Exploring the Effects of Corticosteroids on the Human Hippocampus

Depression Clinical Trial

Official title:

Exploring the Effects of Corticosteroids on the Human Hippocampus Using Neurocognitive Testing and High Resolution Neuroimaging

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03896659
• Other study ID #: STU-2018-0360
• Secondary ID: 1R01MH115932-01A
• Status: Recruiting
• Phase: Phase 4
• Start date: October 1, 2019
• Est. completion date: March 31, 2025

Study information

• Verified date: April 2024
• Source: University of Texas Southwestern Medical Center
• Contact: Shuchi Lakhanpal
• Phone: 214-645-6954
• Email: Shuchi.Lakhanpal[@]UTSouthwestern.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 188
• Est. completion date: March 31, 2025
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• 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)

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)

Related Conditions & MeSH terms

• Depression
• Healthy Volunteers
• Hydrocortisone

Intervention

Drug:
• Hydrocortisone Oral
Hydrocortisone 160 mg tablet
• Placebo Oral Tablet
Hydrocortisone-matched Placebo tablet

Locations

Country	Name	City	State
United States	UT Southwestern Medical Center	Dallas	Texas

Sponsors (3)

Lead Sponsor	Collaborator
University of Texas Southwestern Medical Center	National Institute of Mental Health (NIMH), University of California, Irvine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hippocampal subfield activation	Task-based hippocampal activation during functional neuroimaging.	3 days
Primary	Hippocampal subfield volume	High resolution structural neuroimaging will be used to generate regional hippocampal subfield volume.	3 days