Clinical Medicine Insights: Therapeutics

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Donepezil: A Review of Pharmacological Characteristics

and Role in the Management of Alzheimer Disease

Vesna Jelic1 and Taher Darreh-Shori2

Karolinska Institutet, Department of Neurobiology, Care Sciences and Society (NVS); 1Division of Geriatric Medicine,
Karolinska University Hospital Huddinge, Stockholm, Sweden. 2Division of Alzheimer Neurobiology, Karolinska University
Hospital Huddinge, Stockholm, Sweden. Corresponding author email: vesna.jelic@ki.se

Abstract: Donepezil is a potent, selective, noncompetitive, and rapidly reversible inhibitor of acetylcholinesterase (AChEI) licensed
for the treatment of Alzheimer disease (AD); and is the first and only AChEI licensed for the treatment of severe AD. Its efficacy
as monotherapy, or in combination with the NMDA-agonist, memantine, has been documented in several randomised double-blind,
­placebo-controlled, short-term clinical trials, as well as long-term extension trials and observational studies. Donepezil is a well ­tolerated
drug that is generally safe as demonstrated even in patients with multiple co-morbidities receiving polypharmacy. It has been shown that
donepezil improves cognition and global function in patients with mild-to-moderate AD; and long-term efficacy is maintained for up to
50 weeks. There is a dose-response relationship, with higher doses more likely to produce symptomatic benefit. Furthermore, donepezil-
treated patients may improve cognitively and show global clinical improvement in all disease stages, including severe AD. Less consis-
tent results in all disease stages were obtained on measures of function and behavior, and observations of mood. No effect on transition
to AD has been found in long-term, randomized clinical trials in mild cognitive impairment (MCI). Cost-effectiveness of the treatment
has been questioned by one long-term open-label societal study of 2-years duration. This study reported modest improvement of cogni-
tion but no statistically significant benefits during donepezil treatment as compared to placebo, in terms of rates of institutionalization
and progression toward greater disability. However, there is a need for further research on clinically meaningful outcomes and treatment
benefits favored by patients and caregivers, which are traditionally not defined as outcomes in clinical trials. Likewise, we need to know
how to select responders, what is an optimal AChE inhibition particularly during the long-term treatment, in which patients the dosage
should be increased for a sustained benefit, what is the optimal duration of treatment and when is meaningful to stop the treatment. After
almost two decades of donepezil use in everyday clinical practice these issues are still unresolved.

Keywords: acetylcholinesterase-inhibitors, donepezil, Alzheimer disease, clinical trials, treatment efficacy

Clinical Medicine Insights: Therapeutics 2010:2 771–788

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Clinical Medicine Insights: Therapeutics 2010:2 771

Jelic and Darreh-Shori
Introduction
Alzheimer disease (AD) is a neurodegenerative disease
that affects primarily the elderly. It is characterized by
progressive dementia exhibiting typical neuropatho-
logical findings and neurochemical deficiencies in
selectively vulnerable regions of the brain.
Numerous neurotransmitter systems are affected in
the disease, but the most consistent and pronounced
changes are those described in relation to the cholin-
ergic nervous system.1,2 Cholinergic deficiency con-
tributes to cognitive decline and possibly behavioral
symptoms in AD and is shown to be the best neu-
rochemical correlate of dementia severity in AD.3–5
Against this background, four acetylcholinesterase
inhibitors (AChEIs) had been developed during the
nineties for therapeutical intervention in AD. Among
the three AChEIs remaining on the market donepezil,
first second-generation non-competitive inhibitor of
AChE introduced in 1997, is the most widely used
in the treatment of AD patients with more than three
billion patient days of Aricept, marketing name for
donepezil (www.emaxhealth.com/91/7904.html). It is
efficacious as a monotherapy or in combination with
NMDA-agonist memantine as documented in several
randomized double-blind, placebo-controlled, short-
term clinical trials.6–10 They have consistently reported
either improvement or stabilization on the basis of
cognitive and functional performance measures or by
means of a measure of global clinical change across
the severity spectra of AD.
Furthermore, a positive effect of long-term done-
pezil treatment was also reported on functional and
structural neuroimaging surrogate markers of a dis-
ease process, such as reduced decline in regional cere-
bral blood flow as measured by SPECT and slowing
of progression of hippocampal atrophy as measured
by MRI volumetric analysis after one year of continu-
ous treatment.11,12 These findings suggest both neuro-
protective effect and preservation of functional brain
activity. Extended post-marketing studies have shown
some long-term benefits and good safety profile of
AChEIs in general, and donepezil in ­particular.13
­Donepezil has also been approved for a treatment of
severe AD in the USA, being the first AChEI used
for the treatment of the entire clinical spectra of the
disease. However, some regulatory bodies still favor
donepezil for a treatment of a subgroup of AD patients
with mild to moderate AD (www.nice.org.uk/TA111).
772 Clinical Medicine Insights: Therapeutics 2010:2
In this review authors would like to present a
pharmacological profile of the drug, including its
mechanisms of action, efficacy and safety, as demon-
strated in pivotal and observational open-label trials,
as well as cost-effectiveness. Furthermore, problems
in translation of positive findings from clinical trials
(efficacy) to desirable effects in clinical practice in
individual patients (effectiveness) will be discussed.
Mechanism of Action
Donepezil is a potent, selective, noncompetitive and
rapidly-reversible inhibitor of AChE. For comparison,
galantamine and phenserine seem to be quite selective
and reversible AChE inhibitors, with weak-moderate
potency, while rivastigmine is a pseudo-irreversible
inhibitor of both AChE and butylcholinesterase
(BuChE) enzymes.14 Tacrine, also a rapidly-reversible
inhibitor of both enzymes, is no longer used in clini-
cal practice due to poor tolerability.
The clinical importance of the selectivity of
ChEIs for AChE over BuChE is not clear. Based
upon recent data it is evident that BuChE is capable
of compensating for some function of AChE in the
brain, particularly in AD patients.15,16 There are also
reports demonstrating that selective BuChE inhibi-
tors may elevate extracellular levels of cortical ACh,
­augment learning and lower AD Aβ peptide in rodent
brain.17,18
The rapidly-reversible inhibitors, ie, donepezil,
galantamine and tacrine inhibit AChE by binding to
hydrophobic binding sites, while leaving the enzyme
intact. In this dynamic process, neither the inhibitors
nor the enzyme are transformed by their interaction.
Thus, for a rapidly-reversible inhibitor, the drug con-
centration and enzyme inhibition correspond nega-
tively to each other, showing graphically as mirror
images. The presence of the drug causes inhibition,
and consequently, its elimination rate is a key aspect
of the pharmacokinetics.14
Pharmacokinetic Profile
The profile of donepezil concerning its absorp-
tion, metabolic pathways, drug-drug interaction and
clearance is well established (for a review see19).
We hence focus here on the long-term concentra-
tion profile of donepezil in plasma and CSF of AD
patients. Due to its half-life of 70 hours, donepezil
has the convenient once-daily administration dosage.

