Rationale: 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. Objectives: 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.
Bibliographical noteFunding Information:
We thank Drs. Ovidio DeLeon, Gretchen Haas, Robert Marvin, Debra Montrose, Cherise Rosen, Hugo Solari, Peter Weiden, and the clinical core staff of the Center for the Neuroscience of Mental Disorders (MH45156, David Lewis MD, Director) for their contributions to diagnostic and psychopathological assessments. Main results of this study were presented at the Pharmacogenomics in Psychiatry Annual Meeting 2013. This study was supported by the National Institute of Health (NIH) grants MH083888, MH062134, MH083126, MH45156, MH63480, RR024153, CTSA Grant UL1TR000050 and NIH/NCRR/GCRC Grant RR00056, American College of Clinical Pharmacy, Vahlteich Foundation, Janssen Pharmaceuticals, and the Alexander von Humboldt Foundation. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of NIH.
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