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.