Abnormalities in nitric oxide synthase system function and their association with cognitive function in first-episode schizophrenia patients

Cognitive deficits are a core feature of schizophrenia, emerging early and strongly influencing functional outcomes. However, the role of the nitric oxide (NO) signaling pathway in drug-naïve, first-episode schizophrenia remains unclear. To investigate the relationship between the nitric oxide synthase (NOS) system and cognitive function, we studied 98 first-episode, drug-naïve schizophrenia patients and 96 matched healthy controls. Plasma levels of inducible NOS (iNOS), total NOS (TNOS), the iNOS/TNOS ratio, malondialdehyde (MDA), and hydrogen peroxide (H₂O₂) were measured. Psychopathological symptoms and cognitive performance were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively. Group differences and associations among NOS markers, cognitive domains, and symptom severity were examined. Patients exhibited marked NOS system dysfunction, characterized by reduced iNOS and TNOS levels, a lower iNOS/TNOS ratio, elevated MDA levels, and reduced H₂O₂ concentrations. TNOS levels were positively associated with RBANS total score and multiple cognitive domains, independent of PANSS total score, whereas iNOS levels were associated only with immediate memory. The iNOS/TNOS ratio showed no independent association with cognition. In addition, TNOS levels were correlated with PANSS total score, suggesting that overall NOS function reflects disease burden. These findings indicate that early schizophrenia is characterized by NOS system dysfunction. Overall NOS activity, rather than relative NOS subtype expression, is closely linked to multidimensional cognitive impairment and is partly independent of symptom severity.