546. REIMAGINING THE DIATHESIS-STRESS MODEL: TRANSDIAGNOSTIC FACTORS TO PRECISION PSYCHIATRY

Abstract Background We recently reported evidence that commonly comorbid early onset psychiatric disorders are predicted by a biopsychosocial model composed of adolescent externalizing (EXT) behaviors, early life adversity, and midbrain dopamine autoreceptor availability, as measured with positron emission tomography (PET). Aims & Objectives Here, we tested whether two variants of this model could (i) reproduce the transdiagnostic predictions, and (ii) make disorder-specific predictions. Method In Study 1, participants were 1338 IMAGEN database members who had Childhood Trauma Questionnaire (CTQ) data, adolescent EXT scores, and functional magnetic resonance imaging (fMRI) measured responses during the monetary incentive delay (MID) task. Regions of interest were the midbrain dopamine cell bodies, ventral striatum, caudate, putamen, and anterior cingulate cortex. DSM-IV diagnoses were made using the Development and Wellbeing Assessment at ages 14, 16, and 19. Binary logistic regression models tested whether a combination of EXT traits, childhood trauma, and MID fMRI contrasts at either 14 or 19 years of age identified participants with a DSM-IV disorder by age 19. In Study 2 (n = 44), EXT behaviors were measured between ages 10 and 16, and both CTQ data and mesocorticolimbic activations to alcohol and juice cues were collected at age 18. Seven years later, participants completed the Alcohol Use Disorders Identification Test (AUDIT). Binomial logistic regression analyses tested whether these three factors predicted high vs low AUDIT scores at the age 25 follow-up. Results In Study 1, all tested three-factor models predicted who had a DSM-IV disorder by age 19 at a high level of statistical significance (p < 1.0 x 10-21). In every model, EXT and CTQ scores were individual predictors (p < 0.001). At age 14, reward anticipation responses were significant predictors in the ventral striatum, caudate, putamen, and anterior cingulate. At age 19, significant predictors were in the ventral striatum. The relation 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 cingulate (p = 0.0038) and putamen (p = 0.014) at age 14. Low striatal reward anticipation responses were associated with higher anhedonia. In Study 2, the combination of high mesocorticolimbic responses to Alcohol vs. Juice cues, high EXT scores, and high CTQ scores predicted future alcohol use problems (p < 0.05). fMRI responses were significant contributors to the model in the ventral striatum, associative striatum, anterior and posterior cingulate cortices, and ventromedial prefrontal cortex (p ≤ 0.05). Discussion & Conclusions These findings tentatively identify constituents of a hierarchical diathesis-stress model that has (i) transdiagnostic predictive value for commonly comorbid early onset disorders, and (ii) narrower predictive value for future alcohol problems. For the latter, high mesocorticolimbic responses to disease-specific cues might imbue the stimuli with aberrant salience leading to distinct symptoms and disorders – these perturbations might be best identified after controlling for early life adversity and behavioral trajectories.