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Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics

European Journal of Human Genetics (2023)Cite this article

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Abstract

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy. A guideline describing the gene-drug interaction between the genes CYP2D6, CYP3A4 and CYP1A2 and antipsychotics is presented here. The DPWG identified gene-drug interactions that require therapy adjustments when respective genotype is known for CYP2D6 with aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol, and for CYP3A4 with quetiapine. Evidence-based dose recommendations were obtained based on a systematic review of published literature. Reduction of the normal dose is recommended for aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol for CYP2D6-predicted PMs, and for pimozide and zuclopenthixol also for CYP2D6 IMs. For CYP2D6 UMs, a dose increase or an alternative drug is recommended for haloperidol and an alternative drug or titration of the dose for risperidone. In addition, in case of no or limited clinical effect, a dose increase is recommended for zuclopenthixol for CYP2D6 UMs. Even though evidence is limited, the DPWG recommends choosing an alternative drug to treat symptoms of depression or a dose reduction for other indications for quetiapine and CYP3A4 PMs. No therapy adjustments are recommended for the other CYP2D6 and CYP3A4 predicted phenotypes. In addition, no action is required for the gene-drug combinations CYP2D6 and clozapine, flupentixol, olanzapine or quetiapine and also not for CYP1A2 and clozapine or olanzapine. For identified gene-drug interactions requiring therapy adjustments, genotyping of CYP2D6 or CYP3A4 prior to treatment should not be considered for all patients, but on an individual patient basis only.

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Data availability

All data and material are either included in the Supplementary information or publicly available (i.e., the published articles, PubMed). The guidelines and background information are available on the website of the Royal Dutch Pharmacists Association (KNMP) (Pharmacogenetic Recommendation Text. Available from: https://www.knmp.nl/). The guidelines and background information will also be available on PharmGKB.org.

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Acknowledgements

We want to thank Leonora Grandia and Anna de Goede for performing the systematic reviews in 2005 and 2006, Mandy van Rhenen for performing the 2013 update of clozapine and CYP2D6 and the 2014 updates of pimozide and risperidone and CYP2D6, and Yasmina Laouti for performing the 2020 updates of clozapine, haloperidol and zuclopenthixol and CYP2D6.

Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 668353. The DPWG received funding from the Royal Dutch Pharmacists Association.

Author information

Authors and Affiliations

  1. Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, the Netherlands

    Lianne Beunk & Jan van der Weide

  2. Royal Dutch Pharmacists Association (KNMP), The Hague, the Netherlands

    Marga Nijenhuis & Bianca Soree

  3. Pharmacy Boterdiep, Groningen, the Netherlands

    Nienke J. de Boer-Veger

  4. Pharmacy De Katwijkse Apotheek, Katwijk, the Netherlands

    Anne-Marie Buunk

  5. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands

    Henk Jan Guchelaar & Jesse J. Swen

  6. Department of Public Health and Primary Care (PHEG), Leiden University Medical Center, Leiden, the Netherlands

    Elisa J. F. Houwink

  7. National eHealth Living Lab (NELL), Leiden, the Netherlands

    Elisa J. F. Houwink

  8. Department of Clinical Pharmacy, Wilhelmina Hospital, Assen, the Netherlands

    Arne Risselada

  9. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands

    Gerard A. P. J. M. Rongen

  10. Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands

    Gerard A. P. J. M. Rongen

  11. Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands

    Ron H. N. van Schaik

  12. Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands

    Daan Touw

  13. Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    Daan Touw

  14. Department of Psychiatry, Parnassia Group, Amsterdam, the Netherlands

    Roos van Westrhenen

  15. Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands

    Roos van Westrhenen

  16. Institute of Psychiatry, Psychology&Neuroscience (IoPPN), King’s College London, London, UK

    Roos van Westrhenen

  17. Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands

    Vera H. M. Deneer

  18. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands

    Vera H. M. Deneer

Authors
  1. Lianne Beunk
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Contributions

LB drafted the manuscript and contributed to interpretation of results. JvW supervised drafting of the manuscript and contributed to conceiving the work and interpretation of the results. MN contributed to conceiving the work and interpretation of the results, and performed the data extraction. BS drafted and published English versions of clinical decision support texts. NBV, AB, HG, EH, AR, GR, RvS, JS, DT, RvW, and VD contributed to conceiving the work and interpretation of the results. In addition, all authors revised the manuscript and approved the final version as well as agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Marga Nijenhuis.

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Beunk, L., Nijenhuis, M., Soree, B. et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. Eur J Hum Genet (2023). https://doi.org/10.1038/s41431-023-01347-3

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