1/4/2020 Cholinesterase inhibitors in the treatment of Alzheimer disease - UpToDate

Official reprint from UpToDate®

www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Cholinesterase inhibitors in the treatment of Alzheimer

disease
Authors: Daniel Press, MD, Michael Alexander, MD
Section Editors: Steven T DeKosky, MD, FAAN, FACP, FANA, Kenneth E Schmader, MD
Deputy Editor: Janet L Wilterdink, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Oct 30, 2019.

INTRODUCTION

Cholinesterase inhibitors and memantine are the only currently available symptomatic medications for
cognition and global functioning in patients with dementia. Cholinesterase inhibitors target the
acetylcholine deficit arising from loss of neurons in the nucleus basalis of Meynert and its projections
in patients with dementia. They are considered symptomatic therapies and are not believed to be
neuroprotective or to alter the underlying disease trajectory.

This topic will discuss the use of cholinesterase inhibitors in the treatment of dementia. Topics on
other aspects of the treatment of dementia include:

● (See "Treatment of dementia".)

● (See "Management of neuropsychiatric symptoms of dementia".)

● (See "Safety and societal issues related to dementia".)

● (See "Care of patients with advanced dementia".)

INDICATIONS

Alzheimer disease — The majority of patients with newly diagnosed Alzheimer disease (AD) should
be offered a trial of a cholinesterase inhibitor for symptomatic treatment of cognition and global
functioning. As discussed below, the degree of expected benefit is modest, and therapy should not be

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continued indefinitely in patients who do not appear to be benefiting or who have significant side
effects. There is no convincing evidence that cholinesterase inhibitors are neuroprotective or have the
ability to alter the underlying disease trajectory. (See 'Duration of therapy' below.)

Cholinesterase inhibitors have been studied in patients with varying severities of dementia. Although
eligibility criteria are not uniform across all trials and cutoffs are variably defined, dementia severity
can generally be categorized by Mini-Mental State Examination (MMSE) scores, Montreal Cognitive
Assessment (MoCA), or clinical dementia rating (CDR) (table 1) as follows:

● Mild dementia – MMSE 19 to 26; MoCA 12 to 16; CDR 1

● Moderate dementia – MMSE 10 to 18; MoCA 4 to 11; CDR 2

● Severe dementia – MMSE <10; MoCA <4; CDR 3

The assessment and diagnosis of cognitive impairment and dementia are reviewed in detail
separately. (See "Evaluation of cognitive impairment and dementia".)

Mild to moderate dementia — The average benefit of cholinesterase inhibitors in patients with
mild to moderate dementia (eg, MMSE 10 to 26) is a small improvement in cognition, neuropsychiatric
symptoms, and activities of daily living (ADLs) [1-8].

The degree of benefit is summarized by a meta-analysis of 13 randomized trials of donepezil,

galantamine, or rivastigmine versus placebo in more than 3000 patients with AD (mostly mild to
moderate disease severity) [6]. When assessed at 6 to 12 months, cholinesterase inhibitors led to
modest improvements on the 70-point Alzheimer Disease Assessment Scale-Cognitive Subscale
(ADAS-Cog; mean difference 2.7 points, 95% CI 2.3-3.0) and MMSE (mean difference 1.37 points,
95% CI 1.13-1.61) as well as global impression by caregivers and ADLs. One analysis estimated that
these effects would be similar to preventing a two-months-per-year decline in a typical patient with AD
[1]; another concluded that for every 12 patients treated, one would benefit by achieving minimal
improvement or better and one would develop a treatment-related adverse effect [9].

Whether these drugs significantly improve long-term outcomes, such as the need for nursing home
admission or maintaining critical ADLs, remains in doubt, and the evidence is conflicting [1,10-14].
The AD2000 study, one of few nonindustry-sponsored trials of a cholinesterase inhibitor versus
placebo with long-term follow-up, found no significant benefit of donepezil compared with placebo for
the two primary endpoints: entry to institutional care and progression of disability [10].

