Prazosin for Agitation in Alzheimer’s Disease: PEACE‐AD

Abstract

Background: Disruptive agitation is a major source of distress to patients and caregivers and is a common precipitant of long‐term care placement. High central nervous system (CNS) noradrenergic signaling at the alpha‐1 adrenoreceptor (AR) in Alzheimer's disease (AD) appears to contribute to disruptive agitation. Prazosin, a CNS active alpha‐1 AR antagonist, was effective for reducing disruptive agitation and was well tolerated in our previous single site pilot study. Methods: In this multi‐site randomized controlled trial (RCT) in which recruitment was substantially handicapped by the COVID‐ 19 pandemic, participants were randomized to prazosin or placebo using a 2:1 permuted block randomization. Prazosin was titrated over 4 weeks to a maximum possible dose of 4 mg mid‐morning and 6 mg at bedtime based on tolerability and persistent agitation. Adverse events and orthostatic blood pressure and heart rate were monitored. Primary outcome measure was the ADCS‐Clinical Global Impression of Change‐ Agitation (CGIC‐A) targeting disruptive agitated behaviors. Secondary outcomes were the 17‐item Neuropsychiatric Inventory (NPI), Cohen Mansfield Agitation Inventory (CMAI), ADCS‐Activities of Daily Living (ADCS‐ADL) for severe dementia, and total number study days completed. An exploratory outcome was the NPI 5‐item subscale reflecting agitation. Results: Thirty‐five participants were randomized 2:1 to prazosin or placebo for 12 weeks. Mixed Models Repeated Measures analysis was performed. There were no significant differences in the CGIC‐A or total NPI scores. However, reduction in CMAI score significantly favored prazosin (p = 0.04) and the 5‐item NPI Agitation subscale numerically favored prazosin. The adverse event (AE) profile was as anticipated for prazosin; AEs that occurred in >5% of prazosin participants and >2X the occurrence in the placebo group included syncope, dizziness, nausea, and somnolence. Conclusions: This study provides a modest signal for prazosin efficacy for disruptive agitation in AD. Both the efficacy and safety data were limited by the small N, particularly in the placebo group. A larger multi‐center study of prazosin for moderate‐severe disruptive agitation in home‐ and long‐term care‐residing Alzheimer's disease patients is necessary to extend these results.