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Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies
Open accessAbstract
IMPORTANCE: Alterations in glutamatergic neurotransmission may be fundamental to the pathophysiology of schizophrenia, and the glutamatergic system is a target for novel therapeutic interventions in the disorder. OBJECTIVE: To investigate the nature of brain glutamate alterations in schizophrenia by conducting a meta-analysis of glutamate proton magnetic resonance (MRS) spectroscopy studies. DATA SOURCES: The MEDLINE database was searched for studies published from January 1, 1980, to April 1, 2015. Search terms included magnetic resonance spectroscopy, schizophrenia, psychosis, clinical or genetic high risk, and schizoaffective. Inclusion criteria were single voxel 1H-MRS studies reporting glutamate, glutamine or Glx values for a patient or risk group in comparison to a healthy volunteer group. STUDY SELECTION: Fifty-nine studies were identified, which included 1686 patients and 1451 healthy individuals serving as controls. DATA EXTRACTION AND SYNTHESIS: A random-effects, inverse-weighted variance model was used to calculate the pooled effect size. Mean values were extracted and verified independently. Effect sizes were determined for glutamate, glutamine, and Glx in brain regions that had been examined in at least 3 different studies. A secondary analysis grouped studies into those examining patients at different stages of illness (high risk, first-episode psychosis, or chronic schizophrenia). Effects of age, antipsychotic dose, and symptom severity were determined using meta-regression. RESULTS: In schizophrenia, there were significant elevations in glutamate in the basal ganglia (Hedges g = 0.63; 95% CI, 0.15-1.11), glutamine in the thalamus (g = 0.56; 95% CI, 0.02-1.09), and Glx in the basal ganglia (g = 0.39; 95% CI, 0.09-0.70) and medial temporal lobe (g = 0.32; 95% CI, 0.12-0.52). No region showed a reduction in glutamate metabolites in schizophrenia. Secondary analyses revealed that elevated medial frontal Glx levels were evident in individuals at high risk for schizophrenia (g = 0.26; 95% CI, 0.05-0.46) but not in those with first-episode psychosis or chronic schizophrenia, whereas elevated Glx in the medial temporal lobe was seen with chronic schizophrenia (g = 0.40; 95% CI, 0.08-0.71) but not in the high-risk or first-episode groups. Meta-regression found no association with age, symptom severity, or antipsychotic dose. CONCLUSIONS AND RELEVANCE: Schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential.
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“Evidence from magnetic resonance spectroscopy suggests that alterations in glutamatergic neurotransmission may change over the course of schizophrenia (96, 97).”
From The Predictive Coding Account of Psychosis (2018) · cites this paper as [96]
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- Szulc A, Galinska B, Tarasów E, et al. Glutamatergic system dysfunction in schizophrenia: a proton magnetic resonance spectroscopy ( 1 H MRS) study. Pol J Radiol. 2004;69(1):33-36.
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The Predictive Coding Account of Psychosis
Sterzer, P., Adams, R. A., Fletcher, P., Frith, C., Lawrie, S. M., Muckli, L., Petrovic, P., Uhlhaas, P., Voss, M., & Corlett, P. R. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.05.015 · Cited by 941
“Evidence from magnetic resonance spectroscopy suggests that alterations in glutamatergic neurotransmission may change over the course of schizophrenia (95,96).”
BackgroundCognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment
McCutcheon, R. A., Keefe, R. S. E., & McGuire, P. K. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-01949-9 · Cited by 861
“…it is not possible to disambiguate intracellular and intrasynaptic signals in MRS data, and there is heterogeneity in the direction of reported fi ndings, which may re fl ect differences in acquisition methods and medication exposure as much as pathophysiological heterogeneity [219, 221 – 223].”
BackgroundDopamine and glutamate in schizophrenia: biology, symptoms and treatment
McCutcheon, R. A., Krystal, J. H., & Howes, O. D. (2020) · World Psychiatry · doi:10.1002/wps.20693 · Cited by 612
Prevention of Psychosis: Advances in Detection, Prognosis, and Intervention
Fusar-Poli, P., Salazar de Pablo, G., Correll, C. U., Meyer-Lindenberg, A., Millan, M. J., Borgwardt, S., Galderisi, S., Bechdolf, A., Pfennig, A., Kessing, L. V., et al. (2020) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2019.4779 · Cited by 476
Glutamate hypothesis in schizophrenia
Uno, Y., & Coyle, J. T. (2019) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12823 · Cited by 389
Metadata
- Authors
- Merritt, K., Egerton, A., Kempton, M. J., Taylor, M. J., & McGuire, P. K.
- Affiliations
- King's College London (GB)
- Corresponding author
- Merritt, Kate
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2016-07-01
- Volume
- 73
- Issue
- 7
- Pages
- 665
- ISSN
- 2168-622X (ISSN-L)
- OpenAlex
- W2424710696
- Cited by
- 367
- References
- 82
- Citations by year
- 2026: 26 · 2025: 23 · 2024: 25 · 2023: 37 · 2022: 33 · 2021: 50 · 2020: 55 · 2019: 44 · 2018: 41 · 2017: 28 · 2016: 5
- FWCI
- 34.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- National Institute for Health and Care Research
- King's College London
- Medical Research Council (MR/L003988/1, MR/J008915/1)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- schizophrenia, glutamate, glutamine, glutamatergic neurotransmission, basal ganglia, thalamus, medial temporal lobe, medial frontal cortex, first-episode psychosis, clinical high risk for psychosis, chronic schizophrenia, schizoaffective disorder, antipsychotic dosing, symptom severity, neuroimaging biomarkers
- MeSH terms
- Brain, Brain Mapping, Glutamine, Humans, Synaptic Transmission, Reference Values, Risk Factors, Schizophrenia, Glutamic Acid, Genetic Predisposition to Disease, Proton Magnetic Resonance Spectroscopy
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