Mitochondrial and inflammatory markers as promising tools to enrich the diagnosis of schizophrenia and bipolar disorder

Mitochondrial dysfunction and low-grade inflammation have both been implicated in major mood and psychotic disorders, yet their interplay and association with specific symptom profiles and potential as diagnostic biomarkers 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 lactate levels and with decreased mtDNA-cn during acute episodes. Mitochondrial markers correlated with inflammatory markers and clinical outcomes. 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 global functioning and disease onset. These findings support a contribution of mitochondrial and inflammatory alterations to the biological profile of severe psychiatric disorders. If replicated, such potential biomarkers may help refine diagnostic stratification and improve the characterization of clinical profiles.