Cytochrome P450 Phenotyping/Genotyping in Patients Receiving Antipsychotics

Abstract

Many antipsychotics, including perphenazine, zuclopenthixol, thioridazine, haloperidol and risperidone, are metabolised to a significant extent by the polymorphic cytochrome P450 (CYP) 2D6, which shows large interindividual variation in activity. Significant relationships between CYP2D6 genotype and steady-state concentrations have been reported for perphenazine, zuclopenthixol, risperidone and haloperidol when used in monotherapy. Other CYPs, especially CYP1A2 and CYP3A4, also contribute to the interindividual variability in the kinetics of antipsychotics and the occurrence of drug interactions. For many antipsychotics, the role of the different CYPs at therapeutic drug concentrations remains to be clarified. Some studies have suggested that poor metabolisers for CYP2D6 would be more prone to oversedation and possibly parkinsonism during treatment with classical antipsychotics, whereas other, mostly retrospective, studies have been negative or inconclusive. For the newer antipsychotics, such data are lacking. Whether phenotyping or genotyping for CYP2D6 or other CYPs can be used to predict an optimal dose range has not been studied so far. Genotyping or phenotyping can today be recommended as a complement to plasma concentration determination when aberrant metabolic capacity (poor or ultrarapid) of CYP2D6 substrates is suspected. The current rapid developments in molecular genetic methodology and pharmacogenetic knowledge can in the near future be expected to provide new tools for prediction of the activity of the various drugmetabolising enzymes. Further prospective clinical studies in well-defined patient populations and with adequate evaluation of therapeutic and adverse effects are required to establish the potential of pharmacogenetic testing in clinical psychiatry.