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11/11/2016
Management of Agitation in Dementia
2016 Update
Relevant Disclosures
Current or past
• Grant support (research or CME)
Constantine G. Lyketsos, MD, MHS
Interim Chair of Psychiatry, Johns Hopkins Medicine
Elizabeth Plank Althouse Professor, Johns Hopkins University
[email protected]
– NIMH, NIA, Associated Jewish Federation of Baltimore,
Weinberg Foundation, Forest, Glaxo-Smith-Kline, Eisai, Pfizer,
Astra-Zeneca, Lilly, Ortho-McNeil, Bristol-Myers, Novartis,
National Football League, Elan, Functional Neuromodulation
• Payment as consultant or advisor
– Astra-Zeneca, Glaxo-Smith Kline, Eisai, Novartis, Forest,
Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly,
Pfizer, Genentech, Elan, NFL Players Association, NFL
Benefits Office, Avanir, Zinfandel, BMS, Abvie, Janssen,
Orion, Otsuka, Servier, Astellas
Wisconsin Alzheimer’s Institute
14th Annual Update
18 November 2016
• Honorarium or travel support
– Pfizer, Forest, Glaxo-Smith Kline, Health Monitor
Outline
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NPS in Alzheimer disease (AD)
Focus on agitation
Treatment considerations
The pipeline
Algorithm
35.5 million people have dementia today
The number of living cases doubles every 20 years
115.3 million people with dementia by 2050—NEW CASES
11/11/2016
Alzheimer’s
Disease International
World Alzheimer’s Report, September 21, 2009
Dementia has higher societal and economic
impact than other important chronic diseases
NIH research funding lags far behind
Heart disease
Cancer
Annual ($bn)
Care
NIH
$102
$3.75
$77
$ 7.00
Dementia
$109
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Facing reality:
balancing “cure” with “care”
• Near and medium term outcome: extend the time
course of MCI and dementia higher prevalence
• We must take proper care of 100+ million
patients & caregivers worldwide
$1.68
NIH Categorical Spending: http://report.nih.gov/categorical_spending.aspx#bpopup
RAND Corp.: N Engl J Med 2013; 368:1326-1334April 4, 2013DOI: 10.1056/NEJMsa1204629.
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“There exists currently an effective, systematic care &
treatment model for patients with dementia…” (2006)
Potentially modifiable factors
•
•
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•
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Medical co-morbidity
FDA approved meds
Neuropsychiatric symptoms
Judicious use of psychotropic medications
Early activities, especially mental
Caregiver closeness, coping style
The common view of dementia
The real view of dementia
Cumulative prevalence of NPS = 98%
NPS fluctuate after dementia onset
Cache County Dementia Progression Study
Cache County Dementia Progression Study
Percentage
Five-year period prevalence of NPI sym ptom s (NPI>0)
100
90
80
70
60
50
40
30
20
10
0
NPI total
Aberrant Motor
Behavior
4.1 years=61
Irritability/Lability
3.0 years=106
Disinhibition
Anxiety
1.5 years=236
Elation/Euphoria
Apathy/Indifference
Depression/Dysphoria
Agitation/Aggression
Hallucinations
Delusions
baseline=408
Steinberg et al, Int J Ger Psychiatry 2008
5.3 years=36
Tschanz et al, Am J Geriatr Psychiatry 2012
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NPS are “bad” for patients & caregivers
NPS and onset of severe dementia
Cache County Dementia Progression Study
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Greater ADL impairment1
Worse quality of life2
Earlier institutionalization3
Major source of caregiver burden4
$10,000/year additional care costs5
Shorter time to severe dementia6
Accelerated mortality6
1Lyketsos
et al, 1997; 2Gonzales-Salvador et al, 1999; 3Steele et al, 1990;
4Lyketsos
et al, 1999; 5 Murman et al, 2002; Peters et al, 2015
Etiologies of NPS
Rabins et al, Alzheimer’s & Dementia 2012
How do we develop Rx targets for NPS?
