Exploring the Effects of Corticosteroids on the Human Hippocampus

NCT03896659 | Completed Phase 4 Results DMC FDA Drug

• 2 other identifiers: STU-2018-03601R01MH115932-01A1
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hydrocortisone; Depression; Healthy Volunteers

Outcome Measures

Primary Outcomes (4)

• Hippocampal Subfield Activation (Left Hemisphere)

  The z-scores of hippocampal subregions and hemispheres represent the standardized difference in activation between correct and incorrect conditions of the mnemonic discrimination task, where a Z-score of 0 represents the mean difference across all voxels, and each unit reflects one standard deviation from that mean. To compare brain activation between conditions, separate beta weights were estimated for correct and incorrect trials across all trials. These beta weights represent the voxel-wise blood oxygen level (BOLD)-dependent signal, reflecting changes in neural activity associated with each condition. Positive z-scores indicate greater activation for correct relative to incorrect trials, whereas negative z-scores indicate greater activation for incorrect relative to correct trials. Larger absolute z-scores indicate stronger condition-related effects; there are no established clinical thresholds for these experimental activation differences.

  3 days

• Hippocampal Subfield Activation (Right Hemisphere)

  The z-scores of hippocampal subregions and hemispheres represent the standardized difference in activation between correct and incorrect conditions of the mnemonic discrimination task, where a Z-score of 0 represents the mean difference across all voxels, and each unit reflects one standard deviation from that mean. To compare brain activation between conditions, separate beta weights were estimated for correct and incorrect trials across all trials. These beta weights represent the voxel-wise blood oxygen level (BOLD)-dependent signal, reflecting changes in neural activity associated with each condition. Positive z-scores indicate greater activation for correct relative to incorrect trials, whereas negative z-scores indicate greater activation for incorrect relative to correct trials. Larger absolute z-scores indicate stronger condition-related effects; there are no established clinical thresholds for these experimental activation differences.

  3 days

• Hippocampal Subfield Volume (Left Hemisphere)

  High resolution structural neuroimaging will be used to generate regional hippocampal subfield volume.

  3 days

• Hippocampal Subfield Volume (Right Hemisphere)

  High resolution structural neuroimaging will be used to generate regional hippocampal subfield volume.

  3 days

Study Arms (4)

Depressed: Hydrocortisone, then Placebo

EXPERIMENTAL

Participants in the "depressed' arm will receive a Hydrocortisone 160 mg tablet every day for 3 days. After a washout period of 25 days, they then will receive a Placebo tablet (matching Hydrocortisone 160 mg tablet) every day for 3 days.

Drug: Hydrocortisone Oral; Drug: Placebo Oral Tablet

Depressed: Placebo, then Hydrocortisone

EXPERIMENTAL

Participants in the "depressed' arm will receive a Placebo tablet (matching Hydrocortisone 160 mg tablet) every day for 3 days. After a washout period of 25 days, they then will receive a Hydrocortisone 160 mg tablet every day for 3 days.

Drug: Hydrocortisone Oral; Drug: Placebo Oral Tablet

Healthy Controls: Hydrocortisone, then Placebo

EXPERIMENTAL

Participants in the "healthy control" arm will receive a Hydrocortisone 160 mg tablet every day for 3 days. After a washout period of 25 days, they then will receive a Placebo tablet (matching Hydrocortisone 160 mg tablet) every day for 3 days.

Drug: Hydrocortisone Oral; Drug: Placebo Oral Tablet

Healthy Controls: Placebo, then Hydrocortisone

EXPERIMENTAL

Participants in the "healthy control" arm will receive a Placebo tablet (matching Hydrocortisone 160 mg tablet) every day for 3 days. After a washout period of 25 days, they then will receive a Hydrocortisone 160 mg tablet every day for 3 days.

Drug: Hydrocortisone Oral; Drug: Placebo Oral Tablet

Interventions

Hydrocortisone Oral DRUG

Hydrocortisone 160 mg tablet

Depressed: Hydrocortisone, then Placebo; Depressed: Placebo, then Hydrocortisone; Healthy Controls: Hydrocortisone, then Placebo; Healthy Controls: Placebo, then Hydrocortisone

Placebo Oral Tablet DRUG

Hydrocortisone-matched Placebo tablet

Depressed: Hydrocortisone, then Placebo; Depressed: Placebo, then Hydrocortisone; Healthy Controls: Hydrocortisone, then Placebo; Healthy Controls: Placebo, then Hydrocortisone

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Men and women age 18-50 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)

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• University of California, Irvine: collaborator
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Depression

Interventions

Hydrocortisone

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids

Results Point of Contact

• Title: Dr. E. Sherwood Brown
• Organization: University of Texas Southwestern Medical Center

sherwood.brown@utsouthwestern.edu

214-645-6950

Study Officials

• Sherwood Brown, MD, PhD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry

Study Record Dates

• First Submitted: March 28, 2019
• First Posted: April 1, 2019
• Study Start: October 1, 2019
• Primary Completion: September 16, 2024
• Study Completion: September 16, 2024
• Last Updated: December 16, 2025
• Results First Posted: December 16, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)