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Inflammatory and Glutamatergic Mechanisms of Sustained Threat in Adolescents With Depression: Toward Predictors of Treatment Response and Clinical Course (TIGER)

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ClinicalTrials.gov Identifier: NCT05329441
Recruitment Status : Not yet recruiting
First Posted : April 15, 2022
Last Update Posted : April 15, 2022
Sponsor:
Collaborators:
University of California, Los Angeles
University of Southern California
University of California, Irvine
Columbia University
Mayo Clinic
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
University of California, San Francisco

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 an FDA-approved antidepressant, and whether these stress-related biomarkers predict 18-month clinical course.

Condition or disease Intervention/treatment
Depression in Adolescence Behavioral: Trier Social Stress Test

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 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.

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Study Type : Observational
Estimated Enrollment : 160 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Inflammatory and Glutamatergic Mechanisms of Sustained Threat in Adolescents With Depression: Toward Predictors of Treatment Response and Clinical Course
Estimated Study Start Date : November 2022
Estimated Primary Completion Date : October 2026
Estimated Study Completion Date : November 2027

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Study Participants
All depressed participants will undergo the same study procedures
Behavioral: Trier Social Stress Test
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




Primary Outcome Measures :
  1. Glutamate [ Time Frame: baseline and 90 min. follow-up ]
    Change in glutamate (institutional units) in corticolimbic regions following TSST

  2. Glutamate [ Time Frame: baseline and 12-week follow-up ]
    Change in glutamate (institutional units) in corticolimbic regions after SSRI treatment

  3. Inflammation [ Time Frame: baseline and 90 min. follow-up ]
    Change in composite score of peripheral levels of IL-6, TNF-a, and CRP (sum of z-scores) following TSST

  4. Inflammation [ Time Frame: 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 :
  1. IL-6 [ Time Frame: baseline and 90 min. follow-up ]
    Change in peripheral levels of IL-6 (pg/mL) following TSST

  2. IL-6 [ Time Frame: baseline and 12-week follow-up ]
    Change in peripheral levels of IL-6 (pg/mL) after SSRI treatment

  3. TNF-a [ Time Frame: baseline and 90 min. follow-up ]
    Change in peripheral levels of TNF-a (pg/mL) following TSST

  4. TNF-a [ Time Frame: baseline and 12-week follow-up ]
    Change in peripheral levels of TNF-a (pg/mL) after SSRI treatment

  5. CRP [ Time Frame: baseline and 90 min. follow-up ]
    Change in peripheral levels of CRP (pg/mL) following TSST

  6. CRP [ Time Frame: baseline and 12-week follow-up ]
    Change in peripheral levels of CRP (pg/mL) after SSRI treatment



Information from the National Library of Medicine

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Ages Eligible for Study:   13 Years to 19 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Adolescents presenting to school counseling cetners, community clinics, and/or medical centers (primary care, psychiatry, etc)
Criteria

Inclusion Criteria:

  • All sexes and genders
  • All ethnicities
  • Ages 13-19
  • Postpubertal (Tanner stage > 3)
  • 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)
  • Currently being seen by a clinician who will treat the participant with fluoxetine or escitalopram
  • The ability to provide assent, understand, and complete all study procedures
  • Caregiver consent (if applicable)

Exclusion Criteria:

  • Primary mental health diagnosis other than a depressive disorder according to DSM-V
  • Any contraindications to MRI scanning, phlebotomy, or SSRI treatment
  • Stimulant usage
  • A concussion within the last 6 weeks or any lifetime concussion with loss of consciousness for at least 10 minutes
  • 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
  • First-degree relative with a current, past, or suspected diagnosis of bipolar disorder

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05329441


Contacts
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Contact: Tiffany Ho, Ph.D. 4154797519 tiffany.ho@ucsf.edu

Locations
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United States, California
University of California, San Francisco
San Francisco, California, United States, 94143-2211
Contact: Tiffany Ho, Ph.D.    415-476-7519      
Principal Investigator: Tiffany C Ho, Ph.D.         
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
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Principal Investigator: Tiffany Ho, Ph.D. University of California, San Francisco
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT05329441    
Other Study ID Numbers: TIGER R01
First Posted: April 15, 2022    Key Record Dates
Last Update Posted: April 15, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymized demographic and clinical data as well as anonymized curated (i.e., after preprocessing and quality control) MRI-based metrics and cytokine levels

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of California, San Francisco:
depression
adolescence
Additional relevant MeSH terms:
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Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders