Dysregulated oxidative stress and lactate levels in treatment-resistant schizophrenia

Schizophrenia is a severe and clinically heterogeneous mental disorder, with approximately 30 % of patients developing treatment resistance to standard antipsychotics. To elucidate the pathophysiological mechanisms underlying treatment-resistant schizophrenia (TRS), we performed a comparative proteomic analysis of plasma-derived extracellular vesicles (EVs) from TRS patients, non-TRS (NTRS) patients, and healthy controls (n = 29, 29, and 31, respectively). EVs from TRS and NTRS patients induced schizophrenia-like behavioral deficits in mice, such as impaired prepulse inhibition and reduced social interaction, while healthy control-derived EVs ameliorated these deficits in an MK-801-induced model. In vitro, TRS-EVs triggered concurrent proliferation and apoptosis in astrocytes and induced dendritic abnormalities in neurons more prominently than NTRS-EVs. Proteomic profiling revealed significant dysregulation in TRS-derived EVs, featuring decreased oxygen transport and antioxidant proteins (e.g., HBG1, HBB, PRDX2) and elevated glycolytic enzymes (e.g., LDHA, PKM), indicative of a metabolic shift toward lactate production. Consistent with this, TRS patients showed increased plasma lactate levels and reduced PRDX2 expression, which correlated with clinical severity. These metabolic perturbations were also observed in EV-treated mice and astrocytes. Importantly, pharmacological inhibition of lactate production with dichloroacetate (DCA) reversed the behavioral and neuronal deficits, underscoring the role of metabolic dysregulation in TRS and highlighting lactate modulation as a promising therapeutic strategy for treatment-resistant cases.