ALZHEIMER'S IN LONG TERM PROPRANOLOL FOR AGITATION

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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.