Propranolol for disruptive behaviors in nursing home residents with probable or possible Alzheimer disease: a placebo-controlled study.

OBJECTIVE: Enhanced behavioral responsiveness to central nervous system (CNS) norepinephrine (NE) in Alzheimer disease (AD) may contribute to the pathophysiology of disruptive behaviors such as aggression, uncooperativeness with necessary care, irritability, and pressured pacing. We evaluated the efficacy of the beta-adrenergic antagonist propranolol for treatment-resistant disruptive behaviors and overall behavioral status in nursing home residents with probable or possible AD. METHODS: Thirty-one subjects (age 85 +/- 8 [SD]) with probable or possible AD and persistent disruptive behaviors that interfered with necessary care were randomized to propranolol (n = 17) or placebo (n = 14) in a double-blind study. Stable doses of previously prescribed psychotropics were maintained at pre-study dose during the study. Following a propranolol or placebo dose titration period of up to 9 days (per a dosing algorithm), subjects were maintained on maximum achieved dose for 6 weeks. Primary outcome measures were the Neuropsychiatric Inventory (NPI) and the Clinical Global Impression of Change (CGIC). RESULTS: Propranolol augmentation (mean achieved dose 106 +/- 38 mg/d) was significantly more effective than placebo for improving overall behavioral status on the total NPI score and CGIC. Improvement in individual NPI items within propranolol subjects was significant only for "agitation/aggression" and "anxiety," and reached borderline statistical significance favoring propranolol over placebo only for "agitation/aggression." Pressured pacing and irritability did not appear responsive to propranolol. In propranolol subjects rated "moderately improved" or "markedly improved" on the CGIC at the end of the double-blind study phase, improvement of overall behavioral status had diminished substantially after 6 months of open-label propranolol treatment. CONCLUSION: Short-term propranolol augmentation treatment appeared modestly effective and well tolerated for overall behavioral status in nursing home residents with probable or possible AD complicated by disruptive behaviors. Propranolol may be helpful specifically for aggression and uncooperativeness (the behaviors assessed by the NPI "agitation/aggressiveness" item). However, the usefulness of propranolol in this very old and frail population was limited by the high frequency of relative contraindications to beta-adrenergic antagonist treatment and diminution of initial behavioral improvements over time.

Prazosin reduces trauma-related nightmares in older men with chronic posttraumatic stress disorder.

Trauma-related nightmares in posttraumatic stress disorder (PTSD) rarely respond to pharmacologic treatment. Neurobiologic data suggest that enhanced brain responsiveness to adrenergic stimulation may contribute to the pathophysiology of trauma-related nightmares in PTSD. Nine older men with chronic PTSD secondary to military or Holocaust trauma were prescribed the lipophilic alpha-1 adrenergic antagonist prazosin for treatment-resistant trauma-related nightmares. Prazosin 2 mg to 4 mg 1 hour before bedtime substantially reduced nightmares and moderately or markedly reduced overall PTSD severity in 8 of 9 subjects. Prazosin was well tolerated. These open-label results are consistent with demonstrated therapeutic efficacy of prazosin for PTSD nightmares and sleep disturbance in a recent placebo-controlled trial in Vietnam veterans.

Familial dementia with Lewy bodies with an atypical clinical presentation.

The authors report a case of a 64-year-old male with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) pathology at autopsy who did not manifest the core symptoms of DLB until very late in his clinical course. His initial presentation of early executive and language dysfunction suggested a cortical dementia similar to frontotemporal lobar degeneration (FTLD). Core symptoms of DLB including dementia, hallucination, and parkinsonian symptoms were not apparent until late in the course of his illness. Autopsy revealed both brainstem and cortical Lewy bodies and AD pathology. Family history revealed 7 relatives with a history of dementia including 4 with possible or probable DLB. This case is unique because of the FTLD-like presentation, positive family history of dementia, and autopsy confirmation of DLB.

Pharmacologic treatments of dementia.

The management of dementia patients encompasses pharmacologic, behavioral, and psychosocial intervention strategies. Before pharmacologic intervention is instituted, it is important that sources of excess disability and comorbidity be eliminated or reduced. Identification of comorbid medical and psychiatric conditions, such as depression and delirium, should be identified and appropriately treated. Providing caregivers with education, support, and practical advice is a critical component of the management of the demented patient. The current standard of care for pharmacologic management of the cognitive and functional disabilities of AD consists of the combination of a cholinesterase inhibitor and high-dose vitamin E. This standard is based on the results of large-scale, double-blind, placebo-controlled trials. Cholinesterase inhibitors are the only FDA-approved pharmacologic treatments for AD. Cholinesterase inhibitors have been shown to be effective in the treatment of the cognitive, behavioral, and functional deficits of AD. Large-scale placebo-controlled trials of tacrine, donepezil, rivastigmine, and galantamine have demonstrated moderate benefits in patients with mild to moderate AD. Donepezil, rivastigmine, and galantamine are the first-line choices in the treatment of AD because of their lack of hepatotoxicity, ease of administration, few significant drug-drug interactions, and mild to moderate side effects. There are few contraindications to the use of cholinesterase inhibitors. Known hypersensitivity to a specific drug or its derivatives is the only true contraindication. Cautious administration of cholinesterase inhibitors is advised in patients who have a previous history of allergy or adverse reactions to prior cholinesterase inhibitors, severe liver disease, preexisting bradycardia, peptic ulcer disease, current alcoholism, asthma, or chronic obstructive pulmonary disease. Nausea, vomiting, diarrhea, and anorexia are the most common side effects of cholinesterase inhibitors. These gastrointestinal side effects can be minimized by gradual dose increases, administration with food, adequate hydration, and judicious use of an antiemetic. Vitamin E has been demonstrated to slow the progression of AD in several small and one large placebo-controlled trials. Because of its low cost and safety, it is recommended in addition to a cholinesterase inhibitor for the treatment of AD. There are no FDA-approved treatments for DLB and VaD. One small placebo-controlled trial demonstrated that rivastigmine may be effective in the treatment of DLB. More large-scale placebo-controlled trials are needed to confirm the results of this study. Treatment of VaD focuses on the control, identification, and management of cerebrovascular disease and vascular risk factors. Although there are no peer-reviewed reports on the efficacy of cholinesterase inhibitors for VaD or mixed AD/VaD, early reports suggest that these agents may also be effective for mixed AD/VaD. The indications for the use of cholinesterase inhibitor drugs are eventually likely to broaden to include DLB, mixed AD/VaD, and AD in its more advanced stages.