Abstract / Summary
Schizophrenia (SCZ) remains one of the most disabling psychiatric disorders, in large part because current antipsychotics (APs) inadequately address negative symptoms and cognitive deficits. Converging evidence implicates a set of interconnected mechanisms, NMDAR hypofunction, oxidative stress, and a possible low-grade neuroimmune activation, that converge on parvalbumin-positive GABAergic interneuron dysfunction, the likely substrate of these refractory symptom domains. N-Acetylcysteine (NAC) is an adjunctive candidate because it may act on several of these pathways: it replenishes glutathione (GSH), restores redox balance, and modulates glutamatergic transmission, while its immunomodulatory effects remain poorly characterized in SCZ. This comprehensive review synthesizes evidence from preclinical models and clinical trials, showing that NAC produces replicated but modest benefits for negative symptoms and cognitive function, with inconsistent effects on positive symptoms. Notably, null findings in clinical-high-risk and treatment-resistant populations, together with a single exploratory subgroup analysis in early psychosis in which a peripheral redox index (erythrocyte glutathione peroxidase activity) was associated with positive-symptom response, raise the hypothesis that NAC efficacy may depend on a pre-existing, measurable antioxidant deficit. Adequately powered, biomarker-enriched trials that stratify patients by redox status are therefore needed to determine whether NAC is an effective targeted therapy for a mechanistically defined SCZ subgroup. Such trials would resolve whether the modest effect sizes observed in unselected populations reflect true but limited efficacy or dilution by enrolment of redox-normal patients unlikely to benefit.