TIGER: Inflammatory and Glutamatergic Mechanisms of Sustained Threat in Adolescents With Depression
Study Details
Study Description
Brief Summary
Despite the prevalence and significant public health concern over depression among adolescents, up to 40% of depressed adolescents do not respond to first-line antidepressants (herein termed treatment non-response, TNR). The goal of this project is to recruit and assess 160 treatment-seeking depressed adolescents and test whether acute stress impacts peripheral levels of inflammation and downstream levels of glutamate in corticolimbic regions previously associated with depression, whether these stress-related biomarkers predict TNR to a 12-week trial of either fluoxetine or escitalopram, and whether these stress-related biomarkers predict 18-month clinical course.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Detailed Description
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, the investigators will test the 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, the investigators will conduct a prospective 18-month study of 160 unmedicated treatment-seeking depressed adolescents 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), the investigators 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). The investigators also will use a well-validated functional magnetic resonance imaging (fMRI) task designed to probe behavioral and neural responses to negative peer evaluation, a salient form of social threat for adolescents. At Time 1, the investigators will test if TSST induces increases in inflammation and glutamate in corticolimbic circuits in unmedicated adolescents with depression. At Time 2, the investigators 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; the investigators will also test whether glutamate in corticolimbic circuits mediates the association between baseline levels of inflammation and TNR. Finally, as an exploratory aim, the investigators 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 the use of 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 changes in treatment (and other related factors, including stressful life events). Results from this work will motivate future studies testing alternative therapeutics for depressed adolescents at risk for treatment resistant depression.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Study Participants All depressed participants will undergo the same study procedures |
Behavioral: Trier Social Stress Test (TSST)
In this mechanistic study, all participants will undergo a laboratory-based stress test and the investigators will examine primary and secondary outcomes before and after this test
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Outcome Measures
Primary Outcome Measures
- Glutamate [baseline and 90 min. follow-up]
Change in glutamate (institutional units) in corticolimbic regions following TSST
- Glutamate [baseline and 12-week follow-up]
Change in glutamate (institutional units) in corticolimbic regions after SSRI treatment
- Inflammation [baseline and 90 min. follow-up]
Change in composite score (sum of z-scores) of peripheral levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-a), and C-reactive protein (CRP) following TSST
- Inflammation [baseline and 12-week follow-up]
Change in composite score of peripheral levels of IL-6, TNF-a, and CRP (sum of z-scores) after SSRI treatment
Secondary Outcome Measures
- IL-6 [baseline and 90 min. follow-up]
Change in peripheral levels of IL-6 (pg/mL) following TSST
- IL-6 [baseline and 12-week follow-up]
Change in peripheral levels of IL-6 (pg/mL) after SSRI treatment
- TNF-a [baseline and 90 min. follow-up]
Change in peripheral levels of TNF-a (pg/mL) following TSST
- TNF-a [baseline and 12-week follow-up]
Change in peripheral levels of TNF-a (pg/mL) after SSRI treatment
- CRP [baseline and 90 min. follow-up]
Change in peripheral levels of CRP (pg/mL) following TSST
- CRP [baseline and 12-week follow-up]
Change in peripheral levels of CRP (pg/mL) after SSRI treatment
Eligibility Criteria
Criteria
Inclusion Criteria:
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All sexes and genders
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All ethnicities
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Ages 13-19
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Postpubertal (Tanner stage > 3)
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No medications that will interfere with the study (including antidepressants, mood stabilizers, hormone supplements, steroids, etc) for at least 4-6 weeks (depending on exact medication)
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Currently being seen by a clinician who will treat the participant with fluoxetine or escitalopram
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The ability to provide assent, understand, and complete all study procedures
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Caregiver consent (if applicable)
Exclusion Criteria:
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Primary mental health diagnosis other than a depressive disorder according to DSM-V
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Any contraindications to MRI scanning, phlebotomy, or SSRI treatment
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Stimulant usage
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A concussion within the last 6 weeks or any lifetime concussion with loss of consciousness for at least 10 minutes
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Any major neurological or developmental disorders which could impact the participant's ability to comply with study procedure, or meeting for current or lifetime criteria of mania or psychosis, diagnosis of bipolar disorder or any substance use disorders
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First-degree relative with a current, past, or suspected diagnosis of bipolar disorder
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of California, San Francisco | San Francisco | California | United States | 94143-2211 |
Sponsors and Collaborators
- University of California, San Francisco
- University of California, Los Angeles
- University of Southern California
- University of California, Irvine
- Columbia University
- Mayo Clinic
- National Institute of Mental Health (NIMH)
Investigators
- Principal Investigator: Tiffany Ho, Ph.D., University of California, San Francisco
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TIGER R01