Submit Manuscript  

Article Details

Novel Treatment for the Most Resistant Schizophrenia: Dual Activation of NMDA Receptor and Antioxidant

[ Vol. 21 , Issue. 6 ]


Chieh-Hsin Lin, Yu-Ming Chen and Hsien-Yuan Lane*   Pages 610 - 615 ( 6 )


Clozapine has been regarded as the last-line antipsychotic agent for patients with refractory schizophrenia. However, many patients remain unresponsive to clozapine, referred to as “clozapineresistant”, “ultra-treatment-resistant”, or remain in incurable state. There has been no convincing evidence for augmentation on clozapine so far. Novel treatments including numerous N-methyl-Daspartate (NMDA) receptor (NMDAR) enhancers, such as glycine, D-serine, D-cycloserine, and Nmethylglycine (sarcosine) failed in clinical trials.

Earlier, the inhibition of D-amino acid oxidase (DAAO) that may metabolize D-amino acids and activate NMDAR has been reported to be beneficial for patients with schizophrenia receiving antipsychotics except for clozapine. A recent randomized, double-blind, placebo-controlled clinical trial found that add-on sodium benzoate, a DAAO inhibitor, improved the clinical symptoms in patients with clozapine- resistant schizophrenia, possibly through DAAO inhibition (and thereby NMDAR activation) and antioxidation as well; additionally, sodium benzoate showed no obvious side effects, indicating that the treatment is safe at doses up to 2 g per day for 6 weeks. More studies are warranted to elucidate the mechanisms of sodium benzoate for the treatment of schizophrenia and the etiology of this severe brain disease. If the finding can be reconfirmed, this approach may bring new hope for the treatment of the most refractory schizophrenia.

This review summarizes the current status of clinical trials and related mechanisms for treatmentresistant, especially, clozapine-resistant schizophrenia. The importance of understanding the molecular circuit switches is also highlighted which can restore brain function in patients with schizophrenia. Future directions in developing better treatments for the most difficult to cure schizophrenia are also discussed.


Schizophrenia, clozapine, clozapine-resistant schizophrenia, NMDAR, DAAO, DAAO inhibitor, sodium benzoate, antioxidant.


Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Graduate Institute of Biomedical Sciences, China Medical University, Taichung

Graphical Abstract:

Read Full-Text article