Pharmacogenetics of antipsychotic treatment: lessons learned from clozapine

The reintroduction of clozapine, the prototype of atypical antipsychotics, in the late 1980s has led to significant advances in the pharmacological management of schizophrenia. Since then, there has been a rapid development of novel "atypical" antipsychotic agents that have been pharmacologically modeled, to a certain extent, after their predecessor clozapine. As with all antipsychotics, there is variability among individuals in their response to these "atypical" drugs. Pharmacogenetics can provide a foundation for understanding this interindividual variability in antipsychotic response. This review first provides a rationale for the pharmacogenetic investigation of this variable trait. Studies of pharmacokinetic and pharmacodynamic factors of antipsychotic therapy are considered in the development of this rationale. Next, the molecular genetic techniques used to study this interindividual variation in response are described. This is followed by a review and discussion of the published studies examining genetic factors involved in clozapine response. From this, several recommendations for future pharmacogenetic investigations of antipsychotic response are proposed. Although still in its early stages, psychiatric pharmacogenetics should provide a basis for individualized pharmacotherapy of schizophrenia, and may also lead to the development of newer, more efficacious antipsychotic agents.