R01MH127176

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

Los Angeles University Of California

THE MISSION OF THE NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH) IS TO TRANSFORM THE UNDERSTANDING AND TREATMENT OF MENTAL ILLNESSES THROUGH BASIC AND CLINICAL RESEARCH, PAVING THE WAY FOR PREVENTION, RECOVERY, AND CURE. WE FULFILL THIS MISSION BY SUPPORTING AND CONDUCTING RESEARCH ON MENTAL ILLNESSES, HEALTH SERVICES, AND THE UNDERLYING BASIC SCIENCE OF THE BRAIN AND BEHAVIOR; SUPPORTING THE TRAINING OF SCIENTISTS TO CARRY OUT BASIC AND CLINICAL MENTAL HEALTH RESEARCH; AND COMMUNICATING WITH SCIENTISTS, PATIENTS, PROVIDERS, AND THE PUBLIC ABOUT MENTAL HEALTH RESEARCH ADVANCES AND PRIORITIES. IN MAY 2024, NIMH RELEASED ITS STRATEGIC PLAN FOR RESEARCH. THE STRATEGIC PLAN BUILDS ON THE SUCCESSES OF PREVIOUS NIMH STRATEGIC PLANS BY PROVIDING A FRAMEWORK FOR SCIENTIFIC RESEARCH AND EXPLORATION, AND ADDRESSING NEW CHALLENGES IN MENTAL HEALTH.THE NEW STRATEGIC PLAN OUTLINES FOUR HIGH-LEVEL GOALS: GOAL 1: DEFINE THE BRAIN MECHANISMS UNDERLYING COMPLEX BEHAVIORS GOAL 2: EXAMINE MENTAL ILLNESS TRAJECTORIES ACROSS THE LIFESPAN GOAL 3: STRIVE FOR PREVENTION AND CURES GOAL 4: STRENGTHEN THE PUBLIC HEALTH IMPACT OF NIMH-SUPPORTED RESEARCH THESE FOUR GOALS FORM A BROAD ROADMAP FOR THE INSTITUTES RESEARCH PRIORITIES OVER THE NEXT FIVE YEARS, BEGINNING WITH THE FUNDAMENTAL SCIENCE OF THE BRAIN AND BEHAVIOR, AND EXTENDING THROUGH EVIDENCE-BASED SERVICES THAT IMPROVE PUBLIC HEALTH OUTCOMES.

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

Los Angeles, California 90095 United States

Single Zip Code

Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required) (PA-20-184)

Amendment Since initial award the End Date has been extended from 04/30/27 to 04/30/28 and the total obligations have increased 249% from $900,156 to $3,138,807.