Abstract
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.
Author Contributions
Conceptualization, C.W. and D.P.; methodology, C.W., C.V. and D.P.; software, C.V., D.P. and N.K.; validation, C.W.; formal analysis, C.W.; investigation, D.P., N.K. and the PRONIA Consortium; resources, N.K. and P.F.; data curation, C.W. and C.V.; writing—original draft preparation, C.W.; writing—review and editing, C.W., C.V., J.R., U.K.H., K.S., P.F., N.K. and D.P.; visualization, C.W.; supervision, D.P. and N.K.; project administration, C.W., D.P. and N.K.; funding acquisition, N.K. and P.F. The PRONIA Consortium contributed to participant recruitment, clinical assessment and multimodal data acquisition across the participating study sites. All authors have read and agreed to the published version of the manuscript.
Funding
The PRONIA study was funded by the European Union’s Seventh Framework Programme (FP7) under grant agreement no. 602152.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the local research ethics committees of all participating PRONIA sites. Trial registration: DRKS00005042.
Informed Consent Statement
Written informed consent was obtained from all adult participants. Minors (<18 years) provided written assent, and their guardians provided written informed consent.
Data Availability Statement
The datasets presented in this article are not readily available because they are subject to the data sharing policy of the PRONIA consortium. Requests to access the datasets should be directed to the PRONIA consortium.
Conflicts of Interest
N.K. is a co-holder of the issued patent US20160192889A1 (“Adaptive pattern recognition for psychosis risk modeling”). As a member of Spring Health’s Scientific Advisory Board, N.K. has advised that company on the development of tools to predict treatment outcomes for depression and psychosis; he holds no equity and has received no financial compensation from this company. P.F. has received research support and/or honoraria for lectures or advisory activities from BMS, Boehringer-Ingelheim, JNJ, Lundbeck, Otsuka, Richter and Rovi. All other authors declare no conflicts of interest.
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