Cholinergic Antagonist for Postmenopausal Cognitive Decline

(CHAMP Trial)

No longer recruiting at 1 trial location

Overseen By Jenna Makarewicz, BS

Age: 18+

Sex: Female

Trial Phase: Phase < 1

Sponsor: University of Vermont

Must not be taking: Hormone therapy, SSRIs, SERMs, others

Disqualifiers: MCI, Dementia, Cardiovascular disease, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 2 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how hormonal changes after menopause affect the brain and might increase the risk of cognitive decline, such as in Alzheimer's disease (AD). Researchers are testing a treatment that blocks a specific brain chemical (a cholinergic antagonist, also known as an anticholinergic agent) to assess its impact on memory and brain function in postmenopausal women. Women who have gone through menopause, are not on certain medications, and have no serious health issues might be suitable for this study. The goal is to identify who is more at risk for conditions like AD and to better tailor future treatments. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking discoveries.

Do I have to stop taking my current medications to join the trial?

Yes, you must stop taking certain medications. Participants cannot be on hormone therapy, SSRIs, phytoestrogens, SERMs, or antiestrogen medications for at least one year before joining the trial. Additionally, you cannot use medications that are on the prohibited medications list.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that mecamylamine, a medication that blocks certain nerve signals, is generally safe and well-tolerated. One study found that participants took mecamylamine without major problems. The highest drug level in the body occurred just over two hours after a 20 mg dose, with no serious side effects reported.

However, drugs like mecamylamine have sometimes been linked to memory or thinking problems, especially with long-term use. While mecamylamine appears safe for short-term use in studies, it's important to be aware of potential effects on memory or thinking. Prospective trial participants should consider discussing any concerns with healthcare professionals. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard treatments for postmenopausal cognitive decline, which typically focus on hormone replacement or cognitive enhancers, mecamylamine offers a unique approach. Mecamylamine is a cholinergic antagonist, meaning it targets the cholinergic system by blocking certain receptors, which may help improve cognitive function. Researchers are excited about this treatment because it offers a novel mechanism of action that could potentially address cognitive decline in a way that current therapies do not. The hope is that by exploring this new pathway, the treatment might offer relief where traditional approaches have been less effective.

What evidence suggests that this trial's treatments could be effective for postmenopausal cognitive decline?

This trial will compare the effects of mecamylamine, a cholinergic antagonist, with a placebo on cognitive function in postmenopausal women. Research has shown that drugs like mecamylamine, which block certain brain signals, can impact thinking skills. Studies have found that people taking these drugs often perform worse on memory and attention tests. This suggests a connection between these drugs and a decline in thinking abilities, especially in tasks requiring focus and quick thinking. Early research indicates that estrogen is important for normal brain function, and its loss can lead to thinking problems. This supports the idea that changes in thinking during menopause might be linked to changes in brain signals, which are being further studied with mecamylamine in this trial. ^{1 2 3 6 7}

Who Is on the Research Team?

JUlie A Dumas, Ph.D.

Principal Investigator

University of Vermont

Paul A Newhouse, M.D.

Principal Investigator

Vanderbilt University

Are You a Good Fit for This Trial?

The CHAMP study is for women aged 50-70 who are postmenopausal, non-smokers, and in good physical health without serious psychiatric or cognitive disorders. Participants should not have cardiovascular disease (except mild hypertension), be off certain hormone therapies and medications for a year, and must have normal IQ and neuropsychological test results.

Inclusion Criteria

I am a woman aged between 50 and 70.

I have gone through menopause.

Your IQ is higher than 80, which means it is in the normal range.

Exclusion Criteria

Your blood pressure is higher than 160/100 without taking any medication for it.

I have asthma or COPD.

I have an overactive thyroid.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a cholinergic challenge with either a placebo or mecamylamine to assess cognitive function and brain activation

2 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the cholinergic challenge

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cholinergic antagonist

Trial Overview This trial investigates how hormonal changes after menopause might affect the risk of Alzheimer's Disease by studying the brain's cholinergic system. It involves testing memory performance, brain activation, and brain structure following administration of a cholinergic antagonist to assess cognitive resilience.