Donepezil plasma concentration reaches its steady
state within three months of treatment and remains
unchanged.20 Long-term donepezil concentration is
dose-­proportional in the plasma,20 which is in agree-
ment with its short-term concentration profile.21–23 The
plasma concentrations of donepezil are 30 ng/mL in
patients receiving 5 mg/day, and 60 ng/mL in patients
on 10 mg/day of the drug.20,21
Reports pertaining to the distribution of donepezil in
CSF as a surrogate of the concentrations in the CNS are
very scarce. However, one report shows that the long-
term donepezil concentration profile in CSF differs
from that in the plasma.20 The CSF-donepezil concen-
tration appears approximately ten times lower than the
plasma level, but shows a similar dose-proportional pat-
tern, namely 4–5 ng/mL in patients taking 5 mg/day and
7–8 ng/mL in those receiving 10 mg/day.20 In addition,
there are indications of time-dependent pharmacokinet-
ics for donepezil in CSF but not in plasma.20 Donepezil
concentration in CSF is found to increase by 50%
between the 12 and 24 months treatment in AD patients
receiving the same dose during both intervals.20
Pharmacodynamics
Few studies are available that describe long-term
pharmacodynamic profiles of donepezil either in
blood or, particularly, in CSF. To our knowledge,
only one report is available in which the effects of up
to two years of chronic donepezil treatment on blood
and CSF AChE activities, as well as the CSF AChE
protein expression have been evaluated in relation to
the drug concentration and cognitive changes of AD
patients.20,24
Most studies utilize a measurement of blood-AChE
inhibition as a surrogate for inhibition in the brain. The
main reason is that no simple method for estimating
CSF-AChE inhibition in donepezil-treated patients is
available due to its rapidly-reversible nature, as well
as due to the necessity of diluting the samples dur-
ing the currently available enzyme activity assay of
AChE.20,24–25 However, it has been shown that by com-
bining enzyme data derived from a direct colorimetric
assay and an AChE protein level assay, an estimate
can be obtained that rather accurately approximates
the enzyme’s inhibition level to the in vivo brain-
AChE inhibition, as assessed by PET-tracer follow-
ing administration of the ­rapidly-reversible inhibitors,
donepezil and galantamine.20,25
Clinical Medicine Insights: Therapeutics 2010:2 773
Donepezil in the management of Alzheimer disease
Red blood cell (RBC) AChE inhibition ­following
short-term (up to three months) donepezil treat-
ment appears to be dose-dependent and quite strong
(about 19%, 44%, 64% and 77% inhibition in
patients receiving 1, 3, 5 and 10 mg/day of the drug,
respectively).21–23
In a long-term report, the inhibition of RBC-AChE
activity after donepezil treatment has been estimated to
be about 20%–30% in a dose-dependent manner, which
strongly correlates with an approximately 20%-higher
degree of CSF-AChE inhibition.20 This moderate
RBC-AChE inhibition is hence generally lower than
earlier reports that suggested 50%–75% RBC-AChE
inhibition.21–23 Although, methodological differences
may to some degree account for these discrepancies,
due to the lack of assay’s details in these reports we can-
not deduce the reason for these apparent discrepancies.
The moderate level of RBC-AChE inhibition
reported by Darreh-Shori et  al20 however, is more
compatible with reported levels in CSF and with the
20%–30% cortical-AChE inhibition in AD patients
after short-term donepezil treatment measured by
PET.26,27
As mentioned above, the long-term donepezil
concentration in CSF of AD patients show a time-
dependent profile in CSF, which may imply a lower
short-term CSF-donepezil concentration compared
to after 1–2 years of chronic donepezil treatment.
This in turn may explain the discrepancy between the
20%–30% in vivo brain-AChE inhibition after short-
term donepezil treatment, as measured by PET,26,27
and the observed 35%–55% CSF-AChE inhibition
following the chronic donepezil treatment.20
Protein levels of AChE in CSF increase after long-
term treatment with all rapidly-reversible AChEIs
used in AD patients (50% increase after tacrine treat-
ment; four-fold increase after donepezil treatment and
two-fold increase after galantamine treatment.20,25,28–31
However, it is unlikely that this increase in protein
expression reflects a tolerance effect because as men-
tioned above the estimated long-term AChE inhibi-
tion in CSF in AD patients receiving 5–10 mg once
daily ranges between 35%–55% in a dose-dependent
manner, which strongly correlates with the CSF done-
pezil concentration.20
Nonetheless, there are also some indications
that a tailored dosage may increase efficacy of the
donepezil. This is because not all the patients that
Jelic and Darreh-Shori
receive 10  mg/day of donepezil will reach higher
CSF ­donepezil concentration than those receiving
5 mg/day. ­Furthermore, inhibition levels of AChE in
CSF show inhibition-response relationship with the
patients’ cognitive performance in the MMSE test
after 1 and 2 years of treatment. AD patients with 45%
or stronger CSF AChE inhibition show preserved
­cognition up to two years of donepezil treatment,
while patients having 30% or less display cognitive
deterioration regardless of the dosage.20
A similar threshold for the AChE inhibition which
is needed for detection of a therapeutic response to
donepezil has also been reported after short-term
treatment of AD patients with this drug.27
Other pharmacodynamic properties have been
suggested recently, which seem to be related to the
inhibitory action of ChEIs on their target enzyme, ie,
an increase in the cholinergic tone on immune cells
such as suppression of microglial activation.32–34
There are also reports suggesting that donepezil
may stimulate neuroprotective and/or neurogenic
processes by elevating back the plasma concentra-
tion of the hematopoietic growth stem cell factor
in AD patients to the levels observed in control
subjects.35
In summary, a high variation in pharmacodynamic
responses is expected within the patients in both the
5- and 10-mg treatment groups, which calls for indi-
vidualization of (and perhaps increasing) the drug
regimen based on the AChE inhibition level, particu-
larly following long-term treatment. A CSF-AChE
inhibition level of 45%–55% seems to be the optimal
level in donepezil-treated AD patients, as lower lev-
els seem ineffective; whereas higher levels may cause
hyper-excitation of the vulnerable but still functional
cholinergic neurons in the AD brain.
Clinical Efficacy
The Table  1 provides an overview of randomized,
double-blind, placebo-controlled, parallel-group clin-
ical studies of at least 12-weeks duration. The review
begins with pivotal trials in patients with mild-to-
moderate AD, which led to the registration of done-
pezil. In Table 2, open label extension clinical trials or
observational studies are presented. A literature search
in Pub Med, by the terms, “donepezil” and “clinical
trials”, enabled the selection of the reviewed studies.
The basis of each selection is noted in the table head-
774 Clinical Medicine Insights: Therapeutics 2010:2
ings. Since mild cognitive ­impairment (MCI), and
amnestic MCI (aMCI) in particular, are considered
preclinical-AD,36 trials including this patient group
were also included in this review.
Clinical trials methods routinely employ a variety
of scales that measure outcomes that represent four
key symptom domains, including cognitive, func-
tional, and behavioral, as well as a clinical global
assessment of change (Table 1). The latter is a subjec-
tive integrative judgment by an experienced clinician.
Although the aim of this review is not to describe in
detail the efficacy measures used in clinical trials, it
is important to emphasize that the choice of scales, as
well as the assignment of primary and secondary out-
come variables is determined by the disease severity
of the study population.
Mini Mental State Examination (MMSE) and
Alzheimer Disease Assessment Scale-Cognitive
Subscale (ADAS-cog) are the most widely used
cognitive scales that assess change in mild-to-
­moderate stages of the disease. Lowered scores on the
30-point MMSE and elevated scores on the 70-point
ADAS-cog scales denote performance deficits and
cognitive deterioration.37,38 However, these measure-
ments reach plateau in severe disease stages, at which
the Severe Impairment ­Battery (SIB) is a more appro-
priate measure of cognitive deterioration.39
Progression of the disease broadens the spectrum
of symptom domains, including changes in behavior
and activities of daily living (ADL) which has con-
sequences on quality of life, service utilization and
caregiver burden.
The Clinician Global Impression of Change-Plus
(CIBIC-plus) provides a 7-point rating scale of global
change in cognitive ability based on patient and
caregiver interviews by a clinician,40 from marked
improvement to marked worsening. This instrument
is required by FDA for evaluation of efficacy in clini-
cal trials for AD.40
In the absence of a placebo group the estimates
of long-term benefits of donepezil-treated patients
are derived from comparison of their annual decline
on primary outcome measures compared to annual
decline on same measures in historical cohorts of
untreated patients. For example, the estimated annual
lowering of the MMSE score in untreated patients
with ­mild-to-moderate AD has been reported to be
2.8 points.41,42 The annual increase in ADAS-cog

