Pharmacogenetics of classical and new antipsychotic drugs

Several classical antipsychotic drugs, i.e., chlorpromazine, haloperidol, perphenazine, thioridazine and zuclopenthixol; and some new neuroleptic drugs, i.e., risperidone and sertindole, are metabolized predominantly by cytochrome P450 (CYP) 2D6. Significant relationships have been reported between the steady state plasma concentrations (Css) of some classical neuroleptics and the CYP2D6 activity or genotype. Several of these drugs also potently inhibit the CYP2D6 activity. These facts explain several drug metabolic interactions of the classical drugs. Two studies failed to show that the CYP2D6 activity predicts the therapeutic effects of haloperidol or perphenazine. Some studies have suggested that the poor metabolizer phenotype is associated with the development of oversedation during treatment with the classical drugs, but other studies have been inconsistent or negative. The CYP2D6 phenotyping and genotyping appear to be useful in predicting the Css of some classical drugs, but their usefulness in predicting clinical effects must be further explored.