Agitation and Aggression in Dementia Anton P. Porsteinsson MD William B. and Sheila Konar Professor...
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Agitation and Aggression in Dementia Anton P. Porsteinsson MD William B. and Sheila Konar Professor Department of Psychiatry University of Rochester School
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
Slide 2
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 speakers bureau for
Forest; and development of educational presentations for CME Inc.,
PRI, and Albert Einstein University.
Slide 3
The Common View of Dementia
Slide 4
The Caregivers View of Dementia
Slide 5
NPS are UNIVERSAL in dementia Cache County Steinberg et al, Int
J Ger Psychiatry, 2008
Slide 6
NPS arebadfor patients & caregivers 'Greater ADL impairment
1 'Worse quality of life 2 'Earlier institutionalization 3 'Major
source of caregiver burden 4 '$10,000/year additional care costs 5
'Shorter time to severe dementia 6 'Accelerated mortality 6 1
Lyketsos et al, 1997; 2 Gonzales-Salvador et al, 1999; 3 Steele et
al, 1990; 4 Lyketsos et al, 1999; 5 Murman et al, 2002; Peters et
al, under review
Slide 7
NPS severe dementia Cache County Rabins et al, Alzheimers and
Dementia, 2012 Steinberg et al, Poster, AAIC 2012
Slide 8
Provisional research diagnostic criteria for Agitation with
cognitive impairment (IPA, 2014) A. Patient meets criteria for a
cognitive impairment or dementia syndrome (e.g., Alzheimers
dementia, frontotemporal dementia, dementia with Lewy bodies,
vascular dementia, other dementia, a pre-dementia cognitive
impairment syndrome such as mild cognitive impairment [MCI], or
other cognitive disorder) B. Patient exhibits at least one of the
following behaviors which are associated with observed or inferred
evidence of emotional distress (e.g., rapid changes in mood,
irritability, outbursts). The behavior has been sustained or
persistent for a minimum of two weeks duration and represents a
change from the persons usual behavior. Excessive motor activity
(examples include: pacing, rocking, gesticulating, pointing
fingers, restlessness, performing repetitious mannerisms) Verbal
aggression (e.g., yelling, speaking in an excessively loud voice,
using profanity, screaming, shouting) Physical aggression (e.g.,
grabbing, shoving, pushing, resisting, hitting others, kicking
objects or people, scratching, biting, throwing objects, hitting
self, slamming doors, tearing things and destroying property) ' C.
Behaviors are severe enough to produce excess disability which in
the clinicians opinion is beyond that due to the cognitive
impairment alone including at least one of the following:
Significant impairment in interpersonal relationships Significant
impairment in other aspects of social functioning Significant
impairment in ability to perform or participate in daily living
activities D. While co-morbid conditions may be present, the
agitation is not attributable solely to another psychiatric
disorder, medical condition, or the physiological effects of a
substance Cummings et al, International Psychogeriatrics 2015
Slide 9
Slide 10
Etiologic model for agitation: circuit disruption Agitation
phenotype Affective -labile -anxious -irritable Executive
-disorganized -disinhibited -overactive AD brain disease Regional
effects Affective Circuitry Executive Circuitry Both +
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
Slide 13
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
Slide 14
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
Slide 15
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
Slide 16
Evaluation of NPS -1- 'Routine surveillance 'ABCs (Antecedants
Behavior Consequences) 'Behavioral/Environmental Modifications
Define behaviors and symptoms Remove offending triggers Calm
reassurance or distraction Address unmet needs, what could make one
feel better? Positive reinforcement
Slide 17
Evaluation of NPS -2- 'Establish/Revisit Medical Diagnoses
'Establish/Revisit Psychiatric Diagnoses 'Evaluate for offending or
change in medications Anticholinergic Sedative/hypnotics Drug
withdrawal? Drug interactions? 'Consider pain, sensory impairments
'Work-up Delirium
Slide 18
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
Slide 19
Antipsychotics for psychosis or agitation 'Meta-analysis of
typical antipsychotics to treat psychosis and agitation 1 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
efficacy 3,4 Efficacy most evident with risperidone or aripiprazole
4 Higher risk of cerebrovascular incidents and mortality 1
Schneider LS et al. J Am Geriatr Soc. 1990;38:553-563. 2 Devanand
DP et al. Am J Psychiatry. 1998;155:1512-1520. 3 Aarsland D,
Ballard C. Clin Neurosci Res. 2004;3:397-412. 4 Schneider LS et al.
