Clinical Review
AChE Inhibitors and NMDA Receptor
Antagonists in Advanced Alzheimer’s
Disease
Brianna E. Glynn-Servedio, Trisha Seys Ranola
OBJECTIVE: The objective of this article is to review the
available evidence for duration of treatment with, and
considerations for discontinuation of, acetylcholinesterase
inhibitors and N-methyl-d-aspartate receptor antagonists in
Alzheimer’s disease.
DATA SOURCES: Literature searches of clinical trials and meta-
analyses were conducted using PubMed with the search terms
Alzheimer’s, dementia, donepezil, galantamine, memantine,
and rivastigmine. References from included trials were also
used to find additional citations.
STUDY SELECTION/DATA EXTRACTION: 2,925 articles were ini-
tially identified. Twenty-one studies were included that looked
at the use of acetylcholinesterase inhibitors and/or memantine
in the treatment of moderate-to-severe Alzheimer’s dementia.
DATA SYNTHESIS: Several clinical trials have demonstrated
small improvements in measures of cognition and activities of
daily living with medications used to treat dementia. However,
not all patients will benefit from treatment, and the impact of
treatment on long-term outcomes, including institutionaliza-
tion, remains unclear. This paper reviews the available data to
support the use of acetylcholinesterase inhibitors and/or me-
mantine in patients with advanced Alzheimer’s disease, includ-
ing those in nursing facilities, and reviews recommendations
for consideration of therapy discontinuation.
CONCLUSION: The evidence to support a specific time frame
for discontinuation of Alzheimer’s disease treatment is limited.
It is reasonable to stop a medication if there is no noticeable
benefit after the first three months of treatment or once
a patient’s dementia progresses to a point where there would
be no meaningful benefit from continued therapy.
KEY WORDS: Acetylcholinesterase inhibitors, Alzheimer’s
disease, Dementia, Memantine.
ABBREVIATIONS: AChE = Acetylcholinesterase, AD = Alzheimer’s
disease, ADLs = Activities of daily living, AGS = American
Geriatrics Society, CIBIC-plus = Clinician’s Interview-based
Impression of Change with caregiver input, CNS = Central
nervous system, FAST = Functional Assessment Scale, FDA =
THE CONSULTANT PHARMACIST   SEPTEMBER 2017   VOL. 32, NO. 9 511
Food and Drug Administration, GDS = Global Deterioration
Scale, MMSE = Mini-Mental Status Examination, NMDA =
N-methyl-d-aspartate, NPI = Neuropsychiatric Inventory,
SIB = Severe Impairment Battery.
Consult Pharm 2017;32:511-8.
Dementia is a disorder characterized by a decline
in cognition that interferes with daily functioning.
Alzheimer’s disease (AD) is the most common form
of dementia, accounting for 60% to 80% of all cases,
and is increasing in prevalence as the U.S. population
ages. The number of people older than 65 years of age
living with AD is expected to reach 6.7 million by 2025.1
The mainstays of AD treatment include two classes of
medications: acetylcholinesterase (AChE) inhibitors and
N-methyl-d-aspartate (NMDA) receptor antagonists.
Several clinical trials have demonstrated small improve-
ments in measures of cognition and activities of
daily living (ADLs) with AChE inhibitors, but not all
patients will benefit from treatment. Additionally, the
impact of treatment on long-term outcomes, including
institutionalization, remains unclear. This paper reviews
the available evidence for duration of treatment and
considerations for discontinuation of AChE inhibitors
and NMDA receptor antagonists. Literature searches of
clinical trials and meta-analyses were conducted using
PubMed with the search terms Alzheimer’s, dementia,
donepezil, galantamine, memantine, and rivastigmine.
References from the included trials were also used to find
additional citations. The authors initially identified 2,925
articles; 21 studies were included, which looked at the use
of AChE inhibitors and/or memantine in the treatment of
moderate-to-severe Alzheimer’s dementia.
