TY - JOUR
T1 - Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level
T2 - A Mega-analysis of Individual Participant-Level Data
AU - Merritt, Kate
AU - McGuire, Philip K
AU - Egerton, Alice
AU - Aleman, André
AU - Block, Wolfgang
AU - Bloemen, Oswald J N
AU - Borgan, Faith
AU - Bustillo, Juan R
AU - Capizzano, Aristides A
AU - Coughlin, Jennifer Marie
AU - De la Fuente-Sandoval, Camilo
AU - Demjaha, Arsime
AU - Dempster, Kara
AU - Do, Kim Q
AU - Du, Fei
AU - Falkai, Peter
AU - Galinska-Skok, Beata
AU - Gallinat, Jurgen
AU - Gasparovic, Charles
AU - Ginestet, Cedric E
AU - Goto, Naoki
AU - Graff-Guerrero, Ariel
AU - Ho, Beng Choon
AU - Howes, Oliver D
AU - Jauhar, Sameer
AU - Jeon, Peter
AU - Kato, Tadafumi
AU - Kaufmann, Charles A
AU - Kegeles, Lawrence S
AU - Keshavan, Matcheri
AU - Kim, Sang-Young
AU - Kunugi, Hiroshi
AU - Lauriello, John
AU - Liemburg, Edith Jantine
AU - Mcilwain, Meghan E
AU - Modinos, Gemma
AU - Mouchlianitis, Elias D
AU - Nakamura, Jun
AU - Nenadic, Igor
AU - Öngür, Dost
AU - Ota, Miho
AU - Palaniyappan, Lena
AU - Pantelis, Christos
AU - Plitman, Eric
AU - Posporelis, Sotirios
AU - Purdon, Scot E
AU - Reichenbach, Jürgen R
AU - Renshaw, Perry F
AU - Russell, Bruce R
AU - van Amelsvoort, Therese
AU - 1H-MRS Schizophrenia Investigators
N1 - Funding Information:
reported being an employee at COMPASS Pathways plc after the completion of and unrelated to the present work. Dr Bustillo reported receiving royalties from UptoDate outside the submitted work. Dr de la Fuente-Sandoval reported receiving personal fees from Janssen (Johnson & Johnson) during the conduct of the study. Dr Do reported receiving grants from Boehringer Ingelheim outside the submitted work. Dr Falkai reported receiving research grants or personal fees from Abbott, Boehringer Ingelheim, Essex, Janssen, Lundbeck, Otsuka, Recordati, Richter, Servier, and Takeda. Dr Gallinat reported receiving grants from the German Federal Ministry of Education and Research and from German Science Foundation; and receiving personal fees from Boehringer Ingelheim, Eli Lilly and Company, Janssen-Cilag, Lundbeck, and Otsuka. Dr Goldstein is now referred to by her maiden name, Dr Mcilwain. Dr Goto reported receiving personal fees from Meiji Seika, Yoshitomiyakuhin, and Novartis outside the submitted work. Dr Howes reported receiving investigator-initiated research funding or personal fees from Angellini, Autifony, Biogen, Boehringer Ingelheim, Eli Lilly and Company, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Mylan, Neurocrine, Otsuka, Sunovion, Rand, Recordati, and Roche; and having a patent for the use of dopaminergic imaging. Dr Jauhar reported receiving personal fees from Sunovian and nonfinancial support from Lundbeck outside the submitted work. Dr Kato reported receiving grants from Eisai, Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Shionogi & Co, and Takeda Pharmaceutical; and receiving personal fees from Astellas Pharma Inc, Eisai, Eli Lilly Japan, GlaxoSmithKline, Kanae Foundation for the Promotion of Medical Science, Kyowa Hakko Kirin, Kyowa Pharmaceutical Industry, Janssen Asia Pacific, Janssen Pharmaceutical, Meiji Seika Pharma, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Otsuka Pharmaceutical, Pfizer Japan, Shionogi & Co, Sumitomo Dainippon Pharma, Taisho Pharmaceutical, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, and Yoshitomiyakuhin outside the submitted work. Dr Kegeles reported receiving grants from the National Alliance for Research on Schizophrenia and Depression during the conduct of the study. Dr Lauriello reported being on the advisory panel for Alkermes and on the data management safety board for Bioexcel Therapeutic. Dr Liemburg reported receiving grants from AstraZeneca, European Research Council, European Young Investigator Awards, and Stichting Roos during the conduct of the study. Dr McGuire reported receiving personal fees from Sunovion and Takeda. Dr Mcilwain reported receiving grants from the New Zealand Schizophrenia Research Group and a fellowship from the New Zealand Federation of Graduate Women during the conduct of the study; and becoming employed at Syneos Health after the collection and analysis of data for the present work but has not worked on any projects there related to schizophrenia or psychiatry. Dr Palaniyappan reported receiving personal fees from the Canadian Psychiatric Association, Janssen Canada, Otsuka Canada, and the SPMM Course UK outside the submitted work; receiving grants from Janssen Canada, Otsuka Canada, and Sunovion outside the submitted work; and receiving royalties from Oxford University Press. Dr