Data-driven profiles of psychosis stages reveal distinct and overlapping clinical, cognitive, and neuroanatomical phenotypes

Psychotic disorders are increasingly recognized as the extreme end of a progressive psychopathology continuum, with less advanced stages including the asymptomatic familial high-risk state (FHR), the help-seeking clinical high-risk state (CHR), and first episode psychosis (FEP). However, we lack a comprehensive study of clinical, cognitive, functional, and neuroanatomical markers across all three early stages of psychosis, limiting our understanding of how the multimodal phenotypes which define psychotic disorders emerge in the broader course of psychopathology. We leveraged a sample of 70 FEP, 40 CHR, 43 FHR, and 41 healthy participants recruited from the same clinical and sociodemographic setting - the first such dataset to be described in the literature. Several markers were elevated in CHR but did not worsen in FEP, including depression/anxiety and difficulties functioning, while FEP was uniquely defined by cognitive impairments and cortical thickness reductions characteristic of those seen in schizophrenia. Across the sample, the dominant axis of joint brain-behaviour variability captured a relationship between reduced cortical thickness and lower cognitive performance, a pattern which was equally established in both CHR and FEP. Initial longitudinal data revealed that depressive and negative symptoms best predicted lower functioning at 6-month follow-up, regardless of group status. Together, our analysis suggests that affective and functional disturbances emerge in earlier stages of psychosis, while cognitive and anatomical abnormalities characterize more advanced ones - though the overlap we observed across groups demonstrates that clinically relevant phenotypes can cut across group boundaries, requiring personalized care to manage.