Neuroinflammatory and Neuronal Damage Biomarkers in Depression: A Meta-Analysis of HMGB1, S100β, and NSE Levels
TL;DR
Levels of S100β, HMGB1, and NSE show promise as tissue-specific biomarkers in depression, with potential utility in monitoring disease progression and treatment response.
Abstract
Background: Depression is associated with neuroinflammation and dysfunction of neurons and glial cells. Immune activation and damage-associated signals such as S100 calcium-binding protein B (S100β) and high mobility group box 1 (HMGB1) amplify inflammation, leading to neuronal injury. Neuron-specific enolase (NSE) reflects such injury. These molecules may serve as potential biomarkers of depression. Aims: This study compared levels of S100β, HMGB1, and NSE in individuals with depression versus non-depressed controls. Methods: PubMed, Embase, and Web of Science were searched up to April 5, 2025, using the terms “S100B AND Depression”, “neuron specific enolase AND Depression”, and “HMGB1 AND Depression”. Eligible designs included comparative, cross-sectional, clinical trial, and case-control studies. 24 studies assessed S100β, seven assessed NSE, and four assessed HMGB1. Data (mean ± standard deviation and sample size) were analyzed with a random-effects model in Review Manager (RevMan) 5.4.1. Results were expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Heterogeneity was evaluated with I², with subgroup analyses as appropriate. Results: S100β levels were significantly higher in depressed patients compared with controls (SMD = 0.57, 95% CI: 0.25–0.89, p = 0.0005), with stronger effects in plasma (SMD = 0.88, p = 0.03) and serum (SMD = 0.51, p = 0.04), but no difference in cerebrospinal fluid (CSF). Plasma HMGB1 was lower in depression (SMD = -0.44, 95% CI: -0.80 to -0.08, p = 0.02), while serum levels showed no difference. NSE was elevated in CSF (SMD = 1.20, p < 0.0001) and plasma (SMD = 2.03, p = 0.0004), but not in serum. Subgroup analyses indicated elevated S100β in patients without antidepressant use and higher NSE in those receiving antidepressants. Conclusion: S100β, HMGB1, and NSE show promise as tissue-specific biomarkers in depression, with potential utility in monitoring disease progression and treatment response.