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Microglia regulate brain glutamate levels through mechanisms including the cysteine-glutamate antiporter, raising the possibility that microglial dysfunction could underlie glutamatergic dysregulation in schizophrenia. We tested this using a combined cross-sectional\/longitudinal study of individuals with first episode psychosis and healthy controls. We investigated two hypotheses: (1) increase in a positron emission tomography (PET) imaging marker of microglia is associated with increased anterior cingulate (ACC) glutamate levels; and (2) reducing immune trafficking into the CNS using the monoclonal antibody natalizumab would reduce ACC glutamate levels in people with first-episode psychosis. A total of 108 participants (68 patients and 40 healthy controls) underwent simultaneous proton magnetic resonance spectroscopy to quantify ACC glutamate and glutamate\/glutamine (glx) levels and PET imaging with [18\u2009F]DPA-714 to quantify translocator protein (TSPO) levels, a protein highly expressed by microglia in neuroinflammatory conditions. In the longitudinal arm, 50 first-episode psychosis patients were included and either randomised to receive natalizumab or placebo double-blind, or received open-label natalizumab. At baseline, there was no significant association between ACC glutamate concentration and ACC TSPO binding in the entire sample (\u03b2\u2009=\u2009-0.003, SE\u2009=\u20090.006,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.55). In the longitudinal arm, natalizumab did not significantly alter ACC glutamate levels (mean difference\u2009=\u20090.227 i.u., t\u2009=\u20091.52,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.139). These findings do not support the hypothesis that microglial dysfunction drives ACC glutamatergic dysregulation in early psychosis. Microglial dysfunction and glutamatergic dysregulation may therefore represent distinct mechanisms within the neurobiology of schizophrenia.\n                  <\/jats:p>","DOI":"10.1038\/s41386-026-02466-3","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T08:49:08Z","timestamp":1783586948000},"page":"2083-2092","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Does a monoclonal antibody targeting immune cells affect glutamatergic level in schizophrenia? 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TP has received speaker\/consultancy fees from Boehringer Ingelheim, Recordati, Lundbeck, Otsuka, Janssen, CNX Therapeutics, Sunovion, ROVI Biotech, Schwabe Pharma, and Lecturing Minds Stockholm AB; he receives book royalties from Wiley Blackwell; he co-directs a company that designs digital resources to support treatment of mental illness. T.R.M. has received honoraria for speaking and chairing from Lundbeck, Janssen, Astellas and Viatris and received honoraria to participate in advisory boards organised by Angelini Pharmaceuticals. He is an employee and shareholder of Pasithea Therapeutics. O.D.H. has received investigator-initiated research funding from and\/or participated in advisory\/speaker meetings organised by Angelini, Autifony, Biogen, Boehringer Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Janssen, Karuna, Lundbeck, Merck, Neurocrine, Ontrack\/Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris\/Mylan. 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