Pantelis reported receiving grants from the Australian National Health & Medical Research Council during the conduct of the study; grants from Lundbeck Foundation; and personal fees from Lundbeck Australia Pty Ltd outside the submitted work. Dr Purdon reported receiving grants from the Canadian Institute of Health Research during the conduct of the study; and personal fees from Lundbeck Canada outside the submitted work. Dr Schaefer reported receiving grants from The Stanley Medical Research Institute during the conduct of the study; and receiving personal fees from Janssen-Cilag, Gilead Sciences GmbH, Hexal-AG, and Servier outside the submitted work. Dr Shungu reported receiving personal fees from Icahn School of Medicine at Mount Sinai and the US National Institutes of Health outside the submitted work. Dr Stone reported being a principal investigator or subinvestigator on studies sponsored by Takeda, Janssen, and Lundbeck; and attending investigator meetings at Allergan outside the submitted work. Dr Taylor reported receiving grants from the Ontario Mental Health Foundation and the Canadian Institute of Health Research during the conduct of the study. Dr Théberge reported receiving grants from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council, and the Canada Foundation for Innovation during the conduct of the study; and receiving personal fees from Siemens Healthineers Canada. Dr Tibbo reported receiving grants from the Alberta Health Foundation for Medical Research and the Canadian Institutes for Medical Research during the conduct of the study; and personal fees from Janssen, Lundbeck. and Otsuka outside the submitted work. Dr Xin reported receiving grants from the Swiss National Science Foundation and Société des Produits Nestlé SA outside the submitted work. Dr Yamasue reported receiving personal fees from Eli Lilly and Company, Janssen, Meiji Seika Pharma, Merck Sharp & Dohme, Mochida, Otsuka, Pfizer, Sumitomo Dainippon, Takeda, and Yoshitomiyakuhin; and receiving a research grant from Eisai. No other disclosures were reported.
Funding Information:
Funding/Support: This study was supported by a PhD studentship from the UK Medical Research Council and grant MR/S003436/1 from the Medical Research Council to Dr Merritt; grant MR/ L003988/1 from the Medical Research Council to Dr Egerton, and grant HEALTH-F2-2010-242114 from the European Commission within the 7th Framework Programme. This study presents independent research funded in part by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Dr Camilo de la Fuente-Sandoval was awarded research grants 119280, 182279, and 261895 from the Consejo Nacional de Ciencia y Tecnología-Mexico (CONACyT), a grant from CONACyT Sistema Nacional de Investigadores, and grant R21 MH117434 from the US National Institutes of Health. Dr Howes was awarded grant MC_U120097115 from the Medical Research Council-UK, grant 666 from the Maudsley Charity, and grant 094849/Z/10/Z from the Wellcome Trust. Dr Théberge received discovery grant RG-PIN-2016-05055 from the National Science and Engineering Research Council-Canada and was a co-applicant on grant MT-12078 from the Canadian Institutes of Health Research. Dr Palaniyappan received Foundation Grant 375104/2017 from the Canadian Institutes of Health Research and salary support from the Tanna Schulich Chair of Neuroscience and Mental Health. A clinical investigator fellowship was awarded to Kara Dempster from the Schulich School of Medicine. Mr Jeon received salary support from Discovery Grant RGPIN2016-05055 from the Natural Sciences and Engineering Research Council of Canada to Dr Théberge. Data acquisition was supported by the Canada First Excellence Research Fund to BrainSCAN, Western University (Imaging Core).
Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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.
KW - Adult
KW - Age Factors
KW - Antipsychotic Agents/pharmacology
KW - Biomarkers/metabolism
KW - Brain/diagnostic imaging
KW - Female
KW - Glutamic Acid/drug effects
KW - Glutamine/drug effects
KW - Humans
KW - Male
KW - Patient Acuity
KW - Proton Magnetic Resonance Spectroscopy
KW - Schizophrenia/drug therapy
KW - Young Adult
KW - WHITE-MATTER
KW - ANTERIOR CINGULATE
KW - N-ACETYL-ASPARTATE
KW - ULTRA-HIGH-RISK
KW - PREFRONTAL CORTEX
KW - METABOLIC-CHANGES
KW - IN-VIVO
KW - 1ST EPISODE PSYCHOSIS
KW - GAMMA-AMINOBUTYRIC-ACID
KW - 1ST-EPISODE PSYCHOSIS
U2 - 10.1001/jamapsychiatry.2021.0380
DO - 10.1001/jamapsychiatry.2021.0380
M3 - Article
C2 - 33881460
SN - 2168-622X
VL - 78
SP - 667
EP - 681
JO - JAMA Psychiatry
JF - JAMA Psychiatry
IS - 6
ER -