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Transcript of Psychosis and Agitation in Dementia Dilip V. Jeste, MD Estelle & Edgar Levi Chair in Aging,...
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Psychosis and Agitation in Dementia
Dilip V. Jeste, MDEstelle & Edgar Levi Chair in Aging,
Director, Stein Institute for Research on Aging,Distinguished Professor of Psychiatry & Neurosciences,
University of California, San DiegoVA San Diego Healthcare System
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Potential Conflicts of Interest Donation of antipsychotic medications for an
NIMH-funded RO1: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen
Consultant: Solvay/Wyeth, Otsuka, Bristol-Myers Squibb
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Self-Assessment Question 1
Which of the following statements is true?
A. Psychosis and agitation are uncommon symptoms in demented patients.
B. Psychosis, in Alzheimer disease patients, is associated with increased functional impairment.
C. Male gender and higher educational level are associated with increased risk of psychotic symptoms in Alzheimer disease.
D. All of the above
E. None of the above
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Self-Assessment Question 2
Psychosis in AD is associated with which of the following?
A. Frontal lobe neurobehavioral dysfunction
B. Apathy
C. Disinhibition
D. All of the above
E. None of the above
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Self-Assessment Question 3
Which of the following statements is true?
A. Atypical antipsychotics are FDA-approved for treatment of psychosis in Alzheimer disease.
B. Off-label, evidence-based use of medications is legal, and should be accompanied by appropriate disclosure and discussion of rationale, risks, and benefits
C. Atypical antipsychotics are associated with greater mortality risk than conventional antipsychotics.
D. All of the above
E. None of the above
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Self-Assessment Question 4Adverse effects associated with use of atypical
antipsychotic medications in dementia patients with psychosis include which of the following?
A. Sedation/somnolence
B. Postural hypotension
C. Cerebrovascular accidents
D. Increased mortality
E. All of the above
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Self-Assessment Question 5Which of the following medications has been
approved for treating agitation or psychosis in dementia patients?
A. Citalopram
B. Divalproex sodium
C. Carbamazepine
D. Cholinesterase inhibitors
E. None of the above
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Major Points Psychosis and/or agitation are frequent concomitants of
dementia Psychosis in AD is associated with frontal neurobehavioral
dysfunction No drug is FDA-approved for treatment of psychosis or
agitation in dementia Off-label use of antipsychotics, especially the atypicals, is
common, but these drugs FDA’s carry black-box warnings regarding increased mortality in dementia patients
Antidepressants, anticonvulsants, benzodiazepines, and cognitive enhancers have been used for psychosis or agitation in demented patients, but with inconsistent results
Psychosocial treatments have a valid role in treatment Shared decision making is recommended
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Prevalence of Behavioral Disturbances in Alzheimer Disease
Psychosis: 40% - 60%Depression: 20% - 40%Agitation: 70% - 90%
Wragg and Jeste, Am J Psychiatry, 1988;Ropacki and Jeste, Am J Psychiatry, 2005
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Psychosis of Alzheimer Disease: Diagnostic Criteria
Primary diagnosis is Alzheimer diseaseCharacteristic psychotic symptoms:
delusions or auditory/visual hallucinationsDementia onset precedes psychotic
symptomsDuration >1 monthFunctional disruptionExclusion of delirium, schizophrenia, other
causes of psychosis
Jeste DV and Finkel SI. Am J Geriatr Psychiatry. 2000;8:29-34
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Psychosis of AD: Associated Features
1) Agitation
2) Negative symptoms
3) Depression
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Psychosis of AD: Public Health Importance
1) High incidence and prevalence
2) Chronic or recurrent
3) Commonly produces functional disruption
4) May require prolonged treatment
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Cumulative Incidence of Psychosis of Alzheimer Disease (N = 329)
Paulsen JS et al. Neurology. 2000;54:1965-1971
% o
f A
D P
atin
ets
wit
h P
sych
osi
s
0%
20%
40%
60%
80%
100%
Years
1 32 4
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Psychosis of AD: Recent Studies
55 studies, published between 1990 and 2003, with a total N of 9,749
Mean prevalence of psychosis 41% (delusions 36%, hallucinations 18%)
Sx last for several months, but become less prominent after 1 year
Significant association: More severe, & more rapidly progressive cognitive decline
(Ropacki SA & Jeste DV: Am J Psychiatry, 2005)
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Predictors of Development of Psychosis in AD Patients
Predictors: 1) Parkinsonian gait
2) Bradyphrenia
3) Global cognitive decline
4) Semantic memory decline
Non-predictors: 1) Age
2) Gender
3) EducationPaulsen JS et al., Neurology, 2000
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Frontal Neurobehavioral Dysfunction in Psychosis of AD
• FLOPS (Frontal Lobe Personality Scale) given to 20 AD + Psychosis pts & 20 AD – Psychosis pts matched on age, gender, education, & dementia severity
• AD + Psychosis pts had greater frontal neurobehavioral dysfunction, especially disinhibition and apathy
Paulsen et al., J Int’l Neuropsychol Soc 6: 815-820, 2000
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Treatment Modalities
Nonpharmacologic approachesTypical (conventional) antipsychoticsAtypical antipsychoticsOther psychotropics
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Review of Psychosocial Interventions
Sensory, social contact, behavior therapy, staff training, structured activities, environmental, medical / nursing care, combination therapies
Variably positive results, but with methodological limitations
Psychosocial treatments have a valid role to play in treatment of most dementia patients
Cohen-Mansfield J. Am J Geriatr Psychiatry. 2001;9:361-381
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Caveat in Using Drugs in Older Patients with Psychotic
Disorders
Currently no drug (antipsychotic or other) has been approved for treatment of psychosis of Alzheimer disease
Atypical antipsychotics have been approved by the FDA only for treatment of schizophrenia and bipolar disorder
Off-label use of drugs is not illegal and is common in practice, but requires clear justification in individual patients
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Conventional (Typical) Neuroleptics in Patients with Dementia
Effective in <60% of cases1
Improvement rate only 18% greater than with placebo2
Modest clinical effectsEffective doses often produce EPS,
sedation, & other side effects
1. Wragg and Jeste. Psychiatr Clin North Am. 1988;11:195.2. Schneider et al. J Am Geriatr Soc. 1990;38:53.
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Adverse Effects of “Typical”Antipsychotics in Older Patients
Anticholinergic toxicityPostural hypotensionExtrapyramidal symptomsTardive dyskinesiaOther
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Antipsychotic-Induced Tardive Dyskinesia
Potentially persistentAssociated with adverse consequencesOften refractory to treatmentHas medicolegal implicationsMuch more common in older patients
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Cumulative Incidence of Tardive Dyskinesia with Typical Neuroleptics
0%
20%
40%
60%
80%
100%
12 24 36
Months
% S
ubje
cts
wit
h T
D Young Adults
Older Adults
Jeste DV et al. Arch Gen Psychiatry 52:756-765, 1995; Kane JM et al. J Clin Psychopharmacol 1988;8(suppl):52S-56S
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Clozapine in Elderly Patients
Use restricted because of side effects (sedation, hypotension, anticholinergic toxicity) and weekly blood draws (agranulocytosis)
Indication: psychosis in Parkinson’s disease
Lower dosages than in younger adults
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*P < 0.005 vs placebo.BEHAVE-AD = Behavioral Pathology in Alzheimer’s DiseaseKatz IR et al. J Clin Psychiatry. 1999;60:107-115
* *
4.24.8
6.5 6.4
01
23
45
67
Placebo 0.5 mg 1 mg 2 mg n = 161 n = 146 n = 148 n = 162
Risperidone Dose
Po
ints
of
Imp
rove
men
tF
rom
Bas
elin
e sc
ore
Risperidone in Dementia:Total BEHAVE-AD Scores
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Risperidone in Dementia (N = 625):Incidence of EPS
*P ≤ 0.05.Katz IR et al. J Clin Psychiatry. 1999;60:107-115.
21.2
Risperidone Dose
6.7
12.8
7.4
0
5%
10%
15%
20%
25%
Placebo
0.5 mg
1 mg
2 mg
% o
f S
ub
ject
s W
ith
E
xtra
pyr
amid
al S
ymp
tom
s *
n=163 n=149 n=148 n=165
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Tardive Dyskinesia in Older Patients: Haloperidol (N = 61) vs Risperidone (N = 61)
Peto-Prentice P value < 0.05.Jeste DV et al. J Am Geriatr Soc. 1999;47:716-719
Haloperidol 1 mg/d
Risperidone 1 mg/d0%
20%
40%
60%
80%
100%
1 3 6 9
Haloperidol Risperidone
Months
%T
ard
ive
Dys
kin
esia
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Olanzapine in Dementia: NPI-NH Core Total (N = 206)
**P < 0.001, †P < 0.01 vs placebo.LOCF = last observation carried forward.NPI-NH = Neuropsychiatric Inventory–Nursing Home version.Street JS et al. Arch Gen Psychiatry. 2000;57:968-976.
