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Cholinesterase inhibitors in dementia
Daniel Press, MD
Michael Alexander, MD
UpToDate performs a continuous review of over 330 journals and other resources.
Updates are added as important new information is published. The literature review for
version 13.3 is current through August 2005; this topic was last changed on September
11, 2005. The next version of UpToDate (14.1) will be released in February 2006.
INTRODUCTION — Patients with Alzheimer's disease (AD) have reduced cerebral
production of choline acetyl transferase, which leads to a decrease in acetylcholine
synthesis and impaired cortical cholinergic function. This early discovery of a marked
cholinergic deficit in the brains of patients with AD led to the study of therapeutically
augmenting cholinergic activity [1]. However, acetylcholine precursors were found to be
ineffective [2,3], while postsynaptic cholinergic receptor agonists had unacceptable side
effects [4]. By contrast, the results of studies with cholinesterase inhibitors, which
increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft, have
been more encouraging, and these drugs may even have some utility in the non-AD
dementias.
This topic will discuss the use of cholinesterase inhibitors in the treatment of dementia.
Other treatments of dementia are discussed elsewhere. (See "Treatment of dementia").
ALZHEIMER'S DISEASE — Four cholinesterase inhibitors, tacrine, donepezil,
rivastigmine, and galantamine are currently approved for use in Alzheimer's disease (AD)
by the US Food and Drug Administration (FDA). Tacrine was the first agent approved for
use in AD, but it can cause hepatotoxicity and is rarely used [5]. The choice between the
other three agents is largely based upon cost, individual patient tolerability, and
physician experience, as efficacy appears to be similar [6]. (Show table 1).
Donepezil — Donepezil has relatively little peripheral anticholinesterase activity and is
generally well tolerated. This combined with its once-daily dosing has made it a popular
drug in patients with AD. The recommended dose for donepezil is 5 mg per day for 4
weeks, then increasing to 10 mg per day.
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The efficacy of donepezil was demonstrated in a 24-week double-blind study in which
patients with mild to moderate AD were randomly assigned to donepezil (5 or 10 mg/
day) or placebo [7]. Cognition, as measured by the Alzheimer's Disease Assessment
Scale, cognitive subscale (ADAS-cog) [8], and the Clinician's global ratings were
significantly improved in both treatment groups compared with placebo. There was no
consistent effect noted on patient-related quality of life measures.
A second placebo-controlled trial of donepezil (AD2000) enrolled 566 patients referred to
memory clinics with mild to moderate AD, with or without cerebrovascular disease [9].
There was a small but significant beneficial effect of donepezil for cognition compared
with placebo, with a 0.8 point difference in the Mini Mental Status Exam (MMSE) score
(95% CI 0.5-1.2) [9]. This size effect of cognitive improvement was similar to that seen
in other randomized trials of donepezil [10]. Although donepezil slowed the decline in
activities of daily living in patients with moderate to severe AD in an earlier study [11], it
did not delay entry to institutional care in the AD2000 study [9].
A six-week placebo washout was performed after 24 weeks of the study cited above to
examine whether donepezil had any disease-modifying activity [7]. The improvements on
cognitive measures were erased, strongly suggesting that the drug does not effect the
underlying course of disease.
Donepezil may also have benefit for patients who have crossed the threshold from mild
cognitive impairment (MCI) to early stage AD, but the data are limited. One trial enrolled
153 patients with early-stage AD (MMSE scores of 21 to 26 and only mild impairment on
activities of normal living) [12]. Donepezil treatment was associated with a significant,
but clinically modest, 2.3 point improvement on the ADAS-cog at 24 weeks compared
with placebo.
Prolonged treatment with donepezil appears to be safe and effective [13-15]. Cholinergic
side effects (primarily diarrhea, nausea, and vomiting) are transient and generally mild,
occurring in about 20 percent of patients [7].
Donepezil and other cholinesterase inhibitors appear to modestly improve
neuropsychiatric symptoms as well. (See "Treatment of behavioral symptoms related to
dementia", section on Cholinesterase inhibitors).
Rivastigmine — Rivastigmine appears to be beneficial in patients with mild to moderate
AD [16] and has been approved for use by the FDA. Its side-effect profile is related to
cholinergic effects, with significant nausea, vomiting, anorexia, and headaches. It should
be given with food to minimize nausea. One case of esophageal rupture due to severe
vomiting has been reported; the manufacturer advises slow titration of the drug (eg,
initiating therapy at 1.5 mg twice daily with titration every two weeks up to 6 mg twice
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daily) and, if treatment is interrupted for longer than several days, it should be restarted
at the lowest daily dose and then titrated again [17]. While not compared head-to-head
with donepezil, its efficacy appears similar, although it may have more gastrointestinal
side effects [18].
Galantamine — Galantamine (Razadyne; previously marketed as Reminyl) appears to
be effective in patients with mild to moderate AD [19]. At least three randomized
controlled trials found that treatment with galantamine (maintenance dose 24 or 32 mg/
day) slowed the decline in both cognition and activities of daily living compared with
placebo in patients with early AD [20-22]. Cognitive benefits of galantamine have been
sustained for up to 36 months [23]. A secondary analysis [24] of a randomized controlled
trial [21] reported that galantamine-treated AD patients had significantly better overall
ADL scores than the placebo group at five months regardless of dementia severity.
Gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia, weight loss) are the
most common adverse effects of galantamine. Like rivastigmine, galantamine appears to
have similar efficacy to donepezil in patients with AD but may have more gastrointestinal
side effects.
The use of galantamine has been associated with increased mortality in patients with MCI
[25]. (See "Mild cognitive impairment", section on Cholinesterase inhibitors). Increased
mortality has not been observed in patients treated for AD, mixed dementia, or vascular
dementia.
Advanced disease — Although efficacy of cholinesterase inhibitors for cognitive effects
has been established in patients with mild to moderate AD, it is not clear if patients with
advanced AD, including patients in nursing homes, will benefit from therapy. One study
has investigated the use of donepezil in patients with moderate to severe AD (defined as
MMSE score of 5 to 17), including both community-dwelling individuals and those in
assisted living settings who still had measurable functional ability [26]. Donepezil therapy
was well tolerated and was associated with significant improvements in global function,
cognition, behavior, and activities of daily living compared with placebo.
Similar results were reported in a randomized, double-blind, placebo-controlled study of
208 nursing home residents, 70 percent of whom had a MMSE score <20 at baseline
[27]. These data are encouraging but require further confirmation before
recommendations can be made for patients with advanced AD.
OTHER DEMENTIAS — Some controversy exists over who should be treated with
cholinesterase inhibitors [28,29]. Nonetheless, these medications appear to offer similar
or greater benefits for certain non-Alzheimer dementias such as vascular dementia (VaD)
and dementia with Lewy bodies (DLB), and perhaps for dementia or cognitive impairment
associated with Parkinson's disease (PD).
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Vascular dementia — Patients with VaD have shown improvement in cognition,
behavior, and activities of daily living with cholinesterase inhibitors [30]. (See "Treatment
and prevention of vascular dementia").
Mixed dementia — Mixed dementia denotes a condition with clinical and pathological
features of both Alzheimer's disease (AD) and VaD. A systematic review of the literature
published in 2004 concluded that cholinesterase inhibitors provide modest clinical
benefits for patients with mixed dementia; the benefit is similar in magnitude to that
found for cholinesterase inhibitor treatment of AD [31]. Only two trials, one of
galantamine [32] and the other of rivastigmine [33], evaluated patients with mixed
dementia.
Dementia with Lewy bodies — Patients who have dementia with DLB can have marked
improvements in cognition as well as improvements in behavioral symptoms and
hallucinations, warranting a trial of cholinesterase inhibitors whenever this diagnosis is
suspected [34].
Parkinson's disease — In patients with PD, the prevalence of dementia is quite high.
(See "Dementia syndromes", section on Parkinson's disease with dementia). Preliminary
studies suggested that cholinesterase inhibitors were beneficial in patients who had
dementia associated with PD [35,36].
In a randomized clinical trial of 410 patients who had PD with dementia, treatment with
rivastigmine was associated with modest but significant improvement in global ratings of
dementia, cognition, and behavioral symptoms compared with placebo [37]. The
magnitude of the effects were similar to those observed among patients with AD who
were treated with cholinesterase inhibitors. The side effects of rivastigmine were mainly
cholinergic; nausea, vomiting, and tremor were the most common (29, 17, and 10
percent, respectively).
A small, double-blind, crossover trial compared donepezil with placebo in 22 patients with
dementia and PD. The primary outcome measure did not achieve a statistically significant
benefit, but two of four secondary measures (including MMSE) did show a benefit [38].
The power in this study was limited by sample size.
Mild cognitive impairment — The data regarding cholinesterase inhibitors in patients
with MCI are discussed separately. (See "Mild cognitive impairment", section on
Cholinesterase inhibitors).