Additional evidence suggests that the response to cholinesterase inhibitors may be quite variable,
with as much as 30 to 50 percent of patients showing no observable benefit [15,16], while a smaller
proportion (up to 20 percent) may show a greater than average response (≥7-point ADAS-Cog

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improvement) [17,18]. These findings reinforce the importance of making individualized decisions for
each patient based on clinical response and side effects.

Advanced disease — The relative effects of cholinesterase inhibitors appear to be similar for
patients with more severe dementia (eg, MMSE <10) at the time of diagnosis, but fewer studies have
been performed and the absolute effects may be less clinically important than those seen in patients
with mild to moderate dementia.

As in earlier-stage disease, small benefits on some but not all cognitive and functional outcomes have
been noted in short-term trials of either donepezil or galantamine in previously untreated community-
dwelling adults and nursing home residents with moderate to advanced dementia [19-23].

Decisions on long-term use depend on the patient's functional response to treatment and long-term
goals of care, and should be made in consultation with caregivers and family [24]. (See 'Follow-up
and monitoring' below.)

Non-Alzheimer dementia syndromes — Cholinesterase inhibitors are also suggested in most

patients with dementia with Lewy bodies (DLB) and may have comparatively greater symptomatic
benefits than are observed in patients with AD. (See "Prognosis and treatment of dementia with Lewy
bodies", section on 'Cholinesterase inhibitors'.)

There is less consensus on the role of cholinesterase inhibitors in patients with other forms of
dementia, and regulatory approval is more variable for non-AD diagnoses. Most of the studies of
cholinesterase inhibitors have been performed in patients with a clinical diagnosis of AD, and data are
more limited and less consistent for other forms of dementia. Although AD is by far the most common
cause of dementia in older adults, evidence of mixed pathology at the time of autopsy is common,
especially the combination of Alzheimer and vascular pathology [17,25,26]. Many experts therefore
find it reasonable to offer a trial of a cholinesterase inhibitor in patients with a clinical diagnosis of
other types of dementia, including:

● Vascular dementia (see "Treatment of vascular cognitive impairment and dementia", section on
'Cholinesterase inhibitors')

● Parkinson disease dementia (see "Cognitive impairment and dementia in Parkinson disease",
section on 'Cholinesterase inhibitors')

In the aggregate, trials have not provided support for the use of cholinesterase inhibitors for these
indications:

● Preventing progression of mild cognitive impairment to dementia (see "Mild cognitive impairment:
Prognosis and treatment", section on 'Acetylcholinesterase inhibitors')

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● Frontotemporal dementia (see "Frontotemporal dementia: Treatment", section on 'Cognitive

dysfunction')

● Dementia in patients with Huntington disease (see "Huntington disease: Management", section
on 'Cognitive impairment and dementia')

● Cognitive impairment in patients with multiple sclerosis (see "Symptom management of multiple
sclerosis in adults", section on 'Cognitive impairment')

This approach is generally consistent with guidelines from multiple societies including the American
Academy of Neurology [3], American Psychiatric Association [27], Canadian Consensus Conference
[28], National Institute for Health and Care Excellence (NICE) [29], British Association for
Psychopharmacology [30], and European Federation of Neurological Societies (EFNS) [31,32].

CHOICE OF DRUG

Three cholinesterase inhibitors are available for use in a variety of formulations:

● Donepezil, available as a once-daily tablet and a once-daily disintegrating sublingual tablet

● Galantamine, available as a twice-daily tablet or solution and an extended-release once-daily

capsule

● Rivastigmine, available as a twice-daily capsule, a twice-daily solution (in some regions), and a
24-hour transdermal patch

All have demonstrated efficacy compared with placebo, and a limited number of direct comparisons
do not suggest major differences in efficacy or tolerability among the three drugs [33-38]. Selection of
an agent is therefore based largely upon ease of use, individual patient tolerability, cost, and clinician
and patient preference (table 2).

