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

Danielle L Taylor; Arun K Tiwari; Jeffrey A Lieberman; Steven G Potkin; Herbert Y Meltzer; Joanne Knight; Gary Remington; Daniel J Müller; James L Kennedy

doi:10.1159/000449224

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

Mol Neuropsychiatry. 2017 Feb;2(4):185-197. doi: 10.1159/000449224. Epub 2016 Oct 12.

Authors

Danielle L Taylor¹, Arun K Tiwari², Jeffrey A Lieberman³, Steven G Potkin⁴, Herbert Y Meltzer⁵, Joanne Knight⁶, Gary Remington⁷, Daniel J Müller⁸, James L Kennedy⁸

Affiliations

¹ Neuroscience Research Department, Campbell Family Research Institute, Toronto, Ont., Canada; Institute of Medical Science, Toronto, Ont., Canada.
² Neuroscience Research Department, Campbell Family Research Institute, Toronto, Ont., Canada.
³ Department of Psychiatry, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York, N.Y, USA.
⁴ Department of Psychiatry, University of California, Irvine, Calif, USA.
⁵ Northwestern University Feinberg School of Medicine, Chicago, Ill., USA.
⁶ 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.
⁷ Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ont., Canada; Department of Psychiatry, University of Toronto, Toronto, Ont., Canada.
⁸ 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.

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), and GAD1 (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 χ² 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 SLC6A9, SLC1A2, GRM2, and GRIA1. 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 (p_uncorrected = 0.008, p_corrected = 0.08). To clarify the role of SLC6A9 in clinical response to antipsychotic medication, and CLZ in particular, this finding warrants further investigation in larger well-characterized samples.

Keywords: Clozapine; Glutamate; Glycine transporter 1 (SLC6A9); Pharmacogenetics; Schizophrenia.