Treatment Options for Dementia

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Treatment Options for Dementia

• Deb Bynum, MD
• Division of Geriatric Medicine
• University of North Carolina

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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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

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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

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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)

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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

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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)

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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Ziprasidone (Geodon)

• New, clinical data lacking
• Non dose-dependent QT prolongation

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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

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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

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?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

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Future Directions

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

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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

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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!