{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:28:30Z","timestamp":1790800110949,"version":"4.1.0"},"reference-count":72,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T00:00:00Z","timestamp":1586131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007123","name":"Stanley Medical Research Institute","doi-asserted-by":"publisher","award":["13T-012"],"award-info":[{"award-number":["13T-012"]}],"id":[{"id":"10.13039\/100007123","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-\u03b1) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab\u2019s effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-\u03b1 receptors (TNFRs) and nuclear factor-kappa B (NF-\u03baB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab\u2019s effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (\u03c72 = 9.275, p = 0.026), NF-\u03baB (\u03c72 = 13.825, p = 0.003), and inhibitor of NF-\u03baB (I\u03baB\u03b1)\u03b1 (\u03c72 = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (\u03c72 = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = \u22120.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR\/NF-\u03baB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.<\/jats:p>","DOI":"10.3390\/cells9040895","type":"journal-article","created":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T03:58:39Z","timestamp":1586231919000},"page":"895","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression"],"prefix":"10.3390","volume":"9","author":[{"given":"Rodrigo B.","family":"Mansur","sequence":"first","affiliation":[{"name":"Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON M5T 2S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0201-0248","authenticated-orcid":false,"given":"Francheska","family":"Delgado-Peraza","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA\/NIH), Baltimore, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehala","family":"Subramaniapillai","sequence":"additional","affiliation":[{"name":"Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0629-9456","authenticated-orcid":false,"given":"Yena","family":"Lee","sequence":"additional","affiliation":[{"name":"Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada"},{"name":"Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Iacobucci","sequence":"additional","affiliation":[{"name":"Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Rosenblat","sequence":"additional","affiliation":[{"name":"Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON M5T 2S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Brietzke","sequence":"additional","affiliation":[{"name":"Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada"},{"name":"Kingston General Hospital, Providence Care Hospital, Department of Psychiatry, Queen\u2019s University School of Medicine, Kingston, ON K7L 4X3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria E.","family":"Cosgrove","sequence":"additional","affiliation":[{"name":"Department of Psychiatry &amp; Behavioral Sciences, Stanford University, School of Medicine, Palo Alto, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole E.","family":"Kramer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry &amp; Behavioral Sciences, Stanford University, School of Medicine, Palo Alto, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trisha","family":"Suppes","sequence":"additional","affiliation":[{"name":"Department of Psychiatry &amp; Behavioral Sciences, Stanford University, School of Medicine, Palo Alto, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L.","family":"Raison","sequence":"additional","affiliation":[{"name":"School of Human Ecology, University of Wisconsin-Madison, Madison, WI 53706, USA"},{"name":"Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahil","family":"Chawla","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA\/NIH), Baltimore, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2503-965X","authenticated-orcid":false,"given":"Carlos","family":"Nogueras-Ortiz","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA\/NIH), Baltimore, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger S.","family":"McIntyre","sequence":"additional","affiliation":[{"name":"Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON M5T 2S8, Canada"},{"name":"Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2181-3118","authenticated-orcid":false,"given":"Dimitrios","family":"Kapogiannis","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA\/NIH), Baltimore, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/j.jpsychires.2013.05.018","article-title":"Cytokines in bipolar disorder vs. healthy control subjects: A systematic review and meta-analysis","volume":"47","author":"Munkholm","year":"2013","journal-title":"J. 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