1. Lucy Wang, M.D.

2. 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.

3.  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

4.  Examples include: ◦ Resistiveness with care ◦ Verbal and physical aggression (yelling, biting, kicking) ◦ Pressured motor hyperactivity

5.  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)

6.  Address treatable contributors ◦ Pain, infection, medications  Nonpharmacologic treatments preferred  Pharmacologic treatments if nonpharmacologic approaches are not sufficient

7.  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…

8.  “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)

9.  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

10.  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

11.  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

12.  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

13.  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

14.  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

15.  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

16.  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

19. BaselineChange from baseline p-value* SBP Prazosin134  15-2  180.5 Placebo127  151  19 DBP Prazosin74  120  80.8 Placebo73  110  8 *linear mixed effects model

20. PrazosinPlaceboBoth groups combined Sedation336 Confusion245 Hypotension213 Dizziness on Standing 101

21.  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

22. Pre- prazosin Post- prazosin

23. CharacteristicsPre-prazosinPost-prazosinPercent decrease NPIMean Activity Count/min NPIMean Activity Count/min NPIMean Activity Count/min Female, age 95 Nursing home resident MMSE 9 3584.97971.3374%16% Male, age 59 Community dwelling MMSE 6 37258.2719191.8649%26%

24. 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.

25. 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.

26.  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