Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial

Abstract

Objectives Hypofunction of NMDA receptor is implicated in the pathophysiology, particularly cognitive impairment, of schizophrenia. Sarcosine, a glycine transporter I (GlyT-1) inhibitor, and sodium benzoate, a d-amino acid oxidase (DAAO) inhibitor, can both enhance NMDA receptor-mediated neurotransmission. We proposed simultaneously inhibiting DAAO and GlyT-1 may be more effective than inhibition of either in improving the cognitive and global functioning of schizophrenia patients. Methods This study compared add-on sarcosine (2 g/day) plus benzoate (1 g/day) vs. sarcosine (2 g/day) for the clinical symptoms, as well as the cognitive and global functioning, of chronic schizophrenia patients in a 12-week, double-blind, randomised, placebo-controlled trial. Participants were measured with the Positive and Negative Syndrome Scale and the Global Assessment of Functioning Scale every 3 weeks. Seven cognitive domains, recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Committee, were measured at weeks 0 and 12. Results Adjunctive sarcosine plus benzoate, but not sarcosine alone, improved the cognitive and global functioning of patients with schizophrenia, even when their clinical symptoms had not improved. Conclusions This finding suggests N-methyl-d-aspartate receptor-enhancement therapy can improve the cognitive function of patients with schizophrenia, further indicating this pro-cognitive effect can be primary without improvement in clinical symptoms.

Keywords:

• Schizophrenia
• biological psychiatry
• psychopharmacology
• cognitive function
• NMDA receptor

Acknowledgements

This study is supported in part by Hospital Administration Commission, Ministry of Health and Welfare, Taiwan (9814; 9914); Ministry of Science and Technology (NSC-101-2314-B-039-030-MY3; MOST 104-2325-B-039-004); Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105-TDU-B-212-113002); China Medical University Hospital, Taiwan (DMR-103-083); Chang-Hua Hospital Program Grant 102-8. The sponsors were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Statement of interest

Dr Tsai is a director and shareholder of SyneuRx International Corporation, which plans to develop glycine transporter-1 inhibitor and d-amino acid oxidase inhibitors, including sodium benzoate, for the treatment of central nervous system disorders. SyneuRx International Corporation was not involved in the funding or execution of the study. All other authors report no biomedical financial interests or potential conflicts of interest.