Treatment-resistant schizophrenia (TRS) poses a considerable challenge in psychiatric care, with approximately 10–60% of patients

exhibiting non-responsiveness to antipsychotic medication. While early treatment could improve clinical outcomes, the absence of

objective biomarkers hinders timely intervention. General structural changes have been suggestively associated with TRS. However,

there is a lack of clear and robust conclusions due to challenges in obtaining data from TRS cases with large sample sizes. To

address this knowledge gap, we collaborated with Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium

to investigate brain structural changes associated with TRS. Leveraging data from multiple institutions spanning various continents

and ethnic groups, our meta- and mega-analysis revealed a significant reduction in the volume of bilateral putamen and bilateral

hippocampus, as well as the left superior frontal gyrus (SFG) surface area in TRS patients compared with non-TRS patients with

sufficient statistical power. Further analysis, incorporating data from healthy controls (HCs), unveiled a decreasing trend in bilateral

hippocampal volumes and left SFG surface area from HCs to non-TRS patients and further to TRS patients. There were no significant

effects of either clozapine dose or cumulative antipsychotic exposure on bilateral hippocampal volumes or left SFG surface area. In

contrast, the putamen volume exhibited an increase in non-TRS patients compared with HCs, with no significant difference

between TRS patients and HCs. Antipsychotic exposure was significantly correlated with the putamen volume with small effect size.

In conclusion, this study underscores the volume of the hippocampus and SFG as potential biomarkers for TRS.