{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:13:33Z","timestamp":1792188813492,"version":"4.4.0"},"reference-count":220,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T00:00:00Z","timestamp":1645488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The monoamine model of depression has long formed the basis of drug development but fails to explain treatment resistance or associations with stress or inflammation. Recent animal research, clinical trials of ketamine (a glutamate receptor antagonist), neuroimaging research, and microbiome studies provide increasing evidence of glutamatergic dysfunction in depression and other disorders. Glutamatergic involvement across diverse neuropathologies including psychoses, neurodevelopmental, neurodegenerative conditions, and brain injury forms the rationale for this review. Glutamate is the brain\u2019s principal excitatory neurotransmitter (NT), a metabolic and synthesis substrate, and an immune mediator. These overlapping roles and multiple glutamate NT receptor types complicate research into glutamate neurotransmission. The glutamate microcircuit comprises excitatory glutamatergic neurons, astrocytes controlling synaptic space levels, through glutamate reuptake, and inhibitory GABA interneurons. Astroglia generate and respond to inflammatory mediators. Glutamatergic microcircuits also act at the brain\/body interface via the microbiome, kynurenine pathway, and hypothalamus\u2013pituitary\u2013adrenal axis. Disruption of excitatory\/inhibitory homeostasis causing neuro-excitotoxicity, with neuronal impairment, causes depression and cognition symptoms via limbic and prefrontal regions, respectively. Persistent dysfunction reduces neuronal plasticity and growth causing neuronal death and tissue atrophy in neurodegenerative diseases. A conceptual overview of brain glutamatergic activity and peripheral interfacing is presented, including the common mechanisms that diverse diseases share when glutamate homeostasis is disrupted.<\/jats:p>","DOI":"10.3390\/nu14050917","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T22:34:30Z","timestamp":1645569270000},"page":"917","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":116,"title":["Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases"],"prefix":"10.3390","volume":"14","author":[{"given":"Thomas","family":"McGrath","sequence":"first","affiliation":[{"name":"Green Templeton College, University of Oxford, Oxford OX2 6HG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Baskerville","sequence":"additional","affiliation":[{"name":"Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0517-1645","authenticated-orcid":false,"given":"Marcelo","family":"Rogero","sequence":"additional","affiliation":[{"name":"School of Public Health, University of Sao Paulo, Sao Paulo 01246-904, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Castell","sequence":"additional","affiliation":[{"name":"Green Templeton College, University of Oxford, Oxford OX2 6HG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/S0140-6736(18)32279-7","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990\u20132017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"392","author":"James","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/515200a","article-title":"Depression: The best way forward","volume":"515","author":"Monteggia","year":"2014","journal-title":"Nature"},{"key":"ref_3","first-page":"1146","article-title":"Novel drug developmental strategies for treatment-resistant depression","volume":"179","author":"Simon","year":"2021","journal-title":"J. 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