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Exploring the Effects of Corticosteroids on the Human Hippocampus

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ClinicalTrials.gov Identifier: NCT03896659
Recruitment Status : Recruiting
First Posted : April 1, 2019
Last Update Posted : October 23, 2019
Sponsor:
Collaborator:
University of California, Irvine
Information provided by (Responsible Party):
Sherwood Brown, MD, PhD, University of Texas Southwestern Medical Center

Tracking Information
First Submitted Date  ICMJE March 28, 2019
First Posted Date  ICMJE April 1, 2019
Last Update Posted Date October 23, 2019
Actual Study Start Date  ICMJE October 1, 2019
Estimated Primary Completion Date March 31, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 28, 2019)
  • Hippocampal subfield activation [ Time Frame: 3 days ]
    Task-based hippocampal activation during functional neuroimaging.
  • Hippocampal subfield volume [ Time Frame: 3 days ]
    High resolution structural neuroimaging will be used to generate regional hippocampal subfield volume.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03896659 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Exploring the Effects of Corticosteroids on the Human Hippocampus
Official Title  ICMJE Exploring the Effects of Corticosteroids on the Human Hippocampus Using Neurocognitive Testing and High Resolution Neuroimaging
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Condition  ICMJE
  • Hydrocortisone
  • Depression
  • Healthy Volunteers
Intervention  ICMJE
  • Drug: Hydrocortisone Oral
    Hydrocortisone 160 mg tablet
  • Drug: Placebo Oral Tablet
    Hydrocortisone-matched Placebo tablet
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Hydrocortisone Oral
    • Drug: Placebo Oral 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.
    Interventions:
    • Drug: Hydrocortisone Oral
    • Drug: Placebo Oral 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.
    Interventions:
    • Drug: Hydrocortisone Oral
    • Drug: Placebo Oral 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.
    Interventions:
    • Drug: Hydrocortisone Oral
    • Drug: Placebo Oral Tablet
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 28, 2019)
188
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 31, 2024
Estimated Primary Completion Date March 31, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Alexandra Kulikova 2146456950 alexandra.kulikova@utsouthwestern.edu
Contact: Sherwood Brown 2146456950 sherwood.brown@utsouthwestern.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03896659
Other Study ID Numbers  ICMJE 2018-0360
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sherwood Brown, MD, PhD, University of Texas Southwestern Medical Center
Study Sponsor  ICMJE University of Texas Southwestern Medical Center
Collaborators  ICMJE University of California, Irvine
Investigators  ICMJE
Principal Investigator: Sherwood Brown, MD, PhD University of Texas Southwestern Medical Center
PRS Account University of Texas Southwestern Medical Center
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP