Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Impact of CYP1A2, CYP2C19, and CYP2D6 genotype- and phenoconversion-predicted enzyme activity on clozapine exposure and symptom severity

The Pharmacogenomics Journal volume 20, pages 192–201 (2020)Cite this article

Subjects

Abstract

Clozapine is an atypical antipsychotic metabolized by CYP1A2, CYP2D6, and CYP2C19 enzymes. Among 66 adult schizophrenia patients treated with clozapine-based combination therapies, we explored the impact of genotype-predicted CYP1A2, CYP2D6, and CYP2C19 activity on dose-adjusted clozapine concentrations and symptom severity, with and without correction for inhibitors and inducers of these enzymes. Uncorrected activity scores were not associated with dose-adjusted clozapine concentrations or symptom severity. CYP1A2 and CYP2D6 activity scores corrected for known inducers (i.e., smoking) and inhibitors (e.g., concomitant medications) were associated with dose-adjusted clozapine levels and in the case of CYP1A2, symptom severity. However, smoking status and certain inhibitors of clozapine metabolism (i.e., esomeprazole) explained significantly more variance in dose-adjusted clozapine levels relative to corrected activity scores. These findings highlight the clinical importance of nongenetic factors (smoking, concomitant medications) and suggest that the added utility of CYP1A2, CYP2D6, and CYP2C19 activity scores to guide clozapine dosing is currently limited.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Pantelis C, Lambert TJ. Managing patients with “treatment-resistant” schizophrenia. Med J Aust. 2003;178:S62–6.

    Article  PubMed  Google Scholar 

  2. Andreasen NC, Carpenter WT Jr., Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 2005;162:441–9.

    Article  PubMed  Google Scholar 

  3. Warnez S, Alessi-Severini S. Clozapine: a review of clinical practice guidelines and prescribing trends. BMC Psychiatry. 2014;14:102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia AG, et al. Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics. Psychopharmacol (Berl). 2000;148:83–9.

    Article  CAS  Google Scholar 

  5. Freudenreich O, McEvoy J Guidelines for prescribing clozapine in schizophrenia. Waltham, MA 2018.

  6. Piwowarska J, Radziwon-Zaleska M, Dmochowska M, Szepietowska E, Matsumoto H, Sygitowicz G, et al. The usefulness of monitored therapy using Clozapine concentration in the blood serum for determining drug dose in Polish schizophrenic patients. Pharm Rep. 2016;68:1120–5.

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Dragovic S, Gunness P, Ingelman-Sundberg M, Vermeulen NP, Commandeur JN. Characterization of human cytochrome P450s involved in the bioactivation of clozapine. Drug Metab Dispos. 2013;41:651–8.

    Article  CAS  PubMed  Google Scholar 

  9. Jaquenoud Sirot E, Knezevic B, Morena GP, Harenberg S, Oneda B, Crettol S, et al. ABCB1 and cytochrome P450 polymorphisms: clinical pharmacogenetics of clozapine. J Clin Psychopharmacol. 2009;29:319–26.

    Article  CAS  PubMed  Google Scholar 

  10. Brennan MD. Pharmacogenetics of second-generation antipsychotics. Pharmacogenomics. 2014;15:869–84.

    Article  CAS  PubMed  Google Scholar 

  11. Lee ST, Ryu S, Kim SR, Kim MJ, Kim S, Kim JW, et al. Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response. J Clin Psychopharmacol. 2012;32:441–8.

    Article  CAS  PubMed  Google Scholar 

  12. Pouget JG, Shams TA, Tiwari AK, Muller DJ. Pharmacogenetics and outcome with antipsychotic drugs. Dialogues Clin Neurosci. 2014;16:555–66.

    PubMed  PubMed Central  Google Scholar 

  13. Preskorn SH, Kane CP, Lobello K, Nichols AI, Fayyad R, Buckley G, et al. Cytochrome P450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry. 2013;74:614–21.

    Article  CAS  PubMed  Google Scholar 

  14. Shah RR, Smith RL. Addressing phenoconversion: the Achilles’ heel of personalized medicine. Br J Clin Pharm. 2015;79:222–40.

    Article  Google Scholar 

  15. Mostafa S, Kirkpatrick CMJ, Byron K, Sheffield L An analysis of allele, genotype and phenotype frequencies, actionable pharmacogenomic (PGx) variants and phenoconversion in 5408 Australian patients genotyped for CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes. J Neural Transm (Vienna). 2018;8–15.

  16. Seppala NH, Leinonen EV, Lehtonen ML, Kivisto KT. Clozapine serum concentrations are lower in smoking than in non-smoking schizophrenic patients. Pharm Toxicol. 1999;85:244–6.

