Antipsychotic Pharmacogenetics in First Episode Psychosis: Is There a Role for Glutamate Genes?

Symptomatic response to antipsychotic treatment in patients treated for psychotic disorders is highly heterogeneous. The reasons for variable response and tolerability are unclear, but likely multifactorial including biological, environmental, and clinical contributors. Systematically examining these factors is necessary for us to improve current treatment strategies. Biological contributors may involve aberrant glutamate transmission which is thought to contribute to the pathophysiology of psychotic disorders and influence treatment response. In the present study we examined genetic associations between variants in genes related to glutamate signaling and disposition and performed a genome-wide association study to identify other polymorphisms associated with antipsychotic response in first episode psychosis. We found a significant association between negative symptom response and rs274622 in GRM3, which has previously been associated with negative symptom response in schizophrenia. GRM7 and SLC38A1, both previously unstudied in the context of antipsychotic response, showed potential for association although no single SNP in either gene was statistically significant after adjusting for multiple comparisons. Our genome-wide analysis identified two SNPs in GRID2 significantly associated with antipsychotic response. Recent evidence suggests that GluD2, the product of GRID2, interacts with the glutamate neurotransmitter system. Together, our results suggest that genetic polymorphisms related to the glutamate neurotransmitter system may influence antipsychotic response in first episode psychosis.