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 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.

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.

Dr Banaschewski served in an advisory or consultancy role for AGB Pharma; eye level; Infectopharm; Medice; Neurim Pharmaceuticals; Oberberg GmbH and Takeda. He received conference support or speakers fee by Janssen-Cilag; Medice; and Takeda. He received royalities from Hogrefe; Kohlhammer; CIP Medien; Oxford University Press; the present work is unrelated to these relationships. Dr Barker has received honoraria from General Electric Healthcare for teaching on scanner programming courses. Dr Poustka served in an advisory or consultancy role for Roche and Viforpharm and received a speakers fee by Shire. She received royalties from Hogrefe; Kohlhammer; and Schattauer.

This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT- 2007-037286); the Horizon 2020 funded ERC Advanced Grant STRATIFY (Brain network based stratification of reinforcement-related disorders) (695313); Horizon Europe environMENTAL grant no: 101057429; UK Research and Innovation (UKRI) Horizon Europe funding guarantee (10041392 and 10038599); Human Brain Project (HBP SGA 2 785907; and HBP SGA 3 945539); the Chinese government via the Ministry of Science and Technology (MOST); The German Center for Mental Health (DZPG); the Bundesministerium fur Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A 01EE1406B; Forschungsnetz IMAC-Mind 01GL1745B); the Deutsche Forschungsgemeinschaft (DFG project numbers 458317126 [COPE]; 186318919 [FOR 1617]; 178833530 [SFB 940]; 386691645 [NE 1383/14-1]; 402170461 [TRR 265]; 454245598 [IRTG 2773]); the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1); the National Institutes of Health (NIH) funded ENIGMA-grants 5U54EB020403-05; 1R56AG058854-01; and U54 EB020403 as well as NIH R01DA049238; the National Institutes of Health; Science Foundation Ireland (16/ERCD/3797). NSFC grant 82150710554. Further support was provided by grants from the Agence Nationale de la Recherche (ANR-12-SAMA-0004; AAPG2019 - GeBra); the Eranet Neuron (AF12-NEUR0008-01 - WM2NA; and ANR-18-NEUR00002-01 - ADORe); the Fondation de France (00081242); the Fondation pour la Recherche Medicale (DPA20140629802); the Mission Interministerielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA); the Assistance-Publique-Hopitaux-de-Paris and INSERM (interface grant); Paris Sud University IDEX 2012; the Fondation de lAvenir (grant AP-RM-17-013); the Federation pour la Recherche sur le Cerveau. ImagenPathways Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways is a collaborative project supported by the European Research Area Network on Illicit Drugs (ERANID). This study is based on independent research commissioned and funded in England by the National Institute for Health Research (NIHR) Policy Research Programme (project ref. PR-ST-0416-10001). Dr. Leyton was supported by the Canadian Institutes for Health Research (CIHR; Grant Number MOP-453327). C. Caswell was supported by a scholarship from CIHR.

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