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Treatment Options for Dementia

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Modestly effective in treatment of mild to moderate AD (but only at high doses of 6-12 mg/day) ... drug seems to have similar treatment effect at 6 months on ... – PowerPoint PPT presentation

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Title: Treatment Options for Dementia


1
Treatment Options for Dementia
  • Deb Bynum, MD
  • Division of Geriatric Medicine
  • University of North Carolina

2
Objectives
  • 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

3
Overview
  • 1. Cholinesterase inhibitors in the treatment of
    AD, vascular and overlap dementias
  • 2. Memantine
  • 3. Treatment of behavioral symptoms
  • 4. ?Prevention
  • 5. Future Directions

4
The Cholinergic Hypothesis
  • 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

5
Cholinesterase Inhibitors
  • 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

6
Tacrine
  • 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

7
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

8
Rivastigmine
  • 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)

9
Galantamine
  • 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

10
Cholinesterase inhibitors in moderate to severe AD
  • RCT of donepezil vs placebo 24 week
    international trial of 290 patients (MMSE 5-18)
  • 63 of donepezil treated patients were
    stable/better vs 42 in placebo group

11
Comparison of Cholinesterase Inhibitors
  • 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

12
Cholinesterase Inhibitors and AD Summary
  • 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

13
Cholinesterase Inhibitors and Other Dementias
  • Vascular dementia and Dementia with Lewy Bodies
    each account for 10-15 cases
  • Prominence of mixed pathology (especially
    vascular and AD in older population)

14
Galantamine Vascular and AD/Vascular Dementia
  • 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

15
Summary of Galantamine and Vascular dementia
  • 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)

16
Cholinesterase Inhibitors and Other dementias
  • Lewy Body Dementia may respond even more than AD
    patients
  • Frontal Lobe Dementia often respond adversely to
    cholinesterase inhibitors with increased
    agitation and insomnia

17
Memantine
  • 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)

18
Memantine
  • Randomized, double blind, placebo controlled
    study 166 patients with severe dementia (AD and
    vascular, MMSE lt10)
  • 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

19
Memantine
  • 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

20
Memantine Summary
  • 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

21
Behavioral Symptoms Nonpharmacologic Treatment
  • 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

22
Use of Atypical Antipsychotics
  • 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

23
Risperidone
  • Evidence demonstrates efficacy in treatment of
    psychotic and behavior symptoms in patients with
    dementia
  • Exacerbates movement disorder in patients with
    Parkinsons
  • 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

24
Olanzapine
  • 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

25
Quetiapine (Seroquel)
  • 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

26
Ziprasidone (Geodon)
  • New, clinical data lacking
  • Non dose-dependent QT prolongation

27
Clozapine
  • 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

28
Antipsychotics in Dementia Summary
  • 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

29
?Prevention of Dementia
  • HTN and Hyperlipidemia
  • 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

30
Future Directions
  • Amyloid B peptide (plaque component) vaccination
  • Amyloid modulators
  • ?Anti-inflammatory drugs
  • Treatment with statins
  • ?Low flow VP shunting

31
Take Home Points
  • 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

32
Take Home Points
  • 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!
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