A Novel Diathesis-Stress Model of Comorbid Early Onset Psychiatric Disorders

medRxiv [Preprint]. 2025 Apr 10:2025.04.08.25325481. doi: 10.1101/2025.04.08.25325481.

ABSTRACT

IMPORTANCE: Psychiatric comorbidity is the norm. Identifying transdiagnostic risk factors will inform our understanding of developmental pathways and early intervention targets.

OBJECTIVE: We recently reported that many psychiatric outcomes are predicted by a three-factor model composed of adolescent externalizing (EXT) behaviors, early life adversity, and dopamine autoreceptor availability. Here, we investigated whether this model could be reproduced in a large population-based sample using functional magnetic resonance imaging (fMRI) instead of positron emission tomography.

DESIGN: Data were collected by the IMAGEN consortium beginning in 2010 when cohort members were 14 years old, with follow-up testing at ages 16 and 19. These longitudinal data were used to predict psychiatric disorders by 19 years of age.

SETTING: Participants were recruited from secondary schools across Europe.

PARTICIPANTS: Adolescents (n = 1338) with fMRI, behavioural, diagnostic, and early life trauma data.

MAIN OUTCOMES AND MEASURES: Binary regression models tested whether a combination of EXT behaviors, childhood trauma, and mesocorticolimbic reward anticipation responses at age 14 or 19 predicted the presence of a disorder by age 19.

RESULTS: A total of 1338 participants had the required data (52.4% female). In all models, EXT and adversity scores were significant predictors (p < 0.001). Reward anticipation responses in the ventral striatum, caudate, putamen, and anterior cingulate cortex (ACC) at age 14 (p ≤ 0.05) and in the ventral striatum at age 19 (p ≤ 0.029) were predictors in their respective models. The three-factor models overall were highly significant (p < 1.0 × 10^-21), yielding greater predictive strength than each factor alone. They had an accuracy of nearly 75%, accounting for ≥ 11% (Nagelkerke R²) of the variance in psychiatric disorders. The relationship between trauma and diagnoses was partially mediated by higher EXT (indirect path B = 0.0535, 95% CI = 0.0301-0.0835), and moderated by fMRI responses in the ACC (p = 0.0038) and putamen (p = 0.0135) at age 14.

CONCLUSIONS AND RELEVANCE: The results extend our previous findings, increasing confidence in a novel diathesis-stress model of commonly comorbid early onset psychiatric disorders. The results have implications for diagnostic classification schemes and pleiotropic views of psychiatric disorder etiology.

PMID:40297443 | PMC:PMC12036423 | DOI:10.1101/2025.04.08.25325481