Pharmacogenetics of Response to Antipsychotics in Patients with Schizophrenia

This review presents the findings of pharmacogenetic studies exploring the influence of gene variants on antipsychotic treatment response, in terms of both symptom improvement and adverse effects, in patients with schizophrenia. Despite numerous studies in the field, replicating findings across different cohorts that include subjects of different ethnic groups has been challenging. It is clear that non-genetic factors have an important contribution to antipsychotic treatment response. Differing clinical, demographic and environmental characteristics of the cohorts studied have added substantial complexity to the interpretation of the positive and negative findings of many studies. Pharmacogenomic genome-wide investigations are beginning to yield interesting data although they have failed to replicate the most robust findings of candidate gene studies, and are limited by the sample size, especially given the need for studying homogeneous cohorts. Most of the studies conducted on cohorts treated with single antipsychotics have investigated clozapine, olanzapine or risperidone response. These studies have provided some of the most replicated associations with treatment efficacy. Serotonergic system gene variants are significantly associated with the efficacy of clozapine and risperidone, but may have less influence on the efficacy of olanzapine. Dopamine D-3 receptor polymorphisms have been more strongly associated with the efficacy of clozapine and olanzapine, and D-2 genetic variants with the efficacy of risperidone. Serotonin influences the control of feeding behaviour and has been hypothesized to have a role in the development of antipsychotic-induced weight gain. Numerous studies have linked the serotonin receptor 2C (5-HT2C) -759-C/T polymorphism with weight gain. The leptin gene variant, -2548-G/A, has also been associated with weight gain in several studies. Pharmacogenetic studies support the role of cytochrome P450 enzymes and dopamine receptor variants in the development of antipsychotic-induced movement disorders, with a contribution of serotonergic receptors and other gene variants implicated in the mechanism of action of antipsychotics. Clozapine-induced agranulocytosis has been associated with polymorphisms in the major histocompatibility complex gene (HLA).