How Is the Trial Designed?

Group I: Placebo Challenge Experimental Treatment 1 Intervention

One of the two study days will be the oral placebo.

Group II: Mecamylamine Challenge Experimental Treatment 1 Intervention

One of the two study days will be the oral mecamylamine.

Who Is Running the Clinical Trial?

University of Vermont

Lead Sponsor

Trials

283

Recruited

3,747,000+

Vanderbilt University Medical Center

Collaborator

Trials

922

Recruited

939,000+

Published Research Related to This Trial

Anticholinergic medications are linked to a moderate to strong risk of cognitive decline and dementia in older adults, based on multiple studies regardless of their design or methodology.

There is a dose-response relationship, meaning that higher use of anticholinergics increases the risk of dementia, suggesting that managing and reducing anticholinergic use could help lower this risk in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergic medications and risk of dementia in older adults: Where are we now? Chatterjee, S., Talwar, A., Aparasu, RR.[2022]

A systematic review of 25 studies involving 968,428 older adults suggests that a higher anticholinergic burden is associated with an increased risk of cognitive decline or dementia, with an odds ratio of 2.63 for those with significant anticholinergic effects.

The Anticholinergic Cognitive Burden scale (ACB scale) was particularly highlighted, showing that as the severity of anticholinergic burden increases, so does the risk of cognitive decline, indicating a potential need for careful medication management in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergic burden (prognostic factor) for prediction of dementia or cognitive decline in older adults with no known cognitive syndrome. Taylor-Rowan, M., Edwards, S., Noel-Storr, AH., et al.[2022]

A systematic review of three trials involving 299 older adults found insufficient evidence to conclude that reducing anticholinergic medication improves cognitive outcomes, with results rated as very low certainty.

While some trials successfully reduced anticholinergic burden, there were no significant improvements in cognitive performance or other clinical outcomes, indicating a need for larger studies to explore the long-term effects of such interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergic deprescribing interventions for reducing risk of cognitive decline or dementia in older adults with and without prior cognitive impairment. Taylor-Rowan, M., Alharthi, AA., Noel-Storr, AH., et al.[2023]

In a pilot study involving six healthy postmenopausal women, the anticholinergic drugs mecamylamine and scopolamine did not significantly impair working memory performance, suggesting that cholinergic modulation may not universally affect cognitive function in this population.

Functional MRI results indicated that brain activation patterns in the frontal lobe were greater during placebo conditions compared to drug conditions, highlighting the sensitivity of brain circuitry to cholinergic modulation and the potential for different effects from nicotinic versus muscarinic receptor blockade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinic versus muscarinic blockade alters verbal working memory-related brain activity in older women. Dumas, JA., Saykin, AJ., McDonald, BC., et al.[2021]

In a study of 40 postmenopausal women aged 50-60, treatment with 1 mg of oral estradiol did not improve cognitive performance under anticholinergic blockade and actually worsened attention task performance compared to a placebo.

Women with higher self-reported cognitive complaints showed poorer performance on working memory tasks, suggesting that these complaints may indicate a decline in cholinergic function that affects cognitive abilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estradiol treatment in young postmenopausal women with self-reported cognitive complaints: Effects on cholinergic-mediated cognitive performance. Conley, AC., Albert, KM., McDonald, BC., et al.[2023]

In a study of 19,114 healthy older adults, a high anticholinergic burden (ACB score of ≥ 3) was linked to a significantly increased risk of ischemic stroke (58% higher risk) and dementia (36% higher risk) after a median follow-up of 4.7 years.

The results suggest that minimizing exposure to anticholinergic medications in older adults is crucial, as these medications may have a vascular effect contributing to the increased risk of cognitive decline and stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults. Lockery, JE., Broder, JC., Ryan, J., et al.[2022]

In a study of 329 elderly patients in a geriatric ward, 40.73% were found to be using at least one anticholinergic drug, with 13.98% experiencing a clinically significant anticholinergic burden, highlighting the prevalence of these medications despite their risks.

