Pharmacogenetics of antipsychoatics.

Abstract

Although a number of antipsychotics have been introduced for the treatment of schizophrenia, inter-individual differences of in antipsychotic response and the number of refractory schizophrenic patients have become two of the most challenging problems in clinical psychiatry. Thus, the pharmacogenetics of antipsychotics have been aimed at providing genetic components of this inter-individual variability in antipsychotic response in order to establish an individually-based pharmacotherapy for schizophrenia and to elucidate the mechanism of antipsychotic response so as to solve the refractoriness of schizophrenia. Pharmacogenetics, which is defined as the science of pharmacological response and its modification by hereditary influence can be divided into two categories: the genetic background of pharmacokinetics, i.e. the absorption, distribution, tissue localization, biotransformation and excretion of drugs, and pharmacodynamics, i.e. the biochemical and physiological consequences of a drug and its mechanism of action. Pharmacokinetics of antipsychotics has been focused mainly on the association between genetic polymorphisms in CYP genes, including CYP2D6, and the metabolism of these drugs. Polymorphism in CYP2D6 enables a division of individuals within a given population into at least two groups, i.e. poor metabolizers (PMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs) of certain drugs. PMs have higher plasma concentrations of and more adverse effects from antipsychotics. UMs could be one of the important factors that induce treatment-refractoriness to antipsychotics. Genetic polymorphisms in serotonin and dopamine receptors that have a high affinity for antipsychotics have so far been extensively investigated in the pharmacodynamics of this type of drug. Not just one gene but multiple genes play a role in complex phenotypes, including the clinical response to medication. Thus, a multiple candidate genes approach has recently been adopted in the pharmacogenetics of antipsychotics. The new field of pharmacogenomics using DNA microarray analysis, which focuses on the genetic determinants of drug response at the level of the entire human genome, is important for development and prescription of safer and more effective individually-tailored antipsychotics.