Inflammatory and Glutamatergic Mechanisms of Sustained Threat in Adolescents With Depression (TIGER)

May 27, 2026 updated by: Tiffany Cheing Ho, PhD, University of California, Los Angeles

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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). 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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
160

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90095
        • Recruiting
        • University of California, Los Angeles
        • Principal Investigator:
          • Tiffany C Ho, Ph.D.
        • Contact:
          • Tiffany Ho, Ph.D.
          • Phone Number: 310-825-0561

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Adolescents presenting to school counseling centers, community clinics, and/or medical centers (primary care, psychiatry, etc)

Description

Inclusion Criteria:

  • All sexes and genders
  • All ethnicities
  • Ages 14-21
  • Postpubertal (Tanner stage > 3)
  • No medications that will interfere with the study (including antidepressants, mood stabilizers, hormone supplements, steroids, etc.) for at least 2-6 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 inflammatory conditions or use of anti-inflammatory medications that may influence study findings
  • Any major neurological or developmental disorders which could impact the participant's ability to comply with study procedure
  • Meeting for current or lifetime criteria of mania or psychosis, diagnosis of bipolar disorder, or any substance use disorders
  • First-degree relative with current, past, or suspected mania or psychosis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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 modified version of the Trier Social Stress Test (TSST), which is a well-validated psychosocial stress paradigm, adapted for adolescents that involves no deception and is considered a very mild stressor. The TSST comprises of two stress tests: a 5-minute arithmetic task and a 5-minute speech task. Due to repeated testing of the TSST, participants will be randomized to one task at T1 and complete the second task at T2 (counterbalanced design). Every 5 minutes, participants will provide ratings of their mood using a visual analogue scale (1-10) of eight mood states (Afraid, Confused, Sad, Angry, Energetic, Tired, Happy, and Tense) that will be used as potential behavioral responses to social stress. Glutamate and inflammation outcomes will be examined acutely and from T1 and T2.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Children's Depressing Rating Scale-Revised
Time Frame: baseline and 12-week follow-up
Clinician-administered assessment of depression severity (dimensional) assessment of depression Clinician-administered assessment of depression severity (dimensional)
baseline and 12-week follow-up
Reynolds Adolescent Depression Scale-2 (RADS-2)
Time Frame: baseline and 12-week follow-up
Self-report measure of depression severity (dimensional)
baseline and 12-week follow-up
Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-PL)
Time Frame: baseline and 12-week follow-up
The K-SADS-PL is a semi-structured clinical interview designed to yield reliable and valid diagnoses of current and past history of Axis I disorders in children and adolescents. We will use the K-SADS-PL to determine whether a participant is currently depressed, in remission, experiencing relapse or a recurrent episode. From this interview, we will also obtain information such as age of depression onset, number of depressive episodes, medication and therapy usage and changes, etc
baseline and 12-week follow-up

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Patient Health Questionnaire-9
Time Frame: baseline and 12-week follow-up
Self-report measure of depression severity (dimensional) used for adults (which will facilitate cross-study comparisons)
baseline and 12-week follow-up
Mood Ratings on the Trier Social Stress Test
Time Frame: Acute (baseline and throughout study procedures)
Visual analogue scale of feeling Afraid, Confused, Sad, Angry, Energetic, Tired, Happy, and Tense from 0 [nothing] to 10 [a bit]
Acute (baseline and throughout study procedures)

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Glutamate
Time Frame: baseline and 12-week follow-up
Change in glutamate (institutional units) in corticolimbic regions after SSRI treatment
baseline and 12-week follow-up
IL-6
Time Frame: baseline and 12-week follow-up
Change in peripheral levels of IL-6 (pg/mL) after SSRI treatment
baseline and 12-week follow-up
TNF-a
Time Frame: baseline and 12-week follow-up
Change in peripheral levels of TNF-a (pg/mL) after SSRI treatment
baseline and 12-week follow-up
CRP
Time Frame: baseline and 12-week follow-up
Change in peripheral levels of CRP (pg/mL) after SSRI treatment
baseline and 12-week follow-up
Generalized Anxiety Disorder-7
Time Frame: baseline and 12-week follow-up
Self-report measure of anxiety severity (dimensional) used for adults (which will facilitate cross-study comparisons)
baseline and 12-week follow-up
Multidimensional Anxiety Scale for Children-2 (MASC-2)
Time Frame: baseline and 12-week follow-up
Self-report measure of anxiety severity (dimensional)
baseline and 12-week follow-up
Glutamate
Time Frame: Acute (baseline and 90 min. follow-up)
Change in glutamate (institutional units) in corticolimbic regions following TSST
Acute (baseline and 90 min. follow-up)
IL-6
Time Frame: Acute (baseline and 90 min. follow-up)
Change in peripheral levels of IL-6 (pg/mL) following TSST
Acute (baseline and 90 min. follow-up)
TNF-a
Time Frame: Acute (baseline and 90 min. follow-up)
Change in peripheral levels of TNF-a (pg/mL) following TSST
Acute (baseline and 90 min. follow-up)
CRP
Time Frame: Acute (baseline and 90 min. follow-up)
Change in peripheral levels of CRP (pg/mL) following TSST
Acute (baseline and 90 min. follow-up)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of California, Los Angeles

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Mental Health (NIMH)
Mayo Clinic
Columbia University
University of Southern California
University of California, San Francisco
University of California, Irvine

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Tiffany Ho, Ph.D., University of California, Los Angeles

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 6, 2023

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 1, 2028

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 30, 2028

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 8, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 8, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 15, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 29, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 27, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • TIGER R01
  • R01MH127176 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD 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

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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