in patients with untreated moderate AD has been
­estimated to be as much as 9–11 points per year.43
The global clinical measure, Clinical Dementia
Rating-Sum of Boxes (CDR-SB), has been esti-
mated to increase by approximately 2.4 points per
year.44 The expected decline without treatment on the
­Neuropsychiatric Inventory (NPI) total scale, measur-
ing behavioral and psychiatric symptoms in patients
with mild-to-moderate AD, has been shown to be
3.9 points at 6 months.45
Double-blind, placebo-controlled
randomized clinical trials
Most of the trials included in this category have satis-
fied at large requirements for internal validity assess-
ment such as randomization, allocation concealment,
similarity of compared groups at the baseline in terms
of demographics and clinical characteristics, and in
a few studies intention-to-treat (ITT) analyses were
conducted as well as monitoring overall and differen-
tial loss to follow-up.46
Mild to moderate AD
Eight trials that included patients with mild-to-mod-
erate AD have been reviewed in the Table 1. Most of
these short-term trials were pivotal phase III-studies
that reported small but consistent improvements in
scores on global, cognitive and functional measures.
One-year-studies by Winblad47 and Mohs48 showed
that benefits of donepezil treatment on global and
cognitive measures and instrumental and basic
activities of daily living (ADL) were maintained
for at least 1-year. Furthermore, Mohs et  al48 dem-
onstrated the median time to attain clinically evi-
dent functional decline was delayed by 5 months for
patients on donepezil when compared to placebo. In
the pivotal trial of Rogers et al49 a beneficial effect
on cognition in a donepezil-treated subjects fell to
the baseline values after a 6-week wash-out period,
indicating either the importance of continuous treat-
ment or the possibility of a wearing-off phenomenon.
A very much debated the AD 2000study,50 not spon-
sored by industry but which recruited typical patients
representative of everyday clinical practice, claimed
that minimal and short-term lasting benefits, as indi-
cated by marginal improvement on MMSE and ADL
measures after 3  months , were not cost-effective
given the absence of risk reduction of progression
Clinical Medicine Insights: Therapeutics 2010:2 775
Donepezil in the management of Alzheimer disease
of ­disability or ­entering institutional care. The study
faced a lot of criticism due to its design and being
underpowered for most of its primary end points.
While recruitment of 3000 patients was planned only
565 were randomized and only 20 patients completed
phase-III treatment.
Moderate- to- severe and severe AD
Two prospective randomized-controlled trials (RCT)
with moderate-to-severe AD patients, one study
reporting post-hoc analysis on a more severe subgroup
of patients, one 12-week study of donepezil treat-
ment of agitation in mostly severe AD patients, and
three studies of patients with severe AD treated with
donepezil were identified through a literature search
(Table 1). The first clinical trial reporting efficacy and
safety of donepezil in a vulnerable patient population
residing in nursing home settings was that of Tariot
et al51 (Table 1). These generally older patients exhib-
ited more severe dementia, more frequent presence
of behavioral and psychiatric symptoms of dementia
(BPSD) and had more co-morbid illness than patients
with mild to moderate AD studied in previous trials.
The primary outcome was not showing significant
difference between the placebo and donepezil group
in scores on NPI due to the relative improvements
in both groups. Secondary sub-item analysis showed
that donepezil produced beneficial effect in 67% of
patients with agitation and aggression which were
the most common symptoms at baseline.52 Further-
more, effects on cognition, overall dementia severity,
safety and tolerability were similar to those reported
in studies performed in outpatient settings on mild-
to-moderate AD, suggesting that advanced age, co-
morbidity and concomitant use of other medication
probably should not limit donepezil treatment.
A following study reported a post-hoc analysis on
a subgroup of patients with more severe AD from a
24-weeks randomized, placebo-controlled trial in
moderate to severe AD (MSAD).53 Analysis of these
results showed small benefits across all three key
symptom domains, including: global function (CIBIC-
plus), cognition (MMSE and SIB), functional disabil-
ity (DAD) and behavior (NPI).54
Three large RCT of 24-weeks duration included
exclusively patients with severe AD: the Swedish
nursing home study,55 the multinational study56 and
the Japanese study57 (Table 1).
Jelic and Darreh-Shori