PRACTICE ISSUES
Degree of benefit — The average benefit of cholinesterase inhibitors in patients with
dementia is a small improvement in cognition and activities of daily living [30,35,39-42].
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Whether these drugs significantly improve long-term outcomes, such as the need for
nursing home admission or maintaining critical activities of daily living (ADLs), remains in
doubt, and the evidence is conflicting [6,9,29,43].
In a meta-analysis of 29 randomized, placebo-controlled trials completed through
December 2001, patients on cholinesterase inhibitors improved 0.1 SDs on ADL scales
and 0.09 SDs on instrumental ADL (IADL) scales compared with placebo, an effect that
would be similar to preventing a two months per year decline in a typical patient with
Alzheimer's disease (AD) [6].
A second meta-analysis concluded that 12 patients would need to be treated for one
to benefit by achieving minimal improvement or better [44]. Treating 12 patients would
also result in one additional patient having a treatment-related adverse event (mostly
gastrointestinal side effects). Similar benefits are seen with cholinesterase inhibitors in
patients with vascular dementia (VaD) [30,39,40], and cholinesterase inhibitors appear
to show greater efficacy in patients with diffuse Lewy body dementia [35].
The AD2000 study, the only nonpharmaceutical industry sponsored trial of
cholinesterase inhibitors, found no significant benefit of donepezil compared with placebo
for the two primary endpoints: entry to institutional care and progression of disability [9].
Additional evidence suggests that the response to cholinesterase inhibitors may be quite
variable, with as many as 30 to 50 percent of patients showing no benefit [45,46], while
a smaller proportion (up to 20 percent) may show a greater than average response ( 7
point ADAS-cog improvement) [31,47].
Duration of therapy — Since cholinesterase inhibitors are a symptomatic treatment and
not disease-modifying, we generally administer them for eight weeks and then review the
patient's response with the family. Treatment is continued if improvement is noted either
on bedside testing or by the family. We stop treatment at this point if there has been no
improvement. The Mini Mental Status Exam (MMSE) is not specific enough for following
response; we generally use a combination of naming, recall at 30 seconds and five
minutes of a four-word list, and semantic fluency (eg, naming as many animals as
possible in one minute).
Occasionally patients will worsen after stopping therapy [48,49]. 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.
Cholinesterase inhibitors can be continued indefinitely. However, while there may be a
clinical benefit in patients with moderately advanced disease [26,27], we generally
discontinue the medication when a patient progresses to advanced dementia, and only
reintroduce it if there is any deterioration.
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Cost-effectiveness — Early analyses suggested that the cost of cholinesterase inhibitors
might be partially or even completely offset by lower home care costs and delayed
nursing home placement [50-53]. However, these findings were based upon a number of
favorable assumptions, including factors such as the duration of drug effect and delayed
nursing home placement, for which controlled data were lacking. Furthermore, the
AD2000 study discussed above found no benefit for donepezil compared with placebo for
entry to institutional care or formal care costs [9].
RECOMMENDATIONS — The following recommendations are based upon our clinical
practice given the existing evidence on therapies for dementia:
Start patients with mild to moderate dementia on a cholinesterase inhibitor. The
choice between donepezil, rivastigmine, and galantamine can be based upon cost,
individual patient tolerance, and physician experience, as efficacy appears to be similar
(show table 1). We do not routinely use tacrine. The cholinesterase inhibitors offer
potential symptomatic benefit that may take time to appear, so they should be started
first.
Cholinesterase inhibitors in patients with dementia produce, on average, small
improvements in measures of cognition and activities of daily living (ADL). Not all
patients benefit. Their impact on long-term outcomes, disability and institutionalization, is
not clear. (See "Degree of benefit" above).
Although most studies of cholinesterase inhibitors have been in patients with
Alzheimer's disease (AD), there is some evidence of benefit for patients with vascular
dementia (VaD), mixed dementia, dementia with Lewy bodies (DLB), and dementia in
Parkinson's disease (PD) that supports treatment trials in these patients as well. (See
"Other dementias" above).
Patients with dementia may also benefit from memantine and other therapies. (See
"Treatment of dementia").
In patients with severe dementia, cholinesterase inhibitors can be discontinued, but
they should be restarted if the patient worsens without the medication. (See "Duration of
therapy" above).
We do not routinely recommend cholinesterase inhibitors for patients with mild
cognitive impairment (MCI), but if memory problems are particularly troubling to the
patient, then a trial for symptomatic benefit may be warranted. (See "Mild cognitive
impairment", section on cholinesterase inhibitors).
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