The pharmacogenetics of symptom response to antipsychotic drugs

Antipsychotic drugs are limited in their efficacy by the relatively poor response of negative and cognitive symptoms of schizophrenia as well as by the substantial variability in response between patients. Pharmacogenetic studies have sought to identify the genetic factors that underlie the individual variability in response to treatment, with a past emphasis on dopamine and serotonin receptors as candidate genes. Few studies have separated effects on positive and negative symptoms, despite the established differences in response to drug treatment between these syndromes. Where this has been done most findings are consistent with the conclusion that dopamine receptor polymorphisms relate to positive symptom response, while negative symptom improvement is influenced by polymorphisms of genes involved in 5-HT neurotransmission. A wide range of polymorphisms in other candidate genes have been investigated, with some positive findings in those genes associated with glutamatergic transmission and/or risk factors for schizophrenia. However, there remains a lack of good replicated findings; furthermore there is little evidence to support drug-specific genetic associations with treatment response. While most past studies focused on single candidate genes, technology now permits genome-wide association studies with response to antipsychotics. Although not without major limitations, these "hypothesis-free" approaches are beginning to identify further important risk factors for treatment response. Again there is little consistency between various studies, although some of the polymorphisms identified are in genes involved in neurodevelopment, which is increasingly being recognized as important in the pathophysiology of schizophrenia.