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*, Philip K. McGuire, Alice Egerton, André Aleman, Wolfgang Block, Oswald J.N. Bloemen, Faith Borgan, Juan R. Bustillo, Aristides A. Capizzano, Jennifer Marie Coughlin, Camilo De La Fuente-Sandoval, Arsime Demjaha, Kara Dempster, Kim Q. Do, Fei Du, Peter Falkai, Beata Galinska-Skok, Jurgen Gallinat, Charles Gasparovic, Cedric E. GinestetNaoki Goto, Ariel Graff-Guerrero, Beng Choon Ho, Oliver D. Howes, Sameer Jauhar, Peter Jeon, Tadafumi Kato, Charles A. Kaufmann, Lawrence S. Kegeles, Matcheri Keshavan, Sang Young Kim, Hiroshi Kunugi, John Lauriello, Edith Jantine Liemburg, Meghan E. McIlwain, Gemma Modinos, Elias D. Mouchlianitis, Jun Nakamura, Igor Nenadic, Dost Öngür, Miho Ota, Lena Palaniyappan, Christos Pantelis, Eric Plitman, Sotirios Posporelis, Scot E. Purdon, Jürgen R. Reichenbach, Perry F. Renshaw, Bruce R. Russell, Akira Sawa, Martin Schaefer, Dikoma C. Shungu, Stefan Smesny, Jeffrey A. Stanley, James M. Stone, Agata Szulc, Reggie Taylor, Katy Thakkar, Jean Théberge, Philip G. Tibbo, Therese Van Amelsvoort, Jerzy Walecki, Peter C. Williamson, Stephen James Wood, Lijing Xin, Hidenori Yamasue

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)667-681
Number of pages15
JournalJAMA Psychiatry
Volume78
Issue number6
DOIs
Publication statusPublished - Jun 2021

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