more efficient and less toxic medications
• Based on phenomenology
– Individual symptoms
– Using DSM-IV categories
– Empirically
• By cause
Kales Gitlin Lyketsos British Medical Journal 2015
Empirical classification
Groups of disturbance (selected examples)
• Ballard et al, Acta Psychiatr Scand 1995
– Agitation (aggression, restlessness); Psychosis
• Hope at al, IJGP 1997
– Overactivity: trailing caregiver, wandering; Aggressive
behavior; Psychosis: hallucinations, delusions
• Lyketsos et al, IJGP 2001
– Affective syndrome (depressive or agitated);
Psychotic syndrome; Mono-symptomatic
• Aalten et al, IPG 2005
– Depressive; Psychotic; Overactive-agitated
Target NPS in Dementia
Accepted by regulators
• Agitation
• Psychosis
Proposed to regulators
• Depression
• Apathy
• Sleep disorders
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Agitation phenotype
Rx options are disappointing
few with proven efficacy—significant risks
• Emotional agitation: distress, upheaval, anger,
tension, anxiety, worry, inability to relax
• Lability: rapid changes in mood, irritability,
unexpected outbursts, overreacting, catastrophizing
• Psychomotor agitation: pacing, rocking,
gesticulating, pointing fingers, restless
• Verbal aggression: yelling, excessively loud voice,
screaming, uses profanity, threatens, "in your face"
• Physical aggression: grabs, shoves, pushes, resists,
hits, kicks, gets in the way
Meta-analysis of 23 RCTs
supporting family caregivers
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Outcomes: NPS and caregiver well-being
Significant treatment effect, effect size=0.34
Variation in dose, intensity and delivery mode
Key features of successful trials
– 9-12 sessions; tailoring to patient and caregiver;
delivered in the home; multiple components
• No adverse effects for any of the trials
Brodaty et al, Am J Psychiatry 2012
• Non-pharmacologic: very few data
– Custom Activity Program (CAP) trial at Hopkins
• Pharmacologic: none approved in US
– FDA approved AD meds (cholinesterase
inhibitors; memantine): weak benefit
– Antipsychotics: widely used, black box warning
– Anticonvulsants: ineffective risky
– Benzodiazepines: ineffective, risky
– Antidepressants: ineffective EXC. CITALOPRAM
Non-pharmacologic: behavioral,
environmental, & caregiver interventions
Numerous expert bodies recommend first-line, but
has largely NOT been translated to real-world care
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Lack of provider training
Lack of reimbursement
Lack of guidelines
Perceived lack of efficacy
Heterogeneity of interventions
Molinari et al, 2010; Cohen-Mansfield et al, 2013
Antipsychotics for agitation: small benefit
The CATIE-AD
Study
Antipsychotics
for agitation
Antipsychotics carry BLACK BOX warning
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Aripiprazole
Olanzapine
AHRQ
Comparative
Effectiveness
Review
2011
Quetiapine
Risperidone
Effect Size
(SMD) = 0.20
Citalopram for Agitation in Alzheimer’s Disease
(CitAD)
Training Meeting 10/11Jun09 – Baltimore, MD
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Antidepressants for agitation or NPS
VA antipsychotic studies
(placebo controlled)
Kales et al, AJP 2007
Kales et al, AJP 2013
Both conventional and atypical antipsychotics associated
with significantly higher 12-month mortality than other
psychotropics. Haloperidol is one of the largest “offenders.”
Trazodone vs.
Buspirone vs.
PBO
Fluoxetine vs.
Haloperidol vs.
PBO
BPRS
DMAS
12 weeks
TRA>PBO
Agitation
4 weeks
FLU=PBO
149 AD
agitation
Haloperidol vs.
trazodone, vs.
behavior mgmt
vs. PBO
ADCS-CGIC
16 weeks
TRA=PBO
22 nondepressed AD
w/ behavioral
disturbance
85 hospital
dementia
Sertraline
100mg/d vs.
PBO
NPI
4 weeks
SER=PBO
Citalopram vs.
perphenezine
vs. PBO
NBRS
17 days
CIT>PBO
24 pAD
outpatients
Sertraline (24)
vs. PBO (120)
after open
donepezil
NPI
CGI-I
8 weeks then 12 SER=PBO
weeks
Lawlor BA 1994
10 AD with
agitation
Auchus AP 1997
15 AD
outpatients
Teri L 2001
Lanctot K 2002
Pollock BG 2002
Finkel SI 2004
Preliminary study
Divalproex for agitation
Tariot P 2001
172 dementia
nursing home and
secondary mania
Valproate 2030mg/kg/d
BRMS
CMAI
CGI
6 weeks
DVS=PBO
Porsteinsson A
2001
56 nursing home
dementia &
agitation
Valproate
individualized vs.
PBO
BPRS-agitation
6 weeks
DVS>PBO ?