Table 1. Randomized double-blind placebo-controlled clinical trials of donepezil in AD and MCI.

Author (year) Study design Sample Age (years) Female %

Mild to moderate AD
Rogers et al (1996)22 Multicenter (US) 40 (p) 56–84 52%
12 weeks 42 (d-1 mg) 55–85 69%
MMSE 6–28 40 (d-3 mg) 54–85 55%
39 (d-5 mg) 55–85 64%

Rogers et al (1998a)92 Multicenter (20, US) 162 (p) 56–88 61%
24 weeks 154 (d-5 mg) 51–86 63%
MMSE 10–26 157 (d-10 mg) 53–94 62%
Rogers et al (1998b)49 Multicenter (23, US) 153 (p) 52–93 61%
15 weeks 157 (d-5 mg) 50–94 69%
MMSE 10–26 158 (d-10 mg) 50–92 61%
Burns et al (1999)102 Multinational (82) 274 (p) 50–90 55%
30 weeks 271 (d-5 mg) 51–91 61%
MMSE 10–26 273 (d-10 mg) 53–93 57%
Homma et al (2000)103 Multicenter (52, 129 (p) 48–90 66%
Japan) 134 (d-5 mg) 52–83 68%
24 weeks
MMSE 10–26
Winblad et al (2001)47 Multicenter 144 (p) 51–88 41%
(28, nordic), 142 (d-10 mg) 49–86 72%
52 weeks
MMSE 10–26
Mohs et al (2001)48 Multicenter (31, US) 217 (p) 49–94 64%
54 weeks 214 (d-10 mg) 50–91 61%
MMSE 12–20
Courtney et al, 2004 Multicenter (UK) 282 (p), 283 (d) p:46–90 60%
(AD 2000)50 12 weeks-run-in: 244 (p), 242 (d) d:54–93 58%
60+ weeks: d: 5–10 mg
MMSE 10–26
Mild AD
Seltzer et al (2004)104 Multicenter (17, US) 57 (p) 52–92 60%
24 weeks 96 (d-10 mg) 50–90 50%
MMSE 21–26

Moderate-to –Severe and Severe AD

Feldman et al (2001)53 Multinational, 146 (p) 48–92 61%
32 sites (Canada, 144 (d-10 mg) 52–92 61%
Australia, France)
24 week
MMSE 5–17
Tariot et al (2001)51 Multicenter (US) 105 (p) 65–102 82%
27 nursing homes 103 (d) 64–98 83%
24 weeks
MMSE 5–26
Winblad et al (2006)55 Multicenter 50 120 (p) 85 ± 6 74%
nursing homes 128 (d-10 mg) 84 ± 6 79%
(Sweden), 24 weeks
MMSE 1–10

776 Clinical Medicine Insights: Therapeutics 2010:2

 Donepezil in the management of Alzheimer disease

Primary outcomes Secondary outcomes Completers Discontinuation?

