Anticholinergic Deprescription in Schizophrenia

Neural Mechanisms of Anticholinergic Burden in Mid- to Late-Life Schizophrenia Spectrum

In this study, the investigators will examine whether a deprescription of unnecessary anticholinergic drugs (benztropine or trihexyphenidyl) can augment quality of life, functioning, and neurocognition in individuals who with schizophrenia. Individuals identified by clinical services who have unneeded prescriptions benztropine or trihexyphenidyl will be eligible for deprescription and study entry. Following a baseline evaluation and magnetic resonance imaging (MRI), participants will will be randomized to either staying on their anticholinergic drugs or undergoing deprescription per routine clinical care, and will undergo follow-up evaluations across 6 months. The investigators predict that reducing and deprescribing these drug, if clinically determined to be unnecessary will will enhance functioning, neurocognition

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Drug: Anticholinergic Deprescription; Drug: No Anticholinergic Deprescription

• Study Type: Interventional
• Enrollment (Estimated): 105
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Deepak K Sarpal, M.D.; Phone Number: 4122465618; Email: sarpaldk@upmc.edu
• Study Contact Backup: Name: Shaun M. Eack, Ph.D.; Phone Number: 412.648.9029; Email: sme12@pitt.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • UPMC Western Psychiatric Hospital/University of Pittsburgh
      • Contact: Tori Blazinski; Email: blazinskit2@upmc.edu
      • Principal Investigator: Deepak K. Sarpal, M.D.
      • Principal Investigator: Shaun M. Eack, Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Primary DSM-defined diagnosis of schizophrenia or schizoaffective disorder verified by the Structured Clinical Interview for DSM-5 (SCID).
2. Prescription of benztropine or trihexyphenidyl for at least 6 months
3. Age 40-70 years.
4. ACBS score >= 3.
5. Mild or absent extrapyramidal symptoms (Determined by clinical pharmacists and prescribers).
6. Competency and willingness to sign informed consent.

Inclusion criteria for the healthy control group:

1. Age 40-70 years.
2. Competency and willingness to sign informed consent.

Exclusion Criteria:

1. Serious anticholinergic side-effects (e.g., fever, blurred vision) indicative of a need for immediate removal of anticholinergics,
2. Serious neurologic or medical condition/treatment that impacts the brain and Neurodegenerative conditions such as Parkinson's, dementia, etc.; autoimmune conditions such as Multiple Sclerosis (MS) and lupus; as well as traumatic brain injury (TBI).
3. Significant risk of suicidal or homicidal behavior.
4. Cognitive or language limitations, or any other factor that would preclude subjects providing informed consent.
5. Contraindications for MR imaging (e.g., a pacemaker).
6. Current SCID-verified substance use disorder will be excluded to avoid the confounding impact of significant substance use comorbidity. Participants with a history of substance use disorder that is in early or full remission will be eligible, to enhance generalizability.
7. Patients concurrently treated with electroconvulsive therapy will be excluded because of its effects on cognition.

Exclusion criteria for Healthy Control (HC) subjects:

1. No history of psychotic illness and no active Axis I disorder as determined by clinical interview using the SCID-NP.
2. Score greater than 1 on the ACB scale.
3. MR imaging contraindications.
4. Neurologic conditions, any serious non-psychiatric disorder that could affect brain functioning, or intellectual disability.
5. HC with family history of psychosis will be excluded, as such individuals show subtle, but significant cognitive and neurobiological abnormalities.
6. Individuals currently taking anticholinergic medications for reasons other than SSD.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Anticholinergic Deprescription; In this arm, clinically determined unneeded benztropine or trihexyphenidyl will be deprescribed, per routine care by clinical providers.	Drug: Anticholinergic Deprescription; per routine clinical care, people in the active arm of the study will undergo deprescription of benztropine or trihexyphenidyl per routine clinical care.
Active Comparator: No Anticholinergic Deprescription; In this arm, no deprescription of benztropine or trihexyphenidyl will occur.	Drug: No Anticholinergic Deprescription; In this arm, no deprescription of benztropine or trihexyphenidyl will occur.
No Intervention: Healthy Controls; In this arm, a healthy control group with minimal anticholinergic burden will be examined longitudinally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cognitive performance	We will examine whether the anticholinergic deprescription group, relative to the non-deprescription group, shows an increase in cognitive performance via scores from the MATRICS Consensus Cognitive Battery.	6 months
Change in scores on quality of life assessments.	We will examine whether the anticholinergic deprescription group, relative to the non-deprescription group, shows an increase in quality of life, measured with the WHOQOL-BREF.	6 months
Change in scores on functional outcome assessments.	We will examine whether the anticholinergic deprescription group, relative to the non-deprescription group, shows an increase in functional outcomes, measured with the Specific Level of Functioning Scale.	6 months
change in brain functional connectivity.	We will examine whether the anticholinergic deprescription group, relative to the non-deprescription group, shows an increase in brain functional connectivity between the basal forebrain and linked structures, such as regions of the cognitive control network, and the globus pallidus.	6 months
change in activation of neurocognitive networks	We will examine whether the anticholinergic deprescription group, relative to the non-deprescription group, shows an increase in brain activation of the cognitive control network via the AX-CPT, and activation of the hippocampus during memory encoding/retrieval via the Relational and Item-Specific Encoding task.	6 months
Brain glutamate concentration	We will examine whether the anticholinergic deprescription group, relative to the non-deprescription group, shows an increase in brain glutamate concentrations in the hippocampus and the dorsal anterior cingulate cortex.	6 months

Collaborators and Investigators

• Sponsor: Deepak K. Sarpal, M.D.
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Deepak K Sarpal, M.D., University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: August 16, 2024
• First Submitted That Met QC Criteria: August 16, 2024
• First Posted (Actual): August 20, 2024

Study Record Updates

• Last Update Posted (Actual): February 9, 2026
• Last Update Submitted That Met QC Criteria: February 5, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Psychotic Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Cholinergic Agents; Cholinergic Antagonists
• Other Study ID Numbers: STUDY24050090; R01MH135096 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data to the National Institute of Mental Health (NIMH) data archive
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes