INTERACTIVE MODULATION OF NMDAR AND OXIDATIVE STRESS FOR THE TREATMENT OF MENTAL DISORDERS
Authors: Lane *Hsien-Yuan 
Published: February 2025

Abstract

Background
NMDA receptor (NMDAR) dysfunction is implicated in several mental disorders, such as schizophrenia (Lin et al., Mol Psychiatry 2014; Lin et al., Int J Neuropsychopharmacol 2023), major depressive disorder (Cheng et al., Neuropharmacology 2023), and Alzheimer’ s disease (Lane &Lin, Int J Neuropsychopharmacol 2022; Lin &Lane, Int J Neuropsychopharmacol 2022; Lane et al., Psychiatry Res 2023). 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 and cognitive function of schizophrenia (Lane et al., Arch Gen Psychiatry 2005; Biol Psychiatry 2018; Fleischhacker et al., Lancet Psychiatry 2021). However, these strategies have failed in the treatment clozapine-resistant) schizophrenia patients (Goff et al., CNS Spectr 2001; Lane et al., Biol Psychiatry 2006).

Aims & Objectives
For further improving the treatment of mental disorders, dual and interactive modulation of NMDAR and oxidative stress is a promising approach against treatment-resistant mental disorders.

Methods
This speech reviews current status of clinical trials on NMDAR and/or redox modulation for the treatment of mental disorders.

Results
Another promising route to strengthen NMDAR activity is inhibition of D-amino acid oxidase (DAAO) for slowing D-serine degradation (Sershen et al., Neurochem Res 2016; Kuo et al., CNS Drug 2022). Initially, we found that sodium benzoate, a pivotal DAAO inhibitor, was more efficacious than other NMDAR enhancers (Lane et al., JAMA Psychiatry 2013). In earlier RDCs, sodium benzoate improved cognitive function of patients with chronic schizophrenia, no matter it improved clinical symptoms or not (Lane et al., JAMA Psychiatry 2013, Lin et al., World J Biol Psychiatry 2017). Consequently, benzoate also improved clinical symptoms of clozapine-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 (1) and follicle-stimulating hormone/ estradiol (2). In addition, while benzoate can alter brain activity (Lane et al., Int J Neuropsychopharmacol 2021), it also improved cognitive function of patients with Alzheimer’ s disease (1) or late-life depression (3). Furthermore, both transcranial direct current stimulation (tDCS) and sodium benzoate can modulate NMDAR and oxidative stress (Chang et al., Front Psychiatry 2018), adjunctive tDCS plus sodium benzoate has been promising for the treatment of mental disorders such as Alzheimer's disease (4).

Discussion & Conclusion
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 (Lin &Lane, Schizophr Res 2023 [Invited Commentary]).

References
1.Lane, H. Y., Wang, S. H., &Lin, C. H. (2023). Endogenous antioxidants predicted outcome and increased after treatment: A benzoate dose-finding, randomized, double-blind, placebo-controlled trial for Alzheimer's disease. Psychiatry and Clinical Neurosciences, 77(2), 102–109.
2.Lin, C. H., Chen, P. K., Wang, S. H., &Lane, H. Y. (2021). Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia: Secondary Analysis of a Randomized Clinical Trial. JAMA Network Open, 4(4), e216156.
3.Lin, C. H., Wang, S. H., &Lane, H. Y. (2022). Effects of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, on Perceived Stress and Cognitive Function Among Patients With Late-Life Depression: A Randomized, Double-Blind, Sertraline- and Placebo-Controlled Trial. The International Journal of Neuropsychopharmacology, 25(7), 545–555.
4.Lane, H. Y., Wang, S.H., &Lin, C. H. (2023). Adjunctive transcranial direct current stimulation (tDCS) plus sodium benzoate for the treatment of early-phase Alzheimer's disease: A randomized, double-blind, placebo-controlled trial. Psychiatry Research. 2023;328:115461.