Clinical implications of CYP2D6 genetic polymorphism during treatment with antipsychotic drugs

CYP2D6 is described as the most relevant enzyme in the metabolism of many antipsychotic drugs. Its contribution to the inter-individual differences in drug response is reviewed here highlighting its role in the kinetics of antipsychotic drugs and the occurrence of drug interactions. The activity of CYP2D6 is inherited as a monogenetic trait and the CYP2D6 gene appears highly polymorphic in humans. The polymorphic alleles may lead to altered activity of the CYP enzymes causing absent, decreased (poor), or increased (ultrarapid) metabolism that in turn influence the disposition of the antipsychotic drugs. Antipsychotic drug biotransformation is mainly determined by genetic factors mediating CYP2D6 gene polymorphism, however the importance of environmental factors (dietary, smoking, diseases, etc.) is also recognized. Additionally, the potential interaction between CYP2D6 and the endogenous metabolism must be taken into consideration. The present review summarizes the relevance of physiological and environmental factors in CYP2D6 hydroxylation capacity, the inhibition of CYP2D6 activity during treatment, the use of drug/metabolite ratio as a tool to evaluate CYP2D6 hydroxylation capacity in a patient, and the relevance of CYP2D6 for drug plasma concentration and for QTc interval lengthening during treatment with antipsychotic drugs.