ADAS-cog (C)* ADL (F) 87% (p) 5% (p)

CGIC (G) CDR-SB (C,F) 81% (d-1 mg) 19% (d-1 mg)
MMSE (C)* 95% (d-3 mg) 5% (d-3 mg)
QoL 87% (d-5 mg) 13% (d-5 mg)
*refers to donepezil-5 mg treatment group
ADAS-cog (C)* MMSE (C)* 80% (p) 7% (p)
CIBIC-plus (G)* CDR-SB (C,F)* 85% (d-5 mg) 6% (d-5 mg)
QoL 68% (d-10 mg) 16% (d-10 mg)
ADAS-cog (C)* MMSE (C)* 93% (p) 5% (p)
CIBIC-plus (G)* CDR-SB (C,F)* 90% (d-5 mg) 11% (d-5 mg)
QoL 82% (d-10 mg) 25% (d-16 mg)
ADAS-cog (C)* CDR-SB (C,F)* 80% (p) 10% (p)
CIBIC-plus (G)* IDDD (F)* 78% (d-5 mg) 9% (d-5 mg)
QoL 74 and (d-10 mg) 18% (d-10 mg)
ADAS-cog (C)* CDR-SB (C,F)* 87% (p) 8% (p)
CGIC (G)* MENFIS (C,B)* 87% (d-5 mg)
CMCS (B,F)*

GBS (G)* MMSE (C)*, PDS (F)*, 67% (p) 4% (p)

NPI (B), GDS (G)* 67% (d-10 mg) 3% (d-10 mg)

Survival time* ADL (F)* 21% (p) 7% (p)

estimates to CDR-SB (C,F)* 33% (d-10 mg) 11% (d-10 mg)
functional decline MMSE (C)*
entry to BADLS (F)*, NPI (B) run-in: run-in:
institutional care, MMSE (F)*, GHQ-30 89% (p), 1% (p),
BADLS (F) 95% (p) 6% (d)

ADAS-Cog (C)* MMSE (C)*, 81% (p) 9% (p)

CDR-SB (C,F), 73% (d-10 mg) 16% (d-10 mg)
CMBT (C)*,
Apathy Scale (B)
Patient Global
Assessment Scale

CIBIC + (G)* MMSE (C)*, SIB (C)*, 86% (p) 6% (p)

DAD (F)*, IADL+ (F)*, 84% (d) 8% (d)
NPI (B)*, FRS (F)*,
PSMS (F)*

NPI-NH (B) CDR-SB (C,F)*, 74% (p) 18% (p)

MMSE (C)* 82% (d) 11% (d)
PSMS (F)

SIB (C)*, MMSE (C)*, 82% (p) 7% (p)

ADCS-ADL- NPI (B), 74% (d) 16% (d)
severe (F)* CGI-I (G)*

(Continued)

Clinical Medicine Insights: Therapeutics 2010:2 777

Jelic and Darreh-Shori

Table 1. (Continued)
Author (year) Study design Sample Age (years) Female%
Black et al (2007) 56
Multinational 167 (p) 78 ± 8 68%
98 sites 176 (d-10 mg) 78 ± 8 73%
24 weeks
MMSE 1–12
Howard et al, (2007)58 Multicenter (UK) 131 (p) 84 ± 8 87%
8 centers, 12 weeks 128 (d-10 mg) 85 ± 7 82%
MMSE 2–24
Homma et al (2008)57 Multicenter (Japan) 102 (p) 80 ± 7 82%
24 weeks 96 (d-5 mg) 78 ± 9 79%
MMSE 1–12 92 (d-10 mg) 77 ± 8 79%
Mild cognitive impairment
Salloway et al, (2004)105 Multicenter (US) 137 (p) 55–89 58%
24-weeks 133 (d) 55–89 56%
MMSE

Petersen et al (2005)63 Multicenter, 69 259 (p) 73 ± 8 47%

sites, US and Canada 253 (d-10 mg) 73 ± 7 44%
36 months 257 (vitamin E) 73 ± 7 46%
MMSE 24–30

Doody et al, (2009)66 Multicenter (US) 409 (d) 70 ± 10 48%

48 weeks 412 (p) 70 ± 10 43%
MMSE 24–28

All 3  studies demonstrated consistently and the likelihood of institutionalization. A 12-week

improvements in cognition and global function.
However, a statistically significant positive differ-
ence on measure of function (ADCS-ADL-sev) was
reported only in the Swedish study which led to the
FDA approval of donepezil for treatment of severe
AD. None of the three studies could demonstrate pos-
itive effects on behavioral and psychological symp-
toms of AD as measured by NPI or BEHAVE-AD.
This symptom cluster occurs invariably and fre-
quently in severe AD, increasing caregiver stress
UK trial investigated treatment of agitation but was
unable to obtain a pre-specified 30% or greater
reduction in agitation, since a similar proportion
of patients (20%) from both treatment groups were
found to be treatment ­responders.58 The mean reduc-
tion in NPI score was 3.8 in the donepezil treated vs.
3.6 in the placebo group. It is not clear at present if
lack of behavioral benefits means lack of efficacy of
donepezil on this ­symptom domain or if behavioral
outcome measures lack ­sensitivity in a presence of

778 Clinical Medicine Insights: Therapeutics 2010:2

 Donepezil in the management of Alzheimer disease

Primary outcomes Secondary outcomes Completers Discontinuation?

