Abstract
<title>Abstract</title> <p>Mitochondrial dysfunction and low-grade inflammation have both been implicated in major mood and psychotic disorders, yet their interplay and clinical relevance remain unclear. We quantified mitochondrial markers including mitochondrial DNA copy number (mtDNA-cn), lactate, and circulating cell-free mitochondrial DNA (ccf-mtDNA) alongside immune markers in 934 individuals from the French I-GIVE cohort, including patients with schizophrenia (SCZ), bipolar disorder (BD), and healthy controls (HC). Both SCZ and BD were associated with increased and lactate levels and with decreased mtDNA-cn during acute episodes. Mitochondrial markers correlated with inflammation and indicators of illness severity. Several inflammatory markers, including IL-1β, IL-6, IL-10, IL-13, IL-16, IL-17, TNF-α, and CRP, were also elevated in patients compared to controls. Models combining mitochondrial and inflammatory markers discriminated patients from controls with high accuracy and moderately distinguished SCZ from BD, while showing more limited performance for symptom severity. These findings support a contribution of mitochondrial and inflammatory alterations to the biological profile of severe psychiatric disorders. If replicated, such biomarkers may help refine diagnostic stratification and improve the characterization of disease severity.</p>