Hydrocortisone for Memory Impairment

Overseen By Shuchi Lakhanpal

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Texas Southwestern Medical Center

Must not be taking: Antidepressants, Antipsychotics, Lithium, others

Disqualifiers: Bipolar, Schizophrenia, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 31 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how hydrocortisone, a type of medication, affects memory and brain function, particularly in people with depression compared to those without. Researchers aim to identify differences in how the brain's memory center responds to this medication. Participants will receive either hydrocortisone or a placebo for three days, with a break in between, to compare results. Individuals with moderate depression who are not on medication or those who are generally healthy might be eligible to participate. As a Phase 4 trial, this research seeks to understand how this FDA-approved and effective treatment benefits more patients.

Will I have to stop taking my current medications?

Yes, participants must stop taking any CNS-acting medications (like antidepressants or antipsychotics) as the depressed group needs to be medication-free.

What is the safety track record for hydrocortisone?

Studies have shown that hydrocortisone, a medication often used to treat inflammation, is generally well-tolerated in humans. Research indicates that while it can affect memory or thinking, these changes are usually not significant. Some studies did not find major effects on memory or other brain functions when using hydrocortisone. However, other studies have linked the use of glucocorticoids (a group of drugs that includes hydrocortisone) to reduced cognitive performance, such as difficulties with memory and problem-solving.

Hydrocortisone has been widely used and studied, and no major safety concerns have been consistently reported. While some people might experience mild changes in thinking, hydrocortisone is generally considered safe when used under medical supervision. Participants should discuss any potential side effects or concerns with the medical team running the trial. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about hydrocortisone for memory impairment because it offers a potentially new approach to enhancing memory. Unlike traditional treatments for memory issues, which often focus on neurotransmitter regulation, hydrocortisone is a steroid hormone that may influence memory by impacting stress-related pathways in the brain. This treatment's unique mechanism could provide benefits over existing options, especially for individuals with memory problems linked to stress or depression. Additionally, hydrocortisone's ability to potentially improve memory over just a few days is a promising feature, contrasting with other treatments that may take longer to show effects.

What evidence suggests that hydrocortisone might be an effective treatment for memory impairment?

This trial will evaluate the effects of hydrocortisone on memory impairment. Research has shown that hydrocortisone can influence memory and thinking skills. Some studies found that it might make it harder to remember locations or relationships between objects. Other research suggests that people taking hydrocortisone experienced fewer symptoms of PTSD and depression and reported an improved quality of life. However, evidence also indicates that using glucocorticoids, like hydrocortisone, can reduce overall thinking abilities. While hydrocortisone works well for some conditions, its effects on memory can be both positive and negative, depending on the situation. Participants in this trial will receive either hydrocortisone or a placebo in different sequences to assess these effects. ^{2 4 6 7 8}

Who Is on the Research Team?

Sherwood Brown, MD, PhD

Principal Investigator

University of Texas Southwestern Medical Center

Are You a Good Fit for This Trial?

This trial is for men and women aged 18-40 with normal to slightly overweight BMI, at least a high school education, and normal memory function. Healthy participants must have minimal depressive symptoms, while the depressed group should have moderate but not severe depression. Participants need good vision (correctable) for MRI tasks.

Inclusion Criteria

My depression is moderate to severe, but not very severe.

My BMI is between 18.5 and 35.

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

I am either not using estrogen-based birth control, am menopausal, or have irregular periods.

You have a history of having problems with drugs or alcohol.

I have a history of neurological disorders like seizures or Parkinson's.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either hydrocortisone or placebo for 3 days, followed by a 25-day washout period, then crossover to the alternate treatment for another 3 days

31 days

Neuroimaging and Testing

High-resolution multimodal neuroimaging and neurocognitive testing are conducted to assess hippocampal subfield volume and activation

3 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Hydrocortisone
• Placebo Oral Tablet

Trial Overview The study tests how a short-term high-dose hydrocortisone treatment affects memory and brain structure/function in healthy individuals versus those with depression. It involves taking either hydrocortisone or a placebo pill and undergoing advanced neuroimaging to observe changes in specific areas of the hippocampus.

How Is the Trial Designed?

Group I: Healthy Controls: Placebo, then Hydrocortisone Experimental Treatment 2 Interventions

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.

Group II: Healthy Controls: Hydrocortisone, then Placebo Experimental Treatment 2 Interventions

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.

Group III: Depressed: Placebo, then Hydrocortisone Experimental Treatment 2 Interventions

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.

Group IV: Depressed: Hydrocortisone, then Placebo Experimental Treatment 2 Interventions

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.

Hydrocortisone is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Hydrocortisone for:

• Adrenal insufficiency
• Allergic reactions
• Asthma
• Severe acute pancreatitis

Approved in United States as Hydrocortisone for:

• Adrenal insufficiency
• Allergic reactions
• Asthma
• Severe acute pancreatitis

Approved in Canada as Hydrocortisone for:

• Adrenal insufficiency
• Allergic reactions
• Asthma
• Severe acute pancreatitis

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

University of California, Irvine

Collaborator

Trials

580

Recruited

4,943,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

A single low-dose administration of hydrocortisone (10 mg) significantly improved cognitive performance in HIV-infected women, enhancing verbal learning, delayed memory, and other cognitive functions at both 30 minutes and 4 hours post-administration.

The cognitive benefits of low-dose hydrocortisone were associated with reductions in inflammatory cytokines and increased cortisol levels, suggesting that targeting the hypothalamic-pituitary-adrenal axis could be a promising approach for improving cognitive function in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single low dose of hydrocortisone enhances cognitive functioning in HIV-infected women. Rubin, LH., Phan, KL., Keating, SM., et al.[2020]

In a study of 66 healthy volunteers, high-dose hydrocortisone (0.45 mg/kg) significantly impaired the recall of specific autobiographical memories and slowed response times, indicating a negative impact on memory retrieval under stress-like conditions.

