The Clinical High Risk (CHR) state for psychosis is consistently associated with widespread cortical thinning. However, the

underlying mechanisms driving this neuroanatomical phenotype remain poorly understood. Here, we integrated the ENIGMA CHR

Working Group’s large pooled dataset (N = 1782 CHR, N = 1333 healthy controls) with an open-source PET molecular atlas to

identify, for the first time, potential neurochemical drivers of cortical thinning associated with psychosis risk, transition, and its core

symptoms. Using multilinear model analysis, we show that local chemoarchitecture significantly explains CT differences associated

with CHR case-control status, the severity of negative symptoms, and future psychosis transition after excluding medication

confounds. PET-based maps of dopamine, GABA, glutamate, serotonin, and norepinephrine consistently emerged as the strongest

predictors of lower CT in CHR and psychosis transition (total dominance range: 62–69% and 58–87%, respectively), with

contributions of monoamine systems being especially sensitive to medication exposure (8–23% change in dominance range).

Negative symptom-associated cortical thinning was best explained by PET-based maps of dopamine, histamine, serotonin and

opioid systems (total dominance range: 60–81%), with contributions of histamine being sensitive to medication exposure (9–19%

change in dominance range). Combined, these results uniquely identify specific neurochemical systems – particularly

monoaminergic, glutamatergic, and GABAergic pathways – as key molecular mechanisms associated with cortical thinning in

people at high risk of developing psychosis.