Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia with Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data


Kate Merritt, UCL Faculty of Brain Sciences
Philip K. McGuire, King's College London
Alice Egerton, King's College London
André Aleman, Shenzhen University
Wolfgang Block, Universitätsklinikum Bonn
Oswald J.N. Bloemen, Universiteit Maastricht
Faith Borgan, King's College London
Juan R. Bustillo, UNM School of Medicine
Aristides A. Capizzano, University of Michigan Medical School
Jennifer Marie Coughlin, Johns Hopkins School of Medicine
Camilo De La Fuente-Sandoval, Instituto Nacional de Neurología y Neurocirugía
Arsime Demjaha, King's College London
Kara Dempster, Dalhousie University, Faculty of Medicine
Kim Q. Do, Centre Hospitalier Universitaire Vaudois
Fei Du, Harvard Medical School
Peter Falkai, Klinikum der Universität München
Beata Galinska-Skok, Uniwersytet Medyczny w Bialymstoku
Jurgen Gallinat, Universitätsklinikum Hamburg-Eppendorf
Charles Gasparovic, The Mind Research Network
Cedric E. Ginestet, King's College London
Naoki Goto, Kokura Gamo Hospital
Ariel Graff-Guerrero, University of Toronto
Beng Choon Ho, University of Iowa Carver College of Medicine
Oliver D. Howes, King's College London
Sameer Jauhar, King's College London
Peter Jeon, The University of Western Ontario
Tadafumi Kato, Juntendo University Graduate School of Medicine
Charles A. Kaufmann, New York State Psychiatric Institute
Lawrence S. Kegeles, New York State Psychiatric Institute
Matcheri Keshavan, Harvard Medical School
Sang Young Kim, Philips Healthcare Nederland
Hiroshi Kunugi, National Center of Neurology and Psychiatry Kodaira

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JAMA Psychiatry





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Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome∗ or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection: In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9= 4.311, P =.04) and Glx (F1,1079.2= 5.287, P =.02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9= 3.622, P =.06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4= 47.533, P <.001; cerebrospinal fluid-corrected Glu, F1,1216.7= 5.610, P =.02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose. Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia..