Toward a Computationally-Informed, Personalized Treatment for Hallucinations

NCT04366518 | Recruiting Early Phase 1 FDA Drug

• 2 other identifiers: 2000024774R21MH122940
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• Number of conditioned hallucinations exhibited during saline vs placebo administration

  Participants will perform the Conditioned Hallucinations task while in the scanner; the authors hypothesize that number of conditioned hallucinations exhibited during the task will be higher under placebo than physostigmine, but only in those who have high prior weighting on baseline assessment.

  During fMRI scans / task completion which will take approximately 90 minutes

Secondary Outcomes (2)

• Prior-Weighting Parameter of the Hierarchical Gaussian Filter

  During fMRI scans / task completion which will take approximately 90 minutes

• Functional correlation with model belief trajectories

  During fMRI scans / task completion which will take approximately 90 minutes

Study Arms (2)

Aim 2: Those with psychosis/hallucinations

EXPERIMENTAL

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

Drug: Rivastigmine Transdermal System; Drug: Placebo Patch

Aim 1: Healthy Controls

PLACEBO COMPARATOR

Healthy controls will be given scopolamine patches versus placebo patch.

Drug: Scopolamine; Drug: Placebo Patch

Interventions

Rivastigmine Transdermal System DRUG

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.

Aim 2: Those with psychosis/hallucinations

Scopolamine DRUG

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.

Aim 1: Healthy Controls

Placebo Patch DRUG

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

Aim 2: Those with psychosis/hallucinations

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Yale University: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Connecticut Mental Health Center

New Haven, Connecticut, 06519, United States

RECRUITING

MeSH Terms

Conditions

Hallucinations; Psychotic Disorders

Interventions

Scopolamine

Condition Hierarchy (Ancestors)

Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Scopolamine Derivatives; Tropanes; Azabicyclo Compounds; Aza Compounds; Organic Chemicals; Belladonna Alkaloids; Solanaceous Alkaloids; Alkaloids; Heterocyclic Compounds; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring

Study Officials

• Albert Powers, MD, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Albert Powers, MD, PhD

CONTACT

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

Silmilly Toribio

CONTACT

silmilly.toribio@yale.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Rivastigmine vs Placebo

Study Record Dates

• First Submitted: March 24, 2020
• First Posted: April 29, 2020
• Study Start: July 15, 2021
• Primary Completion (Estimated): August 1, 2032
• Study Completion (Estimated): August 1, 2032
• Last Updated: June 5, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)