In a pragmatic, open-label trial of 196 older adults with possible or probable AD who were initiating
treatment with a cholinesterase inhibitor at one of four memory care practices in the United States,
patients were randomly assigned to donepezil, galantamine, or rivastigmine using dosing and
formulations at the discretion of the treating clinician [37]. At 18 weeks, rates of discontinuation for
any reason (including study withdrawal/loss to follow-up) were similar for the three drugs (39, 53, and
59 percent, respectively; p = 0.06). The most common reasons for discontinuation were adverse
events (56 percent) and cost (29 percent). Among the three drugs, donepezil was the most likely to be
titrated to the maximum dose (53, 5, and 29 percent) and the least likely to be discontinued for cost-
related reasons (0, 26, and 30 percent). Side-effect rates and profiles were largely similar among

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groups. Other studies have also found higher discontinuation rates for rivastigmine and similar rates
for donepezil and galantamine [33,39].

ADMINISTRATION

Contraindications and precautions — Cholinesterase inhibitors enhance vagal tone and are
contraindicated in patients with baseline bradycardia or known cardiac conduction system disease
(eg, sick sinus syndrome, incomplete heart block) due to risk of syncope, falls, and fractures.

Caution should be used when any of the three drugs are used in combination with drugs that induce
bradycardia or alter atrioventricular (AV) nodal conduction (eg, beta blockers, calcium channel
blockers, lacosamide). Specific drug interactions may be determined by use of the Lexicomp drug
interactions tool (Lexi-Interact) included with UpToDate.

Galantamine should not be used in patients with end-stage kidney disease or severe hepatic
impairment, and the rivastigmine patch requires dose adjustments for hepatic impairment and low
body weight.

Specific drugs — Although side effects are largely similar across drugs, dose and formulation vary
among the three cholinesterase inhibitors.

Donepezil — Donepezil is the oldest cholinesterase inhibitor still in use and remains a preferred
and widely prescribed drug in this class due to its once-daily dosing and ease of use.

The recommended starting dose of donepezil is 5 mg per day, increasing to 10 mg per day after four
to six weeks. Donepezil is available in pill form and also as an oral disintegrating tablet for those
unable or unwilling to swallow a pill. Because nightly dosing can be associated with vivid dreaming or
nightmares, we typically start with morning dosing to avoid sleep disturbances and then switch to
nightly dosing if daytime nausea occurs.

A 23 mg noncrushable tablet of donepezil is available, but evidence does not support a clinically
important advantage to the higher dose and it is associated with increased side effects [40].

Gastrointestinal symptoms (upset stomach, nausea, diarrhea, anorexia) are the most common side
effects with prolonged use of donepezil, occurring in approximately 20 to 30 percent of patients
[37,41-44]. Symptomatic bradycardia can occur and is also related to cholinergic toxicity [45,46]. Rare
cases of rhabdomyolysis and/or neuroleptic malignant syndrome have been reported in postmarketing
surveillance [47].

No dose adjustments are needed for renal or hepatic impairment.

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Galantamine — Galantamine is available as a twice-daily tablet or solution and as a once-daily

extended-release capsule. The latter is preferred unless patients cannot swallow capsules.

The recommended starting dose is 8 mg once daily (4 mg twice daily for immediate release),
increasing to 16 mg once daily (8 mg twice daily for immediate release) after four weeks and then to a
target maintenance dose of 24 mg once daily (12 mg twice daily for immediate release) after four
more weeks.

Gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia, weight loss) are the most common
adverse effects and may be more likely with galantamine than with donepezil. Galantamine should be
given with meals to decrease the risk of nausea.

Galantamine should not be used in patients with end-stage kidney disease or severe hepatic
impairment. A maximum dose of 12 mg is advised in patients with moderate renal (creatinine
clearance 9 to 59 mL/minute) or hepatic impairment.

The use of galantamine has been associated with increased mortality in patients with mild cognitive
impairment [48] (see "Mild cognitive impairment: Prognosis and treatment", section on
'Acetylcholinesterase inhibitors'). Increased mortality has not been observed in patients treated for
AD, mixed dementia, or vascular dementia.

Rivastigmine — Rivastigmine is available in oral and transdermal formulations. The transdermal

patch is preferred over the oral formulation because it has better tolerability and similar efficacy [49].

Three dose levels of the transdermal patch are available: 4.6, 9.5, and 13.3 mg/24 hours. The
recommended starting dose of 4.6 mg/24 hours can be titrated upwards every four weeks. The patch
can cause skin irritation, and application sites should be rotated. Two trials have shown a possible
dose effect, with greater cognitive improvement on some but not all outcome measures with higher-
dose patches [50,51].

The transdermal patch should be used at the lowest dose only (4.6 mg/24 hours) in patients with mild
to moderate hepatic impairment, and the patch has not been studied in patients with severe hepatic
impairment. The lowest dose should also be used in patients with low body weight (<50 kg).

If used, oral rivastigmine should be given with food and titrated more slowly than the other drugs due
to increased risk of nausea, vomiting, anorexia, and headaches. Rivastigmine pill or solution is started
at 1.5 mg twice daily, increasing in two- to four-week intervals by 1.5 mg twice-daily increments. If
treatment is interrupted for longer than several days, it should be restarted at the lowest daily dose
and then titrated again [52]. One trial found that side effects of oral rivastigmine may be ameliorated
and higher daily doses achieved when it is given three times a day, rather than twice daily [53].

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Approach to common side effects — An approach to some of the more common or expected side
effects of cholinesterase inhibitors is presented below. Because the benefits of cholinesterase
inhibitors are modest, clinicians should assess whether the patient is benefiting from the drug before
persisting, and use caution to avoid prescribing cascades (ie, prescribing a new drug to treat an
unrecognized adverse effect of an existing therapy). (See "Drug prescribing for older adults", section
on 'Prescribing cascades'.)

Nausea and diarrhea — The most common side effects of cholinesterase inhibitors are
gastrointestinal (primarily diarrhea, nausea, and vomiting). The toxicity is dose related and often
resolves with time or dose reduction.

For oral rivastigmine, taking smaller doses more frequently or changing to a patch formulation may
help. Both galantamine and oral rivastigmine should be taken with meals [54].

Donepezil seems to be less likely to cause gastrointestinal upset than the other two drugs, so
switching to donepezil may be reasonable in patients who do not tolerate galantamine or rivastigmine.

Anorexia and weight loss — Weight loss occurs more commonly with cholinesterase inhibitors
than placebo, but the clinical importance of this effect can be difficult to determine in individual
patients, as dementia itself is often associated with weight loss.

In a case-control study that included 1188 patients with dementia who were started on a
cholinesterase inhibitor (mostly donepezil and galantamine) and 2189 propensity score-matched
controls, the mean weight loss over one year was 3.1 pounds in treated patients and 2.5 pounds in
controls (p = 0.02) [55]. The proportion of patients who developed significant weight loss (10 pounds
or more over one year) was also significantly higher in treated patients (29 versus 23 percent). In a
meta-analysis of nine placebo-controlled randomized trials with a median follow-up of five months, the
risk of any weight loss was twofold higher in patients randomized to receive a cholinesterase inhibitor
(6 versus 3 percent; odds ratio [OR] 2.18, 95% CI 1.50-3.17) [56].

In patients who are noted to be losing weight while on a cholinesterase inhibitor, we typically pursue
nutritional counseling before stopping therapy and monitor the trend in weight over time. AD is often
associated with anosmia, which detracts from taste. Enhancing the taste of food with spices, sweet
and sour flavoring, or soy sauce can help with appetite. For patients with comorbid depression,
mirtazapine is a good choice of antidepressant because it can augment appetite.

Bradycardia and hypotension — Bradycardia, heart block, and syncope can arise due to
enhanced vagal tone. Cholinergic therapy should be discontinued in patients who develop
symptomatic bradycardia and/or hypotension for which no other addressable cause is identified (eg,
concomitant antihypertensive therapy). Cholinesterase inhibitors should be avoided in patients with

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baseline bradycardia or known cardiac conduction system disease. (See 'Contraindications and
precautions' above.)

In one population-based cohort, the incidence of hospitalization for syncope was 3.2 events per 100
person-years for individuals taking cholinesterase inhibitors (68 percent were taking donepezil) [46].
This event rate was 1.7 times higher than in a control group. Similarly, a meta-analysis of 54
randomized trials found that cholinesterase inhibitors were associated with 1.5-fold greater risk of
syncope than placebo [57].

