Symptom Dimension-Specific Neurotransmitter Correlates of Psychopathology and Cognition in Early Psychosis

Extended duration of under-treated psychosis (DUP) is among the strongest predictors of poor outcome, yet diagnostic heterogeneity impedes treatment matching, with approximately 50% of patients failing to respond to first-line antipsychotics. Negative symptoms and cognitive impairment are particularly refractory, lacking effective pharmacological treatments. Identifying neurotransmitter systems associated with specific symptom dimensions could accelerate targeted therapeutic development and reduce DUP. We applied Partial Least Squares correlation (PLSc) to derive whole-brain resting-state functional connectivity (RSFC) and anatomical (cortical thickness and subcortical volume) signatures associated with five psychopathology dimensions (positive symptoms, negative symptoms, general psychopathology, mania, and cognition) in a transdiagnostic sample from the Human Connectome Project-Early Psychosis (HCP-EP; n=124). We tested associations with potential confounds including antipsychotic medication dosage and substance use. Signatures were spatially correlated with 21 Positron Emission Tomography (PET)-derived receptor and transporter maps across 9 neurotransmitter systems using the neuromaps toolbox. Significant RSFC signatures emerged for positive symptoms, negative symptoms, general psychopathology, and cognition, but not mania. The negative symptom RSFC signature correlated with norepinephrine transporter (NET; ρ=.40, q=.030) and vesicular acetylcholine transporter (VAChT; ρ=.38, q=.048) distributions. The cognition signature similarly correlated with VAChT (ρ=.48, q=.025). Anatomical signatures were associated with positive symptoms, general psychopathology, and cognition, but were more susceptible to confounding by medication and substance use. No significant receptor associations were detected for anatomical signatures. These findings implicate cholinergic and noradrenergic systems as molecular targets for negative symptoms and cognitive impairment, supporting prioritization of these systems in pharmacotherapy development in early psychosis.