Moderate-dose hydrocortisone (0.15 mg/kg) did not significantly affect memory performance, suggesting that the effects of cortisol on memory retrieval are dose-dependent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-dependent effects of hydrocortisone infusion on autobiographical memory recall. Young, K., Drevets, WC., Schulkin, J., et al.[2021]

In a study involving 16 healthy elderly participants, hydrocortisone administration did not significantly affect cognitive functions such as memory, attention, or executive function, despite a tenfold increase in salivary cortisol levels.

The results suggest that older adults may be less sensitive to the cognitive effects of short-term increases in cortisol, potentially due to reduced sensitivity of glucocorticoid receptors in the hippocampus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of hydrocortisone administration on cognitive function in the elderly. Porter, RJ., Barnett, NA., Idey, A., et al.[2017]

Chronic exposure to high levels of cortisol in patients with Cushing's Syndrome is linked to significant deficits in working memory, including issues with short-term memory volume and delayed recall, based on a study of 30 female participants.

Despite these memory impairments, patients with Cushing's Syndrome did not show significant differences in basic attentional and executive functions compared to healthy controls, indicating that the memory deficits are specifically related to cortisol levels rather than overall cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A clinical profile of memory impairment in humans due to endogenous glucocorticoid excess. León-Carrión, J., Atutxa, AM., Mangas, MA., et al.[2019]

In a study of 80 participants, including 40 patients with mild Alzheimer's disease (AD) and 40 healthy elderly controls, those with AD performed worse on working memory tests and had higher cortisol levels than the controls.

Despite the elevated cortisol levels in AD patients, there was no significant correlation between cortisol levels and working memory performance, suggesting that high cortisol may not directly impact cognitive function in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of cortisol levels on working memory performance in elderly subjects with Alzheimer's disease. Souza-Talarico, JN., Caramelli, P., Nitrini, R., et al.[2019]

This study investigates the use of mifepristone, a glucocorticoid antagonist, to slow cognitive decline in individuals with mild-to-moderate Alzheimer's disease, comparing its effects to a placebo over a 6-month period.

The research aims to determine if higher baseline cortisol levels correlate with greater cognitive decline, using assessments like the Alzheimer's Disease Assessment Scale and the Mini Mental Status Exam to measure changes in cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Slowing the progression of cognitive decline in Alzheimer's disease using mifepristone. Belanoff, JK., Jurik, J., Schatzberg, LD., et al.[2018]

Patients with adrenal insufficiency treated with dual-release hydrocortisone (DR-HC) showed improved cognitive functions, particularly in executive functioning, compared to those on conventional hydrocortisone treatment, suggesting a potential benefit of DR-HC in cognitive performance.

The study also indicated that DR-HC may enhance quality of sleep, as patients on higher doses reported better subjective sleep quality, highlighting the overall well-being improvements associated with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual-release hydrocortisone and its benefits on cognitive function and quality of sleep. Krekeler, C., Kropp, P., Blacha, AK., et al.[2021]

Prolonged overactivity of the HPA axis, often seen in stressed individuals and some depressed patients, can lead to physical changes in the pituitary and adrenal glands, as well as negatively impact memory and mood due to elevated cortisol levels.

High cortisol levels are linked to reduced hippocampal size and impaired memory function, suggesting a cycle where cortisol-induced damage to the hippocampus further exacerbates HPA axis hyperactivity, potentially leading to chronic stress-related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The potential role of excessive cortisol induced by HPA hyperfunction in the pathogenesis of depression. Stokes, PE.[2019]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0039128X23001423

Adverse cognitive effects of glucocorticoids: A systematic ... Eleven included studies were able to demonstrate a correlation between glucocorticoid use and decreased cognition.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/10494574/

The Effects of Chronic Administration of Hydrocortisone on ... Results: Hydrocortisone caused impairments of visuo-spatial memory. These included increased within search errors and impaired use of strategies on the spatial ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5981864/

The efficacy of initial hydrocortisone administration at ... Hydrocortisone recipients reported fewer PTSD and depression symptoms, and had greater improvements in health-related quality of life during the first 3 months ...

4. frontiersin.org frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.694046/full

Sleep, Cognition and Cortisol in Addison's Disease In that study, stress-level doses of cortisone acetate reduced cerebral blood flow to the medial temporal lobe (MTL), a memory network that broadly includes the ...

5. researchgate.net researchgate.net/publication/272199473_The_effects_of_two_different_doses_of_hydrocortisone_on_cognition_in_patients_with_secondary_adrenal_insufficiency-results_from_a_RCT

The effects of two different doses of hydrocortisone on ... (2016) [26] explored the impact of short-and longterm HC replacement therapy showing no significant difference in cognitive functioning between ...

6. academic.oup.com academic.oup.com/edrv/advance-article/doi/10.1210/endrev/bnaf029/8246430

Cognitive Assessment in Adults With Adrenal Cortisol ... Adults with adrenal cortisol insufficiency (ACI) often report cognitive dysfunction, especially in memory processing and executive function.

7. academic.oup.com academic.oup.com/edrv/advance-article-pdf/doi/10.1210/endrev/bnaf029/64197087/bnaf029.pdf

Cognitive Assessment in Adults With Adrenal Cortisol ... Adults with adrenal cortisol insufficiency (ACI) often report cognitive dysfunction, especially in memory processing and executive function.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/11949774/

Effects of Hydrocortisone Administration on Cognitive ... No significant effects were found on memory or a range of other cognitive functions. The lack of effect of this regime of hydrocortisone is in contrast to ...