NMDA receptor modulators – d-amino acids’ pathophysiological roles and therapeutic potential in schizophrenia

Schizophrenia (SCZ) is widely considered to be closely associated with n-methyl-d-aspartate receptor (NMDAR) dysfunction. As important modulators of NMDAR, abnormalities in d-amino acid levels and their metabolic pathways may play a critical role in the pathophysiology of SCZ. Emerging evidence suggests that alterations in d-amino acid-related indicators in the plasma and brain tissue of patients with SCZ are associated with disease progression. Monitoring blood concentrations of d-amino acids may therefore provide novel peripheral biomarkers for the auxiliary diagnosis of schizophrenia. Although direct activation of NMDAR has not yielded satisfactory therapeutic outcomes, preliminary progress has been made by modulating its co-agonist sites for glycine and d-serine. d-serine, d-aspartate, and d-cysteine, as NMDAR agonists, represent potential adjunctive therapeutic strategies for schizophrenia. In contrast, d-cycloserine, a partial NMDAR agonist, has demonstrated mixed clinical efficacy in the treatment of schizophrenia. Furthermore, an alternative strategy for enhancing NMDAR function is the inhibition of d-amino acid oxidase (DAAO). Although a variety of DAAO inhibitors have been developed for the treatment of schizophrenia, most of these agents have not yet entered clinical application. Importantly, whether DAAO inhibition can improve therapeutic outcomes in SCZ by increasing d-amino acid levels remains to be further validated. Future research still requires higher-quality preclinical studies and multicenter clinical trials with longer follow-up periods to further elucidate the efficacy, safety, and potential value of peripheral biomarkers associated with d-amino acid-based interventions.