Exploring the Effects of Corticosteroids on the Human Hippocampus

• ClinicalTrials.gov Identifier: NCT03896659
• Recruitment Status: Recruiting
• First Posted: April 1, 2019
• Last Update Posted: February 17, 2023
• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: University of California, Irvine; National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Sherwood Brown, MD, PhD, University of Texas Southwestern Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hydrocortisone; Depression; Healthy Volunteers	Drug: Hydrocortisone Oral; Drug: Placebo Oral Tablet	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 188 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Exploring the Effects of Corticosteroids on the Human Hippocampus Using Neurocognitive Testing and High Resolution Neuroimaging
• Actual Study Start Date: October 1, 2019
• Estimated Primary Completion Date: March 31, 2024
• Estimated Study Completion Date: March 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Depressed: Hydrocortisone, then Placebo; 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; Hydrocortisone 160 mg tablet; Drug: Placebo Oral Tablet; Hydrocortisone-matched Placebo tablet
Experimental: Depressed: Placebo, then Hydrocortisone; 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; Hydrocortisone 160 mg tablet; Drug: Placebo Oral Tablet; Hydrocortisone-matched Placebo tablet
Experimental: Healthy Controls: Hydrocortisone, then Placebo; 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; Hydrocortisone 160 mg tablet; Drug: Placebo Oral Tablet; Hydrocortisone-matched Placebo tablet
Experimental: Healthy Controls: Placebo, then Hydrocortisone; 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; Hydrocortisone 160 mg tablet; Drug: Placebo Oral Tablet; Hydrocortisone-matched Placebo tablet

Outcome Measures

Primary Outcome Measures :

1. Hippocampal subfield activation [ Time Frame: 3 days ]
   Task-based hippocampal activation during functional neuroimaging.
2. Hippocampal subfield volume [ Time Frame: 3 days ]
   High resolution structural neuroimaging will be used to generate regional hippocampal subfield volume.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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)

Contacts and Locations

Contacts

Contact: Josh Raitt; 2146456967; Josh.Raitt@UTSouthwestern.edu

Contact: Sherwood Brown; 2146456950; sherwood.brown@utsouthwestern.edu

Locations

United States, Texas

UT Southwestern Medical Center; Recruiting

Dallas, Texas, United States, 75390

Contact: Traci Holmes 214-645-6959 traci.holmes@utsouthwestern.edu

Sponsors and Collaborators

University of Texas Southwestern Medical Center

University of California, Irvine

National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Sherwood Brown, MD, PhD; University of Texas Southwestern Medical Center

More Information

• Responsible Party: Sherwood Brown, MD, PhD, Professor of Psychiatry, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT03896659
• Other Study ID Numbers: STU-2018-0360; 1R01MH115932-01A1 ( U.S. NIH Grant/Contract )
• First Posted: April 1, 2019
• Last Update Posted: February 17, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Depression; Behavioral Symptoms; Hydrocortisone; Anti-Inflammatory Agents