-8
-6
-4
-2
0
Placebo
5 mg
10 mg
15 mg
†
Mean ChangeFrom Baseline
(LOCF)
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Olanzapine in Dementia (N = 206): Incidence of Movement Disorders
*No change.LOCF = last observation carried forward.Street JS et al. Arch Gen Psychiatry. 2000;57:968-976
-2
-1.5
-1
-0.5
0
0.5
Placebo
5 mg
10 mg
15 mg
Simpson-Angus
Abnormal Involuntary
Movement ScaleBarnes
Akathisia
*Mean
Change From
Baseline (LOCF)
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Double-Blind Trial of Quetiapine in AD Patients With Psychosis
Quetiapine compared with haloperidol and placebo for improving psychotic symptoms in patients with AD (n=284)
Ten-week, randomized trial followed by a two-week washout period
Flexible dosing adjusted to patient response and tolerability
Tariot PN et al. Abstract, Am J Geriatr Psychiatry 2002;10(2), Supplement:93.
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Quetiapine in AD Patients With Psychosis: Results
All treatment groups improved psychotic symptoms, but no difference among the 3 groups (Quetapine, Haloperidol, Placebo)
Quetiapine and Haloperidol improved agitation more than Placebo
Quetiapine showed better tolerability than Haloperidol, & similar EPS and anticholinergic effects as Placebo
Tariot PN et al. Abstract, Am J Geriatr Psychiatry 2002;10(2), Supplement:93.
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Aripiprazole for Psychosis of AD: 10-Week Double-Blind, Placebo-Controlled
Trial (N = 208)
Outpatient study in Europe Flexible dosage Dose range 2-15 mg once per day Mean dose at end point 10 mg/d
Efficacy measures NPI psychosis [hallucinations and
delusions] BPRS psychosis [hallucinatory behavior
and unusual thought content]
DeDeyn, Jeste et al., J Clinical Psychopharmacology, 2005
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Aripiprazole vs Placebo for Psychosis of AD: Summary
Efficacy
Significant reduction in BPRS core and psychosis scores, but
not in NPI psychosis score at end point (the primary outcome
measure)
Safety and tolerability
No drug-placebo differences in incidence of EPS-related AE or orthostatic events
Low rate of discontinuation due to AEs
Somnolence was mild and not associated with falls
DeDeyn, Jeste et al., J Clinical Psychopharmacology, 2005
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Ziprasidone
Efficacious in patients with schizophreniaLow risk of sedationLow risk of extrapyramidal symptomsLow risk of weight gainPossible issue: QTc prolongationNo controlled data in dementia patients
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0%
20%
40%
60%
80%
100%
0 1 3 6
Months
Typical Antipsychotics (n=130)
Atypical Antipsychotics (n=88)
% W
ith
Defi
nit
ive T
D%
Wit
h D
efi
nit
ive T
D
* P <.001 (Peto-Prentice); * P <.001 (Peto-Prentice);
DDolder & Jeste. Biol Psychiatry. 2003, 53:1142-45older & Jeste. Biol Psychiatry. 2003, 53:1142-45
**
Cumulative Incidence of Definitive TD in Older Patients With Borderline Dyskinesia
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Efficacy of Atypical Antipsychotics in AD
Atypical antipsychotics generally better than placebo for agitation, aggression, and overall behavioral problems in patients with psychosis of AD
Efficacy for specific psychotic symptoms in AD patients less certain
High placebo response rate in psychosis of ADUseful dose ranges tend to be restricted Use of antipsychotics in dementia patients is off-
label
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Short-Term Side Effects of Atypical Antipsychotics in Elderly
PatientsMore common
Sedation/somnolencePostural hypotension and fallsExtrapyramidal symptoms and gait
abnormalityIncreased risk with higher dosesSome selectivity for different drugs
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Long-Term Side Effects
Weight gainType 2 diabetes mellitusHyperprolactinemiaCardiac conduction disordersCerebrovascular accidentsIncreased mortality
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FDA Warnings About Antipsychotic Use
In all patients: Weight gain, Diabetes, Dyslipidemia
In dementia patients: Increased incidence of strokes
with risperidone, olanzapine, and aripiprazole
Increased overall mortality with all atypical antipsychotics as a class
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New FDA Public Health Advisory on Antipsychotics for Elderly patients with
Behavioral Disturbances
Data pooled from 17 placebo-controlled trials in dementia patients with behavioral disorders
Mortality with antipsychotics was 1.6 to 1.7 times greater than with placebo
15/17 Studies showed numerically higher mortality;
the most common causes were cardiac (heart failure) and infectious (pneumonia)
Limited available data suggest that first-generation antipsychotics are associated with comparable increase in mortality
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Caution in Interpreting Data on Strokes & Mortality with Antipsychotics
The patients in these trials were typically 80+ years old, and had multiple risk factors for strokes and mortality
No cause- and-effect relationships between the antipsychotics and these adverse events in individual patients have so far been clearly established
However, the possibility of a causal relationship cannot be excluded
