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

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Abstract Glutamatergic dysfunction is implicated in the pathoaetiology of schizophrenia, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls, using the log coefficient of variation ratio (CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data using Hartigan’s unimodality dip test. MEDLINE and EMBASE databases were searched from inception to October 2021 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia patients compared to controls. 116 studies reporting on 7,844 patients and 7,305 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.16, p = 0.003; Glx: CVR = 0.11, p = 0.003), dorsolateral prefrontal cortex (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). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z=-0.03,p = 0.003, symptoms: z = 0.007,p = 0.02), MFC (glutamine with symptoms: z = 0.01,p = 0.01) and temporal lobe (glutamate with age: z=-0.03,p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate levels (g=-0.18,p = 0.02), higher thalamic glutamine (g = 0.53,p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28,p < 0.001). Proportion of males was negatively associated with MFC glutamate (z=-0.02,p = 0.002) and frontal white matter Glx (z=-0.03,p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in patients relative to controls in BG (z = 0.01,p = 0.01) and temporal lobe (z = 0.05,p = 0.008). Further research into the mechanisms underlying greater variability in glutamatergic metabolites in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies. Word count: 300/300

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