Rivastigmine + Scopolamine for Auditory Hallucinations

Overseen By Silmilly Toribio

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Yale University

Must be taking: Dopamine-2 antagonists

Must not be taking: Cholinergics, Anticholinergics

Disqualifiers: Substance dependence, Neurological problems, Pregnancy, others

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

35 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore new treatments for people with auditory hallucinations, especially those who haven't responded to usual medications. Researchers are testing rivastigmine, a drug that improves brain function, to determine if it can reduce these distressing hallucinations. One group of participants, who experience frequent auditory hallucinations, will receive either rivastigmine or a placebo (an inactive pill). Another group, consisting of healthy controls, will receive a placebo or scopolamine, a drug used to prevent nausea and motion sickness. Individuals diagnosed with conditions like schizophrenia and who experience auditory hallucinations at least weekly might be suitable for this study. As an Early Phase 1 trial, this research focuses on understanding how rivastigmine works in people, offering participants a chance to contribute to groundbreaking treatment development.

Will I have to stop taking my current medications?

The trial requires that you stop taking any cholinergic or anticholinergic medications before participating.

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

Research has shown that rivastigmine, a treatment often used for Alzheimer's disease, is generally safe. Studies have found that using rivastigmine as a patch may cause fewer side effects, such as nausea and vomiting, compared to capsules. It has also been used to help with symptoms in conditions like Parkinson's disease, indicating prior testing in individuals with brain-related issues.

While specific data from studies about its use for hearing voices is lacking, its history in treating other conditions suggests it is well-tolerated. As this trial is in an early stage, researchers are still learning about its safety and effectiveness for this particular use. Participants in the trial will receive close monitoring for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because Rivastigmine, typically used for Alzheimer's, is being explored for auditory hallucinations, potentially providing a new option for those experiencing psychosis. Unlike standard antipsychotic drugs that often focus on dopamine systems, Rivastigmine works as a cholinesterase inhibitor, enhancing the function of acetylcholine, a neurotransmitter involved in memory and learning. This unique approach could offer benefits for those who don't respond well to current antipsychotic treatments. Additionally, the use of both capsule and transdermal patch forms provides flexibility in how the medication can be administered, potentially improving compliance and convenience for patients.

What evidence suggests that this trial's treatments could be effective for auditory hallucinations?

Research has shown that rivastigmine, a type of medication, can help reduce hallucinations. In studies with Alzheimer's patients, those taking rivastigmine experienced fewer hallucinations than those who took a placebo, a pill with no active medicine. Another study found that rivastigmine decreased the frequency and volume of musical hallucinations. It also reduced hallucinations in people with dementia with Lewy bodies. In this trial, participants with psychosis and frequent auditory hallucinations will receive either rivastigmine capsules or placebo capsules to evaluate its effectiveness in reducing hearing-related hallucinations in mental health conditions where other treatments have not worked. ^{1 3 4 6 7}

Who Is on the Research Team?

Albert Powers, MD, PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for English-speaking adults aged 18-65 with a diagnosis of schizophrenia or related disorders, who experience weekly auditory hallucinations. They must be right-handed and not have metal implants, pacemakers, or severe claustrophobia that would prevent MRI scans. Pregnant individuals, those using certain medications, or with a history of substance dependence, significant cognitive impairments, seizures, violence, or specific medical conditions are excluded.

Inclusion Criteria

You are right-handed.

I speak English.

I have been diagnosed with a schizophrenia spectrum disorder.

Exclusion Criteria

You have a history of being physically aggressive or violent.

I have a history of seizures.

There are signs of heart problems on an EKG test.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive scopolamine or rivastigmine to assess effects on conditioned hallucinations and prior weighting

6 weeks

Weekly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Physostigmine Salicylate
• Placebo
• Placebo Capsule
• Placebo Patch
• Rivastigmine Capsule
• Rivastigmine Transdermal Product
• Saline
• Scopolamine

Trial Overview The study tests if Rivastigmine (a capsule), Scopolamine (a patch), and placebo versions can influence the occurrence of auditory hallucinations in psychosis. It's based on computational models linking brain activity to these symptoms and aims at personalized treatment by pharmacologically altering brain processes involved in hallucinations.

How Is the Trial Designed?

Group I: Aim 2: Those with psychosis/hallucinations Experimental Treatment 2 Interventions

Participants who have a psychosis spectrum diagnosis and frequent auditory hallucinations will be given Rivastigmine capsule versus placebo capsule.

Group II: Aim 1: Healthy Controls Placebo Group 2 Interventions

Healthy controls will be given scopolamine patches versus placebo patch.

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

Approved in United States as Exelon for:

• Alzheimer's disease
• Parkinson's disease dementia

Approved in European Union as Exelon for:

• Alzheimer's disease
• Parkinson's disease dementia

Approved in Canada as Exelon for:

• Alzheimer's disease
• Parkinson's disease dementia

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

The rivastigmine patch, a transdermal treatment for Alzheimer's disease, demonstrated significant cognitive improvements in 1,195 patients over 24 weeks compared to placebo, with the 10-cm² patch showing similar efficacy to oral capsules but with fewer side effects like nausea and vomiting.

