title: Genetic association analysis of N-methyl-D-aspartate receptor subunit gene GRIN2B and clinical response to clozapine.
abstract: OBJECTIVE
  Approximately 30% of patients with schizophrenia fail to respond to antipsychotic therapy and are classified as having treatment-resistant schizophrenia. Clozapine is the most efficacious drug for treatment-resistant schizophrenia and may deliver superior therapeutic effects partly by modulating glutamate neurotransmission. Response to clozapine is highly variable and may depend on genetic factors as indicated by twin studies. We investigated eight polymorphisms in the N-methyl-D-aspartate glutamate receptor subunit gene GRIN2B with response to clozapine.
  
  
  METHODS
  GRIN2B variants were genotyped using standard TaqMan procedures in 175 European patients with schizophrenia deemed resistant or intolerant to treatment. Response was assessed using change in Brief Psychiatric Rating Scale scores following six months of clozapine therapy. Categorical and continuous response was assessed using chi-squared test and analysis of covariance, respectively.
  
  
  RESULTS
  No associations were observed between the variants and response to clozapine. A-allele carriers of rs1072388 responded marginally better to clozapine therapy than GG-homozygotes; however, the difference was not statistically significant (p = 0.067, uncorrected).
  
  
  CONCLUSIONS
  Our findings do not support a role for these GRIN2B variants in altering response to clozapine in our sample. Investigation of additional glutamate variants in clozapine response is warranted.
authors.affiliation: Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Taylor
authors.affiliation: Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, 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 City, New York, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.affiliation: Department of Psychiatry, University of California, Irvine, Irvine, California, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Potkin
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.affiliation: Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Jo
authors.initials: J
authors.lastname: Knight
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Remington
authors.affiliation: Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.affiliation: Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D003024:Clozapine / Q000627:therapeutic use*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
chemical_list: D014150:Antipsychotic Agents; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D003024:Clozapine
keywords: GRIN2B; clozapine; glutamate; pharmacogenetics; schizophrenia