SIB (C)*, ADCS-ADL-sev (F), 76% (p) 11% (p)
CIBIC + (G)* NPI (B), 66% (d) 19% (d)
MMSE (C)*,
CBQ, RUSP
CMAI (B) NPI (B), 85% (p) ?
MMSE (C), 90% (d) ?
CGIC (G)
SIB (C)*, ADCS-ADL-severe (F), 80% (p) 10% (p)
CIBIC-plus (G)* BEHAVE-AD (B) 87% (d-5 mg) 8% (d-5 mg)
79% (d-10 mg) 13% (d-10 mg)

NYU Paragraph Modified-ADAS- 83% (p) 7% (p)

Delayed Recall (C), cog(C)*, PGA (G)*, 68% (d-10 mg) 22% (d-10 mg)
ADCS CGIC-
MCI(G) neuropsychological measures (attention* & psychomotor speed*)

Clinically possible MMSE (C)*, ADAS- 74% (p) –

or probable AD Cog (C)*, 64% (d-10 mg) –
(*for 12 months) CDR (C,F), 72% (vitamin E) –
CDR-SB (C,F)*,
ADCS-MCI-ADL (F),
GDS (G)*, Neuropsychological test battery(*for first 18 months)

Modified—ADAS- SDMT (C), MMSE (C), 66% (p) 8% (p)

cog(F)* DSB (C), 55% (d-10 mg) 18% (d-10 mg)
CDR-SB (G) NPI (B), PDQ (G),
CGIC-MCI (G)*, PGA (G)*
Notes: ?Discontinuation was due to adverse event related to the study drug. p: placebo; d: donepezil; C: cognitive domain; B: behavioral domain; F:
functional domain; G: global domain; bold text and *: indicate statistically significantly positive results in favor of donepezil; ADAS-cog: Alzheimer’s
Disease Assessment Scale-cognitive subscale; CGIC: Clinical Global Impression of Change; QoL: Quality of Life; CIBIC-plus: Clinician’s Interview-Based
Impression of Change with caregiver input; MMSE: Mini Mental State Examination; CDR-SB: Clinical Dementia Rating Scale-Sum of Boxes; IDDD:
Interview for Deterioration in Daily Living Activities in Dementia; CGIC: MENFIS: Mental Function Impairment Scale; CMCS: caregiver-rated modified
Crichton scale; GBS: Gottfries-Bråne-Steen scale; PDS: Progressive Deterioration Scale; NPI: Neuropsychiatric Inventory; GDS: Global Deterioration
Scale; CMBT: Computerized Memory Battery Test; NPI-NH: Neuropsychiatric Inventory-Nursing Home Version; PSMS: Physical Self-Maintenance Scale
(caregivers rating of ADL); CIBIC+: Clinician’s Interview-Based Impression of Change with caregiver input; SIB: Severe Impairment Battery, DAD: Disability
Assessment for Dementia, IADL+: modified Instrumental Activities of Daily Living Scale, FRS: Functional Rating Scale, ADCS-ADL-severe: Alzheimer’s
Disease Cooperative Study activities of daily living inventory for severe Alzheimer disease; CGI-I: Clinical Global Impression of Improvement scale;
BEHAVE-AD: Behavioral Pathology in Alzheimer’s Disease rating scale; CBQ: Caregiver Burden Questionnaire; RUSP: Resource Utilization for Severe
Alzheimer Disease Patients; BADLS; Bristol activities of daily living scale; GHQ-30: general health questionnaire, psychological well-being of the primary
caregiver, SDMT: Symbol Digit Modalities Test; DSB: Digit Span (Backwards) ; PDQ: Perceived Deficits Questionnaire; PDQ-R: PRDQ-relatives; PGA:
Patient Global Assessment; NYU Paragraph Delayed Recall: New York University Paragraph Delayed Recall test; CMAI: Cohen-Mansfield Agitation
Inventory.

psychotropic ­medication.59 A pooled-efficacy analysis
of the three RCT in severe AD, including only
patients receiving 10-mg donepezil daily, showed that
­donepezil-treated patients were 2–3 times more likely
to achieve positive combined-domain response.60
Positive combined-domain response is defined as an
observable benefit across more than one domain with
varied stringency across 3 definitions—each patient
having a unique profile—relative to placebo-treated
patients by the endpoint of the study.60,61 Cognitive
­responders defined as improvement of $4 or $8 points
of SIB showed significantly greater reduction in total
NPI scores (-5.5 and 6.4, respectively), indicating
positive relation between cognitive and behavioral
improvement. A 12-week, multicenter, open-label
study in 103 patients with ­moderate-to-severe AD
focused on switch to donepezil therapy after discon-
tinuation of memantine monotherapy due to poor
­tolerability or lack of efficacy.62 The study reported
that re-initiation of donepezil treatment in patients
with moderate-to-severe AD showed benefits on cog-
nition measuring an approximate increase of 2 points

Clinical Medicine Insights: Therapeutics 2010:2 779

 Table 2. Open-label clinical and observational studies of donepezil in AD.

780
Author (year) Study design Sample Completers Main results
Rogers et al Multicenter (US) ITT 133 1st year: 83% Clinical improvement during
(2000)106 open-label, Age: 54–85 years 2nd year: 35% first 6–9 months of treatment on ADAS-
extension trial Females: 61% 3rd year: 21% cog and CDR-SB.
14* + 240 weeks ADAS-cog: 27.4 (mean)
Matthews et al Southampton memory Clinic 89 (ITT 80) 6 months: 55% Improvement at 3 months on MMSE
Jelic and Darreh-Shori

