prazosin : treating agitation & aggression in veterans with alzheimer’s disease

Prazosin: Treating Agitation & Aggression in Veterans with

Alzheimer’s Disease

Lucy Wang, M.D.

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.

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?

Examples include:◦ Resistiveness with care◦ Verbal and physical aggression (yelling, biting,

kicking)◦ Pressured motor hyperactivity

What is agitation and aggression in AD?

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

Address treatable contributors◦ Pain, infection, medications

Nonpharmacologic treatments preferred Pharmacologic treatments if

nonpharmacologic approaches are not sufficient

Current Approach to Treatment

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

“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

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

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

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

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

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

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

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

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

Results – Change in NPI scores

Results - CGIC

Results – Blood PressureBaseline Change

from baseline

p-value*

SBP Prazosin 134 15 -2 18 0.5 Placebo 127 15 1 19DBP Prazosin 74 12 0 8 0.8 Placebo 73 11 0 8

*linear mixed effects model

Results – Adverse effectsPrazosin Placebo Both groups

combined

Sedation 3 3 6

Confusion 2 4 5

Hypotension 2 1 3

Dizziness on Standing

1 0 1

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

Actigraphy as a measure of response

Pre-prazosin

Post-prazosin

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

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.

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.

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