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

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $775,706

## Abstract

PROJECT SUMMARY
Schizophrenia spectrum disorders (SSD) are associated with significant morbidity and mortality across the world.
A considerable portion of healthcare and societal costs associated with the illness are secondary to poor
functional outcomes driven by cognitive impairments. To date, remarkably little is known about the neural and
molecular contributors to functional outcome in mid- to late-life SSD. Iatrogenic effects from the over-prescription
of anticholinergic medicines, including benztropine and trihexyphenidyl, that is common in the chronic phases of
SSD, represents an important and preventable contributor to cognitive impairment, functional disability, and poor
quality of life in mid- to later phases of this condition. Studies from our own and other groups have demonstrated
the negative impact of anticholinergic burden (ACB) in SSD on diverse areas of cognition, which may be
mediated by reductions in prefrontal cortical gray matter and activity. Further, we have shown that connectivity
across a variety of regions linked with neural circuitry of the basal forebrain consistently predicts functional
disability in chronic SSD. In addition, exciting preliminary data from our large SSD outpatient treatment program
showed that it was feasible to deprescribe anticholinergic medications in many long-term patients with clear
benefits to verbal memory and recall, as well as quality of life. Understanding the neural mechanisms of ACB
holds the potential for identifying novel treatment targets in mid- to late-life SSD and is consistent with NIMH
strategic plans to leverage existing treatment strategies (ACB reduction via deprescription) that may optimize
treatment outcomes and develop clinically relevant biosignatures that contribute to our understanding of illness
trajectories. In response to PAR-24-023, “Schizophrenia and related disorders during mid- to late-life”, this
project proposes to conduct a prospective study of the neural, molecular, and functional impacts of
anticholinergic reduction via deprescription in mid- to late-life patients with SSD. A total of 80 individuals with
SSD, ages 40-70, will be studied over the course of 6 months in a randomized controlled trial with half of the
patients (N=40) receiving ACB reduction and the other half (N=40) continuing with their usual care. A separate
sample of 25 healthy volunteers will also be studied to provide normative estimates on study measures and their
reliability. Specific aims focus on understanding the impact of ACB reduction on (1) cognition and quality of life,
(2) neural mechanisms underlying cognitive control and memory, and (3) glutamatergic changes in hippocampus
and anterior cingulate cortex. We address these aims with a diverse team of researchers with expertise in SSD
research, lived experience, psychopharmacology, psychosocial treatment, outcomes research, geriatric
psychiatry, and neuroimaging. Findings are expected to yield new insights into neural and molecular
con...

## Key facts

- **NIH application ID:** 10976880
- **Project number:** 1R01MH135096-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** SHAUN M EACK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $775,706
- **Award type:** 1
- **Project period:** 2024-08-09 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10976880

## Citation

> US National Institutes of Health, RePORTER application 10976880, Neural Mechanisms of Anticholinergic Burden in Mid- to Late-Life Schizophrenia Spectrum Illness (1R01MH135096-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10976880. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*