Journal article
Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis
Molecular psychiatry, Vol.28(5), pp.2039-2048
05/2023
DOI: 10.1038/s41380-023-01991-7
PMCID: PMC10575771
PMID: 36806762
Abstract
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.
Details
- Title: Subtitle
- Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis
- Creators
- Kate Merritt - Institute of Mental HealthRobert A McCutcheon - University of OxfordAndré Aleman - University Medical Center GroningenSarah Ashley - Division of Psychiatry, UCL, Institute of Mental Health, London, UKKatherine Beck - King's College LondonWolfgang Block - University Hospital BonnOswald J N Bloemen - Maastricht UniversityFaith Borgan - King's College LondonChristiana Boules - King's College LondonJuan R Bustillo - University of New MexicoAristides A Capizzano - Department of Radiology, Division of Neuroradiology, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USAJennifer M Coughlin - Johns Hopkins University School of MedicineAnthony David - Division of Psychiatry, UCL, Institute of Mental Health, London, UKCamilo de la Fuente-Sandoval - Instituto Nacional de Neurología y NeurocirugíaArsime Demjaha - King's College LondonKara Dempster - Dalhousie UniversityKim Q Do - Center for Psychiatric Neuroscience (CNP), Department of Psychiatry, Lausanne University Hospital-CHUV, Prilly-Lausanne, SwitzerlandFei Du - Harvard Medical SchoolPeter Falkai - Department of Psychiatry, University Hospital, LMU Munich, Nussbaumstrasse 7, 80336, Munich, GermanyBeata Galińska-Skok - Department of Psychiatry, Medical University of Bialystok, Bialystok, PolandJürgen Gallinat - University Medical Center Hamburg-EppendorfCharles Gasparovic - Mind Research NetworkCedric E Ginestet - King's College LondonNaoki Goto - Department of Psychiatry, Kokura Gamo Hospital, Kitakyushu, Fukuoka, 8020978, JapanAriel Graff-Guerrero - University of TorontoBeng-Choon Ho - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USAOliver Howes - King's College LondonSameer Jauhar - King's College LondonPeter Jeon - Department of Medical Biophysics, University of Western Ontario, London, ON, CanadaTadafumi Kato - Juntendo UniversityCharles A Kaufmann - Columbia UniversityLawrence S Kegeles - Columbia UniversityMatcheri S Keshavan - Harvard Medical SchoolSang-Young Kim - Philips Healthcare, Seoul, 0463, Republic of KoreaBridget King - King's College LondonHiroshi Kunugi - National Center of Neurology and PsychiatryJ Lauriello - Thomas Jefferson University HospitalPablo León-Ortiz - Instituto Nacional de Neurología y NeurocirugíaEdith Liemburg - University Medical Center GroningenMeghan E Mcilwain - University of AucklandGemma Modinos - Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, SE5 8AF, UKElias Mouchlianitis - King's College LondonJun Nakamura - Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, JapanIgor Nenadic - University Medical Center Hamburg-EppendorfDost Öngür - Harvard Medical SchoolMiho Ota - National Center of Neurology and PsychiatryLena Palaniyappan - Douglas Mental Health University InstituteChristos Pantelis - Florey Institute of Neuroscience and Mental HealthTulsi Patel - Division of Psychiatry, UCL, Institute of Mental Health, London, UKEric Plitman - McGill UniversitySotirios Posporelis - South London and Maudsley, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, BR3 3BX, UKScot E Purdon - University of AlbertaJürgen R Reichenbach - Jena University HospitalPerry F Renshaw - University of UtahFrancisco Reyes-Madrigal - Instituto Nacional de Neurología y NeurocirugíaBruce R Russell - University of OtagoAkira Sawa - Johns Hopkins UniversityMartin Schaefer - Charité - Universitätsmedizin BerlinDikoma C Shungu - Department of Radiology, Weill Cornell Medical College, New York City, NY, USAStefan Smesny - Jena University HospitalJeffrey A Stanley - Wayne State UniversityJames Stone - University of SussexAgata Szulc - Medical University of WarsawReggie Taylor - Lawson Health Research InstituteKatharine N Thakkar - Michigan State UniversityJean Théberge - University of LondonPhilip G Tibbo - Dalhousie UniversityThérèse van Amelsvoort - Maastricht UniversityJerzy Walecki - Postgraduate Medical School, Warsaw, PolandPeter C Williamson - University of LondonStephen J Wood - The University of MelbourneLijing Xin - École Polytechnique Fédérale de LausanneHidenori Yamasue - Hamamatsu University School of MedicinePhilip McGuire - King's College LondonAlice Egerton - King's College London1H-MRS in Schizophrenia Investigators
- Resource Type
- Journal article
- Publication Details
- Molecular psychiatry, Vol.28(5), pp.2039-2048
- DOI
- 10.1038/s41380-023-01991-7
- PMID
- 36806762
- PMCID
- PMC10575771
- NLM abbreviation
- Mol Psychiatry
- eISSN
- 1476-5578
- Grant note
- MR/S003436/1 / RCUK | Medical Research Council (MRC) MR/L003988/1 / RCUK | Medical Research Council (MRC)
- Language
- English
- Electronic publication date
- 02/17/2023
- Date published
- 05/2023
- Academic Unit
- Psychiatry
- Record Identifier
- 9984371159202771
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