Multimodal Correlates of Aggression Potential in Early-Stage Psychosis: Integrating Brain Structure, Polygenic Risk, and Social Adversity

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Introduction: Aggression in early-stage mental disorders imposes a substantial clinical and societal burden and is shaped by environmental, neurobiological, and genetic factors. Understanding their joint contribution could aid risk assessment and early intervention. Methods: We used data from the prospective, multicentric European PRONIA project, comprising 402 minimally medicated participants (mean [SD] age = 25.34 [5.84]; female sex = 49.5%) with clinical high-risk states for psychosis (n = 116), recent-onset depression (n = 146) or psychosis (n = 140). Multi-block sparse partial least squares (MB-SPLS) algorithm was employed within a nested cross-validation framework to detect multivariate associations between aggression potential (excited component of the PANSS), social adversity, structural and diffusion MRI, and polygenic risk. Post hoc analyses examined specificity to overall illness severity and associations with personality, emotion recognition, coping, resilience, and functional remission. Results: MB-SPLS linked higher aggression potential in recent-onset psychosis to greater discrimination, emotional and physical trauma, bullying, higher polygenic risk for anxiety, schizophrenia, tension, and bipolar disorder, ventricular enlargement, reduced fronto-parietal-temporal white matter volume, and microstructural alterations of commissural, association, and limbic tracts. This signature was related to, but not fully explained by, illness severity and was associated with lower agreeableness, impaired emotion recognition, and poorer functional remission. Conclusions: Aggression potential in early psychosis corresponds to a distinct, multilevel biotype spanning environmental adversity, genetic liability, and predominantly white matter alterations, and is related to but not reducible to overall illness severity. Associations with social cognition, personality, and functional outcome highlight its clinical relevance and potential target points for early identification and intervention.

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