NMDA receptor (NMDAR) dysfunction is implicated in several mental disorders. For enhancing NMDAR activity to treat schizophrenia, NMDAR co-agonists (including glycine, D-serine) were examined in randomized, double-bind, placebo-controlled clinical trials (RDCs), albeit with unsatisfactory results. Alternatively, inhibition of glycine transporter-I, showed promising potential in improving clinical symptoms of schizophrenia. However, these strategies have failed in the treatment of ultra-resistant schizophrenia patients. Another promising route to strengthen NMDAR activity is inhibition of D-amino acid oxidase (DAAO) for slowing D-serine degradation (Kuo et al., CNS Drug 2022). Initially, we found that sodium benzoate, a food preservative and a pivotal DAAO inhibitor, was more efficacious than other NMDAR enhancers. In the early RDC, sodium benzoate improved cognitive function of patients with schizophrenia (Lane et al., JAMA Psychiatry 2013). Consequently, benzoate also improved clinical symptoms of ultra-resistant schizophrenia patients in a RDC (Lin et al., Biol Psychiatry 2018). Moreover, sodium benzoate has been found to target at other pathways, such as the antioxidants (Lane et al., Psychiatry Clin Neurosci 2023) and follicle-stimulating hormone/ estradiol (Lin et al., JAMA Netw Open 2021). In addition, benzoate also improved cognitive function of patients with Alzheimer’s disease (Lin et al., Biol Psychiatry 2014) or late-life depression (Lin et al., Int J Neuropsychopharmacol 2022; Cheng et al., Neuropharmacology 2023). If these findings can be reconfirmed, modulation of NMDAR and redox may instill hope for the treatment of mental disorders. Nonetheless, more novel compounds are still needed for better treatment of mental disorders. 

Professor & Director Hsien-Yuan Lane, MD, PhD has been devoted to clinical and translational research for brain disorders for decades, and have been leading in clinical studies on NMDA receptor (NMDAR)-related biomarkers and enhancer, such as sodium benzoate (the pivotal D-amino acid oxidase [DAAO] inhibitor), for early detection and treatment of schizophrenia and other brain disorders with cognitive dysfunction. I have got encouraging findings; and several papers have been published on first-rate journals, including JAMA Psychiatry, Molecular Psychiatry, Biological Psychiatry, JAMA Network Open, and Psychiatry and clinical neurosciences.