Sleep disturbances — Insomnia, vivid dreams, and other sleep disturbances may be more
common with donepezil than the other two drugs. If vivid dreams or nightmares arise on donepezil,
switching to morning dosing or to an alternative drug may help [54].

Additional strategies for the management of sleep disturbances in patients with dementia are
reviewed separately. (See "Sleep-wake disturbances and sleep disorders in patients with dementia",
section on 'Management'.)

FOLLOW-UP AND MONITORING

Patients who are started on a cholinesterase inhibitor should be seen for follow-up at three and six
months to assess drug tolerance and response. A phone call at two weeks can be useful to
troubleshoot early side effects. Patients on a stable dose of drug are then seen every 6 to 12 months
thereafter. Routine laboratory monitoring is not required for any of the cholinesterase inhibitors.

Assessment of response — Response to cholinesterase inhibitors can be subtle and gradual. We

typically counsel patients and families to anticipate a six-month trial before making a decision about
whether the medication is helping or not.

The Mini-Mental State Examination (MMSE) is not specific enough for following response; we
generally use a combination of naming, recall of a four-word list or story at 30 seconds and five
minutes, and semantic fluency (eg, naming as many animals as possible in one minute). The
Montreal Cognitive Assessment (MoCA) can be administered at each visit to track change over time.
The MoCA is accessible online and in multiple languages at www.mocatest.org. It is a 30-point test
that takes approximately 10 minutes to administer. Other brief cognitive tests are reviewed separately.
(See "The mental status examination in adults", section on 'Cognitive screening tests'.)

Caregiver impression of change, behavioral symptoms, sleep, and other neuropsychiatric symptoms
should also be assessed at each visit. (See "Management of neuropsychiatric symptoms of
dementia", section on 'Symptom assessment'.)

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There is conflicting evidence that pharmacogenetics may influence the response to cholinesterase
treatment, such that some patients are either hyper- or hypometabolizers of these agents [58-61]. As
an example, some studies have suggested that patients with a specific CYP2D6 allele have a poorer
response to donepezil treatment, particularly if they also have the apolipoprotein E (APOE) epsilon 4
allele [59,61]. However, these associations do not appear to have a consistent effect on treatment
response and have no clear association with adverse effects. Thus, we do not test for these alleles
and instead assess and respond to the observed clinical effects and/or side effects.

Duration of therapy — There is no consensus on how long to continue cholinesterase inhibitors in

patients who are tolerating therapy, and even patients who respond initially will ultimately progress.

Patients who do not respond initially — Since cholinesterase inhibitors are a symptomatic
treatment and not disease modifying, some clinicians, patients, and families choose to stop treatment
after a six-month trial if there has been no subjective or objective improvement. Unless the medication
is already at the lowest dose, it should be tapered by 50 percent for two to three weeks before
stopping to minimize risk of worsening. An alternative cholinesterase inhibitor is not typically used in
this setting unless a patient is unable to achieve a target dose on the initial chosen drug due to side
effects or formulation. Memantine can be added or substituted in patients with moderate to severe
dementia. (See 'Role of memantine' below.)

Others feel that it is not possible to determine which patients are responders based on initial response
to medication and therefore suggest continuing medication as long as the patient agrees to it and
tolerates it [62]. Support for this approach is also drawn from a clinical trial of 295 patients with
moderate to severe AD who were already taking donepezil, which compared the efficacy of four
treatment strategies: no therapy (donepezil discontinued), donepezil continued alone, donepezil
continued with memantine added, and memantine therapy alone [13,14]. After one year, patients
assigned to receive donepezil therapy had, on average, a higher score on the MMSE (1.9 points) and
a better score on the Bristol Activities of Daily Living Scale (BADLS; 3.0 points) compared with those
not receiving donepezil. The average differences in the MMSE score, but not the BADLS, met the
prespecified threshold considered by the investigators to be clinically important. The trial was stopped
early due to slow recruitment. A post hoc analysis suggested that discontinuation of donepezil might
increase the risk of nursing home placement over the next 12 months, but not over the prespecified
four-year follow-up period [14].

