Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis
Authors: Merritt Kate , McCutcheon Robert A. , Aleman André , Ashley Sarah , Beck Katherine , Block Wolfgang , Bloemen Oswald J. N. , Borgan Faith , Boules Christiana , Bustillo Juan R. , Capizzano Aristides A. , Coughlin Jennifer M. , David Anthony , de la Fuente-Sandoval Camilo , Demjaha Arsime , Dempster Kara , Do Kim Q. , 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 A. , Kegeles Lawrence S. , Keshavan Matcheri S. , Kim Sang-Young , King Bridget , Kunugi Hiroshi , Lauriello J. , León-Ortiz Pablo , Liemburg Edith , Mcilwain Meghan E. , Modinos Gemma , Mouchlianitis Elias , Nakamura Jun , Nenadic Igor , Öngür Dost , Ota Miho , Palaniyappan Lena , Pantelis Christos , Patel Tulsi , Plitman Eric , Posporelis Sotirios , Purdon Scot E. , Reichenbach Jürgen R. , Renshaw Perry F. , Reyes-Madrigal Francisco , Russell Bruce R. , Sawa Akira , Schaefer Martin , Shungu Dikoma C. , Smesny Stefan , Stanley Jeffrey A. , Stone James , Szulc Agata , Taylor Reggie , Thakkar Katharine N. , Théberge Jean , Tibbo Philip G. , van Amelsvoort Thérèse , Walecki Jerzy , Williamson Peter C. , Wood Stephen J. , Xin Lijing , Yamasue Hidenori , McGuire Philip , Egerton Alice ,   the 1H-MRS in Schizophrenia Investigators, de la Fuente-Sandoval Camilo , van Amelsvoort Thérèse , McGuire Philip K. 
Published: February 2023

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, 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 (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 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 = 0.15,p = 0.003; Glx: CVR = 0.11,p = 0.002), 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) and temporal lobe (glutamate with age:z = −0.03,p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age:z = 0.01,p = 0.02, glutamine with symptoms:z = 0.01,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 (g = −0.15,p = 0.03), 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 < 0.001) 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 BG (z = 0.01,p = 0.01) and temporal lobe (z = 0.05,p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.