ESHGwww.nature.com/ejhgARTICLE周Check for updatesDutch Pharmacogenetics Working Group(DPWG)guideline forthe gene-drug interaction between CYP2D6,CYP3A4 andCYP1A2 and antipsychoticsLianne Beunk',Marga Nijenhuis2 Bianca Soree?,Nienke J.de Boer-Veger,Anne-Marie Buunk,Henk Jan Guchelaar,Elisa J.F.Houwink7,Arne Risselada,Gerard A.P.J.M.Rongen10,Ron H.N.van Schaik'1,Jesse J.Swen5,Daan Touw1213,Roos van WestrhenenVera H.M.Deneer and Jan van der WeideThe Author(s),under exclusive licence to European Society of Human Genetics 2023The Dutch Pharmacogenetics Working Group(DPWG)aims to facilitate pharmacogenetics implementation in clinical practice bydeveloping evidence-based guidelines to optimize pharmacotherapy.A guideline describing the gene-drug interaction betweenthe genes CYP2D6,CYP3A4 and CYP1A2 and antipsychotics is presented here.The DPWG identified gene-drug interactions thatrequire 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 obtainedbased on a systematic review of published literature.Reduction of the normal dose is recommended for aripiprazole,brexpiprazole,haloperidol,pimozide,risperidone and zudopenthixol for CYP2D6-predicted PMs,and for pimozide and zudopenthixol also forCYP2D6 IMs.For CYP2D6 UMs,a dose increase or an alternative drug is recommended for haloperidol and an alternative drug ortitration of the dose for risperidone.In addition,in case of no or limited dinical effect,a dose increase is recommended forzudopenthixol for CYP2D6 UMs.Even though evidence is limited,the DPWG recommends choosing an alternative drug to treatsymptoms of depression or a dose reduction for other indications for quetiapine and CYP3A4 PMs.No therapy adjustments arerecommended for the other CYP2D6 and CYP3A4 predicted phenotypes.In addition,no action is required for the gene-drugcombinations CYP2D6 and clozapine,flupentixol,olanzapine or quetiapine and also not for CYP1A2 and clozapine or olanzapine.Foridentified gene-drug interactions requiring therapy adjustments,genotyping of CYP2D6 or CYP3A4 prior to treatment should not beconsidered for all patients,but on an individual patient basis only.European Journal of Human Genetics;https://doi.org/10.1038/s41431-023-01347-3INTRODUCTIONDPWG develops evidence-based drug-specific PGx-guided ther-The study of effects of heritable genetic variation on drugapeutic recommendations based on systematic literature review,response is referred to as pharmacogenetics(PGx).Although theof which the identity of incuded guidelines is based on thevalue of PGx is widely recognized,its implementation in dailyneed for them in clinical practice.In addition,it implementsclinical practice remains challenging [1],also in psychiatry [2,3].these recommendations into computerized systems usedBarriers for implementation in clinical settings include the lack ofnationwide
