Triple-Blind Randomized Clinical Trial of Tocilizumab vs Placebo: Potential Use of an IL-6 Antagonist as an Adjuvant to Standard Treatment for Treatment-Resistant Major Depression in the Brazilian Public Health System (SUS)

• Tocilizumab (Biological): Single infusion tocilizumab, 8 mg/kg, diluted in 100 mL of normal saline
• Normal Saline (0.9% NaCl) (Drug): Placebo, same volume as intervention

Primary outcomes

• Reduction in depressive symptoms (HDRS) [Baseline and follow-ups (day 7, day 14, day 28 and month 6)]: ≥50% reduction in score

Secondary outcomes

• Cognitive performance (Montreal Cognitive Test) [Baseline and follow-ups (day 7, day 14, day 28 and month 6)]
• Quality of life (EUROHISQOL8) [Baseline and follow-ups (day 7, day 14, day 28 and month 6)]
• BDNF levels [Baseline and third follow-up post-intervention (28th day)]: Serum Brain-Derived Neurotrophic Factor level
• ECT indication after invervention [Follow-ups (day 7, day 14, day 28 and month 6)]
• General psychiatric symptoms improvement (BPRS) [Baseline and follow-ups (day 7, day 14, day 28 and month 6)]
• Clinical global improvement (CGI) [Baseline and follow-ups (day 7, day 14, day 28 and month 6)]
• CRP levels [Baseline and follow-ups (day 7, day 14, day 28 and month 6)]: Serum C-Reactive Protein levels
• IL-6 levels [Baseline (for healthy controls) and baseline and follow-ups for intervention arm(day 7, day 14, day 28 and month 6)]: Serum IL-6
• Psychiatric hospitalization rate in 6 months [6 months follow-up]
• Suicidal ideation (MINI) [Elegibility and follow-ups (day 7, day 14, day 28 and month 6)]
• Quality of life (WHOQOL-BREF) [Baseline, follow-ups (day 7, day 14, day 28 and month 6)]

Sex: All, ages: 18 Years to 65 Years, accepts healthy volunteers

Inclusion Criteria:

Age ≥ 18 years Provide informed consent Understand written and spoken Portuguese Able and willing to consent to blood sampling Willing to abstain from strenuous exercise for 72 hours prior to assessment Meet DSM-5/MINI criteria for a diagnosis of depression resistant to at least two adequate courses of treatment at the time of eligibility assessment Baseline HDRS score of 19 or higher at Serum/plasma CRP level ≥3 mg/L

Exclusion Criteria:

Diagnosis of bipolar disorder or personality disorder History of substance use disorder in the past six months. Presence of active/recent infection (including TB, Hepatitis B, Hepatitis C, or HIV) or autoimmune disease Pregnancy or breastfeeding History of significant cardiovascular disease, recent cancer, or hematological disorders BMI >40 kg/m² or weight >100 kg Hypersensitivity to tocilizumab or any of its excipients. CRP ≥20 mg/L Active liver disease or transaminase elevation >1.5× the upper limit of normal

Inclusion criteria to the 10 healthy controls recruited for comparison of inflammatory biomarkers:

Age ≥ 18 No current or lifetime psychiatric diagnosis, as measured by the SRQ-20 Provide informed consent Understand written and spoken Portuguese Able and willing to consent to blood sampling

• Results publication: Portal PHG, Peixoto GN, de Matos MR, da Silva LCN, Alexandrino GB, Dutra PHG, Carniel BP, da Rocha NS. 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. BMJ Open. 2026 Jun 12;16(6):e111421. doi: 10.1136/bmjopen-2025-111421. PMID 42285573

• Neusa Sica da Rocha, PhD, Study director, Federal University of Rio Grande do Sul (UFRGS)