Other reasons for discontinuation — Aside from lack of perceived benefit, other reasons for
discontinuation of cholinesterase inhibitors include:

● Intolerable side effects despite dose reduction. If the main reason for discontinuation of a drug is
gastrointestinal side effects, sometimes switching to a different formulation or drug can help.

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Memantine is also an option in patients with moderate to severe disease and may be better
tolerated. (See 'Approach to common side effects' above and 'Role of memantine' below.)

● Rate of cognitive, functional, or behavioral decline is greater on treatment compared with

pretreatment baseline. Of note, fluctuations in cognition and behavior are common in patients
with dementia and are often multifactorial. An approach to the evaluation and management of
neuropsychiatric symptoms of dementia is presented separately. (See "Management of
neuropsychiatric symptoms of dementia".)

● Comorbidities or nonadherence make continued use of the drug unacceptably risky or futile.

● Progression to an advanced stage of dementia (eg, Functional Assessment Stage 7 (table 3)), in
which there is little hope for a clinically meaningful benefit to continued therapy. (See "Care of
patients with advanced dementia", section on 'Continuation of anti-dementia and other chronic
medications'.)

Patients who worsen when drug is stopped — Occasionally patients will worsen after stopping
therapy, even when appropriately tapered over a two- to three-week period [63-65]. It is not clear if
this is a sign that they benefited from the medication, but we generally reintroduce it when clinical
decline is closely temporally linked with medication withdrawal. While data from clinical trials
suggested that treatment gaps (periods in which the patient did not take cholinesterase inhibitor) were
associated with worse outcomes, a large observational study of older adult patients prescribed
cholinesterase inhibitors found that the risk of institutionalization or death did not appear to be
increased among those who experienced treatment gaps [66].

Role of memantine — Memantine is commonly added to cholinesterase inhibitor therapy when

patients reach a moderate stage of AD (MMSE ≤18), based on moderate-quality data that the
combination therapy leads to modest symptomatic benefits on cognition and behavior. Memantine can
also be used as a single agent among patients who do not tolerate cholinesterase inhibitors. (See
"Treatment of dementia", section on 'Memantine'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Cognitive impairment and dementia".)

INFORMATION FOR PATIENTS

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UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These articles
are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Dementia (including Alzheimer disease) (The Basics)" and
"Patient education: Tips for caregivers of people with Alzheimer disease (The Basics)")

● Beyond the Basics topics (see "Patient education: Dementia (including Alzheimer disease)
(Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Cholinesterase inhibitors target the acetylcholine deficit arising from loss of neurons in the
nucleus basalis of Meynert and its projections in patients with dementia. They are considered
symptomatic therapies and are not believed to be neuroprotective or to alter the underlying
disease trajectory. (See 'Introduction' above.)

● For patients with newly diagnosed Alzheimer disease (AD) dementia, we suggest a trial of a
cholinesterase inhibitor (Grade 2A). Patients with dementia of mild to moderate severity (eg,
Mini-Mental State Examination [MMSE] 10 to 26) may be the most likely to derive clinical benefit,
which is typically modest and must be balanced with the risk of adverse effects. Decisions should
be individualized in patients with very advanced dementia (eg, MMSE <5) at the time of
diagnosis. (See 'Alzheimer disease' above.)

● Lower-quality data support a trial of a cholinesterase inhibitor in patients with other forms of
dementia, including dementia with Lewy bodies (DLB), vascular dementia, and Parkinson
disease dementia. Recommendations for treatment of these disorders are discussed separately.
(See "Prognosis and treatment of dementia with Lewy bodies", section on 'Cholinesterase
inhibitors' and "Treatment of vascular cognitive impairment and dementia", section on
'Cholinesterase inhibitors' and "Cognitive impairment and dementia in Parkinson disease",
section on 'Cholinesterase inhibitors'.)

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● Cholinesterase inhibitors enhance vagal tone and are contraindicated in patients with baseline
bradycardia or known cardiac conduction system disease (eg, sick sinus syndrome, incomplete
heart block) due to risk of syncope, falls, and fractures. They should be used with caution in
combination with drugs that induce bradycardia or alter nodal conduction. (See 'Contraindications
and precautions' above.)

