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

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

contributions to outcome in mid- to late-life SSD and identify novel mechanisms to improve functional outcomes and quality of life in this greatly underserved population.