Understanding the role of inflammation in depression and cognitive functioning

Abstract

Inflammation is implicated in the pathogenesis of depression, where inflammatory proteins
such as interleukin 6 (IL-6) play a central role. My doctoral research aimed to provide novel
insights into the inflammatory mechanisms implicated in depression and associated cognitive
dysfunction and to assess the therapeutic potential of targeting IL-6 signalling.
To examine the nature and extent of immune dysregulation in depression, I conducted a
systematic review and meta-analysis of the cellular immunophenotype of depression. This
study showed evidence consistent with dysfunctions in both the innate and adaptive immune
response in patients. Second, to further examine the role of IL-6 in depression, I used a novel
multi-protein-derived biomarker reflecting IL-6 activity/bioavailability and found
associations with clinical and cognitive outcomes in individuals with depression. This novel
biomarker performed comparably to traditionally used single protein-based markers of
inflammation.
Third, to corroborate evidence of causality and the treatment potential of the IL-6
pathway in depression, I analysed data from a proof-of-concept randomised controlled trial of
tocilizumab (anti-IL-6 receptor monoclonal antibody) vs placebo in patients with depression
and evidence of inflammation. I found evidence indicating IL-6 inhibition with tocilizumab
possibly improves certain clinical and cognitive measures in depression. Fourth, analyses of
immunological data showed that tocilizumab treatment led to a rapid and sustained reduction
in systemic inflammation. This work also identified specific immune cell subsets that are
more responsive to IL-6 signalling compared to other cell types examined.
Together, my PhD research adds to evidence base supporting the presence of extensive
immune dysregulation in depression and corroborates evidence of causality and treatment
potential of the IL-6 pathway in this condition. Tentative findings from this small and short
duration trial now require further evaluation using larger samples. My work should inform
the selection of preferred outcome, likely effective sizes, and choice of target population.

Date of Award	4 Feb 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Golam Khandaker (Supervisor), Marcus R Munafo (Supervisor), Hannah J Jones (Supervisor) & Christina Dardani (Supervisor)