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Background: Inflammatory cytokines like interleukin-6 (IL-6) are implicated in depression, but most studies have hitherto focused on circulating levels of IL-6 rather than its activity. IL-6 trans-signalling is thought to be responsible for most of the pathogenic effects of IL-6 and is implicated in autoimmune diseases like rheumatoid arthritis. We tested the association between a multi-protein-derived measure of IL-6 trans-signalling and clinical and cognitive outcomes in patients with depression. We hypothesised that this novel measure of IL-6 activity/bioavailability would be associated with clinical and cognitive measures previously reported to be associated with inflammation in depression., Methods: Using data from 86 patients with International Classification of Diseases-10 diagnosis of depression, we calculated a ratio score representing IL-6 activity/bioavailability using serum IL-6, soluble IL-6 receptor (sIL-6R), and soluble glycoprotein 130 levels. We tested the relationship of this novel biomarker with 12 cytokines using correlation analyses and with cognitive and clinical measures using multivariable linear regression, following z-transformation of all immune exposures., Results: The novel measure of IL-6 activity/bioavailability was correlated with IL-6 (r=0.42, P=0.03), C-reactive protein (CRP) (r=0.42, P=0.03), sIL-6R (r=0.91, P<0.01), and tumour necrosis factor alpha (r=0.43, P=0.03). The IL-6 activity/bioavailability measure was associated with higher somatic symptoms of depression (β=1.09; 95% CI 0.30, 1.88; P FDR =0.01), fatigue (β=4.34; 95% CI 1.26, 7.42; P FDR =0.03), depression severity (β=3.06; 95% CI 0.71, 5.40; P=0.02), poorer quality of life (β=-0.07; 95% CI -0.13, -0.01; P FDR =0.045), and decreased psychomotor speed (β=-5.46; 95% CI -9.09, -1.84; P FDR =0.01),. There was little evidence of associations with reaction time, anhedonia, anxiety, emotional perception and recall, executive function, and sustained attention (Ps>0.05). The effect estimates for the associations of the novel measure with depression outcomes were comparable to those for individual immune proteins (i.e., IL-6, CRP, sIL-6R)., Conclusion: A novel multi-protein-derived measure of IL-6 activity/bioavailability shows robust associations with various inflammation-related clinical and cognitive outcomes in depression and performs well in comparison to single inflammatory proteins. We need replication of these findings in other samples, experiments for mechanistic validity of this novel biomarker, and clinical studies to assess its usefulness as a marker of illness risk and prognosis., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis., Methods and Analysis: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6<0.7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis., Ethics and Dissemination: The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010; IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means., Trial Registration Number: ISRCTN23256704., Competing Interests: Competing interests: NMB holds shares and is a Director of Celentyx, other authors have no conflicts of interest to report., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)