(2000)107 (UK)18 months open-label 12 months: 33% (24% $ 3), ADAS.cog (39% $ 4), NPI
clinical study 18 months: 11% (37% $ 4);
sustained benefit for18 months on MMSE.
and NPI, for 6 months on the ADAS-cog.
Doody et al Multicenter (US) ITT 763 1st year: 76% Patients receiving 10 mg daily
(2001a)108 open-label, extension trial 2nd year: 49% uninterrupted, performed after 1 year
15*and 30* + 144 weeks 3rd year: 7% better than baseline (ADAS- cog;
CDR-SB). After long
discontinuation benefits are not recovered.
Doody et al Multicenter (US) observational Donepezil: 53 ? Annualized mean MMSE change on
(2001b)109 1 year follow-up (dose?) Untreated: 21 donepezil (-1.5),untreated (-3.7).
Geldmacher et al Multicenter (US) observational 763 patients from – Significant delay in nursing home
(2003)110 up to 8 years follow-up 3 RCT () placement after 9–12 months of treatment.
Dose 5 mg or .
Relkin et al Multicenter (US) 255 site ITT 1035 12 weeks: 86% Improved cognition (MMSE + 1.5) and
(2003)83 12 weeks open label mild AD: 84, moderate: 912 good tolerability in AD patients with
severe:39, dose 5 mg or . co-morbid medical illnesses.
Hager et al Multicenter (Germany) 2092 mild AD: 830 77% Improved MMSE 63% $ 1, 36% $ 3,
(2003)71 observational clinical study moderate: 640 10% $ 6 points.
3 months severe: 190 Greater cognitive and functional
improvement in severe AD.
Boada-Rovira et al International 1113 89% Improved cognition (MMSE, +1.7 ± 0.1),
(2004)82 246 centres, 18 countries mild AD: 426 social interaction,
open-label moderate: 687 engagement and interest(caregiver diary).
12 weeks Dose: 5 mg or .
Froelich et al Multicenter (Germany) 237 (ITT 233) 79% 68% improved or remained stable on
(2004)111 37 centers open-label mild to moderate AD MMSE ($ 3 p 35%,$ 6 p 10%);
clinical trial 24-weeks (MMSE $ 10) Dose: 5 mg 80%: improvement on CGI-C;
or .
Winblad et al Multicenter (Nordic) 157 (open-label phase) 76% Continuous vs delayed start donepezil
(2006)112 28 centers mild to moderate AD (from open-label treatment showed significant improvement
open-label extension study Dose: 5 mg or . phase) in GDS, GBS subscales (intellectual and
52 week*+ 2 years ADL functions) and less decline on MMSE
(4.9 vs. 6.2).#

Clinical Medicine Insights: Therapeutics 2010:2

 Donepezil in the management of Alzheimer disease

on MMSE, on global assessment of change measured

Notes: *Designates duration of randomized, double-blind, placebo-controlled short-term clinical trial; #Numbers in parentheses mean score on respective scale; ITT: Intention-to-treat
population; TOPS: Top Symptoms checklist; IndiSS: Individual Symptom Score; MAT: Memory Alteration Test, a verbal episodic and semantic memory test; ADFACS: an informant-based
corresponding mprovement on ADAS-Cog,
Improvement on individual symptom score
(IndiSS) and CGI, Mean improvement on

unchanged ( 6 months: 74%, 12 months:

End of study: mean MMSE decline (3.8),

greater in mild AD; significant worsening

by CGI-I, and in patient social behavior as rated by

Significanlty lower ADAS-cog scores in

20%: improvement in most symptoms;

stable during 6 months; improvement

Cognition(MMSE and M@T) remains
a caregiver; but no change in behavior was indicated
checklist): 43%: some improvement,

ADAS-cog (8.2),CIBIC improved or

of function (ADFACS) both groups

in NPI scores. Forty-two percent of the patients in
this study received before study entrance a long-term
Symptom improvement (TOPS

therapy with AChEI which was discontinued due

to lack of efficacy. This implies that in clinical set-
49%, 36 months: 30%).

tings, a decision for discontinuation of the treatment

the APOE e4 group.

might have been done prematurely and that realistic
evaluation of treatment benefits should include not
only improvement and stabilization but also less-
MMSE 1.1.

than-expected decline.

Mild cognitive impairment

So far three randomized, placebo-controlled clinical
trials with donepezil treatment of this particular patient
group were reported: a short 6-month trial, 3-year
secondary prevention study (the Memory Impairment
99% (?)

Study, MIS), and 1-year study (Table  1). While no

91%

95%

39%

effect on disease progression to AD has been found

?

in long term, all three studies consistently showed

small but consistent benefit on ADAS-cog in favor
of donepezil. Moreover, the effect may be modified
by the presence of APOE ε4 genotype.63 Interestingly,
mild to moderate AD

although it had a weak effect, these data appeared to

Dose: 5 mg or .

Dose: 5 mg or .

Dose: 5 mg or .

.(9.3 ± 1.8 mg)

contradict observations from earlier trials in AD that

Moderate: 251
Dose: 5 mg or
Mild AD: 152

showed no effect,64 as well as a stronger treatment

mild AD: 89

Dose: 5 mg
101 (ITT)

effect obtained among e4 non-carriers.65 Only the

one-year study by Doody et al66 demonstrated short-
2046

435

408

lasting effect on a global clinical measure at week 6

40

of the trial.
Multicenter (Spain), 200 centers
open-label, observational Study

Inefficacy of AChEIs at an early stage of the dis-

open-label primary care study
Multicenter (US), 11 centers,

ease is one possible explanation for these negative

results on primary outcomes and the appearance of
Multicenter (Germany)

relatively weak benefits in secondary outcomes;

Multicenter (Sweden)

observational study

observational study

observational study

scale for the assessment of activities of daily living.

however other explanations have been suggested,

open-label, clinical

open-label, clinical

open-label, clinical

including, for example, insensitivity of traditional

measurement instruments.67 High order instrumental
6-months

6-months

tasks that have predictive validity for future conver-

6 months
3 years

3 years

sion from MCI to AD could not be reliably measured

using functional measures typically used in AD trials.
Further criticism is that a duration of the MCI-trials
results in a higher drop-out rates, as it was around
40% in the 3-year-study. Drop-out bias could not be
Molinuevo et al
et al (2007)113

Kanaya et al

understood by simply analyzing a random selection of

Wallin et al
Riepe et al
Rockwood

drop-out patients, rather a retrieved drop-out analysis

(2007)114

(2010)115
(2007)70

(2009)69

should be considered while interpreting the results of

the trials.