According to the Diagnostic and Statistical Manual
version 5, a diagnosis of dementia, also referred to as
major neurocognitive disorder, includes the following:
significant impairment in at least one cognitive domain
(learning and memory, language, executive function,
complex attention, perceptual-motor function, and
social cognition), the impairment must be acquired
and represent a significant decline from previous level
of functioning, must not occur exclusively during the
Clinical Review
course of delirium or be accounted for by another
mental disorder, and must interfere with independence
in everyday activities.2 The major types of dementia
include AD, dementia with Lewy bodies, frontotemporal
dementia, vascular dementia, and Parkinson’s disease
dementia. AD will be the primary focus of this discussion,
as the evidence for treatment in other types of dementia
is limited.
Four AChE inhibitors have been approved by the Food
and Drug Administration (FDA): tacrine, donepezil,
rivastigmine, and galantamine. Tacrine is no longer
in use because of hepatotoxicity and poor tolerability.
Patients with AD have reduced cerebral content of
choline acetyltransferase, which leads to a decrease in
acetylcholine synthesis and impaired cortical cholinergic
function. AChE inhibitors inhibit acetylcholinesterase
in the synaptic cleft, which increases cholinergic
transmission. A summary of the AChE inhibitors in use is
found in Table 1. Donepezil and transdermal rivastigmine
are FDA-approved for use in patients with mild-to-
severe AD, while oral rivastigmine and galantamine
are approved for use in patients with mild-to-moderate
AD. Unfortunately, AChE inhibitors do not affect the
underlying course of the disease; a phase 3 placebo-
Table 1. Comparison of Available Acetylcholinesterase Inhibitors
Agent Available Formulations
Donepezil Oral tablet; oral disintegrating
tablet
Galantamine Immediate-release oral tablet
and solution; extended-
release tablet
Rivastigmine Oral tablet
Rivastigmine Transdermal patch
Abbreviations: AD = Alzheimer’s disease, bid = Twice daily, ER = Extended-release, FDA = Food and Drug Administration, GI = Gastrointestinal, hr = hour,
IR = Immediate-release.
512 THE CONSULTANT PHARMACIST   SEPTEMBER 2017   VOL. 32, NO. 9
controlled study of donepezil in patients with AD found
that any improvement on cognitive measures during the
initial 24-week study was erased after a six-week placebo
washout.3
Memantine is the only NMDA receptor antagonist
available, and has been FDA-approved for use in
patients with moderate-to-severe AD. It is thought
that overstimulation of glutamate receptors in the
central nervous system (CNS) leads to excitotoxicity
and neuronal cell death, which may contribute to the
pathogenesis of AD. Memantine is a noncompetitive
antagonist of the NMDA type of glutamate receptors,
but functions as an effective receptor blocker only
under conditions of excessive stimulation, thus it does
not affect normal neurotransmission. Unlike AChE
inhibitors, several in vitro studies have demonstrated
the neuroprotective properties of memantine.4 However,
any potential disease-modifying activity remains to be
demonstrated in humans. Memantine appears to have
modest benefits in patients with moderate-to-severe AD.
