# Biobehavioral Predictors of Illness Progression in Adolescent Depression

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $732,647

## Abstract

PROJECT SUMMARY / ABSTRACT
 Adolescent depression is a major public health concern associated with significant morbidity and mortality. We
know that adolescent depression varies considerably in severity and course, but its underlying mechanisms
remain unknown. This proposal addresses this concern, aiming to identify biobehavioral predictors of illness
trajectory in adolescents to inform treatment influencing its course. Our overall hypothesis is that reward
dysfunction and its underlying neuro-immunological mechanisms contribute to maintenance of depression in
youth. We propose the following model: (1) peripheral inflammation (e.g., cytokines, kynurenines) is associated
with anhedonia; (2) inflammation extends to the CNS, inducing oxidative stress [↓glutathione (GSH, antioxidant)]
and GABA (inhibitory neurotransmitter) deficits; (3) such neuro-chemical changes alter the reward circuitry,
leading to anhedonia, and contribute to depression progression. In support, we documented that of adolescent
depression’s core symptoms, only anhedonia—reflecting deficits in reward processes—and not irritability was
associated with worse outcome, including suicidality and chronicity. We also reported associations between
circulatory cytokines and kynurenines with both anhedonia and reward neurocircuitry. Utilizing proton MR
spectroscopy (1H MRS), we showed that decreased anterior cingulate cortex (ACC) GABA in adolescent
depression was driven by anhedonia. Additionally, using fMRI, we mapped striatal-based connectivity in relation
to anhedonia and documented distinct neural activation patterns of reward anticipation and attainment—both
reward processes that contribute to anhedonia. In pilot studies, we found that ACC GABA and reward-
anticipation brain activation predicted anhedonia severity at 2-year follow-up. Building upon our compelling
findings to date, we propose a prospective study of reward processes and neuroimmunological mechanisms,
with the goal to identify modifiable pathways predictive of depression course in adolescents. We will study 120
adolescents with depressive symptoms. Three in-laboratory comprehensive clinical evaluation and computerized
reward task sessions will be done at baseline, 12-, and 24-month follow-ups. At baseline and 12 months, visits
will include: a) immune blood collection for kynurenine metabolites, immune cell profiling, and cytokine secretion
post immune stimulation (as a biological stressor); b) fMRI resting state and tasks examining distinct reward
processes (e.g., anticipation, attainment, learning); and c) 1H MRS to probe ACC GABA and striatal GSH as
indices for inflammatory neurometabolic consequences in reward-related brain regions. Outcome measures will
include anhedonia severity (primary), along with depression severity, functioning, anxiety, and suicidality.
Principled variable selection approach will address multiple comparison concerns. Dynamic causal modeling and
machine learning classification methods will expl...

## Key facts

- **NIH application ID:** 11004468
- **Project number:** 7R01MH120601-05
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Vilma Gabbay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $732,647
- **Award type:** 7
- **Project period:** 2020-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11004468

## Citation

> US National Institutes of Health, RePORTER application 11004468, Biobehavioral Predictors of Illness Progression in Adolescent Depression (7R01MH120601-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11004468. Licensed CC0.

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