Characterization and Treatment of Adolescent Depression

Objective Depression has a prevalence of 19% in the US population and close to 350 million people suffer from the disorder worldwide. The chronic course of depression and its early onset - a maximal incidence in adolescence and young adulthood - contribute to it being a leading cause of disability worldwide. Yet, compared to many other medical conditions, we know little about the mechanisms underlying depression. In recent years, reward processing has been proposed to underlie several key behavioral and neural aberrations observed in depression. This has led to the promise that targeting reward processing may lead to much needed breakthroughs in the field. In this protocol we seek to characterize and treat depression in youth by integrating methodological and conceptual approaches that specifically focus on reward processing. Patients and their families can elect to participate in standard outpatient clinical care in this protocol. Our objective is to answer four key questions: 1. What is the concordance of measures of reward processing in depression over time? Measurement is fundamental to answering substantive questions in science. Our review of the literature identified gaps in the reliability of reward measurement, the concordance between measures, and a dearth of studies that employ repeated-measure designs. We propose to tackle this using a multi-method approach in a longitudinal design. 2. Are reward processing aberrations in depression similar to those in other common problems of childhood, such as anxiety and irritability? Specificity - in this case establishing which reward aberrations are unique to a certain phenotype as opposed to a generic finding related to psychopathology - is important for both nosology (disease classification) and for designing rational treatments for psychiatric problems. Below, we describe how we propose to answer this question by characterizing reward processing in those with depression and comparing it to processing in those with other common psychiatric problems in youth, such as anxiety and irritability. 3. How does reward processing interact with systems subserving sense of agency? As described above, decision-making is an intricate part of reward processing. It is assumed that higher-order cognitive processes, such as the sense of ownership of one's actions - referred to as sense of agency - influence reward processing. Establishing the role of such higher-order processes in depression could lead to developing treatments that boost cognition and restore reward processing in depression. Below, we propose to answer this question by testing whether inter-individual differences in sense of agency explain variation in depression via reward processing (a mediation model). 4. How is reward processing affected by environmentally-generated stress? Studies from our own group demonstrate that stress in early life has an impact on how rewards and punishers are processed in the brain several years later. Similarly, there is good evidence for the acute effects of stress on reward processing, as indicated in our recent metanalysis. And, of course, there is ample evidence for the role on how stressful events worsen symptoms of depression. The current protocol will utilize the Trier Social Stress Test, one of the best established paradigms for examining the acute impact of stress on people, to examine associations among stress responsitivity, reward function, and psychopathology. We also wish to explore more deeply the role of family environment on stress in teens with major depression. There is a substantial literature on the role of family environment in moderating or exacerbating stress in teens, and measures and methods to assess this would be important to understand its role in teen depression. Study population We will study three populations: (1) Healthy volunteer children and adults (HVs; n=600); (2) Participants with Major Depressive Disorder (MDD; n=500); (3) parents (biological or legal guardians) of children with MDD or HVs who are enrolled in this protocol (N=800 total as 400/200/200 respectively). Study participants will be aged 11-17 years at initial enrollment in Characterization; this is a longitudinal study and participants who turn 18 may continue in it for up to two years. Previously we enrolled 4 cohorts. Youths with Subthreshold Depression (s-MDD) (n=200 were to be enrolled; we have enrolled n=8 over the life of the protocol and no subjects with s-MDD have been enrolled after Dec 2021) Design This is a Characterization study that, as of 2022, includes longitudinal observation of two adolescent cohorts. HV and MDD subjects will take part in a longitudinal, observational study that involves clinical assessment, computer tasks, fMRI and MEG scanning and continue to return for up to two years. A sample of young adult HVs (18-30 years old) will also be enrolled as a comparison cohort. Those previously enrolled as subthreshold MDD (s-MDD) will be followed for up to two years (from their initial enrollment); with Amendment J, we ceased enrolling this population; no new participants with s-MDD have been enrolled since Dec, 2021. Adolescent patients who still suffer from current MDD will be offered standard outpatient care with clinically indicated treatments. During and following outpatient clinical care, participants with MDD will continue in Characterization. Outcome measures For Objective 1 Primary Outcomes fMRI: Carnival Task, AX-CPT Task; Flanker Task; Mood Induction Task AX-CPT Task, Flanker Task For Objective 2 Primary outcomes fMRI: Carnival Task, AX-CPT Task; Flanker Task; Mood Induction Task Questionnaires: MFQ, ARI, SCARED, PROMIS-A-SR, PROMIS-A-PR For Objective 3 Primary outcomes: Carnival Task, AX-CPT Task; Flanker Task; Mood Induction Task Questionnaires: SCSC, MFQ fMRI/MEG: Activity in prefrontal cortex and striatum in response to rewards and to events engaging cognitive control For Objective 4 Primary outcomes: Carnival Task, AX-CPT Task; Flanker Task; Mood Induction Task Questionnaires: MFQ, ARI, SCARED, PROMIS-A-SR, PROMIS-A-PR Questionnaires: Family-function measures (FAD), quality of life measure (PQ-LES-Q) Behavioral task: Five Minute Speech Sample, Parent-Child Discussion Task, SMT, Mood Induction task, Parent-Child Discussion Task (PCDT)