Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia

Antipsychotic treatment response is highly heterogeneous and unpredictable in terms of both efficacy and side effects. A combination of factors influences treatment outcome, including clinical, demographic, environmental and genetic factors. No comprehensive studies have quantified the relative contributions of these factors to date. Two decades of pharmacogenetic and pharmacogenomic studies have attempted to identify key gene variants associated with antipsychotic response, with a dual goal of better understanding the mechanisms underlying drug response and guiding prescribing decisions in clinical care. Pharmacogenetic studies have succeeded in identifying several genes that are associated with antipsychotic treatment efficacy or side effects. However, the strength of these associations is modest and they are of limited clinical value. Genome-wide association studies, moving beyond hypothesis-based discovery, have greater potential to identify novel gene associations, although only a few genome-wide association studies have been conducted and they have not revealed clearly significant findings. The first pharmacogenetic tests to guide the selection or dosing of antipsychotic drugs are now commercially available. Their uptake has been limited by the modest level of prediction they offer, compounded by the lack of data supporting their clinical or economic benefits. Advances in genomic analysis techniques, the better characterization of larger subject cohorts and an improved understanding of the role of environmental factors and gene-environment interactions are renewing hope that future research will identify genetic variants with stronger associations with treatment outcome. Tests incorporating such genetic data, with environmental and clinical variables, may offer the potential to personalize medicine and significantly improve the efficacy and tolerability of antipsychotic treatment.