Behavioral Decompensation in Alzheimer

1
Behavioral Decompensation in Alzheimers
DiseaseA Systematic and Multimodal Approach to
Patient Management
2
Case Study

• 81 y/o veteran longtime smoker w/ COPD, dx AD x 2
  yrs, recently dx w/ inoperable lung CA sent
  from NH for control of combative behavior and
  hospice consultation pt lost 20 over past
  month, anorexic, largely unresponsive.
• Rx includes 1,500mg divalproex, risperidone 0.5mg
  qAM, 1mg qHS, recent addition of haloperidol
  0.5mg IM TID to allow for care administration

3
Peak Frequency ofBehavioral Symptoms as AD
Progresses
100
80
Agitation
DiurnalRhythm
60
Irritability
Depression
Frequency ( of Patients)
Wandering
SocialWithdrawal
Aggression
40
MoodChange
SociallyUnacc.
Anxiety
Hallucinations
Paranoia
20
Delusions
SuicidalIdeation
Accusatory
Sexually Inappropriate
0
-40 -30 -20 -10 0
10 20 30
Months Before/After Diagnosis
Jost BC, Grossberg GT. J Am Geriatr Soc. 1996
441078-1081
4
Keys To Evaluation Of BehavioralProblems In
Dementia

• Identify the problem behavior (WHAT)
• Timing / frequency of the behavior (WHEN)
• Surroundings / environment (WHERE)
• Others involved? (WITH WHOM)
• Very troubling / dangerous?
• Evaluation physical cognitive status
• Recommendations

Gray KF. Clin Geriatr Med. 2004(Feb)20(1)69-82
5
The Delicate Balance of ClinicalDecision-making
RISKS
BENEFITS
6
Behavioral and Psychological Symptoms in
Dementia BPSD

• General descriptive term for heterogeneous group
  of non-cognitive symptoms behaviors occurring
  in dementia
• Symptom Clusters within BPSD include
• Depressive 20 - 40
• Psychotic 30 - 40
• Agitation/aggressive 50 - 80

B. A. Lawlor. J.Clin.Psychiatry 65 Suppl 115-10,
2004
7
Criteria for Depression of Alzheimers Disease

• A. (Need 3 or more over 2 wks...)
• Depressed mood and/or
• Decreased positive affect or pleasure
• Appetite disruption
• Sleep disruption
• Psychomotor retardation / agitation
• Irritability
• Fatigue or loss of energy
• Worthlessness, hopelessness, guilt
• Thoughts of death or suicidal ideation
• B. All criteria met for dx of AD
• C. Sx cause clinically significant distress or
  disruption in fxn

J. T. Olin, et al. Am.J.Geriatr.Psych
10(2)125-128, 2002 P. B. Rosenberg, et al.
Int.J.Geriatr.Psychiatry 20 (2)119-127, 2005
8
TREAT Depression ofAlzheimers Disease!

• Rx Mood, anxiety
• Rx Sleep?
• Rx agitation?

9
AAN Practice Parameters 2001Guideline-Reaffirmed
10/18/2003

• AAN practice parameters support the use of
  first-line nonpharmacologic strategies for
  agitation, especially when identifiable causes
  such as pain or environmental triggers are
  responsible

Doody RS, Stevens JC, Beck C, et al. Neurology.
2001(May 8)56(9)1154-1166
10
Principles ofNonpharmacologic Management

• Safety
• Control risk physical, financial, driving
• Serenity
• Manage affects avoid overt frustration and anger
• Structure
• Increase organization maintain schedules,
  facilitate good habits
• Sanity
• Reduce caregiver strain seek social support, use
  respite services

Gray KF. Clin Geriatr Med. 2004(Feb)20(1)69-82
11
AAN Practice Parameters 2001Guideline-Reaffirmed
10/18/2003

• Educational programs should be offered to family
  caregivers to improve caregiver satisfaction and
  to delay the time to NH placement (Guideline)
• Staff of long-term care facilities should also be
  educated about AD to minimize the unnecessary use
  of antipsychotic medications (Guideline)
• Behavior modification, scheduled toileting, and
  prompted voiding reduce urinary incontinence
  (Standard)
• Functional independence can be increased by
  graded assistance, skills practice, and positive
  reinforcement (Guideline)

R. S. Doody, et al. Neurology 56 (9)1154-1166,
2001
12
Medication Considerations ForNon-urgent/Emergent
Agitation
Cholinesterase Inhibitors and Memantine
13
NPI Scores Following Treatment with Different
ChEIs
Mean Change Per Item After 6 Months in Five
Studies
3 2 1 0 1 2 3
N 98
N 113
N 125
N 103
N 119
N 103
N 106
N 106
Mean change from baseline
Improvement
Placebo
Placebo
10 mg/d
Open-label 312 mg/d
10 mg/d
Open-label 312 mg/d
24 mg/day
Placebo
Rivastigmine
Galantamine
Aricept
Baseline
MMSE 14.4 MMSE 11.8 MMSE ?12
MMSE 9.2 MMSE 10.8 NPI-121
NPI-122 NPI-103 NPI-124 NPI-125
Nursing Community/ Community
Nursing Nursing home assisted
living home home
1Tariot et al., 2001 2Feldman et al., 2001
3Wilkinson et al., 2002 4Cummings et al., 2000
5Bullock et al., 2001 Cummings, et al., 2004
14
Impact of Galantamine on Behavioral Symptoms
Efficacy measure Galantamine (N 1,327) Placebo (N 686) P
Individual NPI domain scores
Delusions -0.04 (2.43) 0.19 (2.23) 0.10
Hallucinations -0.02 (1.58) 0.07 (1.24) 0.068
Agitation/aggression 0.10 (2.64) 0.27 (2.30) 0.050
Depression/dysphoria 0.11 (2.40) 0.13 (2.26) 0.97
Anxiety -0.05 (2.66) 0.19 (2.48) 0.044
Elation/euphoria 0.01 (0.96) 0.00 (1.02) 0.86
Apathy/indifference -0.22 (3.25) -0.13 (3.21) 0.28
Disinhibition 0.00 (1.61) 0.09 (1.33) 0.020
Irritability/lability 0.12 (2.60) 0.20 (2.36) 0.71
Aberrant motor behavior -0.15 (2.96) 0.12 (2.91) 0.050
a Effect size difference in mean change scores
(galantamine minus placebo) divided by the pooled
within-group SD (Cohenss ?). p lt.05 for
between-group comparisons (Val Elteren test, df
1). lt.05 for within-group comparisons
(Wilcoxon signed-rank tests).
N. Herrmann, et al. Am.J.Geriatr.Psychiatry 13
(6)527-534, 2005
15
Effects of Donepezil on Neuropsychiatric Symptoms
in Patients with Dementia and Severe Behavioral
Disorders

• The total score of the NPI was significantly
  reduced over the 20 weeks of therapy with
  donepezil
• 62 pts had at least a 30 reduction in total NPI
  score - significantly greater than the number
  with no meaningful response
• More patients had total or partial resolution of
  depression and delusions than those who had no
  meaningful change
• Clinically meaningful treatment effect sizes were
  notable for the delusion factor (0.340) and the
  mood factor (0.39).
• Significant correlations between the Clinical
  Global Impression-Improvement and reductions in
  mood and agitation scores
• The results suggest that donepezil reduces
  behavioral symptoms, particularly mood
  disturbances and delusions, in pts with AD with
  relatively severe psychopathology

J. L. Cummings, et al. Am.J Geriatr.Psychiatry 14
(7)605-612, 2006
16
Memantine in Moderate to SevereAD Study Impact
on Behavior - NPI

• At End Point
• There was no statistically significant difference
  between the 2 groups for total NPI scores
• There was a statistically significant difference
  between the treatment groupsin favor of
  memantine in the following domains
• Delusions P .0386
• Agitation/aggression P .0083

