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Effectiveness of second-generation
antipsychotics in dementia-related
psychosis and agitation
Evidence-Based Medicine Seminar
October 26, 2006
Brian J. Mickey
Overview
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Case presentation
Clinical question
Literature search results
CATIE-AD trial: recent results from phase 1
Group discussion/debate/melee
– special guests: Chandra Sripada and the Depression Team
Case Presentation
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Ms D is a 75-year-old widowed
retired office clerk with a diagnosis
of Alzheimer disease who was
brought to the Emergency
Department (PES) by her 3
daughters in January 2006 for
worsening delusions.
About 3 years prior to evaluation,
she had presented with short-term
memory decline and was
diagnosed with probable
Alzheimer disease.
About 3 months prior to
evaluation, she developed
paranoid ideation about men
trying to harm her, and one man in
particular who rubbed noxious
lotion on her back.
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Over the prior 2-3 days, her
delusions intensified and became
more distressing to her and her
daughters.
She perceived men outside all
night shining lights into the house.
She barricaded her doors and
started carrying a knife for
protection.
She also endorsed mildly
depressed mood, low energy,
sleep disruption, and daytime
somnolence. No manic
symptoms.
Case Presentation (cont’d)
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Past psychiatric history
– mild-to-moderate depression
for 30 years
– antidepressants prescribed by
PCP for 8 years
– no psychosis, hospitalizations,
suicidality
– AD diagnosis by neurologist
2003
Substance use history
– none
General medical history
– probable Alzheimer disease
– CAD, MI and stent in July
2005
– dyslipidemia
– hypertension
– asymptomatic meningioma
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Medications
– escitalopram 20 mg daily
– rivastigmine 6 mg qam, 3 mg
qhs
– memantine 20 mg bid
– plavix 75 mg daily
– famotidine 20 mg daily
– metoprolol 20 mg bid
– lisinopril 20 mg daily
– pravachol 80 mg qhs
– vitamins
Family history
– depression (daughters,
mother)
– no dementias or psychoses
Case Presentation (cont’d)
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Social history
– lives alone in her own home
– husband died in 1990
– 5 children, daily contact
– retired office clerk
– daughter is DPOA
Functional assessment
– independent in ADLs
– cooking less
– not driving
– unable to manage money
– frequently misses medication
Physical examination
– T 97.8 HR 49 BP 171/64
– no rash
– mild tremor, pronator drift, and
satelliting on the right
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Mental status examination
– good grooming and
cooperation
– alert and attentive to interview
– cannot recite days of the week
in reverse
– oriented to year, month, and
city only
– recalls 0/3 items at 2 minutes
– recalls current but not past US
presidents
– verbal repetition intact, but
word finding difficulties and
paraphrasias noted
– extensive delusions
– visual, auditory, and possibly
tactile hallucinations
Case Presentation (cont’d)
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Laboratory studies
– CBC, comprehensive panel,
TSH, UA, UDS were
unremarkable
Neuropsychological testing
(2003)
– verbal IQ lower than predicted
– deficits in memory,
concentration, attention,
calculation, language,
visuospatial abilities
– MMSE: 21/30
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Brain MRI (2003)
– 1.5-cm enhancing mass near
the cribriform plate consistent
with meningioma
– diffuse volume loss
– minimal periventricular FLAIR
signal
– follow-up scan unchanged in
2004
SPECT perfusion scan (2003)
– hypoperfusion to medial
temporal lobes bilaterally
– milder hypoperfusion to
parietal lobes
Clinical Question
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Patient
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In a 75-year-old patient with AD
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Intervention
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do second-generation antipsychotics ...
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Comparison
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in comparison to no treatment (placebo) ...
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Outcomes
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improve symptoms of psychosis and
agitation, and improve functioning?
Clinical Question
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A related clinical question:
What is the risk of serious adverse
events when using secondgeneration antipsychotics in
dementia-related
psychosis/agitation?
effectiveness
adverse effects
Literature search results
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Schneider LS, Dagerman KS, Insel P. Risk of death with atypical
antipsychotic drug treatment for dementia: meta-analysis of randomized
placebo-controlled trials. JAMA. 2005 Oct 19;294(15):1934-43.
