Transcript Agitation And Aggression

Agitation and Aggression in
Dementia
Anton P. Porsteinsson MD
William B. and Sheila Konar Professor
Department of Psychiatry
University of Rochester
School of Medicine & Dentistry
Dr. Porsteinsson reports receipt of a grant to his
institution from AstraZeneca, Avanir, Baxter, BMS, Eisai,
Elan, Eli Lilly, Forum, Genentech/Roche, Janssen Alzheimer
Initiative, Merck, Medivation, Pfizer, Toyama, the National
Institutes of Health (NIH), the National Institute of
Mental Health (NIMH), The National Institute on
Aging (NIA), and the Department of Defense; paid
consultancy for Elan, Janssen Alzheimer Initiative,
Pfizer, and TransTech Pharma; membership on data
safety and monitoring boards for Quintiles,
Functional Neuromodulation, and the New York
State Psychiatric Institute; participation on a speaker’s
bureau for Forest; and development of educational
presentations for CME Inc., PRI, and Albert Einstein
University.
The Common View of Dementia
The Caregiver’s View of
Dementia
NPS are UNIVERSAL in dementia
Cache County
Steinberg et al, Int J Ger Psychiatry, 2008
NPS are“bad”for patients & caregivers
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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, under review
Etiologic model for agitation:
circuit disruption
Affective
-labile
-anxious
-irritable
Agitation
phenotype
Affective
Circuitry
Both +
Executive
-disorganized
-disinhibited
-overactive
Executive
Circuitry
AD brain
disease
Regional
effects
Hierarchical approach to NPS groups
Affective disturbance
Dementia-Associated Affective
Disorder, depressive
Dementia-Associated
Affective Disorder, agitated
Psychotic disturbance
Sleep disturbance Apathetic syndrome
Executive dysfunction
Epidemiology of NPS -1' Prevalence:
– Up to 95% pts at some point during course of dementia
– 43-59% with MCI
Lyketsos et al. Am J Psychiatry 2000; Lyketsos et al. JAMA 2002;
Feldman et al. Neurology 2004; Aalten et al. Int J Geriatr Psychiatry 2005
Epidemiology of NPS -2' Most common sxs in DEMENTIA
– Apathy (27-36%)
– Depression (24-32%)
– Agitation/aggression (24-30%)
' Most common sxs in MCI
– Depression (20%)
– Apathy (15%)
– Irritability (15%)
Lyketsos et al. Am J Psychiatry 2000; Lyketsos et al. JAMA 2002
NPS Characteristics
• Often see multiple sxs simultaneously (>40%)
• Often intermittent/fluctuating NPS that persist
over time
– Approx 65% with sxs over 2 y
– Associated with dementia stage (mild,
mod, severe)
– Longer: apathy, aberrant motor, agitation
– Shorter: hallucinations, euphoria,
disinhibition
Lyketsos et al. JAMA 2002; Aalten et al. Int J Geriatr Psychiatry 2005;
Lyketsos et al. Int J Geriatr Psychiatry 2001;
Tun et al. Am J Geriatr Psychiatry 2007
Agitation
' Often stage-specific for AD
' Characterized by:
– Verbal/physical aggression
– Repetitive/hyperactive talk, vocalizations, behaviors
– Disinhibition or inappropriate talk or actions
' Higher risk of disability, distress, injury and
nursing home placement
Lyketsos et al., Am J Psychiatry 2000; Lyketsos et al., JAMA 2002;
Phillips et al., JAGS 2003
Evaluation of NPS -1' Routine surveillance
' ABC’s (Antecedants – Behavior –
Consequences)
' Behavioral/Environmental Modifications
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Define behaviors and symptoms
Remove offending triggers
Calm reassurance or distraction
Address unmet needs, what could make one feel better?
Positive reinforcement
Evaluation of NPS -2' Establish/Revisit Medical Diagnoses
' Establish/Revisit Psychiatric Diagnoses
' Evaluate for offending or change in
medications
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Anticholinergic
Sedative/hypnotics
Drug withdrawal?
Drug interactions?
' Consider pain, sensory impairments
' Work-up Delirium
NPS Rx options disappointing
' Non-pharmacologic promising but unproven,
costly, hard to implement
' Many pharmacologic treatments have failed
or raised serious safety concerns
' Drug classes assessed:
– Antipsychotics, SSRI antidepressants, anticonvulsants,
benzodiazepines
Antipsychotics for psychosis or agitation
' Meta-analysis of typical antipsychotics to treat psychosis
and agitation1
– Modest effects, significant side effects
' Moderate dose haloperidol (1-2mg) for delusions and
hallucinations reduces these symptoms by 60%2
' Studies utilizing atypical antipsychotics suggest modest
efficacy3,4
– Efficacy most evident with risperidone or aripiprazole4
– Higher risk of cerebrovascular incidents and mortality
1Schneider
LS et al. J Am Geriatr Soc. 1990;38:553-563.
2Devanand DP et al. Am J Psychiatry. 1998;155:1512-1520.
3Aarsland D, Ballard C. Clin Neurosci Res. 2004;3:397-412.
4Schneider LS et al. Am J Ger Psychiatry. 2006 14:191-210
Cerebrovascular Adverse Events:
Updated Pooled Analyses of Dementia RCTs
Sample Size
CVAEs
(patient years)
(D/P)
Risperidone
1009/712
33/8
Olanzapine
1175/478
15/2
Aripiprazole
598/340
Quetiapine
355/213
Ziprasidone
Exposure
RR (95% CI)
(D/P)
171.8/118.9
2.85 (1.29–7.15)
336.7/134.2
2.99 (0.7–26.9)
8/2
95.2/54.1
2.27 (0.45–22.0)
3/4
54.7/32.7
0.50 (0.11–2.33)
no available clinical trials data in dementia patients
Haloperidol
1.27 (0.30–4.20)
NB: 95% CI includes 1 for nearly all drugs studied !!
