Although treatment-resistant schizophrenia (TRS) was described 50 years ago and has a gold standard treatment with clozapine based on well-defined criteria, there is still a matter of great interest and controversy. In terms of the underlying mechanisms of the development of TRS, progress has been made for the elucidation of the neurochemical mechanisms. Structural neuroimaging studies have shown that patients with TRS have significant reduction of the prefrontal cortex volume when compared with non- TRS. This article updates and enhances our previous review with new evidence mainly derived from new studies, clinical trials, systematic reviews, and meta-analyses.