Ballard C, Waite J. The effectiveness of atypical antipsychotics for the
treatment of aggression and psychosis in Alzheimer's disease. Cochrane
Database Syst Rev. 2006 Jan 25;(1):CD003476.
Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of
atypical antipsychotics for dementia: meta-analysis of randomized, placebocontrolled trials. Am J Geriatr Psychiatry. 2006 Mar;14(3):191-210.
Ballard C, Howard R. Neuroleptic drugs in dementia: benefits and harm.
Nat Rev Neurosci. 2006 Jun;7(6):492-500.
Schneider LS et al. for CATIE-AD Study Group. Effectiveness of atypical
antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med.
2006 Oct 12;355(15):1525-38.
Literature search results
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Schneider LS, Dagerman KS, Insel P. Risk of death with atypical
antipsychotic drug treatment for dementia: meta-analysis of randomized
placebo-controlled trials. JAMA. 2005 Oct 19;294(15):1934-43.
Ballard C, Waite J. The effectiveness of atypical antipsychotics for the
treatment of aggression and psychosis in Alzheimer's disease. Cochrane
Database Syst Rev. 2006 Jan 25;(1):CD003476.
Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of
atypical antipsychotics for dementia: meta-analysis of randomized, placebocontrolled trials. Am J Geriatr Psychiatry. 2006 Mar;14(3):191-210.
Ballard C, Howard R. Neuroleptic drugs in dementia: benefits and harm.
Nat Rev Neurosci. 2006 Jun;7(6):492-500.
Schneider LS et al. for CATIE-AD Study Group. Effectiveness of atypical
antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med.
2006 Oct 12;355(15):1525-38.
CATIE-AD trial
• Clinical Antipsychotic Trials of Intervention Effectiveness – Alzheimer
Disease
• NIH sponsored (minimal influence from pharmaceutical industry)
• Phase 1 compares:
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risperidone
olanzapine
quetiapine
placebo
• Phase 2 includes a switch to a different antipsychotic or citalopram
Design
• 421 outpatients with
Alzheimer disease
and psychosis,
aggression, or
agitation
• multi-site,
double-blind,
placebo-controlled
• randomized to
risperidone,
quetiapine,
olanzapine, or
placebo
• flexible dosing
• followed 36 weeks
Outcome measures
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Primary outcome measure
– time to discontinuation of treatment (TDT) for any reason
Secondary outcome measures
– number of patients with at least minimal improvement in CGIC at 12
weeks
– time to discontinuation of treatment due to lack of efficacy
– time to discontinuation of treatment due to intolerability or adverse
events
Contrasts with typical outcome measures in industry-sponsored trials
– e.g., Neuropsychiatric Inventory score at pre-specified time point
– outcomes not used in routine clinical practice
– efficacy (pharmaceutical trial) vs effectiveness (real world)
Clinical characteristics
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age: 78 ± 8 yr
residence
– own home
– family’s home
– assisted living
baseline ratings
– MMSE
15 ± 6
– ADAS
35 ± 13
– NPI
37 ± 18
– BPRS
28 ± 12
doses (initial / last)
– olanzapine
– quetiapine
– risperidone
73%
10%
10%
(0-30)
(0-70)
(0-144)
(0-108) delusions 82%
3.2 / 5.5 mg
34 / 57 mg
0.5 / 2.5 mg
hallucinations 49%
Primary outcome
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No significant
differences in
TDT for any
reason
Medians:
5.3–8.1 wk
Secondary outcome
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TDT due to
lack of
efficacy
Olanzapine
was superior
to placebo
(p<0.001)
Risperidone
was superior
to placebo
(p=0.01)
Quetiapine
did not differ
from placebo
(p=0.24)
Secondary outcome
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TDT due to
intolerability
or adverse
events
Placebo was
superior to
each
antipsychotic
medication
(p<0.005)
Secondary outcome
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Clinical Global Impression of Change (CGIC) indicating at least minimal
improvement
– olanzapine: 32%
– risperidone: 29%
– quetiapine: 26%
– placebo: 21%
– no significant differences between treatments (p=0.22)
Possible discussion points
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Implications for my patient?
Interpretation of the results more generally?
Effects of population heterogeneity?
Psychosis vs agitation vs aggression?
Quetiapine underdosed?
What study should be done next?
Table 1
Table 2
Table 3