A 28-week randomized trial of 252 patients with mean
Mini-Mental Status Examination (MMSE) scores of 8 at
study entry found that memantine significantly reduced
deterioration on multiple scales of clinical efficacy.5 An
Dose FDA-Approved Use Other Notes
5-10 mg daily; may in- Mild-to-severe AD Generally well tolerated
crease to 23 mg daily
IR: 4-12 mg bid Mild-to-moderate AD GI side effects more common, take
ER: 8-24 mg daily with food
1.5-6 mg bid Mild-to-moderate AD GI side effects more common, take
with food
4.6 mg/24 hr Mild-to-severe AD Generally better tolerated
9.5 mg/24 hr
13.3 mg/24 hr

open-label extension study demonstrated benefits for
patients previously taking placebo in all efficacy measures
relative to their previous rate of decline and confirmed the
favorable adverse event profile seen in the original study.6
Cholinesterase inhibitors and memantine are also
often used in combination, particularly in moderate-to-
severe AD, and a donepezil/memantine combination
capsule was FDA-approved in 2014. The DOMINO-
AD (Donepezil and Memantine in Moderate-to-Severe
Alzheimer’s Disease) trial looked at 295 patients with
moderate-to-severe AD already treated with donepezil
and compared four treatment strategies: no therapy
(donepezil discontinued), donepezil continued as
monotherapy, donepezil continued and memantine
added, and memantine therapy alone.7 After 12 months,
patients who continued donepezil showed modest
cognitive and functional benefits; the improvement
in MMSE scores exceeded the prespecified minimum
clinically important difference, but the difference in
Bristol ADL Scale scores did not. Those assigned to
receive memantine had a higher MMSE score and a lower
score on the Bristol ADL Scale, which both imply benefit,
compared with those not receiving memantine, but
neither differences met the minimum clinically important
difference. Unfortunately, this study was stopped early
because of slow recruitment.
The efficacy of AChE inhibitors on cognition has
been well studied in patients with mild-to-moderate
AD, but there are less data in patients with advanced
AD, including those in nursing facilities. Five placebo-
controlled trials of AChE inhibitors in patients with
advanced dementia have been reported. In a study of 290
patients living at home or in assisted living with baseline
MMSE scores of 5 to 17, 24 weeks of donepezil treatment
was associated with significant improvements in all
primary and secondary outcomes measured, including
MMSE and CIBIC-plus (Clinician’s Interview-based
Impression of Change with caregiver input).8 In a study
of 208 nursing facility residents, most of whom had a
baseline MMSE score of < 20, donepezil was associated
with significantly improved Clinical Dementia Rating
and MMSE scores at six months, compared with placebo-
treated patients, who declined. There was no difference
THE CONSULTANT PHARMACIST   SEPTEMBER 2017   VOL. 32, NO. 9 513
Advanced Alzheimer’s Disease
between groups in the primary outcome measure of
the Neuropsychiatric Inventory (NPI).9 In 248 nursing
facility residents with severe AD with baseline MMSE of
1 to 10, donepezil-treated patients showed significantly
improved cognitive ability on the Severe Impairment
Battery (SIB), while placebo-treated patients worsened.
Treatment with donepezil was also associated with less-
severe decline in ADLs.10 In 343 community-dwelling
patients with severe AD (baseline MMSE score 1 to 12),
those who were assigned to donepezil improved on a
number of cognitive and functional measures, including
SIB, MMSE, and CIBIC-plus, but not on others including
ADL scales, NPI, caregiver burden scales, and resource
utilization scales.11 In 407 nursing facility residents with
baseline MMSE scores of 5 to 12, patients treated with
galantamine had significantly improved SIB scores, while
patients treated with placebo had significantly worsened
SIB scores; however, ADL scores worsened in both groups
and did not differ significantly between the galantamine
and placebo groups.12
These studies provide evidence for starting or
continuing treatment for AD. However, they do not
specifically address duration of therapy. With the
exception of the AD2000 trial of donepezil in mild
cognitive impairment (discussed below), and the
DOMINO-AD study discussed above, the duration of
all available trials is less than one year, so the long-term
effects of treatment are unknown. Available clinical
guidelines do not offer specific recommendations
regarding optimal duration of therapy. The clinical
practice guidelines for the pharmacologic treatment of