Am J Ger Psychiatry. 2006 14:191-210
Slide 20
The CATIE-AD Study
Slide 21
Cerebrovascular Adverse Events: Updated Pooled Analyses of
Dementia RCTs Sample Size CVAEsExposure RR (95% CI) (patient years)
(D/P) (D/P) Risperidone 1009/712 33/8171.8/118.92.85 (1.297.15)
Olanzapine 1175/478 15/2 336.7/134.22.99 (0.726.9) Aripiprazole
598/340 8/2 95.2/54.12.27 (0.4522.0) Quetiapine 355/213 3/4
54.7/32.70.50 (0.112.33) Ziprasidone no available clinical trials
data in dementia patients Haloperidol1.27 (0.304.20) Adapted from
Schneider L. AAGP; San Diego, CA; March 5, 2005 NB: 95% CI includes
1 for nearly all drugs studied !!
Slide 22
Mortality in dementia RCTs: Pooled analyses Relative Risk 95%
CI Olanzapine2.311.00-5.35 Risperidone1.350.85-2.14
Aripiprazole1.990.86-4.62 Quetiapine1.350.85-2.14
OVERALL1.651.19-2.29 Schneider L et al JAMA, 2005 Antipsychotics
have BLACK BOX warning for use in dementia
Slide 23
Divalproex or carbamazepine for agitation Tariot P 2001172
dementia nursing home and secondary mania Valproate 20- 30mg/kg/d
BRMS CMAI CGI 6 weeksDVS=PBO Porsteinsson A 2001 56 nursing home
dementia & agitation Valproate individualized vs. PBO
BPRS-agitation6 weeksDVS>PBO ? Sival RC 200242 dementia
hospitalized ValproateSADS-9 target aggression 3 weeksDVS=PBO
Tariot P 2005153 nursing home pAD with agitation Valproate target
750/d vs. placebo BPRS CMAI 6 weeksDVS=PBO Hermann N 200714 ADMMSE
below 10 ValproateNPI CMAI 6 weeksDVSPBO Cooney C 19966 AD
outpatientsCarbamazepine up to 600mg/d vs. PBO RAGE- aggression 8
weeksCRB>PBO Tariot PN 199851 nursing home dementia
Carbamazepine vs. PBO BPRS CGIC 6 weeksCRB>PBO Olin JT 200121 AD
failed antipsychotics CarbamazepineCGIC BPRS 6 weeksCRB>PBO
Slide 24
Antidepressants for agitation ( placebo controlled ) Lawlor BA
199410 AD with agitation Trazodone vs. Buspirone vs. PBO BPRS DMAS
12 weeksTRA>PBO Auchus AP 199715 AD outpatients Fluoxetine vs.
Haloperidol vs. PBO Agitation4 weeksFLU=PBO Teri L 2001149 AD
agitation Haloperidol vs. trazodone, vs. behavior mgmt vs. PBO
ADCS-CGIC16 weeksTRA=PBO Lanctot K 200222 non- depressed AD w/
behavioral disturbance Sertraline 100mg/d vs. PBO NPI4 weeksSER=PBO
Pollock BG 200285 hospital dementia Citalopram vs. perphenezine vs.