Sival RC 2002
42 dementia
hospitalized
Valproate
SADS-9 target
aggression
3 weeks
DVS=PBO
Tariot P 2005
153 nursing home
pAD with agitation
Valproate target
750/d vs. placebo
BPRS
CMAI
6 weeks
DVS=PBO
Hermann N 2007
14 AD—MMSE
below 10
Valproate
NPI agitationaggression
CMAI
6 weeks
DVS<PBO
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Main finding
Citalopram for Agitation in Alzheimer’s Disease
(CitAD)
Training Meeting 10/11Jun09 – Baltimore, MD
A Double-Blind Comparison of Citalopram and Risperidone
for the Treatment of Psychotic Symptoms Associated with
Dementia (n = 103)
12
Citalopram
Risperidone
Observed NBRS Score
10
8
6
4
2
N ( ): 53
0
51
N ( ): 50
44
0
2
39
34
30
31
28
23
4
28
29
22
6
24
8
10
12
Week
29
Citalopram for Agitation in Alzheimer’s Disease
(CitAD)
Training Meeting 10/11Jun09 – Baltimore, MD
Pollock BG et al. Am J Geri Psych 15 (11): 942-952, 2007
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CitAD (N=186): focus on “big effect”
citalopram 40% v. placebo 26%
Big benefit: 26% placebo 40% citalopram
Porsteinsson et al, JAMA 2014
R01AG031348; PI: Lyketsos
Placebo response (28%) by week 3
Citalopram (40%) response 9+ weeks
Benefit to “psychotic” symptoms
Table 2 Neuropsychiatric Inventory (NPI) domains at week 9
All participants*
Placebo
Citalopram
Number with week 9 NPI data
n†
86
(%)
n†
83
(%)
Participants reporting symptom**
Citalopram
Placebo
OR* (95% CI)
p-value
Median (IQR)**
Median (IQR)** p-value
Individual domains
Delusions
Hallucinations
Agitation/aggression
Depression/dysphoria
Anxiety
Elation/euphoria
Apathy/indifference
Disinhibition
Irritability/lability
Aberrant motor behavior
Sleep and nighttime behavior
Appetite and eating disorders
22
11
66
24
36
3
41
27
49
34
21
22
(26 %)
(13 %)
(77 %)
(28 %)
(42 %)
(3 %)
(48 %)
(31 %)
(57 %)
(40 %)
(24 %)
(26 %)
35
13
70
30
54
5
42
34
61
47
30
18
(42 %)
(16 %)
(84 %)
(36 %)
(65 %)
(6 %)
(51 %)
(41 %)
(73 %)
(57 %)
(36 %)
(22 %)
0.40 (0.18, 0.91)
1.53 (0.50, 4.71)
0.63 (0.28, 1.41)
0.69 (0.34, 1.39)
0.43 (0.22, 0.84)
0.45 (0.09, 2.21)
0.92 (0.47, 1.80)
0.71 (0.35, 1.46)
0.38 (0.19, 0.76)
0.49 (0.24, 0.99)
0.56 (0.27, 1.16)
1.32 (0.62, 2.82)
0.03
0.46
0.26
0.30
0.01
0.32
0.82
0.35
0.01
0.05
0.12
0.47
4 (2, 8)
1 (1, 3)
3 (2, 8)
3 (1, 6)
4 (2.5, 8)
1 (1, 8)
4 (3, 8)
4 (2, 8)
4 (2, 6)
4 (3, 8)
4 (3, 12)
4 (4, 8)
4 (3, 8)
6 (4, 6)
6 (3, 8)
3 (2, 6)
4 (3, 6)
3 (2, 6)
6 (4, 8)
4 (2, 6)
6 (3, 8)
4 (3, 8)
3 (2, 6)
4 (3, 8)
0.46
<0.01
0.05
0.35
0.78
0.55
0.36
0.73
0.13
0.96
0.03
0.84
78
72
28
(91%)
(84%)
(33%)
79
78
37
(95%)
(94%)
(45%)
††0.48 (0.10, 2.00)
0.33 (0.11, 1.03)
0.67 (0.31, 1.44)
0.41
0.06
0.30
8.5 (5, 17)
7 (4, 14.5)
4 (2, 6)
14 (8, 24)
12 (6, 20)
6 (4, 9)
<0.01
0.04
0.02
Summary scores
Non-mood score
Affective score
Psychotic score
Leonpacher et al, Am J Psychiatry 2016
Weintraub et al, Am J Geriatric Psych 2015
CitAD: adverse events
QTc Prolongation
• Anorexia, diarrhea, fever more
common on citalopram (p<0.05)
• MMSE decline of 1pt on
citalopram (P<0.05)
• QTc prolongation on citalopram
Porsteinsson et al, JAMA 2014
Drye et al, PLOS ONE 2014
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Response limited to a subgroup
Response probability
J Clinical Pharmacology, in press
Response depends on
Affective vs. Executive phenotype
What’s next? S-CitAD
test the “Affective Agitation” hypothesis
N=589
Charu et al, under review
R01AG052510; PI: Lyketsos
Novel medications for agitation
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Dextromethorphan (Avanir)
Prazosin (ADCS)
Dronabinol (AbbVie)
Brexpiprazole (Otsuka/Lundbeck)
• Scyllo-inositol (Transition)
• PF-05212377 (SAM-760) (Pfizer)
• ORM-12741 (Orion/Janssen)
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Published in final edited form as:
Am J Geriatr Psychiatry. 2009 September ; 17(9): 744–751. doi:10.1097/JGP.0b013e3181ab8c61.