dementia from the American College of Physicians and
the American Academy of Family Physicians state that,
based on the duration of trials, the beneficial effect of
treatment, if any, would generally be observed within
three months. It also states that if slowing decline of
cognition is no longer a goal, treatment with memantine
or a cholinesterase inhibitor is no longer appropriate.13
The American Academy of Family Physicians treatment
algorithm for AD suggests continuing treatment
with AChE inhibitors while the patient’s condition is
stable, adding memantine when the patient’s condition
deteriorates to moderate-to-severe AD, and discontinuing
Clinical Review
medications if the patient does not adhere, continues
to deteriorate, develops serious comorbid disease or
is terminally ill, or the patient or caregiver chooses to
discontinue treatment.14 The Fourth Canadian Consensus
Conference on the Diagnosis and Treatment of Dementia
suggests that AChE inhibitors should be discontinued
when the patient/caregiver makes an informed decision
to stop therapy after being apprised of the risks and
benefits; the patient is nonadherent; the patient’s rate of
cognitive, functional, or behavioral decline is greater on
treatment compared with that before being treated; the
patient experiences intolerable side effects; the patient’s
comorbidities make continued use unacceptably risky
or futile (e.g., terminal illness); or the patient’s dementia
progresses to a stage (e.g., Global Deterioration Scale
stage 7) where there would be no meaningful benefit
from continued therapy. It also recommends to consider
reinstating therapy if an observable decline occurs after
discontinuation.15 The list of Ten Things Physicians and
Patients Should Question, which was developed by The
American Geriatrics Society (AGS), recommends that
cholinesterase inhibitors should not be prescribed for
dementia without periodic assessment of perceived
cognitive benefits and adverse gastrointestinal effects.16
The 2015 revision includes expanded rationale for this
recommendation, specifically that it is unclear if cognitive
changes with AChE inhibitors are clinically meaningful.
The AGS recommends that AChE inhibitors should be
discontinued if the desired effects, including stabilization
of cognition, are not perceived by the patient, caregiver,
and/or clinician within about 12 weeks.
A meta-analysis of five randomized, double-blind,
placebo-controlled studies investigated the effect of
AChE inhibitor discontinuation on community-dwelling
patients with AD.17 AD patients discontinuing an AChE
inhibitor demonstrated a significant worsening of
cognition on MMSE from baseline to study endpoint,
compared with patients who continued an AChE
inhibitor. Three of the five studies reported data on
neuropsychiatric symptoms using the NPI. Out of
these three studies, patients who discontinued an
AChE inhibitor demonstrated a significant worsening
of neuropsychiatric symptoms from baseline to study
514 THE CONSULTANT PHARMACIST   SEPTEMBER 2017   VOL. 32, NO. 9
endpoint, compared with those who continued AChE
inhibitor use. In terms of an absolute rate decline
estimated over 52 weeks, the discontinuation groups
experienced a mean decline of -2.6 MMSE points,
while continuation groups experienced a mean decline
of -1.0 MMSE points; the discontinuation groups also
experienced a mean increase of 3.8 NPI points, compared
with the continuation groups.
It has been theorized that these cognitive declines
could be explained as either a loss of therapeutic benefit
upon removal of the AChE inhibitor, or as a withdrawal
effect. Case reports have described delirium, confusion,
cognitive decline, anxiety, and agitation in patients five
to six days following AChE inhibitor discontinuation.18,19
Prolonged administration may cause drug tolerance
because of upregulation of AChE and downregulation of
acetylcholine receptors in the CNS. However, in all of the
studies included in the meta-analysis, the discontinuation
group maintained poorer cognitive performance at each
follow-up time point, compared with the continuation
group. There was also low heterogeneity in each outcome,
suggesting the differences in the rate of withdrawal in the
discontinuation groups did not have a substantial effect
on changes in cognition or neuropsychiatric symptoms.
It would be more consistent with withdrawal syndrome
if patients experienced an acute increase in the rate of
decline shortly after discontinuation, followed by a return
to the typical level of cognitive function of that AD stage.
