Glutamate-mediated excitotoxicity in schizophrenia: a review

Eric Plitman; Shinichiro Nakajima; Camilo de la Fuente-Sandoval; Philip Gerretsen; M Mallar Chakravarty; Jane Kobylianskii; Jun Ku Chung; Fernando Caravaggio; Yusuke Iwata; Gary Remington; Ariel Graff-Guerrero

doi:10.1016/j.euroneuro.2014.07.015

Glutamate-mediated excitotoxicity in schizophrenia: a review

Eur Neuropsychopharmacol. 2014 Oct;24(10):1591-605. doi: 10.1016/j.euroneuro.2014.07.015. Epub 2014 Aug 1.

Affiliations

¹ Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
² Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; Geriatric Mental Health Division, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
³ Experimental Psychiatry Laboratory, Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico; Neuropsychiatry Department, Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico.
⁴ Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Geriatric Mental Health Division, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
⁵ Cerebral Imaging Centre, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada; Departments of Psychiatry and Biomedical Engineering, McGill University, Montreal, Quebec, Canada.
⁶ Department of Medicine, Queen׳s University, Kingston, Ontario, Canada.
⁷ Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
⁸ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Campbell Institute Research Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Schizophrenia Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
⁹ Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Geriatric Mental Health Division, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Campbell Institute Research Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada. Electronic address: [email protected].

Abstract

Findings from neuroimaging studies in patients with schizophrenia suggest widespread structural changes although the mechanisms through which these changes occur are currently unknown. Glutamatergic activity appears to be increased in the early phases of schizophrenia and may contribute to these structural alterations through an excitotoxic effect. The primary aim of this review was to describe the possible role of glutamate-mediated excitotoxicity in explaining the presence of neuroanatomical changes within schizophrenia. A Medline(®) literature search was conducted, identifying English language studies on the topic of glutamate-mediated excitotoxicity in schizophrenia, using the terms "schizophreni" and "glutam" and (("MRS" or "MRI" or "magnetic resonance") or ("computed tomography" or "CT")). Studies concomitantly investigating glutamatergic activity and brain structure in patients with schizophrenia were included. Results are discussed in the context of findings from preclinical studies. Seven studies were identified that met the inclusion criteria. These studies provide inconclusive support for the role of glutamate-mediated excitotoxicity in the occurrence of structural changes within schizophrenia, with the caveat that there is a paucity of human studies investigating this topic. Preclinical data suggest that an excitotoxic effect may occur as a result of a paradoxical increase in glutamatergic activity following N-methyl-D-aspartate receptor hypofunction. Based on animal literature, glutamate-mediated excitotoxicity may account for certain structural changes present in schizophrenia, but additional human studies are required to substantiate these findings. Future studies should adopt a longitudinal design and employ magnetic resonance imaging techniques to investigate whether an association between glutamatergic activity and structural changes exists in patients with schizophrenia.

Keywords: Excitotoxicity; Glutamate; Glutamine; MRS; Psychosis; Schizophrenia.

Publication types

Review

MeSH terms

Animals
Brain / pathology*
Brain / physiopathology*
Glutamic Acid / metabolism*
Humans
Receptors, N-Methyl-D-Aspartate / metabolism
Schizophrenia / pathology*
Schizophrenia / physiopathology*

Substances

Receptors, N-Methyl-D-Aspartate
Glutamic Acid

Grants and funding

114989-1/Canadian Institutes of Health Research/Canada