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. This study was supported by funding from Agence Nationale de la Recherche (ANR-11-IDEX-0004-02 and ANR-10-COHO-10-01 and ERANET Neuron-ANR-18-0008-01) and from the French National Research Agency for France 2030 with the reference ANR-22-EXPR-0013, INSERM (Institut National de la Santé et de la Recherche Médicale), by Fondation FondaMental (www.fondation-fondamental.org) to create the french I-GIVE cohort.

We thank all the patients who participated to this study, the clinical teams from the University department of psychiatry and addictology of Henri Mondor hospital (DMU IMPACT) as well as the team from the Biobank and CIC of Henri Mondor Hospital (AP-HP). Translational Neuropsychiatry laboratory, Psychiatry and Addictology Department (DMU IMPACT INSERM U955 IMRB, AP-HP), Hôpital Henri Mondor (AP-HP), Paris Est Créteil University (UPEC), Fondation FondaMental, Créteil, France Jérémy Bernard, Wahid Boukouaci, Ching-Lien Wu, Jihène Bouassida, Ophélia Godin, Jean-Romain Richard & Marion Leboyer Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, Mitochondrial Innovation Initiative (MITO2i), University of Toronto, Toronto, Canada Jérémy Bernard, Jaehyoung Choi & Ana C. Andreazza Plateforme de Ressources Biologiques, HU Henri Mondor, AP-HP, Créteil, France Jérémy Bernard, Ching-Lien Wu, Jihène Bouassida, Ophélia Godin, Lauren Hasty & Marion Leboyer Inserm, Centre d’Investigation Clinique 1430 et AP-HP, Hopitaux Universitaires Henri Mondor,Universitaires Paris Est Créteil, Créteil, France The authors declare no competing interests.

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