LOCF analysis Reisberg B, et al. N Engl J
Med. 20033481333-1341
17
Memantine Donepezil in Moderate toSevere AD
Study Impact on Behavior
Memantine Donepezil Treatment Associated With
Superior Outcomes in Key AD Domains
P.002
P.001
Worsening
Mean Change From Baseline


Improvement
NPI
BGP-Care
LOCF analysis. Bars indicate 95 confidence
intervals Tariot P, et al. JAMA.
2004291317-324
18
Behavioral effects of memantine in AD pts
receiving donepezil treatment

• Pts treated with memantine had significantly
  lower NPI total scores than pts treated with
  placebo
• Significant effects for memantine on
  agitation/aggression, eating/appetite, and
  irritability/lability
• Pts w/ agitation/aggression at baseline Rx w/
  memantine showed significant reduction of
  symptoms compared with placebo-treated pts
• Memantine-treated pts without agitation/aggression
  at baseline evidenced significantly less
  emergence of this symptom compared with similar
  pts receiving placebo
• Caregivers of pts receiving memantine registered
  significantly less agitation-related distress

J. L. Cummings, et al. Neurology 67 (1)57-63,
2006
19
AAN Practice Parameters 2001(Reaffirmed 10-18-03)

• Treat agitation, psychosis and depression
• The patient's paranoia, suspiciousness,
  combativeness or resistance to maintaining
  personal hygiene can seem overwhelming to
  families and caregivers and significantly impact
  quality of life. Evidence indicates that several
  strategies can decrease problem behaviors. If
  environmental manipulation fails to eliminate
  agitation or psychosis, use antipsychotics

R. S. Doody, et al. Neurology 56 (9)1154-1166,
2001 Full guidelines available at www.aan.com
20
Diagnostic Criteria forPsychosis of AD

• Diagnosis of Alzheimers dementia
• Exclusion of schizophrenia or other causes of
  psychotic symptoms
• Hallucinations and/or delusions
• Late-onset
• Present intermittently for ?1 month
• Disruptive to patient functioning
• Associated agitation, negative symptoms, and
  depression
• Disturbances do not correlate exclusively with
  delirium

D. V. Jeste and S. I. Finkel. Am.J.Geriatr.Psychia
try 8 (1)29-34, 2000 L. S. Schneider, et al.
Am.J.Geriatr.Psychiatry 11 (4)414-425, 2003
21
ANTIPSYCHOTIC USE FOR AGITATION

• Persistent DANGER to self or others?
• Behaviors impair function?

C. Ballard and J. Cream. Int.Psychogeriatr. 17
(1)4-12, 2005
22
The Delicate Balance of ClinicalDecision-making
RISKS
BENEFITS
23
Antipsychotic Documentation

• Severity of symptoms
• Danger to patient and others
• Lack of response to alternative approaches
• Awareness of risks of treatment
• Judgment that potential benefits outweigh risks
• Previous benefit?
• Previous tolerability?
• Discussion with family
• Monitoring plan
• Plan for dose reduction when stable

(Thanks to Ira Katz, MD)
24
Atypical Antipsychotic Treatment for Psychosis
Dangerous Behavioral Dyscontrol in Dementia

• Olanzapine 2.5 10 mg, oral loading pts in
  urgent settings 15-20 mg 1st 24 hr IM
• Risperidone 0.5 2 mg, caution w/ doses gt 1 mg
• Quetiapine 25-150 mg, especially w/ parkinsonism,
  Lewy Body Dementia
• Aripiprazole 5-10 mg, non-urgent use
• Ziprasidone 20-60 mg BID, emerging option IM

J. S. Street et al. Arch Gen Psychiatry.
200057(10)968-976 and R. W. Baker et al. J
Clin Psychopharmacol. 200323(4)342-348 I. R.
Katz et al. J Clin Psychiatry. 199960(2)107-115
and P. P. de Deyn et al. Clin Neurol Neurosurg.
2005 P. N. Tariot and M. S. Ismail. J Clin
Psychiatry. 200263 suppl 1321-26 De Deyn et
al. AAGP 16th Annual Meeting, 2003 A.
Berkowitz. J Psychiatric Practice. 20039(6)
469-473
25
Efficacy and Adverse Effects of Atypical
Antipsychotics for DementiaMeta-analysis of
Randomized, Placebo-controlled Trials

