# Inflammatory and Glutamatergic Mechanisms of Sustained Threat in Adolescents with Depression: Toward Predictors of Treatment Response and Clinical Course

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $1

## Abstract

ABSTRACT
Despite the prevalence and public health significance of depression, up to 40% of depressed adolescents do
not respond to first-line antidepressants (i.e., serotonin selective reuptake inhibitors [SSRIs]). Adolescents with
treatment non-response (TNR) are at high risk for physical and mental health difficulties associated with
ineffectively treated depression, including cardiovascular disease and suicide. Thus, identifying the
neurobiological mechanisms that underlie TNR in adolescents is a critical step toward optimizing treatment
plans for those who do not respond to first-line treatments. In this context, sustained threat to social stressors,
as measured by elevated inflammatory profiles to stressful stimuli, has been shown to drive the onset and
maintenance of depression among adolescents and is associated with TNR. The mechanisms by which
elevated inflammation impact the brain in depressed adolescents, however, are unclear. To address these
gaps in our knowledge, we will test our central hypothesis that excessive glutamate (Glu) in depression-related
corticolimbic circuits—including the anterior cingulate cortex, ventromedial prefrontal cortex, amygdala, and
hippocampus—is a critical mediator between peripheral inflammation and TNR in depressed adolescents.
Specifically, we will conduct a prospective 18-month study of 160 unmedicated treatment-seeking depressed
adolescents (ages 14-18) using state-of-the-art multimodal neuroimaging data at 7 Tesla. At Time 1 (prior to
SSRI treatment) and Time 2 (after an open-label 12-week SSRI trial), we will assess peripheral measures of
pro-inflammatory cytokines and glutamate in corticolimbic circuits before and after a well-validated adolescent-
version of the Trier Social Stress Test (TSST). We also will use a well-validated fMRI task designed to probe
behavioral and neural responses to negative peer evaluation, a salient form of social threat for adolescents. At
Time 1, we will test if TSST induces increases in inflammation and glutamate in corticolimbic circuits in
unmedicated adolescents with depression. At Time 2, we will use machine learning methods to identify multi-
level predictors of TNR based on behavioral, inflammatory, and neural indicators of sustained threat to social
stress; we will also test whether glutamate in corticolimbic circuits mediates the association between baseline
levels of inflammation and TNR. Finally, we will continue to clinically assess depression symptoms and collect
information on social stressors (e.g., context, severity, duration) every 3 months for 15 months following Time 2
(i.e., from Time 3 to Time 7), which will enable us to use functional clustering analyses to identify subgroups of
adolescents on the basis of depression trajectories (e.g., persistent depression, gradual remission, etc), and
identify predictors of these subgroups and other related clinical outcomes (e.g., remission status), while
accounting for the effects of TNR status and any change...

## Key facts

- **NIH application ID:** 10445166
- **Project number:** 1R01MH127176-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** TIFFANY CHEING HO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1
- **Award type:** 1
- **Project period:** 2022-06-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445166

## Citation

> US National Institutes of Health, RePORTER application 10445166, Inflammatory and Glutamatergic Mechanisms of Sustained Threat in Adolescents with Depression: Toward Predictors of Treatment Response and Clinical Course (1R01MH127176-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10445166. Licensed CC0.

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