pharmacogenomics. – 2016. – Vol. 17 (18). – Pр. 2039–2069. – https://doi.org/10.2217/pgs.16.18
  51. Li M., Mei L., He C. et al. Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis // Genet Med. – 2019. – Vol. 21 (12). – Pр. 2744–2754. – https://doi.org/10.1038/s41436-019-0594-y
  52. Tukey R.H., Strassburg C.P. Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract // Mol Pharmacol. – 2001. – Vol. 59 (3). – Pр. 405–414. – https://doi.org/10.1124/mol.59.3.405
  53. Malhi V., Nowicka M., Chen Y.C. et al. UGT1A4 Polymorphism is not associated with a clinically relevant change in giredestrant exposure // Cancer Chemother Pharmacol. – 2024. – Vol. 94 (1). – Pр. 117–122.
  54. Breyer-Pfaff U., Wachsmuth H. Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine // Drug Metab Dispos. – 2001. – Vol. 29 (10). – Pр. 1343–1348.
  55. Mori A., Maruo Y., Iwai M. et al. UDP-glucuronosyltransferase 1a4 polymorphisms in a japanese population and kinetics of clozapine glucuronidation // Drug Metabolism and Disposition. – 2005. – Vol. 33 (5). – Pр. 672–675. – https://doi.org/10.1124/dmd.104.002576
  56. Marcuello E., Altеs A., Menoyo A. et al. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer // Br J Cancer. – 2004. – Vol. 91 (4). – Pр. 678–682. –ttps://doi.org/10.1038/sj.bjc.6602042
  57. Erickson-Ridout K.K., Sun D., Lazarus P. Glucuronidation of the second-generation antipsychotic clozapine and its active metabolite N-desmethylclozapine. Potential importance of the UGT1A1 A(TA)7TAA and UGT1A4 L48V polymorphisms // Pharmacogenet Genomics. – 2012. – Vol. 22 (8). – Pр. 561–576. – ttps://doi.org/10.1097/fpc.0b013e328354026b
  58. Yuen J.W.Y., Kim D.D., Procyshyn R.M. et al. A focused review of the metabolic side-effects of clozapine // Front Endocrinol (Lausanne). – 2021. – Vol. 12. – Art. 609240. – https://doi.org/10.3389/fendo.2021.609240
  59. Ying J., Chew Q.H., McIntyre R.S., Sim K. Treatment-resistant schizophrenia, clozapine resistance, genetic associations, and implications for precision psychiatry: A scoping review // Genes (Basel). – 2023. – Vol. 14 (3). – P. 689. – https://doi.org/10.3390/genes14030689
  60. Wu H., Kang H., Liu Y. et al. Roles of ABCB1 gene polymorphisms and haplotype in susceptibility to breast carcinoma risk and clinical outcomes // J Cancer Res Clin Oncol. – 2012. – Vol. 138 (9). – P. 1449–1462. – https://doi.org/10.1007/s00432-012-1209-z
  61. Consoli G., Lastella M., Ciapparelli A. et al. ABCB1 polymorphisms are associated with clozapine plasma levels in psychotic patients // Pharmacogenomics. – 2009. – Vol. 10 (8). – Pр. 1267–1276. – https://doi.org/10.2217/pgs.09.51
  62. Li X. Notable drug-drug interaction between omeprazole and voriconazole in CYP2C19 *1 and *2 (rs4244285, 681G>A) alleles in vitro // Xenobiotica. – 2024. – Pр. 1–8. – https://doi.org/10.1080/00498254.2024.2421513
  63. Smith R.L., Wollmann B.M., Kausberg M. et al. Effects of a novel UGT2B haplotype and UG-T1A4*3 allele variants on glucuronidation of clozapine in vivo // Curr Drug Metab. – 2022. – Vol. 23 (1). – Pр. 66–72. – https://doi.org/10.2174/1389200223666220201152953
  64. Алфимов П.В. Оленева Е.В., Мосолов С.Н. Прогностические факторы терапевтич эффективности клозапина при шизофрении // Современная терапия психических расстройств. – 2013. – №. 2. – С. 21–29. URL: https://ctmd.psypharma.ru/index.php/ctmd/article/view/273

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