Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis
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Published:2023-02-17
Issue:5
Volume:28
Page:2039-2048
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ISSN:1359-4184
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Container-title:Molecular Psychiatry
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language:en
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Short-container-title:Mol Psychiatry
Author:
Merritt KateORCID, McCutcheon Robert A.ORCID, Aleman André, Ashley Sarah, Beck KatherineORCID, Block Wolfgang, Bloemen Oswald J. N., Borgan FaithORCID, Boules Christiana, Bustillo Juan R.ORCID, Capizzano Aristides A.ORCID, Coughlin Jennifer M.ORCID, David Anthony, de la Fuente-Sandoval CamiloORCID, Demjaha Arsime, Dempster Kara, Do Kim Q.ORCID, Du FeiORCID, Falkai Peter, Galińska-Skok BeataORCID, Gallinat Jürgen, Gasparovic Charles, Ginestet Cedric E., Goto Naoki, Graff-Guerrero Ariel, Ho Beng-ChoonORCID, Howes Oliver, Jauhar SameerORCID, Jeon Peter, Kato TadafumiORCID, Kaufmann Charles A., Kegeles Lawrence S., Keshavan Matcheri S., Kim Sang-Young, King BridgetORCID, Kunugi HiroshiORCID, Lauriello J., León-Ortiz Pablo, Liemburg Edith, Mcilwain Meghan E., Modinos GemmaORCID, Mouchlianitis Elias, Nakamura Jun, Nenadic Igor, Öngür Dost, Ota Miho, Palaniyappan LenaORCID, Pantelis ChristosORCID, Patel Tulsi, Plitman EricORCID, Posporelis SotiriosORCID, Purdon Scot E., Reichenbach Jürgen R., Renshaw Perry F.ORCID, Reyes-Madrigal FranciscoORCID, Russell Bruce R., Sawa AkiraORCID, Schaefer Martin, Shungu Dikoma C.ORCID, Smesny Stefan, Stanley Jeffrey A., Stone James, Szulc Agata, Taylor Reggie, Thakkar Katharine N.ORCID, Théberge JeanORCID, Tibbo Philip G., van Amelsvoort Thérèse, Walecki Jerzy, Williamson Peter C., Wood Stephen J., Xin Lijing, Yamasue Hidenori, McGuire PhilipORCID, Egerton AliceORCID, de la Fuente-Sandoval Camilo, van Amelsvoort Thérèse, McGuire Philip K.,
Abstract
AbstractGlutamatergic 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.
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Psychiatry and Mental health,Molecular Biology
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