Predicting treatment resistance from the first stage of psychosis aids in personalized treatment, promotes a better prognosis, and

contributes to healthcare cost savings. Currently, no biomarker accurately predicts treatment resistance in patients with firstepisode

psychosis (FEP). This study aims to investigate the potential of cortical gyrification as a biomarker for predicting resistance

in the first episode of schizophrenia. A cohort of 101 individuals diagnosed with FEP and an equivalent number of age- and sexmatched

healthy controls (HCs) underwent T1-weighted magnetic resonance imaging scans immediately after their initial contact.

Patients received treatment in a naturalistic clinical setting, and treatment resistance was assessed at the final point after a

prolonged follow-up period. A vertex-wise comparison of the local gyrification index (lGI) was conducted among the FEP patients,

HCs, and patients classified as treatment-resistant (TRs) and non treatment-resistant (non-TRs). FEP patients showed hypogyria in

the paracentral area and a region encompassing the precuneus, cuneus, and lingual gyrus, and the insula compared to HCs. TRs

exhibited hypogyria in a region spanning the precuneus, cuneus, and lingual gyrus, while non-TRs displayed hypogyria in the

paracentral region. No significant lGI differences were found between TRs and non-TRs; however, after controlling for antipsychotic

dosage as a covariate, non-TRs showed hypogyria in the parietal region compared to TRs. The observed disparities in gyrification

patterns between TRs and non-TRs suggest the presence of discrete neurodevelopmental anomalies underlying these groups.

These findings indicate that cortical gyrification could serve as a biomarker for the early prediction of treatment resistance in

psychosis.