Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine.

Altered glutamate neurotransmission is implicated in the etiology of schizophrenia (SCZ) and the pharmacogenetics of response to clozapine (CLZ), which is the drug of choice for treatment-resistant SCZ. Response to antipsychotic therapy is highly variable, although twin studies suggest a genetic component. We investigated the association of 10 glutamate system gene variants with CLZ response using standard genotyping procedures. (rs4067 and rs2518461), (rs4354668, rs4534557, and rs2901534), (rs12037805, rs1978195, and rs16831558), (rs2195450), and (rs3749034) were typed in 163 European SCZ/schizoaffective disorder patients deemed resistant or intolerant to previous pharmacotherapy. Response was assessed following 6 months of CLZ monotherapy using change in Brief Psychiatric Rating Scale (BPRS) scores. Categorical and continuous response variables were analyzed using χ tests and analysis of covariance, respectively. We report no significant associations following correction for multiple testing. Prior to correction, nominally significant associations were observed for , , , and . Most notably, CC homozygotes of rs16831558 located in the glycine transporter 1 gene exhibited an allele dose-dependent improvement in positive symptoms compared to T allele carriers (p = 0.008, p = 0.08). To clarify the role of in clinical response to antipsychotic medication, and CLZ in particular, this finding warrants further investigation in larger well-characterized samples.