Inflammatory Biomarkers in Depression and Mental Health

Emerging evidence has repositioned inflammation from a peripheral bystander to a central player in the aetiology and course of depressive disorders. Pro-inflammatory cytokines such as interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), alongside acute-phase reactants like C-reactive protein (CRP), are consistently elevated in subsets of individuals with depression. These biomolecules interact with the hypothalamic–pituitary–adrenal axis, alter neurotransmitter metabolism and affect neural plasticity, thereby linking systemic immune activation to mood regulation. Heterogeneity in clinical presentation appears to reflect distinct inflammatory profiles, with some patients showing predominantly neurovegetative symptoms and others cognitive-affective features. Mendelian randomisation and longitudinal cohort studies further suggest that specific inflammatory mediators may act as causal risk factors for onset, persistence and relapse, offering a rationale for immunomodulatory interventions. The global burden of depression and the limited efficacy of existing treatments underscore the urgency of refining biomarker-guided diagnostics and personalised therapies that target aberrant inflammatory pathways.

Research from Nature Portfolio

A large-scale meta-analysis in elderly cohorts compared peripheral levels of IL-1β, IL-6, TNF-α and CRP in late-life depression and Alzheimer’s disease. Findings revealed that only IL-6 remained significantly elevated in depressed patients after adjustment for multiple testing, while other markers showed no consistent differences relative to healthy controls. This work underscores IL-6 as a robust indicator of systemic inflammation in depression and highlights the need to focus on age-related immunosenescence when interpreting biomarker data.

Inflammatory Biomarkers in Depression and Mental Health publication trend

The graph below shows the total number of articles in inflammatory biomarkers in depression and mental health across all publications each year (not limited to Nature Index journals).

Technical terms

C-reactive protein (CRP): an acute-phase protein synthesised by the liver in response to systemic inflammation, used clinically as a sensitive marker of immune activation.

Interleukin-6 (IL-6): a multifunctional pro-inflammatory cytokine produced by immune and non-immune cells that influences acute-phase responses and central nervous system function.

Tumour necrosis factor-α (TNF-α): a cytokine critical for regulating immune cells and mediating systemic inflammation, implicated in neuroinflammatory processes.

Mendelian randomisation: a genetic epidemiology method that uses inherited genetic variants as proxies for modifiable exposures to test causal relationships between biomarkers and disease outcomes.

References

1. Visualizing the spatial distribution of inflammation in the depressed brain with a targeted MRI nanoprobe in vivo. NPG Asia Materials (2023).
2. Sex differences in the inflammation-depression link: A systematic review and meta-analysis. Brain Behavior and Immunity (2024).
3. IL-1β, IL-6, TNF- α and CRP in Elderly Patients with Depression or Alzheimer’s disease: Systematic Review and Meta-Analysis. Scientific Reports (2018).
4. Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study. Brain Behavior and Immunity (2021).
5. Low-grade inflammation predicts persistence of depressive symptoms. Psychopharmacology (2015).
6. Role of inflammation in depression relapse. Journal of Neuroinflammation (2019).
7. Persistent depressive symptoms, HPA-axis hyperactivity, and inflammation: the role of cognitive-affective and somatic symptoms. Molecular Psychiatry (2019).