The 20-cm² patch provided earlier cognitive improvements and better scores than the 10-cm² patch, while maintaining good tolerability, suggesting that transdermal delivery may be a superior method for administering rivastigmine in treating Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease. Winblad, B., Grossberg, G., Frölich, L., et al.[2022]

The rivastigmine transdermal patch offers a promising alternative to oral capsules for treating dementia, potentially reducing gastrointestinal side effects like nausea and vomiting that are common with oral cholinesterase inhibitors.

Pharmacokinetic studies indicate that the patch provides similar drug exposure to the highest oral dose while minimizing fluctuations in plasma concentration, which may enhance tolerability and improve patient compliance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic rationale for the rivastigmine patch. Cummings, J., Lefèvre, G., Small, G., et al.[2019]

The study demonstrated that the new rivastigmine transdermal patch (RIV-TDS) is bioequivalent to the marketed Exelon patch, meaning they deliver the same amount of the drug into the bloodstream, which is important for consistent treatment of Alzheimer's disease.

RIV-TDS showed better skin adhesion and tolerability compared to the reference product, suggesting it may enhance patient compliance and comfort during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability Study of a Transdermal Patch Formulation of Rivastigmine Compared with Exelon in Healthy Subjects. Morte, A., Vaqué, A., Iniesta, M., et al.[2022]

The transdermal patch for rivastigmine provides a more stable drug exposure compared to the oral capsule, with lower peak levels and less fluctuation in plasma concentrations, which may enhance safety and tolerability for patients with Alzheimer's disease.

In this study involving Alzheimer's patients, the patch demonstrated comparable efficacy to the highest oral dose while allowing for a more gradual increase in drug levels, potentially leading to improved therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients. Lefèvre, G., Sedek, G., Jhee, SS., et al.[2022]

The rivastigmine transdermal patch was found to be safe and well tolerated in patients with probable Alzheimer's disease who could not tolerate or respond to oral cholinesterase inhibitors, with 82% of patients showing improvement or no decline in their condition after 24 weeks.

In a study of 164 patients, 12.2% discontinued due to adverse events, primarily skin lesions, indicating that while the patch is generally safe, some patients may experience localized side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of switching from oral cholinesterase inhibitors to the rivastigmine transdermal patch in patients with probable Alzheimer's disease. Han, HJ., Lee, JJ., Park, SA., et al.[2022]

A study involving 40 healthy men demonstrated that the generic formulation of rivastigmine is bioequivalent to the brand Exelon, with similar pharmacokinetic profiles as shown by comparable AUC and Cmax values.

Both the generic and reference formulations were well tolerated by participants, indicating that the generic version is a safe alternative to the brand-name drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence Study of Rivastigmine 6 mg Capsules (Single Dose) in Healthy Volunteers. Abhyankar, D., Shedage, A., Gole, M., et al.[2018]

In a study involving 1851 caregivers of patients with mild to moderate Alzheimer's disease, 94.3% preferred the transdermal rivastigmine patch over oral treatment, highlighting its user-friendly format.

Caregivers reported high satisfaction (76.5%) with the patch, noting it was easy to apply and had minimal impact on daily activities, while also observing clinical improvements in patients compared to previous oral treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From high doses of oral rivastigmine to transdermal rivastigmine patches: user experience and satisfaction among caregivers of patients with mild to moderate Alzheimer disease. Reñé, R., Ricart, J., Hernández, B.[2015]

Citations

1. psychiatrist.com psychiatrist.com/jcp/questionably-significant-benefits-of-cheis-on-delusions-in-alzheimer-and-parkinson-disease/

Cholinesterase Inhibitors for Delusions and Hallucinations ... The cholinesterase inhibitor (ChEI) drugs donepezil, rivastigmine, and galantamine attenuated the severity of both delusions and hallucinations in both AD and ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/20164585/

Effects of rivastigmine in Alzheimer's disease patients with ... Of 927 patients, 194 (21%) reported hallucinations at baseline. Hallucinators tended to have greater decline on placebo on all outcome measures. On the ADAS-cog ...

3. withpower.com withpower.com/trial/early-phase-1-hallucinations-6-2021-45494

Rivastigmine + Scopolamine for Auditory Hallucinations The rivastigmine patch, a transdermal treatment for Alzheimer's disease, demonstrated significant cognitive improvements in 1,195 patients over 24 weeks ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0140673600033997

Efficacy of rivastigmine in dementia with Lewy bodies Patients taking rivastigmine were significantly less apathetic and anxious, and had fewer delusions and hallucinations while on treatment than ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4387860/

Musical Hallucinations Treated with Acetylcholinesterase ... Within days of starting rivastigmine 1.5 mg, the music became less frequent and less loud (VAS 5/10) and her anger and depressed mood ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3994190/

Treatment of Psychosis and Dementia in Parkinson's Disease Rivastigmine is probably efficacious in treating PD dementia, though the magnitude of benefit is modest (Level B evidence) [22, 44]. In addition, tremor can be ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04366518

Study Details | NCT04366518 | Toward a Computationally- ... Auditory hallucinations are among the most distressing aspects of psychotic illness, and between 10 and 30% of people with hallucinations do not respond to ...