Abstract
BACKGROUND: Mitochondrial dysfunction has been implicated in major depressive disorder (MDD), but reliable, measurable biomarkers remain elusive. As a minimally invasive and quantifiable biomarker, circulating cell-free mitochondrial DNA (ccf-mtDNA) in blood offers potential for objective assessment of mitochondrial stress in MDD. However, evidence linking regarding the association between ccf-mtDNA levels and MDD is limited and inconsistent. METHODS: We systematically searched eight databases, including PubMed, EMBASE, and major Chinese repositories. Thirteen studies with 1370 participants (837 individuals with MDD and 533 controls) were included per PRISMA guidelines. P-values were synthesized using the Lipták-Stouffer Z-score method. Sensitivity and fail-safe N analyses assessed the robustness of the findings and publication bias, and stratified analyses examined the effects of age, antidepressant use, and geographic region. RESULTS: Across studies, elevated blood ccf-mtDNA levels were significantly associated with MDD (p = 0.013). Stratified analyses revealed stronger associations in older adults (≥60 years old; p = 0.0009), unmedicated patients (p = 4.99 × 10⁻⁶), and North American cohorts (p = 4.29 × 10⁻¹¹), but not in younger individuals (p = 0.83), medicated patients (p = 0.97), and Asian/European samples (p = 0.72, p = 0.99). Sensitivity analyses indicated moderate instability overall but confirmed data robustness in key subgroups. CONCLUSIONS: This is the first meta-analysis to establish a significant link between elevated blood ccf-mtDNA and MDD, highlighting age and antidepressant exposure as critical modulators. These findings support the potential of blood ccf-mtDNA to serve as a biomarker for late-life and drug-naïve depression, with implications for objective diagnosis and personalized treatment.