Disruptive agitated behaviors frequently occur in Alzheimer's disease (AD), particularly among nursing home residents. These problem behaviors frequently precipitate nursing home placement and continue to cause patient distress and interfere with necessary care in the nursing home setting. Limited clinical trial data available suggest only modest efficacy and substantial adverse effects for antipsychotic and other psychotropic drugs prescribed for these problems. New approaches to pharmacologic treatment of these problem behaviors would be beneficial. Recent studies suggest increased behavioral sensitivity to central nervous system (CNS) noradrenergic stimulation in AD, and increased CNS noradrenergic outflow in the advanced stages of AD. These CNS noradrenergic characteristics may contribute to the expression of disruptive agitated behaviors in AD. Propranolol is a beta-adrenergic antagonist drug that decreases responsiveness to CNS noradrenergic stimulation. Anecdotal reports and our preliminary findings suggest propranolol decreases disruptive agitated behaviors in AD. The primary goal of this proposal is to evaluate the efficacy and safety of propranolol in the management of disruptive agitated behaviors in nursing home patients with AD. Subjects will be randomized to propranolol (maximum dose 120 mg per day) or placebo in an 8-week parallel design, double-blind trial. Primary outcome measures will be Clinical Global Impression of Change score and change scores from baseline to last observation on the Brief Psychiatric Rating Scale and Neuropsychiatric Inventory. Cognition, functional status, and adverse events will also be assessed. A secondary goal is to evaluate noradrenergic outflow and sensitivity to noradrenergic stimulation as predictors of therapeutic response to propranolol. Although measuring CNS noradrenergic outflow or CNS adrenergic receptors is not feasible in the proposed treatment trial, measurements of plasma norepinephrine (NE) and lymphocyte beta-adrenergic receptor density, affinity, and sensitivity provide achievable estimates of noradrenergic outflow and beta-adrenergic receptor status respectively. We will determine if high plasma NE and/or high lymphocyte beta-adrenergic receptor density, affinity, and/or sensitivity define AD patients with disruptive agitation most responsive to propranolol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018644-04
Application #
6642706
Study Section
Special Emphasis Panel (ZRG1-BBBP-5 (01))
Program Officer
Buckholtz, Neil
Project Start
2000-09-01
Project End
2007-08-31
Budget Start
2003-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$309,800
Indirect Cost
Name
University of Washington
Department
Psychiatry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wang, Lucy Y; Shofer, Jane B; Rohde, Kirsten et al. (2009) Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. Am J Geriatr Psychiatry 17:744-51
Peskind, Elaine R; Tsuang, Debby W; Bonner, Lauren T et al. (2005) Propranolol for disruptive behaviors in nursing home residents with probable or possible Alzheimer disease: a placebo-controlled study. Alzheimer Dis Assoc Disord 19:23-8
Peskind, Elaine R; Bonner, Lauren T; Hoff, David J et al. (2003) Prazosin reduces trauma-related nightmares in older men with chronic posttraumatic stress disorder. J Geriatr Psychiatry Neurol 16:165-71
Bonner, Lauren T; Tsuang, Debby W; Cherrier, Monique M et al. (2003) Familial dementia with Lewy bodies with an atypical clinical presentation. J Geriatr Psychiatry Neurol 16:59-64
Vuletic, Simona; Jin, Lee-Way; Marcovina, Santica M et al. (2003) Widespread distribution of PLTP in human CNS: evidence for PLTP synthesis by glia and neurons, and increased levels in Alzheimer's disease. J Lipid Res 44:1113-23
Bonner, Lauren T (2003) On bridging the gap. Acad Psychiatry 27:29-30
Bonner, Lauren T; Peskind, Elaine R (2002) Pharmacologic treatments of dementia. Med Clin North Am 86:657-74