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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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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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.
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.
The authors declare no competing interests.
This research involves a literature study and no human subjects, human material, or human data. Therefore, no approval by an ethics committee was needed.
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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