About 20-35% of schizophrenia patients do not respond to first-line antipsychotics (treatment-resistant schizophrenia: TRS). The glutamate hypothesis is an important hypothesis that explains the pathophysiology of schizophrenia. As a common biological property of TRS, increased levels of glutamatergic neurometabolites in the anterior cingulate have been consistently reported. However, few studies have examined the pathophysiology underlying TRS and clozapine resistance, and to date no robust neuroimaging correlates for these conditions have been found. Future studies need to elucidate the neuroimaging correlates of TRS and the mechanism of action of clozapine.
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