    Article  CAS  Google Scholar 

  17. Meyer JM. Individual changes in clozapine levels after smoking cessation: results and a predictive model. J Clin Psychopharmacol. 2001;21:569–74.

    Article  CAS  PubMed  Google Scholar 

  18. Barnes TRE, Paton C. Antipsychotic polypharmacy in schizophrenia. CNS Drugs. 2011;25:383–99.

    Article  PubMed  Google Scholar 

  19. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV axis I disorders, clinician version (SCID-CV). Washington, D.C.: American Psychiatric Press, Inc; 1996.

    Google Scholar 

  20. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The mini-international neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22–33. quiz 4-57

    PubMed  Google Scholar 

  21. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261–76.

    Article  CAS  PubMed  Google Scholar 

  22. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–4.

    Article  CAS  Google Scholar 

  23. Mostaid MS, Lee TT, Chana G, Sundram S, Shannon Weickert C, Pantelis C, et al. Elevated peripheral expression of neuregulin-1 (NRG1) mRNA isoforms in clozapine-treated schizophrenia patients. Transl Psychiatry. 2017;7:1280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Enoch MA, Shen PH, Xu K, Hodgkinson C, Goldman D. Using ancestry-informative markers to define populations and detect population stratification. J Psychopharmacol. 2006;20(4 Suppl):19–26.

    Article  PubMed  Google Scholar 

  25. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharm Ther. 2008;83:234–42.

    Article  CAS  Google Scholar 

  26. Hicks JK, Swen JJ, Gaedigk A. Challenges in CYP2D6 phenotype assignment from genotype data: a critical assessment and call for standardization. Curr Drug Metab. 2014;15:218–32.

    Article  CAS  PubMed  Google Scholar 

  27. Mrazek DA, Biernacka JM, O’Kane DJ, Black JL, Cunningham JM, Drews MS, et al. CYP2C19 variation and citalopram response. Pharmacogenet Genomics. 2011;21:1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Saiz-Rodríguez M, Ochoa D, Belmonte C, Román M, Vieira de Lara D, Zubiaur P, et al. Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics. J Psychopharmacol. 2019;33:522–31.

    Article  CAS  PubMed  Google Scholar 

  29. Jeppesen U, Gram LF, Vistisen K, Loft S, Poulsen HE, Brøsen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharm. 1996;51:73–8.

    Article  CAS  Google Scholar 

  30. Harvey AT, Preskorn SH. Fluoxetine pharmacokinetics and effect on CYP2C19 in young and elderly volunteers. J Clin Psychopharmacol. 2001;21:161–6.

    Article  CAS  PubMed  Google Scholar 

  31. Preskorn SH, Greenblatt DJ, Flockhart D, Luo Y, Perloff ES, Harmatz JS, et al. Comparison of duloxetine, escitalopram, and sertraline effects on cytochrome P450 2D6 function in healthy volunteers. J Clin Psychopharmacol. 2007;27:28–34.

    Article  CAS  PubMed  Google Scholar 

  32. Klieber M, Oberacher H, Hofstaetter S, Beer B, Neururer M, Amann A, et al. CYP2C19 phenoconversion by routinely prescribed proton pump inhibitors omeprazole and esomeprazole: clinical implications for personalized medicine. J Pharm Exp Ther. 2015;354:426–30.

    Article  CAS  Google Scholar 

  33. Hägg S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharm. 2001;51:169–73.

    Article  Google Scholar 

  34. Dobrinas M, Cornuz J, Oneda B, Kohler Serra M, Puhl M, Eap CB. Impact of smoking, smoking cessation, and genetic polymorphisms on CYP1A2 activity and inducibility. Clin Pharm Ther. 2011;90:117–25.

    Article  CAS  Google Scholar 

  35. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat SocietySeries B (Methodol). 1995;57:289–300.

    Google Scholar 

  36. Jamovi. The jamovi project. Version 0.9. Jamovi. https://www.jamovi.org; 2019.

  37. Excoffier L, Lischer HE. Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour. 2010;10:564–7.

    Article  PubMed  Google Scholar 

  38. Vasudev K, Choi YH, Norman R, Kim RB, Schwarz UI. Genetic determinants of clozapine-induced metabolic side effects. Can J Psychiatry. 2017;62:138–49.

    Article  PubMed  Google Scholar 

  39. Wiciński M, Węclewicz MM, Miętkiewicz M, Malinowski B, Grześk E, Klonowska J. Potential mechanisms of hematological adverse drug reactions in patients receiving clozapine in combination with proton pump inhibitors. J Psychiatr Pract. 2017;23:114–20.

