Variability and Magnitude of Brain Glutamate Levels in Schizophrenia: A Meta and Mega-Analysis

Brisbane Convention & Exhibition Centre 

Background:
Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. Studies report both increased and reduced levels of brain glutamate in schizophrenia relative to controls, and it has been proposed that glutamate subtypes in schizophrenia may exist in relation to treatment response. To address this, we examine whether patients exhibit greater variability in glutamate measures compared to controls and conduct an updated meta-analysis of glutamate differences.
Methods:
MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx values in schizophrenia patients in comparison to controls. We requested individual patient data from authors as part of a previous mega-analysis.
Outcomes were (1) variability of glutamate measures in patients relative to controls, indexed by coefficient of variation ratio (CVR); (2) mean differences quantified using Hedges g; (3) modal distribution of individual-level glutamate data using Hartigan’s unimodality dip test. Analyses were carried out in R using the “metafor” package and “weights” package.
Results:
123 studies reporting on 8,256 patients and 7,532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex ( glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (DLPFC, glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower medial frontal cortex glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher basal ganglia Glx in patients relative to controls (g = 0.28, p < 0.001).
Conclusions:
The finding of greater variability in patients in the medial frontal cortex, DLPFC and thalamus are consistent with the hypothesis of glutamate subtypes in schizophrenia. Future research focused on these brain regions may inform the identification of patient subgroups for personalised medicine approaches to treatment.