Institutionalization is also an important consideration
in patients with severe dementia. Impairment in ADLs
is thought to be a more important predictor of nursing
facility placement than cognitive impairment.20,21 The
AD2000 trial is the only randomized, controlled, double-
blind trial to directly address nursing facility placement
in patients with AD.22 In this trial, community-dwelling
patients with mild-to-moderate AD (mean MMSE score
of 19) were randomized to receive donepezil 5 mg daily or
placebo for 12 weeks, and then rerandomized to donepezil
5 mg or 10 mg daily or placebo, which was continued as
long as judged appropriate. Primary endpoints were entry
to institutional care and progression of disability, which
was defined as the loss of 2 out of 4 ADLs or 6 out of 11
instrumental ADLs based on the Bristol ADL scale. The

rates of institutionalization did not differ significantly
between the two groups, with 42% of patients in the
donepezil group and 44% of patients in the placebo
group entering institutional care. There were also no
significant differences in behavioral symptoms, caregiver
well-being, caregiver time, or cost. AD2000 was the first
large “real-world” trial of donepezil and was designed to
address concerns that previous studies had been primarily
industry-funded with strict inclusion and exclusion
criteria. The trial was controversial because of its smaller-
than-anticipated enrollment and high rate of attrition, and
also for challenging previous claims that AChE inhibitors
had substantial effects on measures of disability in a cost-
effective way.23
A long-term follow-up of DOMINO-AD looked at
nursing facility placement during the first 52 weeks of the
original trial, and then every 26 weeks for an additional
three years.24 This study found that discontinuation of
donepezil in patients with moderate-to-severe AD doubled
the risk of nursing facility placement within the first year,
compared with continuation of donepezil. However, there
was no difference in risk of nursing facility placement
during the following three years of follow-up. Memantine,
either alone or in combination with donepezil, had no
effect on the rate of nursing facility placement over the
four-year period after randomization. However, the
authors noted that nursing facility placement was a
secondary outcome of DOMINO-AD, and the analysis
was not prespecified, so the results should be deemed
exploratory.
A retrospective cohort study of 178 nursing facility
patients with AD also found that discontinuation of AChE
inhibitors, compared with longer duration of therapy,
was associated with behavioral worsening, increased
frequency of repetitive verbal behaviors and repetitive
health complaints, and less time spent engaging in leisure-
related activities.25
While data from clinical trials suggest that treatment
gaps (periods in which the patient did not take cholin-
esterase inhibitor) are associated with worse outcomes,
a large observational study of elderly patients prescribed
cholinesterase inhibitors found that the risk of institution-
alization or death did not appear to be increased among
THE CONSULTANT PHARMACIST   SEPTEMBER 2017   VOL. 32, NO. 9 515
Advanced Alzheimer’s Disease
those who experienced treatment gaps.26 This suggests
that it may be reasonable to trial off of these medications
without the risk of worse long-term outcomes.
Adverse events from treatment are also considerations
for discontinuation. A population-based cohort study
using health care databases in Canada looked at
community-dwelling adults with dementia who were
prescribed AChE inhibitors (n = 19,803) and who were
not prescribed AChE inhibitors (n = 61,499). This study
found that hospital visits for syncope, bradycardia,
permanent pacemaker insertion, and hip fractures
occurred more frequently in patients receiving AChE
inhibitors.27 A meta-analysis of 54 randomized placebo-
controlled trials looked at patients with cognitive
impairment on AChE inhibitors or memantine to
determine risk of falls, syncope, and related adverse
events.28 The meta-analysis of pooled data from the 40
AChE inhibitor trials found a significant increase in
syncope in the AChE group but no significant differences
in falls, fracture, and accidental injury compared with
placebo. The meta-analysis of pooled data from the 14
memantine trials found no significant difference in falls,
syncope, and accidental injury. Memantine was associated
with a significant decrease in fractures, though the
authors noted that these data were extracted from three
small, unpublished studies.
There are very limited data to support continuation
or discontinuation of AD treatment for patients enrolled
in palliative or hospice care for advanced dementia.
