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Transcript
Treatment Options for Dementia
Deb Bynum, MD
Division of Geriatric Medicine
University of North Carolina
Objectives
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1. Understand the use of cholinesterase inhibitors in
the treatment of alzheimer type, vascular and mixed
dementias
2. Review the current literature regarding the use of
Memantine for severe dementia
3.Understand the appropriate use of
nonpharmacologic strategies for behavioral
problems with dementia
4. Review the appropriate use of antipsychotics for
psychosis and behavioral symptoms in dementia
5. Discuss possible means of preventing dementia
Overview
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1. Cholinesterase inhibitors in the treatment
of AD, vascular and overlap dementias
2. Memantine
3. Treatment of behavioral symptoms
4. ?Prevention
5. Future Directions
The Cholinergic Hypothesis
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Depletion of acetylcholine and nicotinic
receptors thought to occur early and relate to
memory impairment with AD
Focus on AD treatment with
Acetylcholinesterase inhibitors:
Recommended as first line treatment for
patients with mild to moderate AD
Cholinesterase Inhibitors
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Trials in patients with mild to moderate
disease (10-24 on MMSE)
On average these drugs seem to stabilize
cognitive function and activities of daily living
and may have benefits with QOL and
behavioral disturbances for at least one year
Side Effects: GI
Tacrine
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Trials demonstrating delay of cognitive
decline by 6 months
Delayed time to nursing home placement: At
800 days, 45% in low dose or no tacrine
underwent placement vs 21% in high dose
tacrine group
Evidence for long term cost effectiveness
Reversible hepatotoxicity in 50%
Donepezil (Aricept)
Three large RCT demonstrate modest effectiveness in
stabilizing cognitive function
Well tolerated (no difference in adverse events
compared to placebo)
Not hepatoxic, no significant drug-drug interactions
Single bedtime dose: start 5 mg, increase to 10 mg
after 4-6 weeks
Most common side effects: sleep disturbance, GI
Rivastigmine
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May have increased selectivity for hippocampus and
neocortex (areas affected by AD)
Modestly effective in treatment of mild to moderate
AD (but only at high doses of 6-12 mg/day)
Recommended starting dose: 1.5 mg BID with
breakfast and dinner
Minimize GI side effects with 4-6 week titration,
increasing to 3 mg BID, 4.5 mg BID, 6 mg BID
More GI side effects, weight loss (dose dependent)
Galantamine
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Potential second mechanism: modulator at nicotinic
cholinergic receptor
Three large RCTs indicate effectiveness in mild to
moderate AD (same degree as other agents) at
doses of 16, 24, 32 mg/day
Open label 6 month extension of US trial: Possible
disease modifying effect
Starting dose: 4mg BID with meals, increase by
4mg BID every 4-6 weeks
Cholinesterase inhibitors in
moderate to severe AD
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RCT of donepezil vs placebo: 24 week
international trial of 290 patients (MMSE 518)
63 % of donepezil treated patients were
stable/better vs 42% in placebo group
Comparison of Cholinesterase
Inhibitors…
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Cochrane Dementia Group: 3 systematic
reviews on efficacy of donepezil,
rivastigmine, and galantamine
Each drug seems to have similar treatment
effect at 6 months on global and cognitive
rating scales
No double blind head to head trial
Cholinesterase Inhibitors and AD:
Summary
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Approved for treatment of mild to moderate AD
Probably effective in treatment of more severe AD
Goal: stabilization (not miracle drugs)
Delay in nursing home placement, decline in ADLS
Probably benefits behavioral and functional status as
well
Data suggest no big difference in efficacy among the
3 agents, although donepezil is easier to titrate and
better tolerated
Cholinesterase Inhibitors and
Other Dementias…
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Vascular dementia and Dementia with Lewy
Bodies each account for 10-15% cases
Prominence of mixed pathology (especially
vascular and AD in older population)
Galantamine: Vascular and
AD/Vascular Dementia
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Placebo controlled trial, 6 months, 592 patients
50% in study had AD plus radiological evidence of
CVD, 41% had probable vascular dementia, 9%
indeterminant
Results for the whole group were similar to previous
trials in typical AD : 74% galantamine groupwere
improved/stable vs 59% in placebo group
AD-CVD subgroup similar effects to prior trials with
AD patients
Summary of Galantamine and
Vascular dementia
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Patients with typical features of AD mixed with
features of CVD or evidence of CVD on radiological
tests seem to respond similarly to patients with AD
alone
Subgroup with CVD alone does better over long term
(even with placebo)
Surprise: patients with what appears to be only CVD
also seem to have some benefit (these patients not
traditionally felt to have specific degeneration of
cortical cholinergic pathways)
Cholinesterase Inhibitors and
Other dementias
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Lewy Body Dementia: may respond even
more than AD patients
Frontal Lobe Dementia: often respond
adversely to cholinesterase inhibitors with
increased agitation and insomnia
Memantine
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NMDA (glutamate) receptor activation
