Blood circulating cell-free mitochondrial DNA as a potential biomarker for major depressive disorder: a meta-analysis

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.

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.

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.

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.