Pharmacogenetics and association studies in schizophrenia

Abstract We present an overview of the contribution of genetic association studies on understanding schizophrenia pharmacogenomics. Using a MEDLINE search (March 2003), we identified 96 reports on genetic associations of diverse polymorphisms with response to therapy or adverse events from antipsychotics. Most studies have targeted polymorphisms in the cytochrome p450 metabolizing gene system, the dopamine receptor genes, and the serotonin receptors and serotonin transporter genes, but an increasing number of new gene targets is added continuously. We could identify more than 2 published reports only for 16 pharmacogenetic associations, and only 10 of them have had more than 3 published reports. Most of these studies have had small sample size and none recruited >1,000 patients with schizophrenia. Sample size exceeded 600 patients in 3 reports by the same team and no significant association has been found in these reports for 9 distinct polymorphisms of the DRD2 gene, two polymorphisms of the serotonin transporter gene, or the 48‐bp VNTR polymorphism of the DRD4 gene. Meta‐analyses of the 102‐T/C and the His452Tyr polymorphisms of the HTR2A gene and of the Ser9Gly polymorphism of the DRD3 gene suggest a significant association with therapeutic response that is, nevertheless, no longer formally statistically significant when the first, hypothesis‐generating study is excluded. Genetic association studies are a valuable tool in schizophrenia pharmacogenetic research. However, large, carefully conducted studies with appropriately defined analysis and outcomes and full reporting, as well as validation of associations across several studies, are essential for creating a rational knowledge base in this field. Drug Dev. Res. 60:152–163, 2003. © 2003 Wiley‐Liss, Inc.