Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

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) studies.

Data Sources: The MEDLINE database was searched for studies 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 a total of 1686 patients and 1451 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 calculated 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 (P=0.01,g=0.63), glutamine in the thalamus (P=0.04,g=0.56) and Glx in the basal ganglia (P=0.01,g=0.39) and medial temporal lobe (P=0.002,g=0.32). No region showed a reduction in glutamate metabolites in schizophrenia. Secondary analyses revealed that elevated medial frontal Glx levels were evident in high risk subjects but not first episode or chronic patients, whereas elevated Glx in the medial temporal was seen in chronic patients, but not high risk or first episode subjects. Meta-regression found no relationship with age, symptom severity or antipsychotic dose. Conclusions and Relevance: Schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This 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.