• Efficacy on rating scales was observed by
  meta-analysis for aripiprazole and risperidone,
  but not for olanzapine
• There were smaller effects for less severe
  dementia, outpatients, and patients selected for
  psychosis
• Approx 1/3 dropped out w/o overall differences
  between Rx placebo
• Adverse events mainly somnolence UTI or
  incontinence across Rx, and EPS or abnormal gait
  with risperidone or olanzapine

L. S. Schneider, et al. Am.J Geriatr.Psychiatry
14 (3)191-210, 2006
26
Efficacy and Adverse Effects of Atypical
Antipsychotics for Dementia (cont)
Meta-analysis of Randomized, Placebo-controlled
Trials

• Cognitive test scores worsened with drugs
• There was no evidence for increased injury,
  falls, or syncope
• Significant risk for cerebrovascular events,
  especially with risperidone
• Increased risk for death overall was reported
  elsewhere
• The modest efficacy and uncertain response rates
  combined with the risks detailed here suggest
  that antipsychotics should be used with more
  deliberate consideration

L. S. Schneider, et al. Am.J Geriatr.Psychiatry
14 (3)191-210, 2006
27
Risk of Death In Elderly Users of Conventional
vs. Atypical Antipsychotic Medications

• If confirmed, these results suggest that
  conventional antipsychotic medications are at
  least as likely as atypical agents to increase
  the risk of death among elderly persons and that
  conventional drugs should not be used to replace
  atypical agents discontinued in response to the
  FDA warning.

P. S. Wang, et al. N Engl J Med 353
(22)2335-2341, 2005
28
Antipsychotic EquivalenciesBased On D2 Receptor
Occupancy Expert Consensus Guidelines

• Quetiapine 300-400 mg
• Chlorpromazine 100 mg
• Ziprasidone 80 mg
• Aripiprazole 10 mg
• Loxapine 15 mg
• Olanzapine 10 mg
• Risperidone 2.5 mg
• Haloperidol 2 mg

Kane et al. J Clin Psychiatry. 200364 (suppl
12)5-19 Kapur et al. Am J Psychiatry. 2001158(3
)360-369 Schotte et al. Psychopharmacology
(Berl).1996124 (1-2)57-73
29
Non-neuroleptic OptionsFor Agitation ??
LIMITED PROOF OF EFFICACY
K. M. Sink, et al. JAMA 293 (5)596-608, 2005 K.
N. Franco and B. Messinger-Rapport. J Am.Med
Dir.Assoc. 7 (3)201-202, 2006
30
Alternative Rx FOR AGITATION

• SSRI REDUCE IRRITABILITY non-psychotic pts,
  psychosis?
• TRAZODONE (25-50 mg BID-TID) during day, qHS
• DIVALPROEX, CARBAMAZEPINE, GABAPENTIN
• ADJUNCTIVE BENZODIAZEPINES
• HORMONES for SEXUAL AGGRESSION
  (medroxyprogesterone acetate 150 mg IM q4wks)
• Propranolol (100 mg/d)

Gray KF. Clin Geriatr Med. 2004(Feb)20(1)69-82
W. K. Summers. J Alzheimers.Dis. 9 (1)69-75,
2006 E. R. Peskind, et al. Alzheimer
Dis.Assoc.Disord. 19 (1)23-28, 2005
31
Behavioral Decompensation in AD
Last Words for Caregivers

• Medications do not work alone
• Fewer expectations late in day
• Distract with tasks or food
• Remind and assist dont take over!
• Be willing to compromise
• Back off and let patient relax redirect as
  appropriate
• They cant resist if you dont insist

Gray KF. Clin Geriatr Med. 2004(Feb)20(1)69-82