Higher anticholinergic burden scores were significantly linked to conditions such as dementia, increased risk of falls, and severe disability, indicating that careful monitoring of anticholinergic use in older adults is crucial to prevent negative health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergic Burden of Geriatric Ward Inpatients. Wilczyński, K., Gorczyca, M., Gołębiowska, J., et al.[2021]

Discontinuing medications with anticholinergic properties may lead to improved cognitive performance in older adults, as suggested by two prospective cohort studies included in the review.

The overall impact of stopping anticholinergic medications on cognitive function is still not well understood, highlighting the need for more extensive research with larger sample sizes and better assessment methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of anticholinergic discontinuation on cognitive outcomes in older people: a systematic review. Salahudeen, MS., Duffull, SB., Nishtala, PS.[2021]

Anticholinergic medications, which block the neurotransmitter acetylcholine, are commonly prescribed to older adults, with one-third to one-half of their medications having this activity, potentially leading to cognitive and functional impairments.

The cumulative anticholinergic burden is a significant predictor of adverse health outcomes in older adults, suggesting that healthcare providers should aim to minimize this burden by avoiding or reducing the use of these medications when possible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergics: theoretical and clinical overview. Nishtala, PS., Salahudeen, MS., Hilmer, SN.[2022]

Cholinomimetic drugs, particularly acetylcholinesterase (AChE) inhibitors, are effective in treating cognitive impairments in Alzheimer's disease, but their benefits may primarily stem from enhancing attention rather than directly improving cognitive function.

These drugs may also be useful for addressing non-cognitive behavioral changes associated with Alzheimer's, suggesting a broader therapeutic potential beyond just cognitive symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholinergic therapies for Alzheimer's disease: progress and prospects. Palmer, AM.[2005]

In a pilot study involving six healthy postmenopausal women, the use of anticholinergic drugs scopolamine and mecamylamine showed similar patterns of brain activation during memory tasks, indicating that cholinergic modulation may influence cognitive processes after menopause.

The study found increased activation in the hippocampus and frontal areas during memory encoding, suggesting that changes in the cholinergic system could contribute to cognitive changes experienced by postmenopausal women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholinergic modulation of hippocampal activity during episodic memory encoding in postmenopausal women: a pilot study. Dumas, JA., McDonald, BC., Saykin, AJ., et al.[2021]

In a study of 22 postmenopausal women, younger participants (ages 50-62) showed improved verbal memory when pretreated with estradiol before anticholinergic challenges, indicating a beneficial interaction between estradiol and the cholinergic system.

Conversely, older participants (ages 70-81) experienced impaired performance on memory tasks with estradiol treatment, suggesting that the cognitive benefits of estradiol may be more pronounced in younger postmenopausal women and highlighting a critical period for its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis. Dumas, J., Hancur-Bucci, C., Naylor, M., et al.[2021]

In a study of 2058 individuals aged 60-64 over four years, those using anticholinergic medications showed poorer performance on the Symbol Digit Modalities Test, indicating a negative impact on complex attention.

However, the study found no significant evidence that anticholinergic medication use was linked to greater cognitive decline over time, suggesting that while caution is warranted in prescribing these medications, they may not necessarily accelerate cognitive deterioration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of medications with anticholinergic properties and cognitive function in a young-old community sample. Low, LF., Anstey, KJ., Sachdev, P.[2009]

In a study of 177 older adults, it was found that even one anticholinergic drug per day can lead to cognitive and mobility impairments, particularly in those aged 75 and older.

The research indicates that anticholinergic drugs negatively affect cognitive functions and mobility, suggesting that healthcare providers should minimize their use in older patients to prevent these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Effects of Anticholinergic Drugs on Cognition and Mobility: Cutoff for Impairment in a Cross-Sectional Study in Young-Old and Old-Old Adults. Attoh-Mensah, E., Loggia, G., Schumann-Bard, P., et al.[2020]

Citations

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5. frontiersin.org frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1428675/epub

Effect of estradiol with or without micronized progesterone ... These results are important for assessing the impact of combined postmenopausal hormone treatment on cognitive performance that is dependent on ...

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Dementia Associated with Anticholinergic Drugs Used for ... Our results suggest that the use of oxybutynin and solifenacin in older patients might increase the risk of dementia. Possible underlying ...