title: Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia.
abstract: BACKGROUND
  Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated.
  
  
  OBJECTIVE
  The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment.
  
  
  METHODS
  Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients' level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions.
  
  
  RESULTS
  Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment.
  
  
  CONCLUSIONS
  These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects.
authors.affiliation: Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, 833 S. Wood St. Rm 164 (M/C 886), Chicago, IL, 60612, USA, jbishop@uic.edu.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Bishop
authors.forename: James L
authors.initials: JL
authors.lastname: Reilly
authors.forename: Margret S H
authors.initials: MS
authors.lastname: Harris
authors.forename: Shitalben R
authors.initials: SR
authors.lastname: Patel
authors.forename: Rick
authors.initials: R
authors.lastname: Kittles
authors.forename: Judith A
authors.initials: JA
authors.lastname: Badner
authors.forename: Konasale M
authors.initials: KM
authors.lastname: Prasad
authors.forename: Vishwajit L
authors.initials: VL
authors.lastname: Nimgaonkar
authors.forename: Matcheri S
authors.initials: MS
authors.lastname: Keshavan
authors.forename: John A
authors.initials: JA
authors.lastname: Sweeney
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3
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