Characterization and Treatment of Adolescent Depression

Description

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 or inpatient 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 changes in metabolic, inflammatory, and neuroendocrinological markers?

There is mounting evidence for differences in metabolic, inflammatory, and neuroendocrine markers when comparing those with and without MDD; however, the relationship of such differences to reward processing-the focus of this protocol-remain poorly examined. We wish to explore the direction of effect between inflammatory responses and metabolic changes with depression and reward processes. We wish to do this informed by knowledge of an individual s genetic background. The aim is to establish trajectories of stability/change in metabolic and inflammatory markers and relate them to mood changes and reward changes over time. We also wish to align our protocol with Dr Zarate s Protocol 17-M-0060, Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder that focuses on depression in adults. Collecting these data on adolescents will allow us to identify differences and overlaps between adolescents (from this protocol) and the adults in Dr. Zarate s protocol 17-M-0060.

5. 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 emergence of the COVID-19 pandemic presents an unprecedented challenge for the world s physical health, but is also expected to have a profound impact on people s psychological wellbeing. The COVID-19 pandemic is a huge medical challenge to be sure, and, by virtue of being a naturally occurring stress, presents an opportunity for us, using longitudinal methods, to learn more about how humans respond to such environmental influences. Moreover, it offers an opportunity for us to understand more about human behaviour and potentially use such knowledge to inform future interventions. The aim, using remote on-line methods, is to learn about how such environmental stress is experienced by healthy volunteer teens and those with depression, the relationship between stress and self-rated measures of depression, and the association of measures of stress and depression on reward processing.

Study population

We will study four populations: (1) Healthy volunteer children and adults (HVs; n=600); (2) Participants with Major Depressive Disorder (MDD; n=500); (3) Participants with subthreshold depression (s-MDD; n=200); (4) parents (biological or legal guardians) of children with MDD, s-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 the time of screening and initial enrollment in Characterization; this is a longitudinal study and participants who turn 18 may continue in it until they are 25.

Design

This is a Characterization study that includes longitudinal observation of three adolescent cohorts.. HV, s-MDD and MDD subjects will take part in a longitudinal, observational study that involves clinical assessment, computer tasks, blood for inflammatory and neuroendocrinological markers, fMRI and MEG scanning and continue to return until they reach 25 years of age. A sample of young adult HVs (18-30 years old) will also be enrolled as a comparison cohort.

Adolescent patients who still suffer from MDD will be offered outpatient clinical care in the form of open-label Cognitive Behavioral Therapy (CBT; up to 26 weeks). During and following outpatient clinical care, participants with MDD will continue in Characterization. Upon completion of clinical care patients will return to care in the community.

MDD patients who are clinically unstable and are eligible for standard clinical treatment as inpatients or day-patients may enter treatment at NIH. They may do this after starting in Characterization or at their initial enrollment.

Outcome measures

For Objective 1

Primary Outcomes

fMRI: Monetary incentive delay task

Magnetoencephalography: Monetary incentive delay task

Automated Affect encoding: variables obtained through machine learning analysis

For Objective 2

Primary outcomes:

fMRI: Monetary Incentive Delay Task

Questionnaires: MFQ, ARI, SCARED

For Objective 3

Primary outcomes:

Questionnaires: PCSC, SCSC, MFQ

Imaging (fMRI): Activity in prefrontal cortex and striatum in response to controllable setback cues in the Persistence after Setbacks task

For Objective 4

Primary outcomes:

Inflammatory and metabolic markers in blood

fMRI: Monetary Incentive Delay Task

Questionnaires: MFQ, ARI, SCARED

For Objective 5

Pirmary outcomes:

Questionnaires: MFQ, ARI-self, SCARED, COVID-19 Questionnaire,

Behavioral task: SMT

Details