    Article  PubMed  Google Scholar 

  40. van Veggel M, Olofinjana O, Davies G, Taylor D. Clozapine and gastro-oesophageal reflux disease (GORD) - an investigation of temporal association. Acta Psychiatr Scand. 2013;127:69–77.

    Article  CAS  PubMed  Google Scholar 

  41. Piatkov I, Caetano D, Assur Y, Lau SL, Coelho M, Jones T, et al. CYP2C19*17 protects against metabolic complications of clozapine treatment. World J Biol Psychiatry. 2017;18:521–7.

    Article  PubMed  Google Scholar 

  42. Diaz FJ, Eap CB, Ansermot N, Crettol S, Spina E, de Leon J. Can valproic acid be an inducer of clozapine metabolism? Pharmacopsychiatry. 2014;47:89–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Finley P, Warner D. Potential impact of valproic acid therapy on clozapine disposition. Biol Psychiatry. 1994;36:487–8.

    Article  CAS  PubMed  Google Scholar 

  44. Longo LP, Salzman C. Valproic acid effects on serum concentrations of clozapine and norclozapine. Am J Psychiatry. 1995;152:650.

    CAS  PubMed  Google Scholar 

  45. Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol. 2004;24:70–8.

    Article  CAS  PubMed  Google Scholar 

  46. Couchman L, Morgan PE, Spencer EP, Flanagan RJ. Plasma clozapine, norclozapine, and the clozapine:norclozapine ratio in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1993-2007. Ther Drug Monit. 2010;32:438–47.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge the Cooperative Research Centre (CRC) Scientific Advisory Committee, in addition to the contributions of study participants, clinicians at recruitment services, staff at the Murdoch Children’s Research Institute, staff at the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Aging, and research staff at the Melbourne Neuropsychiatry Centre, including coordinators Phassouliotis, C., Merritt, A., and research assistants, Burnside, A., Cross, H., Gale, S., and Tahtalian, S. Participants for this study were sourced, in part, through the Australian Schizophrenia Research Bank (ASRB), which is supported by the National Health and Medical Research Council of Australia (Enabling Grant N. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. The authors acknowledge the financial support of The CRC programme, an Australian Government Initiative. DL was supported by the J.N. Peters Postdoctoral Fellowship awarded by the University of Melbourne. CP was supported by an NHMRC Senior Principal Research Fellowship (1105825), and a Brain and Behavior Research Foundation (NARSAD) Distinguished Investigator Award. CAB was supported by an NHMRC Career Development Fellowship (1127700), The University of Calgary Cumming School of Medicine, and the Alberta Children’s Hospital Foundation. None of the funding sources played any role in the study design; collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Author information

Authors and Affiliations

  1. Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne & Melbourne Health, Melbourne, VIC, Australia

    Dorothea Lesche, Ian Everall, Christos Pantelis & Chad A. Bousman

  2. myDNA Life Australia Limited, South Yarra, VIC, Australia

    Sam Mostafa

  3. Centre for Medicine Use and Safety, Monash University, Parkville, VIC, Australia

    Sam Mostafa

  4. Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom

    Ian Everall

  5. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia

    Ian Everall & Christos Pantelis

  6. The Cooperative Research Centre (CRC) for Mental Health, VIC, Australia

    Ian Everall, Christos Pantelis & Chad A. Bousman

  7. Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Chad A. Bousman

  8. Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Chad A. Bousman

  9. Departments of Medical Genetics, Psychiatry, and Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada

    Chad A. Bousman

Authors
  1. Dorothea Lesche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sam Mostafa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ian Everall
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christos Pantelis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chad A. Bousman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chad A. Bousman.

Ethics declarations

Conflict of interest

SM is an employee of myDNA Inc., a company that provides pharmacogenetic testing. CP has participated on Advisory Boards for Janssen-Cilag, Astra-Zeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by Astra-Zeneca, Janssen-Cilag, Eli-Lilly, Pfizer, Lundbeck, and Shire. CAB is a member of Clinical Pharmacogenetics Implementation Consortium and the Genetic Testing Committee of the International Society of Psychiatric Genetics. He has also received material support from Assurex, CNSDose, Genomind, and AB-Biotics for research purposes and has ongoing research collaborations with MyDNA but does not have equity, stocks, or options in these companies or any other pharmacogenetic companies. The other authors of this manuscript have no relevant disclosures.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lesche, D., Mostafa, S., Everall, I. et al. Impact of CYP1A2, CYP2C19, and CYP2D6 genotype- and phenoconversion-predicted enzyme activity on clozapine exposure and symptom severity. Pharmacogenomics J 20, 192–201 (2020). https://doi.org/10.1038/s41397-019-0108-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-019-0108-y

This article is cited by

Search

Advanced search

Quick links