Must keep in mind FDA’s black-box warnings in dementia patients
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CATIE – AD Trial: Rates of Discontinuation of Tx
Primary outcome measure: Discontinuation due to any reason
Median time to discontinuation:
Olanzapine (8.1 wks); Risperidone (7.4 wks); Quetiapine (5.3 wks); Placebo ( 8.0 wks)
No significant group differences
(Schneider et al., NEJM, 355:1525-1538, 2006)
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Recommended Dose Rangesin Patients with Psychosis of AD
Drug Initial Typical Range(mg/d) (mg/d)
Risperidone 0.25-0.5 0.5-1.5
Olanzapine 2.5-5 5-10
Quetiapine 12.5-25 50-200
Aripiprazole 2-5 7-12
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Alternative Psychotropics
Citalopram Divalproex sodiumCarbamazepine Benzodiazepines (e.g. lorazepam)Trazodone Cognitive enhancers
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Other Psychotropics for Treatment of Psychosis and Agitation
in Dementia Patients
Limitations of the published reports
1. Few large-scale double-blind randomized controlled trials in dementia patients with behavioral problems
2. Known adverse effects with each drug
3. Limited long-term safety data in these patients
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Shared Decision Making
Discussing with patients and caregivers (as appropriate) benefits & risks of different Tx options
Giving an informed opinion with rationaleThe final decision made by the “consumer/s” Issues of Proxy consent, Assent, Advance
directive“Enhancing” the informed consent processDocumenting the discussion
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Clinical Recommendations for Treatment of Dementia Patients General therapeutic considerations Shared decision making Choice of pharmacotherapy and dosages Monitoring efficacy and safety Role of psychosocial interventions Switching or discontinuing pharmacotherapy Coordinating overall patient care
(Jeste et al.: ACNP White Paper: Update on Antipsychotics in Older Patients, Neuropsychopharmacology, 2007, July 18, e-pub)
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Suggested Readings
Teri L. Logsdon RG. McCurry SM. Nonpharmacologic treatment of behavioral disturbance in dementia. Medical Clinics of North America. 86:641-56, 2002
Lawlor B. Bhriain SN. Psychosis and behavioural symptoms of dementia: defining the role of neuroleptic interventions. International Journal of Geriatric Psychiatry. 16 Suppl 1:S2-6, 2001
Jeste DV and Finkel SI: Psychosis of Alzheimer s disease and related dementias: Diagnostic criteria for a distinct syndrome. American Journal of Geriatric Psychiatry 8: 29-34, 2000
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Suggested Readings Jeste DV, Blazer D, Casey DE, Meeks T, Salzman C,
Schneider L, Tariot P and Yaffe K: ACNP White Paper: Update on the use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology (in press, 2007; July 18, e-pub )
Ropacki S and Jeste DV: Epidemiology of and risk factors for psychosis of Alzheimer Disease: A review of 55 studies published from 1990 to 2003. American Journal of Psychiatry, 2005
Sweet RA, Nimgaonkar VL, Devlin B and Jeste DV: Psychotic symptoms in Alzheimer Disease: Evidence for a distinct phenotype. Molecular Psychiatry 8:383-392, 2003
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Self-Assessment Question 1
Which of the following statements is true?
A. Psychosis and agitation are uncommon symptoms in demented patients.
B. Psychosis, in Alzheimer disease patients, is associated with increased functional impairment.
C. Male gender and higher educational level are associated with increased risk of psychotic symptoms in Alzheimer disease.
D. All of the above
E. None of the above
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Self-Assessment Question 2
Psychosis in AD is associated with which of the following?
A. Frontal lobe neurobehavioral dysfunction
B. Apathy
C. Disinhibition
D. All of the above
E. None of the above
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Self-Assessment Question 3
Which of the following statements is true?
A. Atypical antipsychotics are FDA-approved for treatment of psychosis in Alzheimer disease.
B. Off-label, evidence-based use of medications is legal, and should be accompanied by appropriate disclosure and discussion of rationale, risks, and benefits
C. Atypical antipsychotics are associated with greater mortality risk than conventional antipsychotics.
D. All of the above
E. None of the above
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Self-Assessment Question 4Adverse effects associated with use of atypical
antipsychotic medications in dementia patients with psychosis include which of the following?
A. Sedation/somnolence
B. Postural hypotension
C. Cerebrovascular accidents
D. Increased mortality
E. All of the above
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Self-Assessment Question 5Which of the following medications has been
approved for treating agitation or psychosis in dementia patients?
A. Citalopram
B. Divalproex sodium
C. Carbamazepine
D. Cholinesterase inhibitors
E. None of the above
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Answers to Self-Assessment Questions
1) B
2) D
3) B
4) E
5) E