Treating Agitation amp Aggression in Veterans with Alzheimers Disease Lucy Wang MD A 74 year old veteran with Alzheimers 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 ID: 161935
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Slide1
Prazosin: Treating Agitation & Aggression in Veterans with Alzheimer’s Disease
Lucy Wang, M.D.Slide2
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.Slide3
Alzheimer’s disease is a cognitive disorderImpairment in short term memory and other cognitive domainsProgressive courseFunctional impairmentBut, non-cognitive symptoms occurAgitation and aggression describes a set of non-cognitive symptoms common in later stages of AD
What is agitation and aggression in AD?Slide4
Examples include:Resistiveness with careVerbal and physical aggression (yelling, biting, kicking)Pressured motor hyperactivityWhat is agitation and aggression in AD?Slide5
Patient distressBehaviors can pose a threat of harm to self and othersContributes to caregiver burden - a major precipitant for institutionalizationA common psychiatric problem in nursing homes (48 to 82% prevalence)
ImpactSlide6
Address treatable contributorsPain, infection, medicationsNonpharmacologic treatments preferredPharmacologic treatments if nonpharmacologic approaches are not sufficient
Current Approach to TreatmentSlide7
Atypical antipsychotics are a common pharmacologic treatment choiceAtypicals have evidence-based support for modest efficacyBut side effects limit useSedationExtrapyramidal side effectsAnd…
Pharmacologic treatmentsSlide8
“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 warningSlide9
Other pharmacologic agents have promise but have limited evidence in the literatureCholinesterase inhibitors and memantineMay be helpful for milder symptomsConflicting evidence for SSRI’s and anticonvulsants
Other pharmacologic optionsSlide10
Noradrenergic neuronal loss occurs in ADNorepinephrine (NE) and its metabolites in the CSF are increasedNE biosynthesis is upregulatedThere is an increase in alpha-1 receptor number
Prazosin
as a potential alternativeSlide11
This alteration in the noradrenergic system may contribute to agitated behaviorsIn an clinical study, administration of yohimbine (which stimulates noradrenergic outflow) led to agitation in AD patientsIn 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 alternativeSlide12
Used for hypertension and benign prostatic hypertrophyAlpha-1 adrenoreceptor antagonistVasodilation in the peripheryBut also crosses the blood brain barrierRelatively benign side effect profileNo extrapyramidal symptomsNon-sedating
Prazosin
as a potential alternativeSlide13
Pilot studyDouble-blind, placebo-controlled, parallel group designOutcome: Change in neuropsychiatric symptoms after administration of prazosin versus placebo in individuals with agitation and aggression in AD
Study designSlide14
Possible or probably Alzheimer’s diseaseAgitated 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 participantsSlide15
Randomized to prazosin or placeboFlexible dose titration:1mg qhs x 1 day2mg qhs x 3-7 days2mg bid x 3-7 days2mg qam, 4mg qhsDoses are increased if patients were not improved and did not have adverse effects
Study ProcedureSlide16
33 participants screened24 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 participantsSlide17
Results – Change in NPI scoresSlide18
Results - CGICSlide19
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 modelSlide20
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
1Slide21
Larger trial in progress2 phases12 week double-blind placebo controlled12 week open-label extensionHigher prazosin doseExplore NPI subitemsSalivary amylase
Future directionsSlide22
Actigraphy as a measure of response
Pre-
prazosin
Post-
prazosinSlide23
Characteristics
Pre-prazosin
Post-prazosin
Percent decrease
NPI
Mean Activity Count/min
NPI
Mean Activity Count/min
NPI
Mean Activity Count/min
Female, age 95
Nursing home resident
MMSE 9
35
84.97
9
71.33
74%
16%
Male, age 59
Community dwelling
MMSE 6
37
258.27
19
191.86
49%
26%
ActigraphySlide24
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.Slide25
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.Slide26
Agitation and aggression in dementia is a major contributor to patient and caregiver distressTreatment 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