Distinct multimodal biological and functional profiles of symptom-based subgroups in recent-onset psychosis

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Abstract
Symptom heterogeneity characterizes psychotic disorders and hinders the delineation of underlying biomarkers. Here, we identify symptom-based subtypes of recent-onset psychosis (ROP) patients from the multi-center PRONIA (Personalized Prognostic Tools for Early Psychosis Management) database and explore their multimodal biological and functional signatures. We clustered N = 328 ROP patients based on their maximum factor scores in an exploratory factor analysis on the Positive and Negative Syndrome Scale items. We assessed inter-subgroup differences and compared to N = 464 healthy control (HC) individuals regarding gray matter volume (GMV), neurocognition, polygenic risk scores, and longitudinal functioning trajectories. Finally, we evaluated factor stability at 9- and 18-month follow-ups. A 4-factor solution optimally explained symptom heterogeneity, showing moderate longitudinal stability. The ROP-MOTCOG (Motor/Cognition) subgroup was characterized by GMV reductions within salience, control and default mode networks, predominantly throughout cingulate regions, relative to HC individuals, had the most impaired neurocognition and the highest genetic liability for schizophrenia. ROP-SOCWD (Social Withdrawal) patients showed GMV reductions within medial fronto-temporal regions of the control, default mode, and salience networks, and had the lowest social functioning across time points. ROP-POS (Positive) evidenced GMV decreases in salience, limbic and frontal regions of the control and default mode networks. The ROP-AFF (Affective) subgroup showed GMV reductions in the salience, limbic, and posterior default-mode and control networks, thalamus and cerebellum. GMV reductions in fronto-temporal regions of the salience and control networks were shared across subgroups. Our results highlight the existence of behavioral subgroups with distinct neurobiological and functional profiles in early psychosis, emphasizing the need for refined symptom-based diagnosis and prognosis frameworks.

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