thought to be involved in neurodegeneration
Memantine: NMDA antagonist aimed at
protecting neurons from glutamate mediated
excitotoxicity
Approved in Europe in 2002 for treatment of
severe AD (MMSE 3-14)
Memantine
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Randomized, double blind, placebo controlled study:
166 patients with severe dementia (AD and vascular,
MMSE <10)
Cognitive and Behavioral Rating Scale significantly
better with treatment, regardless of dementia type
Other European studies have looked at treatment for
moderate-severe Vascular Dementia, demonstrating
similar efficacy
Memantine
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28 week RCT of 252 patients with severe AD (MMSE
3-14) in NEJM: memantine associated with less
deterioration in cognitive and functional measures
than placebo
Problem: small numbers, high drop out rate
Preliminary study: 400 patients with severe AD, 6
months RCT of memantine plus donepezil vs
placebo plus donepezil: memantine group had
significant benefit in comparison
Memantine: Summary
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Approved for treatment of moderate-severe AD
Likely of benefit also in severe vascular and mixed
dementias as well
Likely will be used in combination with donepezil or
other cholinesterase inhibitors
Cochrane Dementia Group: “memantine is a safe
drug and may be useful for treating AD, vascular and
mixed dementia, although most of the trials so far
reported have been small and not long enough to
detect clinically important benefit”
Behavioral Symptoms:
Nonpharmacologic Treatment
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Depression, agitation, aggression, wandering, sleep
disturbance, paranoia, anxiety
Assess for/treat depression
Assess cause for increased symptoms (caregiver,
environmental changes, medications, infection)
Assess for caregiver depression
ID and avoid triggers of negative behavior
Redirection
Environmental modification for wandering
Sleep hygiene
Use of Atypical Antipsychotics
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Older, “typical” agents such as haloperidol
and thioridazine (mellaril) associated with
significant extrapyramidal symptoms
Theoretically combination of dopamine and
serotonin effects of atypical agents allow
treatment of positive and negative psychotic
symptoms with less EPS
Risperidone
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Evidence demonstrates efficacy in treatment of
psychotic and behavior symptoms in patients with
dementia
Exacerbates movement disorder in patients with
Parkinson’s
Start .25/day, average daily dose 1-1.5mg/day
EPS in dose dependent manner (6mg/day)
Insomnia, hypotension, weight gain
Elevation of prolactin levels
Olanzapine
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Evidence that it is effective in AD patients
Increases motor symptoms in PD patients
Recommended not to use with PD
Start: 1.25-2.5/day, increase to 5/day (dosages of
10-15/day are not more effective!)
More sedating than others (more anticholinergic
effects)
Sedation, weight gain, orthostatic hypotension,
seizures, glucose intolerance
Quetiapine (Seroquel)
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Showing promise in patients with AD and PD
Does not exacerbate movement disorder of PD
May be first line for PD patients with psychosis
12.5 QHS, titrate every 3-5 days
Sedation, HA, orthostatic hypotension
?Cataract formation
Ziprasidone (Geodon)
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New, clinical data lacking
Non dose-dependent QT prolongation
Clozapine
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Very effective in treating psychosis in PD
patients
The most effective agent in treatment of drug
induced psychosis in PD
Some efficacy with AD patients
Start: 6.5mg/day
Agranulocytosis, frequent monitoring limits
use
Antipsychotics in Dementia:
Summary
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Start very low, monitor for hypotension, P450
effects, sedation, EPS
Monitor and avoid use as “chemical restraint”
Avoid if at all possible in Dementia with Lewy
Bodies
?Prevention of Dementia
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HTN and Hyperlipidemia
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Observational studies show less risk of AD in patients on
statin agents (RCTs do not show effect)
Original HTN in Elderly studies: patients initially on placebo
with systolic HTN had persistent elevation in risk of
dementia
Vascular risk factors seem to play role even for AD!
Evidence lacking for Vit E, Estrogen, NSAIDS
Future Directions
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Amyloid B peptide (plaque component)
vaccination
Amyloid modulators
?Anti-inflammatory drugs
Treatment with statins
?Low flow VP shunting
Take Home Points
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Cholinesterase Inhibitors are MODESTLY effective
in treatment of mild to moderate AD
Cholinesterase Inhibitors are probably effective in
more severe AD
No large difference in efficacy between agents, but
Donepezil more easily titrated and tolerated
Evidence to support use of cholinesterase inhibitors
for vascular and vascular/AD dementia
Memantine looks to be effective for more severe AD
and vascular dementia, will likely be used in
combination with cholinesterase inhibitors
Take Home Points
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Behavioral symptoms common, first line of treatment
is nonpharmacologic
Atypical antipsychotics can be effective, but use in
low doses and watch carefully for problems
(especially EPS, hypotension)
For PD, quetiapine (seroquel) may be first line for
psychotic symptoms
Avoid antipsychotics with Lewy Body Disease!