Advanced dementia is often defined as a Global
Deterioration Scale (GDS) score of 7 or a Functional
Assessment Scale (FAST) score of 7, indicating loss
of all or most verbal and psychomotor skills.29,30 One
prevalence study found that 21% of patients with end-
stage dementia were on AChE inhibitors at the time of
hospice enrollment; this study did not mention whether
treatment was discontinued at the time of enrollment.31
A similar study surveyed hospice directors and reported
20% use of AChE inhibitors at the time of hospice
enrollment.32 Clinical practice guidelines for palliative
care and hospice do not address if AChE inhibitors
should be continued in patients who are receiving
hospice care. A retrospective review of 107 deceased
Clinical Review
nursing facility patients found that 63% of patients
continued AChE inhibitors into the week preceding
death.33 Patients were significantly more likely to have
their AChE inhibitor discontinued if they were admitted
to hospice, stayed in hospice care for a longer period of
time, or stayed in the nursing facility for a longer period
of time. A consensus panel of geriatricians identified
cholinesterase inhibitors and memantine among those
drugs that may be inappropriate in advanced dementia.34
The majority of clinical trials of patients with advanced
AD exclude patients with a GDS or FAST score of 7;
therefore, there are very limited data to guide these
decisions.
Conclusion
Overall, the evidence to support a specific time frame for
discontinuation of AD treatment is minimal (a summary
of the trials referenced above is found in Table 2).
The decision-making process should be guided by the
preference of the patient and/or caregiver. It is reasonable
to stop a medication trial if there is no noticeable benefit
after the first three months of treatment, if significant side
effects are noted, or once a patient’s dementia progresses
to a point where there would be no meaningful benefit
from continued therapy. Often, the risks of bradycardia,
syncope, and severe gastrointestinal adverse effects
including esophageal rupture (particularly with AChE
inhibitors) may outweigh the potential benefits of
treatment. It is also reasonable to restart therapy if an
observable decline occurs after discontinuation.
A randomized, double-blind, placebo-controlled
clinical trial registered at clinicaltrials.gov assessing
discontinuation of cholinesterase inhibitors in severe AD
in the long-term care setting was completed in 2015, but
results have not yet been published.35 A second clinical
trial also looking at medication discontinuation in
veterans taking cholinesterase inhibitors for more than
two years is currently enrolling patients.36 The purpose of
these studies is to help clinicians understand when, and
for whom, it is appropriate to stop cholinesterase inhibitor
treatment, and may help shed new light on this topic.
516 THE CONSULTANT PHARMACIST   SEPTEMBER 2017   VOL. 32, NO. 9
Brianna E. Glynn-Servedio, PharmD, BCACP, is clinical pharmacy
specialist—ambulatory care, Durham Veterans Affairs Health Care
System, Raleigh Community-Based Outpatient Clinic, Raleigh,
North Carolina. Trisha Seys Ranola, PharmD, CDE, CGP, is clinical
pharmacy specialist, William S. Middleton Memorial Veterans
Hospital, and assistant director, Office of Global Health—University
of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin.
For correspondence: Brianna E. Glynn-Servedio, PharmD, BCACP,
Ambulatory Care, Durham VA Health Care System, Raleigh
Community-Based Outpatient Clinic, 3305 Sungate Boulevard,
Raleigh, NC 27610; Phone: 908-601-3800; Fax: 919-255-1540;
E-mail: brianna.glynn-servedio@va.gov.
Disclosure: No funding was received for the development of this
manuscript. The authors have no potential conflicts of interest. The
authors were employees of the United States government when this
work was investigated and prepared for publication; it is therefore
not protected by the Copyright Act and there is no copyright that
can be transferred.
© 2017 American Society of Consultant Pharmacists, Inc.
All rights reserved.
Doi:10.4140/TCP.n.2017.511.
