Exploring the Effects of Corticosteroids on the Human Hippocampus

  • STATUS
    Recruiting
  • End date
    Mar 31, 2024
  • participants needed
    188
  • sponsor
    University of Texas Southwestern Medical Center
Updated on 21 March 2022
depressive disorder
depressive symptoms
depressed mood
major depressive disorder
mood disorder
Accepts healthy volunteers

Summary

Chronic corticosteroid (CS) exposure is associated with changes in memory and the hippocampus in both humans and in animal models. The hippocampus has a high concentration of glucocorticoid receptors (GCRs), and the pre-clinical literature demonstrates shortening of apical dendrites in the CA3 region of the hippocampus and decreased neurogenesis in the dentate gyrus (DG) following CS administration. In humans, both stress and CS exposure are associated with a decline in declarative memory performance (a process mediated by the hippocampus). Impairment in declarative memory and hippocampal atrophy are reported in patients with excessive CS release due to Cushing's disease, and, by our group, in patients receiving prescription CS therapy. These findings have important implications for patients with mood disorders, as a large subset of people with major depressive disorder (MDD) show evidence of HPA axis activation, elevated cortisol and, importantly, resistance to the effects of CSs on both the HPA axis and on declarative memory. Thus, resistance to corticosteroids appears to be a consequence of MDD.

this study will examine changes in declarative memory, as well as use state-of-the-art high-resolution multimodal neuroimaging, including structural and functional (i.e., task-based and resting state) MRI, in both men and women healthy controls, and, as an exploratory aim, a depressed group, given 3-day exposures to hydrocortisone (160 mg/day) or placebo. The study will translate preclinical findings to humans, provide valuable data on possible sex differences in the response to cortisol and, for the first time, identify specific hippocampal subfields (e.g., CA3/DG) in humans that are most sensitive to acute CS effects. Using resting state fMRI data and whole brain connectomics using graph theoretical approaches, we will determine the effects of cortisol exposure on functional brain networks. Furthermore, this will be the first study to use neuroimaging to compare the brain's response to CSs in people with depression vs. controls, and determine whether depressed people demonstrate glucocorticoid resistance within the hippocampus. We hypothesize that hippocampal response to acute CSs will be greatest in the CA3/DG subfield, greater in women than in men, and that depressed people will show a blunted hippocampal response to CSs compared to controls. A multidisciplinary research team with extensive experience in CS effects on the brain and hippocampal subfield neuroimaging, and a prior history of research collaboration, will conduct the project.

Details
Condition Hydrocortisone, Depression, Healthy Volunteers
Treatment Placebo Oral Tablet, Hydrocortisone Oral
Clinical Study IdentifierNCT03896659
SponsorUniversity of Texas Southwestern Medical Center
Last Modified on21 March 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Men and women age 18-40 years with vision corrected to at least 20-40 (needed for fMRI tasks)
Education of ≥ 12 years
Baseline RAVLT total words recalled T-score ≥ 40 (normal range)
BMI between 18.5-35.0 (neither underweight nor severely obese)
Baseline QIDS-C ≤ 5 (virtual absence of depressive symptoms) for "healthy controls" and for the "depressed" group a QIDS-C between 11-20 (≥ moderate depressive symptoms but < very severe depressive symptoms)

Exclusion Criteria

History of major psychiatric illness other than MDD for the depressed group, defined as bipolar disorder, posttraumatic stress disorder, schizoaffective disorder, schizophrenia, eating disorders, or MDD with psychotic features. For the control group, a past episode of MDD (per SCID) is also exclusionary
History of drug or alcohol use disorder
History of neurological disorders including seizures, brain surgery, multiple sclerosis, Parkinson's disease
Taking CNS-acting medications (e.g., antidepressants, antipsychotics, lithium, anticonvulsants, sedative/hypnotic/anxiolytics). Thus, the depressed group will be medication free
History of allergic reaction or medical contraindication to hydrocortisone
Metal implants, claustrophobia, or other contraindications to MRI
Significant medical conditions (e.g., cancer, heart disease, diabetes)
Vulnerable population including pregnant or nursing women, prisoners, and people with intellectual disability, history of special education classes, dementia, or other severe cognitive disorders
Current suicidal ideation, a suicide attempt in the past 12 months or more than one lifetime attempt
History of systemic CS use in the past 12 months, lifetime cumulative use of more than 12 weeks, or recent (defined as past 28 days) inhaled CS use
Women who are using estrogen containing oral contraceptive agents (other contraceptives are acceptable, see Protection of Human Subjects section for a list of acceptable birth control methods) or who are post- or peri-menopausal or with irregular menstrual cycles (i.e., inconsistent menstruation patterns)
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