PBO NBRS17 daysCIT>PBO Finkel SI 200424 pAD outpatients
Sertraline (24) vs. PBO (120) after open donepezil NPI CGI-I 8
weeks then 12 weeks SER=PBO
Slide 25
Antidepressants for agitation (active comparator) Sultzer DL
199728 dementiaTrazodone vs. haloperidol Agitation9 weeksTRA=HAL
Gaber S 200123 nursing home dementia and agitation Sertraline vs.
haloperidol CMAI10 weeksSER=HAL Pollock B 2007103 hospitalized,
moderate+ NPS Citalopram vs. risperidone Neurobehavior Rating Scale
(NBRS) 12 weeksCIT=RIS in efficacy but CIT>RIS in
tolerability
Slide 26
CITAD: a multi-center trial 1 ' Study Chair Johns Hopkins
University (Lyketsos) ' Coordinating Center Johns Hopkins Center
for Clinical Trials (Meinert) ' Clinical Centers Columbia
University (Devanand) Johns Hopkins University (Rosenberg) Medical
University of South Carolina (Mintzer) Stanford University
(Yesavage) University of Pennsylvania/VA (Weintraub) University of
Rochester (Porsteinsson) University of Southern California
(Schneider) University of Toronto (Pollock) 1 R01AG031348
Slide 27
Agitation & Aggression as Clinical Entity targeted for
treatment development 'A reasonably homogeneous patient group:
Clinical diagnosis of AD per accepted NIA-AA criteria Focus on
Moderate/Severe to increase homogeneity in underlying biology
'Clinically significant agitation/aggression (operationalized):
Accepted and widely used NPI criteria for significant severity:
NPI- agitation/aggression domain 4 'Relevance to clinical/academic
community: Antipsychotics widely used despite black box safety
warnings Alzheimer Association - NPS expert roundtable (2010)
emphasized the importance of NPS in AD and need for safe and
effective treatments Same experts endorsed utility of NPI-C for
clinical trials Formation of NPS-PIA as part of ISTAART 27
Slide 28
Support This work was supported by: 'NIA and NIMH R01AG031348
and in part by NIH P50 AG05142 'William B. and Sheila Konar Endowed
Professorship
Slide 29
Slide 30
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.
Slide 31
CitAD Study - Design 'Randomized, placebo-controlled, double-
blind, 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
Slide 32
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.
Slide 33
CitAD Study results '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
Slide 34
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, ADCS- ADL 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.
Slide 35
Citalopram FDA warning 'Dose dependent risk of QT prolongation
'Due to post-marketing reports and unpublished FDA study '119
healthy, non-depressed 1945 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
Slide 36
CitAD Study - Design 'Subjects were recruited from 09/2009
01/2013 'FDA safety communication regarding citalopram and QTc
prolongation in 08/2011 'Dose maintained at 30 mg/d 'Modifications
made to entry criteria 'ECGs were added to required study
procedures 'Magnesium added to existing electrolyte monitoring
'Patients with prolonged QTc excluded >450 msec for men >470
msec for women
Slide 37
Slide 38
CitAD Study ECG 'Initiated after 138 patients were randomized
'ECG at screening, wk 3 and first visit at 30 mg/d if on slow
titration 'Available for 48 patients (cit=24; pla=24) 'No
difference in cardiovascular burden between the two groups. 'BL QTc
cit 419 msec; pla 416 msec
Slide 39
CitAD study - ECG 'Of 24 subjects assigned to citalopram at
week 3: 16 on 30 mg/d 3 on 20 mg 2 on 10 mg 1 on 0 mg 2 missed the
week 3 visit
Slide 40
QTc changes BL-wk3
Slide 41
CitAD QT findings
Slide 42
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
Slide 43
CitAD study clinical AE 'At week 3, one patient on citalopram
developed ventricular bigeminy alongside a 48 msec lengthening of
QTc (444 msec to 492 msec) and study drug was discontinued. He was
taking one other medication known to prolong QT (alfuzosin) 'For
the full study, no cardiovascular related deaths. 'For the full
study, two cit subjects had syncope and one pla subject fell and
broke her hip.