● The choice among donepezil, galantamine, and rivastigmine can be based upon ease of use,
individual patient tolerance, cost, and clinician and patient preference, as efficacy appears to be
similar (table 2). (See 'Choice of drug' above.)

• Donepezil is available as a once-daily tablet and a once-daily disintegrating sublingual tablet.

The starting dose is 5 mg once daily. No dose adjustments are needed for renal or hepatic
impairment. (See 'Donepezil' above.)

• Galantamine is available as a once-daily extended-release capsule and twice-daily tablet or

solution. The starting dose is 8 mg once daily for the extended-release capsule (4 mg twice
daily for immediate release), with meals. Dose adjustments are required for renal or hepatic
impairment. (See 'Galantamine' above.)

• Rivastigmine is available as an oral capsule or solution (starting dose 1.5 mg twice daily) and
as a daily transdermal patch (starting dose 4.6 mg/24 hours). The patch is preferred due to
superior pharmacokinetics and tolerability; it requires dose adjustments for hepatic
impairment and low body weight. (See 'Rivastigmine' above.)

● The most common side effects of cholinesterase inhibitors are gastrointestinal (primarily diarrhea,
nausea, and vomiting). The toxicity is dose related and often resolves with time or dose
reduction. Additional side effects include anorexia and weight loss, bradycardia and hypotension,
syncope, and sleep disturbances. (See 'Approach to common side effects' above.)

● There is no consensus on how long to continue cholinesterase inhibitors in patients who are
tolerating therapy, and even patients who respond initially will ultimately progress. Some
clinicians, patients, and families choose to stop treatment after a six-month trial if there has been
no subjective or objective improvement. Others feel that it is not possible to determine which
patients are responders based on initial response and therefore suggest continuing medication
as long as the patient agrees to it and tolerates it. (See 'Duration of therapy' above.)

● Other reasons for discontinuation include poor tolerance despite dose reduction or drug
switching, comorbidities or nonadherence that make continued use unacceptably risky or futile,
and progression to an advanced stage of dementia, in which there is little hope of a meaningful
benefit to continued therapy. (See 'Other reasons for discontinuation' above.)

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● Unless the medication is already at the lowest dose, it should be tapered by 50 percent for two to
three weeks before stopping to minimize risk of worsening. We generally reintroduce therapy if a
clinical decline occurs shortly after medication withdrawal. (See 'Patients who worsen when drug
is stopped' above.)

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GRAPHICS

Clinical dementia rating (CDR): 0, 0.5, 1, 2, 3

Questionable Moderate
Impairment None (0) Mild (1) Severe (3)
(0.5) (2)

Memory No memory loss or Consistent slight Moderate memory Severe memory Severe memory
slight inconstant forgetfulness; loss; more marked loss; only highly loss; only
forgetfulness partial for recent events; learned material fragments
recollection of defect interferes retained; new remain
events with everyday material rapidly
activities lost

Orientation Fully oriented Fully oriented or Moderate difficulty Severe difficulty Oriented to
slight difficulty with time with time person only
with time relationships; relationships;
relationships oriented for place usually
at examination; disoriented in
may have time, often to
geographic place
disorientation
elsewhere

Judgment and Solves everyday Slight impairment Moderate difficulty Severely Unable to make
problem problems and to solving in handling impaired in judgments or
handles business problems, problems, handling solve problems
and financial affairs similarities, similarities, problems,
well; judgment differences differences; social similarities,
good in relation to judgment usually differences;
past performance maintained social judgment
usually impaired

Community Independent Slight impairment Unable to function No pretense of No pretense of

affairs function at usual in these activities independently at independent independent
level in job, these activities function outside function outside
shopping, volunteer though may still be of home; of home;
and social groups engaged in some; appears well appears too ill
appears normal to enough to be to be taken to
casual inspection taken to functions
functions outside outside a family
of family home home

Home and Life at home, Life at home, Mild but definite Only simple No significant
hobbies hobbies, intellectual hobbies, impairment of chores function in
interests well intellectual function at home; preserved; very home
maintained interests slightly more difficult restricted
impaired chores abandoned; interests, poorly
more complicated maintained
hobbies and
interests
abandoned

Personal care Fully capable of self Fully capable of Needs prompting Requires Requires much
care self care assistance in help with
dressing, personal care;
hygiene, keeping frequent
of personal incontinence
effects

Score only as decline from previous usual level due to cognitive loss, not impaired due to other factors.

