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.