Adapted from Schneider L. AAGP; San Diego, CA; March 5, 2005
Mortality in dementia RCTs: Pooled
analyses
Relative Risk
95% CI
Olanzapine
2.31
1.00-5.35
Risperidone
1.35
0.85-2.14
Aripiprazole
1.99
0.86-4.62
Quetiapine
1.35
0.85-2.14
OVERALL
1.65
1.19-2.29
Antipsychotics have BLACK BOX warning for use in dementia
Schneider L et al JAMA, 2005
Divalproex or carbamazepine for
agitation
Tariot P 2001
Porsteinsson A
2001
Sival RC 2002
Tariot P 2005
Hermann N 2007
Tariot PN 1994
Cooney C 1996
Tariot PN 1998
Olin JT 2001
172 dementia
nursing home and
secondary mania
56 nursing home
dementia &
agitation
42 dementia
hospitalized
153 nursing home
pAD with agitation
Valproate 2030mg/kg/d
Valproate
individualized vs.
PBO
Valproate
Valproate target
750/d vs. placebo
14 AD—MMSE
Valproate
below 10
25 nursing home Carbamazepine
dementia
modal 300mg/d
vs. PBO
6 AD outpatients Carbamazepine
up to 600mg/d
vs. PBO
51 nursing home Carbamazepine
dementia
vs. PBO
Carbamazepine
21 AD failed
antipsychotics
BRMS
CMAI
CGI
BPRS-agitation
6 weeks
DVS=PBO
6 weeks
DVS>PBO ?
SADS-9 target
aggression
BPRS
CMAI
3 weeks
DVS=PBO
6 weeks
DVS=PBO
NPI
CMAI
BPRS
CGIC
6 weeks
DVS<PBO
5+5 weeks
CRB>PBO
RAGEaggression
8 weeks
CRB>PBO
BPRS
CGIC
CGIC
BPRS
6 weeks
CRB>PBO
6 weeks
CRB>PBO
Antidepressants for agitation
(placebo
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
controlled)
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
Antidepressants for agitation
(active comparator)
Sultzer DL 1997
28 dementia
Trazodone vs.
haloperidol
Agitation
9 weeks
TRA=HAL
Gaber S 2001
23 nursing
home dementia
and agitation
Sertraline vs.
haloperidol
CMAI
10 weeks
SER=HAL
Pollock B 2007
103
hospitalized,
moderate+ NPS
Citalopram vs.
risperidone
Neurobehavior
Rating Scale
(NBRS)
12 weeks
CIT=RIS in
efficacy but
CIT>RIS in
tolerability
CitAD Study – Importance
' Agitation is common, persistent and
associated with adverse consequences for
patients with AD.
' Pharmacological treatment options are not
satisfactory
' CitAD study evaluated the efficacy and safety
of citalopram for agitation in patients with AD
without depression.
CitAD Study - Design
' Randomized, placebo-controlled, doubleblind, parallel group 9 week trial
' All participants received psychosocial
intervention
' Participants assigned to citalopram (target
dose of 30 mg/d) or placebo in 1:1 ratio
' Primary objective was evaluating efficacy of
citalopram for agitation in patients with AD
' Secondary objectives examined effects on
function, caregiver distress, safety, cognitive
safety, and tolerability
CitAD Study – outcome measures
' Primary – NBRS-A and mADCS-CGIC
' Secondary – NPI total; NPI individual
domains; NPI-CD; CMAI; ADCS-ADL;
cumulative lorazepam rescue dose
' Secondary safety – MMSE; GUG; AEs
assessed through checklist and open ended
questions; ECG added.
CitAD Study – results
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N = 186 (cit=94 and pla=92)
Age = 78
Women = 46%
Caucasian = 65%
Community dwelling 89%
AchEI use in 69%, memantine use in 42%
MMSE = 15.7 (cit=17.0 and pla=14.4)
NPI total 37.3
At week 9, 78% on 30 mg/d and 15% on 20 mg/d
No between-group difference in adherence (80%
remained on treatment) and >90% completion rates
CitAD Study – results
' Citalopram showed significant improvement
over placebo on both primary outcome
measures (NBRS-A and mADCS-CGIC) and on
the secondary outcome measures of CMAI,
NPI total, NPI-CD but not on NPI-A, ADCSADL or rescue lorazepam
' Anorexia, diarrhea, URTI, fever and falls were
more common with citalopram while weight
loss and insomnia were more common on
placebo. Worsening of cognition was seen it
cit group.
Citalopram – FDA warning
' Dose dependent risk of QT prolongation
' Due to post-marketing reports and unpublished FDA
study
' 119 healthy, non-depressed 19–45 year olds
' QTc prolongation:
– 8.5 msec for 20 mg/d
– 18.5 msec for 60 mg/d
' Recc daily maximum dose of 40 mg/d in adults and
20 mg/d in >60 y.o.
' Avoid use in congenital long QT syndrome,
bradycardia, hypokalemia, hypomagnesemia, recent
MI or uncompensated CHF
QTc changes BL-wk3
Summary
' Mean QTc at enrollment was similar to other
studies of older adults
' Compared to placebo, citalopram was
associated with 18.1 msec lengthening of QTc
' This increase is higher than anticipated based
on the FDA safety communication
' The increase was close to FDA guidance of
proarrythmic properties (20 msec)
' Our findings support the FDA warning against
use of citalopram >20 mg in patients over 60
years of age
DM/Q
Sequential Parallel Comparison Design
DM/Q
Safety and Tolerability
DM/Q
DM/Q
Scyllo-inositol