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Novel Treatment for the hardest-to-treat Schizophrenia: Dual Activation of NMDA Receptor and Antioxidant.

  • Lin, Chieh-Hsin1
  • Chen, Yu-Ming1
  • Lane, Hsien-Yuan2
  • 1 Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan. , (Taiwan)
  • 2 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. , (China)
Published Article
Current drug targets
Publication Date
Oct 11, 2019
DOI: 10.2174/1389450120666191011163539
PMID: 31660823


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 "clozapine-resistant", "ultra-treatment-resistant", or "hardest-to-treat". There has been no convincing evidence for augmentation on clozapine so far. Novel treatments including numerous N-methyl-D-aspartate (NMDA) receptor (NMDAR) enhancers such as glycine, D-serine, D-cycloserine, and N-methylglycine (sarcosine) failed in clinical trials. Earlier, Inhibition of D-amino acid oxidase (DAAO) that may metabolize D-amino acids and thereby activate NMDAR has been reported to be beneficial for patients with schizophrenia receiving antipsychotics except 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 the treatment is safe at the 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 thereby 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 current status of clinical trials and related mechanisms for treatment-resistant, especially, clozapine-resistant schizophrenia. We will also highlight the importance of understanding the molecular circuit switches that can restore brain function in patients with schizophrenia and discuss future directions in developing better treatments for the hardest-to-treat schizophrenia. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]

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