Pharmacogenetics of antipsychotic therapy: pivotal research issues and the prospects for clinical implementation

The core hypothesis underlying pharmacogenetics is that genetic factors play a significant role in the well-recognized differences between individuals in response to medication and susceptibility to adverse effects. If these genetic factors can be identified and understood, they may serve as predictors to guide clinicians in tailoring medication to the individual patient. Recent developments in the field of antipsychotic drug treatment suggest that pharmacogenetics could play an important role, permitting the use of first-generation antipsychotics (FGAs) for patients in whom the use of second-generation antipsychotics (SGAs) is limited by efficacy considerations or adverse effects. In this paper, key issues that need to be taken into consideration in designing and interpreting pharmacogenetic studies of antipsychotic drugs are discussed against the background of data emanating from studies on the genetics of tardive dyskinesia (TD), an important adverse effect of FGAs. The issues considered include the advantages and potential pitfalls of case-control association studies of pharmacogenetic traits, the role of demographic factors such as age and gender, additive effects of genes, and gene-gene and gene-environment interaction. The prospects for implementation of pharmacogenetic testing in the clinic are considered in the context of a preliminary model that has been tested for prediction of susceptibility to TD.