DIMENSIONS Summer 2000

SPOTLIGHT ON RESEARCH: PROPRANOLOL FOR THE TREATMENT OF DISRUPTIVE AGITATION IN AD

by Elaine Peskind, M.D.

Disruptive agitated behaviors frequently complicate Alzheimer's disease (AD) and present difficult clinical care problems, particularly among nursing home residents. Common disruptive agitated behaviors include motor hyperactivity (wandering and pacing), irritability, uncooperativeness with essential care (bathing, dressing, and feeding), and verbal and physical agressiveness. These behaviors often co-occur and become more frequent as AD becomes more severe.

Although disruptive agitated behaviors are influenced by environmental and interpersonal factors, it also is likely that behaviorally relevant neurochemical abnormalities lower the threshold for the expression of these behaviors in AD. This latter possibility, together with the low likelihood of completely eliminating the environmental causes of disruptive agitation in even the best nursing home environment, have contributed to widespread prescription of psychotropic medications (such as haloperidol, risperidone, and olanzapine) for disruptive agitated behaviors in AD. However, only a handful of well-designed placebo-controlled clinical trials of such psychotropic drugs have been conducted in nursing home settings. These studies have demonstrated some efficacy, but therapeutic results have been modest. Other agents that effectively reduce disruptive agitated behaviors in AD with acceptable adverse effects are clearly needed.

Recent studies have implicated certain chemicals in the central nervous system (CNS) in the development of agitation in AD. The noradrenergic system is a stress-responsive neurochemical system that uses norepinephrine, an adrenaline-like substance, as its chemical messenger. Patients with AD, particularly those in more advanced stages of disease or with more behavior symptoms, have increased levels of norepinephrine, and a greater density of the noradrenergic receptors in the brain on autopsy. These findings suggest that the noradrenergic system may contribute to the disruptive agitated behaviors that frequently occur in persons in the later stages of AD.

Propranolol is a drug that blocks the noradrenergic receptors in the CNS, and decreases responsiveness to noradrenergic stimulation. Anecdotal reports have suggested the usefulness of propranolol in decreasing agitated behaviors in AD, but a placebo-controlled trial had not been performed. Dr. Elaine Peskind and her associates have recently completed a double-blind, placebo-controlled pilot study of propranolol for disruptive agitation in the nursing home setting.

Sixteen residents of the Caroline Kline Galland Home, a Seattle community skilled nursing facility were studied (13 women and three men between the ages of 69-101 years). Subjects had been diagnosed with AD and had a history of at least one or more disruptive agitated behaviors, occurring at least twice weekly for two or more weeks. The agitated behaviors had to be severe enough to cause patient distress and/or interfere with essential care.

Subjects were randomized to receive propranolol or placebo by mouth three times a day for four weeks: 10 patients were randomized to propranolol and six to placebo. A dose-adjustment phase preceded the four week treatment phase of the study; subjects achieved an average dose of 100 mg per day. Outcome measures were assessments of behavior, cognition, function, and adverse events. At the end of the study, subjects were rated using the Clinical Global Impression of Change (CGIC). The CGIC provides the clinician's overall estimate of whether the patient improved or not. Eight of 10 subjects who had been taking propranolol were rated as improved on the Clinical Global Impression of Change (CGIC). Two subjects were rated "markedly improved", five "moderately improved", and one "minimally improved". The remaining two subjects on propranolol were rated as "unchanged" and "moderately worse". Of the six placebo group subjects, none were rated as improved. Three were rated as unchanged, one as "moderately worse", and two as "markedly worse". Propranolol had no adverse effects on cognition and/or functional status. Seven out of the 10 subjects who had been taking propranolol completed the study. None of the six subjects in the placebo group completed the study. The average number of study days completed in the propranolol group was 25, whereas the placebo group only completed an average of six days.

These initial data suggest that propranolol is safe and effective for the treatment of disruptive agitation in nursing home patients with AD. Large-scale placebo-controlled, double-blind treatment trials of propranolol for disruptive agitated behaviors in nursing home patients with AD are needed. Dr. Peskind and her colleagues have recently received funding from the National Institute on Aging to undertake such a study in four Seattle and Tacoma community nursing homes. This study will begin in July, 2000


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