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

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 x 10 -21 ), yielding greater predictive strength than each factor alone. They had an accuracy of nearly 75%, accounting for ≥ 11% (Nagelkerke R 2 ) 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. Key Points Question What factors contribute to a diathesis-stress model of commonly comorbid psychiatric disorders? Findings A combination of childhood adversity, adolescent externalizing behavior, and lower mesocorticolimbic reward cue reactivity predicted psychopathology by age 19 in a large population-based cohort. Liability was modified by interactions between trauma and mesocorticolimbic responses, with trauma effects larger in those with smaller striatal and anterior cingulate cortex responses. Meaning The study identifies a transdiagnostic diathesis-stress model of early onset psychiatric disorders.

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