Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation

Abstract

IntroductionObservational studies indicate a potentially causal role for interleukin 6 (IL-6), a proinflammatory cytokine, in pathogenesis of depression, but interventional studies based on patients with depression have not been conducted. Tocilizumab, anti-inflammatory drug, is a humanised monoclonal antibody that inhibits IL-6 signalling and is licensed in the UK for treatment of rheumatoid arthritis. The main objectives of this study are to test whether IL-6 contributes to the pathogenesis of depression and to examine potential mechanisms by which IL-6 affects mood and cognition. A secondary objective is to compare depressed participants with and without evidence of low-grade systemic inflammation.Methods and analysisThis is a proof-of-concept, randomised, parallel-group, double-blind, placebo-controlled clinical trial. Approximately 50 participants with International Classification of Diseases 10th revision (ICD-10) diagnosis of depression who have evidence of low-grade inflammation, defined as serum high-sensitivity C reactive protein (hs-CRP) level ≥3 mg/L, will receive either a single intravenous infusion of tocilizumab or normal saline. Blood samples, behavioural and cognitive measures will be collected at baseline and after infusion around day 7, 14 and 28. The primary outcome is somatic symptoms score around day 14 postinfusion. In addition, approximately, 50 depressed participants without low-grade inflammation (serum hs-CRP level <3 mg/L) will complete the same baseline assessments as the randomised cohort.Ethics and disseminationThe study has been approved by the South Central—Oxford B Research Ethics Committee (REC) (Reference: 18/SC/0118). Study findings will be published in peer-review journals. Findings will be also disseminated by conference/departmental presentations and by social and traditional media.Trial registration numberISRCTN16942542; Pre-results.

Assessment of cognitive function in female rheumatoid arthritis patients: associations with cerebrovascular pathology, depression and anxiety

“…Camara et al [44] reported that centrally administered etanercept improved anxiety-like behavior in mice. Khandaker et al [23] presented a protocol of a trial initiated in 2018, where behavioral and cognitive measures will be evaluated in tocilizumabtreated patients. In addition to pharmacotherapy, tailored cognitive behavioral therapy introduced in early RA was found to be beneficial in various studies [45,46].…”

“…Methotrexate (MTX) and corticosteroids have been associated with cognitive impairment [9,20,21]. As inflammation is involved in cognitive dysfunction in RA, the control of disease activity may be beneficial for the patients [22,23].…”

Depression and the risk of rheumatoid arthritis

“…With evidence for pro-inflammatory cytokines being elevated in depression, it is of no surprise that targeted anticytokine therapy is of interest in the primary management of MDD. Clinicaltrials.gov lists an active study for tocilizumab (IL-6 inhibitor) in treatment-refractory MDD, and the trial protocol for the insight study, which will assess the effect of a single intravenous infusion of tocilizumab on somatic symptoms score, has been published [36]. JAK/STAT modulation is also of theoretical benefit, as this pathway is involved in neurogenesis, synaptic plasticity, gliogenesis and microglial activation, and also with some antidepressants having a mechanism of action mediated by JAK/STAT-dependent mechanisms [5 ▪ ].…”

Depression in patients with spondyloarthritis: prevalence, incidence, risk factors, mechanisms and management

“…100 A proofof-concept double blind RCT of the anti-IL-6R mAb tocilizumab in patients with depression is underway, with subjects selected based upon evidence of inflammation and inflammation-related symptoms. 101 Turning to data from patients with AS, the mood improving effects of infliximab is consistent with a potentially shared role of inflammation in pathogenesis of depression, AS and other chronic inflammatory physical illness. 102 Sickness behaviour, a response to inflammation in autoimmune disease or infection, is characterised by fatigue, sleep problems, anhedonia, reduced appetite, concentration and motivation, which are also typical symptoms of depression.…”

“… 100 A proof-of-concept double blind RCT of the anti-IL-6R mAb tocilizumab in patients with depression is underway, with subjects selected based upon evidence of inflammation and inflammation-related symptoms. 101 …”