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Prazosin: Treating Agitation & Aggression in Veterans with
Alzheimer’s Disease
Lucy Wang, M.D.
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A 74 year old veteran with Alzheimer’s disease is referred for assistance in managing agitation. He is living in a nursing home, and he is combative with care on a daily basis. This includes physically resisting, yelling out, and occasionally trying to bite staff when they try to help him with necessary care (dressing, toileting, bathing). Staff are questioning whether he can safely stay at their facility.
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Alzheimer’s disease is a cognitive disorder◦ Impairment in short term memory and other
cognitive domains◦ Progressive course◦ Functional impairment
But, non-cognitive symptoms occur Agitation and aggression describes a set of
non-cognitive symptoms common in later stages of AD
What is agitation and aggression in AD?
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Examples include:◦ Resistiveness with care◦ Verbal and physical aggression (yelling, biting,
kicking)◦ Pressured motor hyperactivity
What is agitation and aggression in AD?
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Patient distress Behaviors can pose a threat of harm to self
and others Contributes to caregiver burden - a major
precipitant for institutionalization A common psychiatric problem in nursing
homes (48 to 82% prevalence)
Impact
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Address treatable contributors◦ Pain, infection, medications
Nonpharmacologic treatments preferred Pharmacologic treatments if
nonpharmacologic approaches are not sufficient
Current Approach to Treatment
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Atypical antipsychotics are a common pharmacologic treatment choice
Atypicals have evidence-based support for modest efficacy
But side effects limit use◦ Sedation◦ Extrapyramidal side effects◦ And…
Pharmacologic treatments
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“FDA ALERT [6/16/2008]: FDA is notifying healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis.”
There was an approximately 1.6- to 1.7-fold increase in mortality rate (4.5 percent,
compared with 2.6 percent in the patients taking placebo)
Black box warning
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Other pharmacologic agents have promise but have limited evidence in the literature
Cholinesterase inhibitors and memantine◦ May be helpful for milder symptoms
Conflicting evidence for SSRI’s and anticonvulsants
Other pharmacologic options
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Noradrenergic neuronal loss occurs in AD Norepinephrine (NE) and its metabolites in
the CSF are increased NE biosynthesis is upregulated There is an increase in alpha-1 receptor
number
Prazosin as a potential alternative
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This alteration in the noradrenergic system may contribute to agitated behaviors◦ In an clinical study, administration of yohimbine
(which stimulates noradrenergic outflow) led to agitation in AD patients
◦ In a post-mortem study, a history of aggressive behaviors and antipsychotic use was associated with higher concentrations of alpha-1 adrenoreceptors
Prazosin as a potential alternative
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Used for hypertension and benign prostatic hypertrophy
Alpha-1 adrenoreceptor antagonist Vasodilation in the periphery But also crosses the blood brain barrier Relatively benign side effect profile
◦ No extrapyramidal symptoms◦ Non-sedating
Prazosin as a potential alternative
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Pilot study Double-blind, placebo-controlled, parallel
group design Outcome: Change in neuropsychiatric
symptoms after administration of prazosin versus placebo in individuals with agitation and aggression in AD
Study design
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Possible or probably Alzheimer’s disease Agitated behaviors at least twice a week for
two weeks “Moderate” on at least one of the following
Brief Psychiatric Rating Scale items:◦ anxiety ◦ tension ◦ hostility ◦ uncooperativity ◦ excitement
Study participants
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Randomized to prazosin or placebo Flexible dose titration:
◦ 1mg qhs x 1 day◦ 2mg qhs x 3-7 days◦ 2mg bid x 3-7 days◦ 2mg qam, 4mg qhs
Doses are increased if patients were not improved and did not have adverse effects
Study Procedure
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33 participants screened 24 enrolled – 12 randomized to placebo, 12
randomized to prazosin (1-6 mg/day) 1 participant in each arm discontinued
during study medication titration (hypotension)
11 participants in each arm included in analysis
Results – study participants
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Results – Change in NPI scores
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Results - CGIC
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Results – Blood Pressure
Baseline Change from baseline
p-value*
SBP
Prazosin 134 15 -2 18 0.5
Placebo 127 15 1 19
DBP
Prazosin 74 12 0 8 0.8
Placebo 73 11 0 8
*linear mixed effects model
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Results – Adverse effects
Prazosin Placebo Both groups combined
Sedation 3 3 6
Confusion 2 4 5
Hypotension 2 1 3
Dizziness on Standing
1 0 1
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Larger trial in progress 2 phases
◦ 12 week double-blind placebo controlled◦ 12 week open-label extension
Higher prazosin dose Explore NPI subitems Salivary amylase
Future directions
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Actigraphy as a measure of response
Pre-prazosin
Post-prazosin
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Characteristics
Pre-prazosin Post-prazosin Percent decrease
NPI Mean Activity Count/min
NPI Mean Activity Count/min
NPI Mean Activity Count/min
Female, age 95Nursing home residentMMSE 9
35 84.97 9 71.33 74%
16%
Male, age 59Community dwellingMMSE 6
37 258.27 19 191.86 49%
26%
Actigraphy
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The staff make several adjustments that decrease the intensity of his symptoms. These include moving him to a quieter area, changing staff members to those he tends to get along with better, and being flexible with the timing of his care. He is evaluated for pain and other medical conditions that might contribute. However, problematic symptoms persist.
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He is already taking galantamine and memantine for his Alzheimer’s disease. He is also taking citalopram for anxiety and depressive symptoms. Prazosin is prescribed to 4mg twice a day, with careful monitoring of his blood pressure. This multi-faceted approach results in a resolution of his agitation.
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Agitation and aggression in dementia is a major contributor to patient and caregiver distress
Treatment involves an individualized approach that includes nonpharmacologic and pharmacologic methods
Current pharmacologic approaches are limited by modest efficacy and side effects
Noradrenergic system abnormalities occur in AD and may contribute to agitation and aggression
Prazosin may be a promising treatment alternative
Summary