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 Advanced Alzheimer’s Disease

Table 2. Summary of Referenced Efficacy-Focused Clinical Trials

Trial Agent Population Duration Memory benefit* Functional benefit*

Rogers SL et al. Donepezil vs. placebo Community-dwelling; 24 weeks Yes (ADAS-cog, Yes (CIBIC-plus); but
Neurology 19983 MMSE score 10-26 MMSE); but no no benefit after
(Prospective RCT) (mean 19.2); N = 473 benefit after 6-week washout
6-week washout
Reisberg B et al. Memantine vs. placebo Community-dwelling; 28 weeks No Yes
N Engl J Med 20035 MMSE score 3-14
(Prospective RCT) (mean 8) and GDS 5-6;
N = 252
Reisberg B et al. Memantine vs. placebo Community-dwelling; 24 weeks No Yes
N Engl J Med 20036 MMSE score 3-14 and
(Open-label extension GDS 5-6; N = 175
of above RCT)
Howard R et al. Memantine or placebo Community-dwelling; 12 months Yes (with continua- No
N Engl J Med 20127 +/–donepezil or placebo MMSE score 5-13 tion of donepezil)
(Prospective RCT) (mean 8); N = 295
Feldman H et al. Donepezil vs. placebo Community-dwelling or 24 weeks Yes Yes
Neurology 20018 assisted living; MMSE
(Prospective RCT) 5-17; N = 290
Tariot PN et al. Donepezil vs. placebo Nursing facility; MMSE 24 weeks Yes (CDR) – no dif- Yes
J Am Geriatr Soc 20019 5-26 (mean =14.4); ference in NPI
(Prospective RCT) N = 208
Winblad B et al. Donepezil vs. placebo Nursing facility; MMSE 6 months Yes Yes
Lancet 200610 1-10; N = 248
(Prospective RCT)
Black SE et al. Donepezil vs. placebo Community dwelling; 24 weeks Yes (MMSE, SIB, Mixed results:
Neurology 200711 MMSE 1-12; N = 343 CIBIC-plus) Yes (SIB, CIBIC-plus)
(Prospective RCT) No (ADL scales, NPI)
Burns A et al. Galantamine vs. placebo Nursing facility; MMSE 24 weeks Yes No
Lancet Neurol 200912 5-12; N = 407
(Prospective RCT)
O’Regan J et al. Any AChEi vs. Community dwelling; 1.5-24 Yes (continuation) Yes (continuation)
J Clin Psychiatry 201517 discontinuation N = 653 months
(Meta-analysis)
Courtney C et al. Donepezil vs. placebo Community dwelling; 2 years Yes Yes (but did not
Lancet 200422 MMSE 10-26; N = 486 decrease institu-
(Prospective RCT) tionalization)
Daiello LA et al. Any AChEi vs. Nursing facility; N =178 n/a No Yes (continuation)
Am J Geriatr Pharmaco­ discontinuation
therapy 200925
(Retrospective)
Pariente A et al. Any AChEi vs. Community dwelling; n/a n/a n/a
Neurology 201226 discontinuation N = 24,394 No difference in
(Observational) institutionalization
or death

*Meeting minimum clinically important difference thresholds.

Abbreviations: AChEi = Acetylcholinesterase inhibitor, ADAS-cog = Alzheimer’s Disease Assessment Scale-cognitive portion, ADL = Activities of daily living, CDR = Clinical
Dementia Rating, CIBIC-plus = Clinician’s Interview-based Impression of Change with caregiver input, FDA = Food and Drug Administration, GDS = Global Deterioration
Scale, MMSE = Mini Mental Status Examination, n/a = Not applicable, NPI = Neuropsychiatric Inventory, RCT = Randomized controlled trial, SIB = Severe Impairment Battery.

THE CONSULTANT PHARMACIST   SEPTEMBER 2017   VOL. 32, NO. 9 517

Clinical Review
9. Tariot PN, Cummings JL, Katz IR et al. A randomized, double-
blind, placebo-controlled study of the efficacy and safety of
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