Major depression in adolescents (10-19 years) represents an enormous public health challenge at clinical, social and economic levels. The World Health Organization’s “Health for the world’s adolescents” report revealed that depression is the predominant cause of illness and disability and among the top three causes of mortality for adolescent boys and girls. It may also represent a risk factor the onset of treatment-resistance depression later on. In the present project, we aim to elucidate, in a translational perspective, neural and cognitive functions implicated in adolescent onset of depression and in treatment response. We will use this information to develop novel neurocognitive interventions to prevent and/or treat depression in youth. To achieve these goals, we will exploit a multidisciplinary and integrated approach that combines preclinical and clinical studies.

Our analyses will range from cellular neuroimaging, electrophysiology, and behavioral phenotyping to clinical intervention, neuroimaging and machine learning techniques. We will exploit three exceptional longitudinal cohorts that have recently completed a long-term follow-up of adolescents at varying risk for depression, two of which involve long-term follow-up of high risk youth after randomized assignment to early, targeted intervention. In addition, we will recruit new participants to determine the role of selected neural and cognitive features in predicting response to psychosocial and pharmacological treatment. In the final year of the project, promising targeted neurocognitive interventions will be identified, adapted and tested at proof-of-concept level in two at-risk adolescent samples: one resistant to psychosocial intervention and the other exposed to severe childhood adversity. Preclinical models will allow for the identification of neurobiological targets implicated in transition to depressive phenotypes and treatment non-response and will provide new knowledge on environmental and neuromodulatory interventions that alter risk trajectories. Neural and cognitive-behavioral measures will be highly harmonized across studies and species.

By focusing on the correspondence between brain systems and cognitive and emotional functions, our project will provide novel insights into the mechanisms underlying the onset of depression in adolescence and its role in treatment resistant depression, and will potentially advance knowledge in prevention and treatment of adolescent depression, a field that has not progressed substantially in recent years.