Recruiting
Early Phase 1

Personalized Treatment

Sponsor:

Yale University

Code:

NCT04366518

Conditions

Hallucinations, Auditory

Psychosis

Eligibility Criteria

Sex: All

Age: 18 - 65

Healthy Volunteers: Not accepted

Interventions

Rivastigmine Transdermal System

Scopolamine

Placebo Patch

Placebo Patch

Study Details

Brief summary:

Auditory hallucinations are among the most distressing aspects of psychotic illness, and between 10 and 30% of people with hallucinations do not respond to antipsychotic medications. The authors have used computational modeling of behavior to link brain activity to development of auditory hallucinations in the hope of guiding new treatment development. The proposed studies take the first step toward individualized treatment approaches to hallucinations by attempting causal, pharmacological manipulation of relevant model parameters underlying these phenomena.

Conditions

Hallucinations, Auditory

Psychosis

Study ID

NCT04366518

Start date

Jul 15, 2021

Status verified date

Jun, 2025

Completion date

Aug, 2032

Anticipated

Primary completion date

Aug, 2032

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 65

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Age 18-65
  • English speaking
  • Right handedness
  • Diagnosed with schizophrenia schizoaffective, schizophreniform, schizotypal, or brief psychotic disorder
  • History of auditory verbal hallucinations occurring at least weekly

Exclusion Criteria:

  • Current substance dependence or active use as determined by drug test.
  • Any neurological, medical or developmental problem that is known to impair cognition significantly
  • Contraindications for MR scanning including metallic implants of any kind, pacemakers and history of accidents with metal, claustrophobia
  • History of seizures
  • History of violence
  • History of suicide
  • Pregnancy (determined by urine pregnancy test)
  • Concurrent participation in any other intervention study
  • History of urinary retention
  • History of delirium
  • Current use of any cholinergic or anticholinergic medication
  • History of asthma, diabetes, and cardiovascular disease
  • Evidence of cardiovascular disease on EKG
  • Individuals who have been on dopamine-2 antagonists for less than 6 months (to limit risk of EPS)

Study Design

Enrollment

35 participants

Anticipated

Allocation

Randomized

Intervention Model

Crossover

Primary purpose

Basic Science

Interventions and Outcome Measures

Arms

experimental: Aim 2: Those with psychosis/hallucinations

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

placebo comparator: Aim 1: Healthy Controls

Healthy controls will be given scopolamine patches versus placebo patch.

Interventions

Rivastigmine Transdermal System

Rivastigmine doses will be administered transdermally using 9.5 mg/24 hr transdermal patches. Participants will be randomized to two treatments with oral rivastigmine vs. placebo separated by a 15-hour washout period (>5 half-lives to eliminate any residual effects). This will require three separate visits: a baseline visit, a visit for the first transdermal treatment and a visit for the second transdermal treatment. All visits include fMRI scans. The first transdermal patch will be administered 8-14 hours before the scan. After the washout period, the second transdermal patch will be administered 8-14 hours before the scan. No study team member except for the unblinded team member will know which capsule the participant receives first. Because we are interested in rivastigmine as a probe for a pre-identified computational/physiological abnormality, we will median-split groups post-hoc for the purposes of analysis.

Scopolamine

The authors have chosen to use scopolamine to determine the effects of cholinergic antagonism, as treatment with scopolamine demonstrates a dose-related increase in propensity toward conditioned hallucinations and in doses much higher than those proposed here, can cause spontaneous hallucinations. At the proposed dose, scopolamine has an excellent safety profile and has been used routinely for nearly 20 years for treatment of nausea due to surgery or motion sickness in adults and children. Scopolamine is available in the US only as a 1mg / 72 hours transdermal patch, and peak plasma levels are reached within 24 hours. This standard dosage level is very well tolerated in the general population.

Placebo Patch

Participants in Aim 2 will receive a placebo patch versus rivastigmine patch.

Placebo Patch

Participants in Aim 1 will receive a placebo patch versus scopolamine patch.

Primary outcome measure

  • Number of conditioned hallucinations exhibited during saline vs placebo administration [ Time Frame: During fMRI scans / task completion which will take approximately 90 minutes ]

Central Contacts and Locations

Central contacts

Albert Powers, MD, PhD

203-974-7329albert.powers@yale.edu

Silmilly Toribio

silmilly.toribio@yale.edu

Locations

Connecticut Mental Health Center

Recruiting

New Haven, Connecticut, United States, 06519

More Information

Sponsor

Yale University

Last update posted

Jun 5, 2025

Last verified

Jun, 2025

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Yale University on 2025-06-05.