PRAZOSIN FOR THE TREATMENT OF BEHAVIORAL SYMPTOMS
IN ALZHEIMER’S DISEASE PATIENTS WITH AGITATION AND
AGGRESSION
Lucy Y. Wang, MD1,2,*, Jane B. Shofer, MS2, Kirsten Rohde, RN1, Kim L. Hart, PA-C1, David
J. Hoff, PA-C1, Yun H. McFall, RPh 1, Murray A. Raskind, MD 1,2, and Elaine R. Peskind,
MD1,2
1VA
Northwest Network Mental Illness Research, Education, and Clinical Center (MIRECC)
2Alzheimer’s
Disease Research Center and Department of Psychiatry and Behavioral Sciences,
University of Washington School of Medicine, Seattle, WA
Abstract
Objectives—Agitation and aggression in Alzheimer’s disease (AD) is a major cause of patient
distress, caregiver burden, and institutionalization. Enhanced behavioral responsiveness to central
nervous system norepinephrine release may contribute to the pathophysiology of agitation and
aggression in AD. Prazosin, a nonsedating generic medication used for hypertension and benign
prostatic hypertrophy, antagonizes norepinephrine effects at brain postsynaptic alpha-1
adrenoreceptors. This pilot study examined the efficacy and tolerability of prazosin for behavioral
symptoms in patients with agitation and aggression in AD.
Design—Double-blind, placebo controlled, parallel group study.
Setting—A university AD center and a nursing home in Seattle.
Participants—Twenty-two nursing home and community dwelling participants with agitation and
aggression and probable or possible AD (mean age 80.6 ± 11.2).
Intervention—Randomization to placebo (n=11) or prazosin (n=11). Medication was initiated at
1mg/day and increased up to 6mg/day using a flexible dosing algorithm.
Measurements—The Brief Psychiatric Rating Scale (BPRS) and Neuropsychiatric Inventory
(NPI) at weeks 1, 2, 4, 6, and 8. The Clinical Global Impression of Change (CGIC) at week 8.
Results—Participants taking prazosin (mean dose 5.7 ± 0.9mg/day) had greater improvements than
those taking placebo (mean dose 5.6 ± 1.2mg/day) on the NPI (mean change -19 ± 21 versus -2 ±
15, X2=6.32, df=1, p=0.012) and BPRS (mean change -9 ± 9 versus -3 ± 5, X2=4.42, df=1, p=0.036)
based on linear mixed effects models, and the CGIC (mean 2.6 ± 1.0 versus 4.5 ± 1.6, Z=2.57, p=0.011
[Mann-Whitney test]). Adverse effects and blood pressure changes were similar between prazosin
and placebo groups.
Conclusion—Prazosin was well tolerated and improved behavioral symptoms in patients with
agitation and aggression in AD.
*Corresponding author: Lucy Y. Wang MD, VA Northwest Network Mental Illness Research, Education, and Clinical Center (MIRECC),
1660 S. Columbian Way, S-116-6E, Seattle, WA 98115, Tel: 206-277-5089, Fax: 206-277-4856, [email protected].
No disclosures to report.
This research was presented in part as a poster at the 11 th International Conference on Alzheimer’s Disease and Related Disorders,
Chicago, Illinois, July 2008.
Combining DICE with
pharmacologic interventions
Kales, Gitlin, Lyketsos, JAGS 2014
Facing reality:
balancing “cure” with “care”
• Near and medium term outcome: extend the time
course of MCI and dementia higher prevalence
• We must take proper care of 100+ million
patients & caregivers worldwide
Potentially modifiable factors
•
•
•
•
•
•
Medical co-morbidity
FDA approved meds
Neuropsychiatric symptoms
Judicious use of psychotropic medications
Early activities, especially mental
Caregiver closeness, coping style
8
11/11/2016
Thank you!

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