SynthesisJAMA psychiatry2021
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.
Synthesis in JAMA psychiatry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers, 5 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
89 citing papers in PubMed, 5 syntheses or guidelines pooled it, 139 citations in OpenAlex.
- Neural excitation/inhibition imbalance and neurodevelopmental pathology in human copy number variant syndromes: a systematic review.Journal of neurodevelopmental disorders · 2025Pooled it
- Glutamatergic neurotransmission in schizophrenia: A systematic review and quantitative synthesis of proton magnetic resonance spectroscopy studies across schizophrenia spectrum disorders.The Australian and New Zealand journal of psychiatry · 2024Pooled it
- Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.Molecular psychiatry · 2023Pooled it
- Medial Prefrontal Cortex Glutamate Is Reduced in Schizophrenia and Moderated by Measurement Quality: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies.Biological psychiatry · 2021Pooled it
- Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder.Translational psychiatry · 2021Pooled it
- Does a monoclonal antibody targeting immune cells affect glutamatergic level in schizophrenia? A multimodal PET/MRS brain imaging study.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Trial
- Diazepam modulates anterior cingulate glutamate levels in people at clinical high-risk for psychosis.The international journal of neuropsychopharmacology · 2026Trial
- Schizophrenia: from mechanism to therapy.Science China. Life sciences · 2026Review
- Group Differences of Multiregion Glutamate Concentration in Clinical High Risk and Schizophrenia.The European journal of neuroscience · 2026Article
- Cannabis use and glutamate across the psychosis spectrum: in vivo evidence from 7T proton magnetic resonance spectroscopy.Molecular psychiatry · 2026Article
- Article
- Glutamate change in the anterior cingulate cortex after starting clozapine: evaluating 1H-MRS pilot data.BMC psychiatry · 2026Article
- Functional and Metabolic Abnormalities in Primary Visual Cortex and Frontal Eye Fields and Candidate Biomarkers of Acute Acquired Comitant Esotropia.Investigative ophthalmology & visual science · 2026Article
- Why Is Clozapine Uniquely Effective in Treatment-Resistant Schizophrenia? A Review and Proposal.Biological psychiatry · 2026Review
- Associations between glutamate and cerebral blood flow in treatment-resistant schizophrenia during clozapine treatment.Journal of psychopharmacology (Oxford, England) · 2026Article
- Investigating the disturbance in cortical glutamate and GABA function in psychosis and its origins and consequences.Molecular psychiatry · 2026Article
- Aging in Schizophrenia: Perspectives on Molecular Mechanisms and a Mini-review.Schizophrenia bulletin · 2026Review
- Interrelations between dopaminergic-, gabaergic- and glutamatergic neurotransmitters in antipsychotic-naïve psychosis patients and the association to initial treatment response.Molecular psychiatry · 2026Article
- The link between GABA levels and P300 abnormalities in schizophrenia spectrum disorders: regional and symptom-based insights.Schizophrenia (Heidelberg, Germany) · 2026Article
- Ketamine for negative and depressive symptoms in schizophrenia: the evidence so far.Frontiers in psychiatry · 2026Review
29 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
67 authors at 20 institutions in 12 countries.
Funding
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.
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