Variability and Magnitude of Brain Glutamate Levels in Schizophrenia: A Meta And Mega-Analysis
Authors: Merritt Kate , McCutcheon Robert , Aleman André , Ashley Sarah , Beck Katherine , Block Wolfgang , Bloemen Oswald , Borgan Faith , Boules Christina , Bustillo Juan , Capizzano Aristides , Coughlin Jennifer , David Anthony , Fuente-Sandoval Camilo de la , Demjaha Arsime , Dempster Kara , Do Kim , Du Fei , Falkai Peter , Galińska-Skok Beata , Gallinat Jürgen , Gasparovic Charles , Ginestet Cedric E , Goto Naoki , Graff-Guerrero Ariel , Ho Beng-Choon , Howes Oliver , Jauhar Sameer , Jeon Peter , Kato Tadafumi , Kaufmann Charles , Kegeles Lawrence , Keshavan Matcheri , Kim Sang-Young , King Bridget , Kunugi Hiroshi , Lauriello John , León-Ortiz Pablo , Liemburg Edith , Mcilwain Meghan , Modinos Gemma , Mouchlianitis Elias , Nakamura Jun , Nenadic Igor , Öngür Dost , Ota Miho , Palaniyappan Lena , Pantelis Christos , Patel Tulsi , Plitman Eric , Posporelis Sotirios , Purdon Scot , Reichenbach Jürgen , Renshaw Perry , Reyes-Madrigal Francisco , Russell Bruce , Sawa Akira , Schaefer Martin , Shungu Dikoma , Smesny Stefan , Stanley Jeffrey , Stone James , Szulc Agata , Taylor Reggie , Thakkar Katharine , Théberge Jean , Tibbo Philip , Amelsvoort Thérèse van , Walecki Jerzy , Williamson Peter , Wood Stephen , Xin Lijing , Yamasue Hidenori , McGuire Philip , Egerton Alice 
Published: September 2022

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