Circulating cell-free DNA and NETosis-related biomarkers in schizophrenia: association with clinical features and treatment.

OBJECTIVES: Schizophrenia is known to be accompanied by chronic sterile inflammation and elevated circulating cell-free DNA (cfDNA) levels, but the cellular sources have not been fully identified. The aim of this study was to test the hypothesis regarding the contribution of NETosis to the increase in cfDNA and to investigate associations between cfDNA and DNA-associated molecules levels with clinical features and antipsychotic dosage in schizophrenia. METHODS: This case-control study included 63 healthy subjects and 60 patients with schizophrenia. Concentrations in plasma of total, nuclear, and mitochondrial cfDNA, total histone H3, and anti-DNA antibodies as non-specific markers of cell stress/death, and also high-mobility group protein B1 (HMGB1) and citrullinated histone H3 (CitH3) as NETosis-related biomarkers, were analysed using fluorimetric analysis, digital PCR, and ELISA. RESULTS: Total cfDNA levels increased concomitantly with increases in nuclear cfDNA, histone H3, and anti-DNA antibodies, indicating a nuclear origin of plasma cfDNA, while mitochondrial cfDNA decreased in schizophrenia. Correlation analysis revealed a decrease in mitochondrial cfDNA with increasing antipsychotic therapy dosage. NETosis-related markers, CitH3 and HMGB1, did not changed significantly. CONCLUSIONS: These findings did not provide direct evidence linking active NETosis to elevated cfDNA levels, suggesting the involvement of other cell death processes; however, they highlighted the associations between cfDNA and clinical features in schizophrenia.