title: Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine.
abstract: 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.GRM2(rs4067 and rs2518461),SLC1A2(rs4354668, rs4534557, and rs2901534),SLC6A9(rs12037805, rs1978195, and rs16831558),GRIA1(rs2195450), andGAD1(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 χ2tests and analysis of covariance, respectively. We report no significant associations following correction for multiple testing. Prior to correction, nominally significant associations were observed forSLC6A9,SLC1A2,GRM2, andGRIA1. Most notably, CC homozygotes of rs16831558 located in the glycine transporter 1 gene(SLC6A9)exhibited an allele dose-dependent improvement in positive symptoms compared to T allele carriers (puncorrected= 0.008, pcorrected= 0.08). To clarify the role ofSLC6A9in clinical response to antipsychotic medication, and CLZ in particular, this finding warrants further investigation in larger well-characterized samples.
authors.affiliation: Neuroscience Research Department, Campbell Family Research Institute, Toronto, Ont., Canada; Institute of Medical Science, Toronto, Ont., Canada.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Taylor
authors.affiliation: Neuroscience Research Department, Campbell Family Research Institute, Toronto, Ont., Canada.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Tiwari
authors.affiliation: Department of Psychiatry, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York, N.Y, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.affiliation: Department of Psychiatry, University of California, Irvine, Calif, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Potkin
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Ill., USA.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.affiliation: Neuroscience Research Department, Campbell Family Research Institute, Toronto, Ont., Canada; Institute of Medical Science, Toronto, Ont., Canada; Department of Psychiatry, University of Toronto, Toronto, Ont., Canada; Lancaster Medical School and Data Science Institute, Lancaster University, Lancaster, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Knight
authors.affiliation: Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ont., Canada; Department of Psychiatry, University of Toronto, Toronto, Ont., Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Remington
authors.affiliation: Neuroscience Research Department, Campbell Family Research Institute, Toronto, Ont., Canada; Institute of Medical Science, Toronto, Ont., Canada; Department of Psychiatry, University of Toronto, Toronto, Ont., Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.affiliation: Neuroscience Research Department, Campbell Family Research Institute, Toronto, Ont., Canada; Institute of Medical Science, Toronto, Ont., Canada; Department of Psychiatry, University of Toronto, Toronto, Ont., Canada.
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
keywords: Clozapine; Glutamate; Glycine transporter 1 (SLC6A9); Pharmacogenetics; Schizophrenia