Title:Novel Treatment for the Most Resistant Schizophrenia: Dual Activation of NMDA Receptor and Antioxidant
Volume: 21
Issue: 6
关键词:
精神分裂症,氯氮平,耐氯氮平的精神分裂症,NMDAR,DAAO,DAAO抑制剂,苯甲酸钠,抗氧化剂。
摘要:
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.