Original Investigation
July 2016

Nature of Glutamate Alterations in SchizophreniaA Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

Author Affiliations
  • 1Psychosis Studies Department, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, England

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Psychiatry. 2016;73(7):665-674. doi:10.1001/jamapsychiatry.2016.0442

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.