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Reproduced with permission from: Morris JC. The clinical dementia rating (CDR): Current version and scoring rules. Neurology
1993; 43:2412. Copyright © 1993 Lippincott Williams & Wilkins.

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Cholinesterase inhibitors used for treatment of dementia: Dose and administration

Starting
Drug Formulations Maintenance dose Comments
dose

Donepezil Tablet or oral 5 mg orally, 10 mg daily (increased after 4

disintegrating once daily to 6 weeks)*
tablet

Galantamine Immediate- 4 mg orally, 12 mg twice daily (increased Give with meals. Maximum 8
release tablet or twice daily in monthly intervals by 4 mg mg twice daily with moderate
solution twice-daily increments) renal or liver impairment. Do
not use with severe renal or
liver impairment.

Extended-release 8 mg orally, 24 mg once daily (increased Maximum 12 mg once daily

capsule once daily in monthly intervals by 8 mg with moderate renal or liver
once-daily increments) impairment. Do not use with
severe renal or liver
impairment.

Rivastigmine Capsule 1.5 mg orally, 6 mg twice daily (increased in Give with meals. Slow and
twice daily 2- to 4-week intervals by 1.5 cautious titration with renal or
mg twice-daily increments) liver impairment or low body
weight.

Transdermal 4.6 mg/24 9.5 to 13.3 mg/24 hours Can cause rash; rotate sites.
patch hours (increased in monthly Fewer side effects than
intervals by 4.6 mg capsule. Maximum dose 4.6
increments) mg/24 hours with mild to
moderate liver impairment or
low body weight. Do not use
with severe liver impairment.

*A 23 mg noncrushable tablet of donepezil is available, but evidence does not support a clinically important advantage
to the higher dose and it is associated with increased side effects.

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Medicare hospice benefit guidelines for determining prognosis in dementia

To be eligible for hospice, patients must meet both of the following criteria:

I. Functional Assessment Staging (FAST): Patient must be at or beyond stage 7; unable to walk, dress, and bathe
without assistance; urinary and fecal incontinence (intermittent or constant); no consistently meaningful verbal
communication (stereotypical phrases only or the ability to speak is limited to six or fewer intelligible words)

II. Medical conditions: Patients must have had at least one of the listed medical conditions over the prior year

I. Functional Assessment Staging (FAST)

Stage Features

1 No objective or subjective difficulties

2 Subjective complaints of forgetting

3 Decreased job functioning evident to coworkers; difficulty traveling to new locations

4 Decreased ability performing complex tasks, eg, planning dinner for guests, handling finances

5 Requires assistance to choose proper clothes for day, season, or occasion

6a Cannot dress without assistance; occasionally or more frequently

6b Cannot bathe without assistance; occasionally or more frequently

6c Cannot toilet without assistance; occasionally or more frequently

6d Incontinent of urine; occasionally or frequently

6e Incontinent of bowel; occasionally or frequently

7a Speech limited to fewer than six intelligible words during an average day

7b Speech limited to single intelligible word during an average day

7c Unable to ambulate independently

7d Cannot sit up independently

7e Cannot smile

7f Cannot hold head up independently

II. Medical conditions

1. Aspiration pneumonia

2. Pyelonephritis

3. Septicemia

4. Decubitus ulcer, multiple, stage 3 to 4

5. Recurrent fever after treatment with antibiotics

6. Inability to maintain sufficient fluid and calorie intake with 10% weight loss during the previous six months or
serum albumin <2.5 g/dL

Source: Centers for Medicare & Medicaid Services. Local Coverage Determination (LCD) for Hospice Determining Terminal
Status (L32015) http://www.cms.gov (Accessed on July 17, 2013).

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