Inflammation as a mediating pathway between social defeat and mental health in humans: A systematic review

Social Defeat (SD), an animal-derived concept characterised by experiences of subordination, may influence biological mechanisms affecting mental health. Despite evidence linking inflammation to mental disorders and animal studies suggesting SD's inflammatory effects, to date, no review has comprehensively examined these relationships in human populations. This systematic review synthesises evidence from human studies examining human SD, inflammation, and mental health, with particular attention to inflammation as a potential mediating pathway in these relationships, to better inform understandings of mental health disparities across marginalised communities.

Embase, MEDLINE, and PsycInfo were searched for eligible observational human studies published from database inception to September 2025. Studies were screened by two reviewers, while a single reviewer extracted data and evaluated study quality and risk of bias. Narrative synthesis revealed overarching themes and patterns.

13 heterogenous studies met the inclusion criteria, predominantly examining social isolation, peer victimisation, discrimination, and childhood adversity. Interleukin-6 (IL-6) and C-Reactive Protein (CRP) with depression were the primarily assessed inflammatory and mental health outcomes. Most studies found SD-inflammation-mental health associations, although some inconsistencies emerged. Sex and SD type arose as potential mediators. However, results were limited by the range of moderate-to-high quality and low-to-high risk of bias across studies.

Various forms of human SD experiences may independently alter immunological profiles and mental health outcomes, providing translational support for animal studies linking SD to inflammatory changes. The mediating role of SD in the relationship between inflammation and mental health remains inconclusive, however. While longitudinal studies may help elucidate the directionality of associations, this study reiterates that SD prevention is paramount for achieving sustainable mental health improvements.