Biomarker evidence for the pathophysiological mechanisms of insomnia: a systematic review and meta-analysis.

BACKGROUND: Insomnia is increasingly recognized as a systemic disorder involving persistent hyperarousal, neuroendocrine dysregulation, immune activation, and impaired stress adaptation. However, circulating biomarkers reflecting these interconnected biological processes have not been comprehensively synthesized. METHODS: We conducted a systematic review and meta-analysis of observational studies comparing circulating biomarkers between adults with insomnia and healthy controls. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using random- or fixed-effects models as appropriate. Subgroup analyses, sensitivity analyses, and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments were performed to evaluate the robustness and certainty of the evidence. RESULTS: Thirty-two studies involving 4578 individuals with insomnia and 28382 healthy controls were included. Cortisol levels were significantly elevated (SMD = 3.65, 95% CI: 2.35 to 4.95). Inflammatory biomarkers, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-2 (IL-2), and interferon-γ (IFN-γ), were significantly increased, whereas interleukin-4 (IL-4) and interleukin-10 (IL-10) showed no significant differences. Neuropeptide Y (NPY) was significantly reduced (SMD = -0.85, 95% CI: -1.27 to -0.43), while corticotropin-releasing hormone (CRH) and brain-derived neurotrophic factor (BDNF) showed no significant pooled differences. TNF-α, IL-1β, IL-6, CRP, and NPY showed generally consistent results in sensitivity analyses. CONCLUSIONS: Insomnia is associated with alterations in circulating biomarkers reflecting hypothalamic-pituitary-adrenal (HPA) axis activity, low-grade systemic inflammation, and potential reductions in stress-buffering capacity. This multidomain biomarker pattern provides insights into the biological basis of insomnia and highlights potential candidate biomarkers for future biological stratification. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD420261396725.