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Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia

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Abstract

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.

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Acknowledgments

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.

Disclosures

Dr. Bishop has received research funding from Ortho-McNeil Janssen and is on an advisory board for Physician’s Choice Laboratory Services. Dr. Sweeney has received research support from Ortho-McNeil Janssen and has been a consultant to Roche, Pfizer, Takeda, Bristol-Myers Squibb, and Eli Lilly. Dr. Keshavan has received research grant support from Sunovion. Dr. Reilly has received research grant support from Naurex, Inc. The other authors report no disclosures or potential conflicts of interest.

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Authors and Affiliations

  1. 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

    Jeffrey R. Bishop & Shitalben R. Patel

  2. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    James L. Reilly

  3. Jesse Brown Veteran’s Administration Medical Center, Chicago, IL, USA

    Margret S. H. Harris

  4. College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Rick Kittles

  5. Department of Psychiatry, University of Chicago, Chicago, IL, USA

    Judith A. Badner

  6. Department of Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA

    Konasale M. Prasad & Vishwajit L. Nimgaonkar

  7. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    Vishwajit L. Nimgaonkar

  8. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Matcheri S. Keshavan

  9. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    John A. Sweeney

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  1. Jeffrey R. Bishop
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Bishop, J.R., Reilly, J.L., Harris, M.S.H. et al. Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia. Psychopharmacology 232, 145–154 (2015). https://doi.org/10.1007/s00213-014-3649-4

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