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However, interventional studies targeting IL-6 in this population remain scarce. Tocilizumab is a humanised monoclonal antibody that inhibits IL-6 signalling and is approved for the treatment of autoimmune conditions such as rheumatoid arthritis. The primary objective of this study is to examine whether IL-6 inhibition via tocilizumab can impact depressive symptoms, inflammation-related biomarkers and cognition in patients with TRD. A secondary objective is to compare the biological profiles of patients with TRD with elevated inflammation to those of healthy controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This is a proof-of-concept, randomised, parallel-group, triple-blind, placebo-controlled clinical trial. 22 adult outpatients diagnosed with TRD and evidence of low-grade inflammation (serum C reactive protein\u22653\u2009mg\/L) will be randomised (1:1) to receive either one intravenous infusion of tocilizumab (8\u2009mg\/kg; maximum 800\u2009mg) or normal saline, administered as an add-on to their ongoing treatment. Psychiatric, cognitive and biomarker assessments will be performed at baseline and at follow-up visits on days 7, 14 and 28 post-infusion. Additionally, 10 healthy controls with no psychiatric history will undergo the same baseline assessments for biomarker comparison.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study has been approved by the Research Ethics Committee of the Hospital de Cl\u00ednicas de Porto Alegre (Project number: 2025-0245, CAAE: 88904825.7.0000.5327). Findings will be disseminated through peer-reviewed publications, scientific meetings and, on request, lay summaries for participants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT07052058\">NCT07052058<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-111421","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T12:05:37Z","timestamp":1781265937000},"page":"e111421","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Add-on tocilizumab versus placebo for resistant major depression in psychiatric outpatients with low-grade inflammation in a tertiary public hospital in Southern Brazil: randomised triple-blind clinical trial protocol"],"prefix":"10.1136","volume":"16","clinical-trial-number":[{"clinical-trial-number":"nct07052058","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6574-0732","authenticated-orcid":false,"given":"Pedro Henrico Grazziotin","family":"Portal","sequence":"first","affiliation":[{"name":"Graduate Program in Psychiatry and Behavioural Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"},{"name":"I-QOL: Interventions and Innovations for Quality of Life Research Group, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziella Nunes","family":"Peixoto","sequence":"additional","affiliation":[{"name":"Graduate Program in Psychiatry and Behavioural Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"},{"name":"I-QOL: Interventions and 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