{
  "abstract": "Introduction Emerging evidence supports a role for interleukin 6 (IL-6), a pro-inflammatory cytokine, in the pathogenesis of treatment-resistant major depressive disorder (TRD). 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.Methods and analysis 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≥3 mg/L) will be randomised (1:1) to receive either one intravenous infusion of tocilizumab (8 mg/kg; maximum 800 mg) 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.Ethics and dissemination The study has been approved by the Research Ethics Committee of the Hospital de Clínicas 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.Trial registration number NCT07052058.",
  "authors": [
    {
      "affiliations": [
        "Graduate Program in Psychiatry and Behavioural Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil",
        "I-QOL: Interventions and Innovations for Quality of Life Research Group, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"
      ],
      "name": "Pedro Henrico Grazziotin Portal"
    },
    {
      "affiliations": [
        "Graduate Program in Psychiatry and Behavioural Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil",
        "I-QOL: Interventions and Innovations for Quality of Life Research Group, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"
      ],
      "name": "Graziella Nunes Peixoto"
    },
    {
      "affiliations": [
        "Graduate Program in Psychiatry and Behavioural Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil",
        "I-QOL: Interventions and Innovations for Quality of Life Research Group, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"
      ],
      "name": "Marina Ribeiro de Matos"
    },
    {
      "affiliations": [
        "Graduate Program in Psychiatry and Behavioural Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil",
        "I-QOL: Interventions and Innovations for Quality of Life Research Group, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"
      ],
      "name": "Luiz Carlos Nascimento da Silva"
    },
    {
      "affiliations": [
        "Graduate Program in Psychiatry and Behavioural Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil",
        "I-QOL: Interventions and Innovations for Quality of Life Research Group, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"
      ],
      "name": "Giulio Bertollo Alexandrino"
    },
    {
      "affiliations": [
        "Graduate Program in Psychiatry and Behavioural Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil",
        "I-QOL: Interventions and Innovations for Quality of Life Research Group, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"
      ],
      "name": "Paulo Henrique Gonçalves Dutra"
    },
    {
      "affiliations": [
        "Graduate Program in Psychiatry and Behavioural Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil",
        "I-QOL: Interventions and Innovations for Quality of Life Research Group, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"
      ],
      "name": "Bruno Perosa Carniel"
    },
    {
      "affiliations": [
        "Graduate Program in Psychiatry and Behavioural Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil",
        "I-QOL: Interventions and Innovations for Quality of Life Research Group, Federal University of Rio Grande do Sul, Porto Alegre, Brazil",
        "Department of Psychiatry, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil",
        "Psychiatry Service, Center for Clinical and Experimental Research, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"
      ],
      "name": "Neusa Sica da Rocha"
    }
  ],
  "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",
  "uid": "34e8cd96-1dde-5172-b1e9-17bd72be7429"
}