Clinical Medicine Insights: Therapeutics 2010:2 781

Jelic and Darreh-Shori
Open-label and observational studies
Extended placebo-controlled studies addressing
long-term benefits, safety and tolerability of a drug
intended for use over a prolonged period of time are
not ethical. Pivotal studies of clinical efficacy usually
exclude the patients from the “real world” clinical
practice with a broader range of co-morbid illnesses
and concomitant therapy.68 These issues are addressed
by pre- and post-marketing, long-term, open-label,
extended clinical studies, which follow short-term,
placebo-controlled, double-blind clinical trials, and
additionally, by observational surveillance studies of
patients treated by prescription.
Fifteen open-label studies have been included in
this review; four of them were open-label extension
studies of pivotal RCTs (Table 2). All of these studies
have reported findings consistent with previous short-
term studies in terms of stabilization or marginal
improvement on cognitive measures; and with less
consistent results regarding improvement on func-
tional and behavioral measures. Mean MMSE change
during continuous donepezil treatment ranged from
0.5 in mild AD and 0.0 in moderate AD in a 6-month
Spanish study reported by Molinuevo et al69 −3.8 in
a 3-year Swedish study of Wallin et al70 to −4.9 in a
3-year open-label Nordic extension trial of Winblad
et  al.70 While the 6-month Spanish study suggested
greater cognitive improvement in mild AD, the
3-month German study reported intriguingly greater
cognitive and functional improvement in more severe
AD, reporting higher scores on MMSE of +0.8  in
mild, +1.9  in moderate and +2.3  in severe AD.71
Similarly, in the same group of patients donepezil
showed beneficial effects on functional ability. The
latter study also showed that donepezil treatment in
AD patients exhibiting parkinsonian symptoms was
equally effective and as well tolerated as in the over-
all AD population.
Head-to-head evidence of comparative
efficacy of AChEI
There were very few direct comparisons among
candidate AChEI. Four comparative studies were
­identified in the literature, two comparing ­donepezil
with ­galantamine and two with rivastigmine.72–75 In a
12-week, multinational study comparing the tolerability
and cognitive effects of donepezil and rivastigmine in
patients with mild to moderate Alzheimer disease, both
782 Clinical Medicine Insights: Therapeutics 2010:2
treatment groups showed comparable improvement on
the ADAS-cog but relative to the donepezil treated
group fewer subjects in the rivastigmine-­treatment
group completed the study (69% vs. 89%), and more
rivastigmine-treated patients discontinued the study
due to AEs (22% vs. 11%, respectively).75 Another
2-year study comparing donepezil with rivastigmine
found no significant differences on measures of cogni-
tion and behavioral symptoms, but rivastigmine pro-
vided more benefits on measures of global function and
activities of daily living.73 These positive effects were
in secondary analyses demonstrated in apolipoprotein
e4 carriers, patients with vascular risk factors and those
suggestive of concomitant Lewy body disease, women
and those younger than 75 years. However, while the
magnitude of severe AEs did not differ between the
patient groups, rivastigmine treated patients experi-
enced more gastrointestinal side effects such as nausea
and vomiting, in both titration (33% vs. 15%; 28% vs.
6%), and maintenance phase (13% vs. 5%; 15% vs.
4%).
A long-term comparison of galantamine and done-
pezil treatment in a 52-week multicenter UK RCT
reported similar safety and tolerability figures for
both drugs.74 However, in a subgroup of moderate-AD
patients there were significant differences in scores on
cognitive measures, MMSE and ADAS-cog, favor-
ing galantamine. No difference in NPI scores was
observed in this study but more caregivers of patients
receiving galantamine reported reductions in burden
compared with donepezil treated patients.
Different pharmacological and pharmacokinetic
profiles of AChEI could influence efficacy and result
in different safety profiles. Large scale, randomized,
head-to-head comparative studies of AChEI efficacy
are needed to establish relative drug superiority.
Combination therapy
Several studies have focused on a common clini-
cal approach employing combination therapy with
memantine, an N-methyl-d-aspartate (NMDA) recep-
tor antagonist, which is established alternative ­therapy
for AD, and which has been approved for patients
with moderate-to-severe stages of disease.76 Patients
receiving stable dose of donepezil with on average
2.5 years history of treatment are either declining or
worsening on individual ADL items over 6 months,
while those also receiving memantine showed better

functional outcomes with a number of ADL items that
remained unchanged or improved.77 Another explor-
atory reanalysis of a pivotal trial of Tariot et al78 con-
sidered cognitive effect of a combination therapy and
showed that memantine additionally affects key areas
of cognition, namely memory, language and praxis,
as assessed by sub-items from SIB.79 Although these
post-hoc analyses suffer from some weaknesses and
were not corrected for multiple comparisons, they
suggest nevertheless that effects on cognition, lan-
guage skills and praxis, could at least partly explain
improvement in ADL. Indeed, a subsequent responder
analysis using combined outcome measures showed
that best risk reduction is achieved by using SIB and
NPI together in the responder definition, consistent
with finding that a higher percentage of those in the
donepezil + memantine group (42%) were identi-
fied as responders compared to those in the placebo
(donepezil only) group (26%). The combination of
cognitive, functional and global abilities as indicated
by stabilization of a triple outcome index (SIB+CIBIC-
Plus+ADCS-ADL) showed higher response rates in
the memantine + donepezil group (25%) vs. the pla-
cebo (donepezil only) group (15%).
Taken altogether, the data from several studies
suggest that the addition of memantine to patients
already receiving stable dosing of donepezil is asso-
ciated with larger benefits than by donepezil mono-
therapy alone, with regard to cognitive function, ADL
and some aspects of behavior.
Safety and Tolerability Profile
In general donepezil treatment has been found to be
safe and well tolerated in numerous studies.80 Overall
reported AEs are around 80% across the RCTs. Observed
AEs include those that are cholinergic in nature, such as
nausea, vomiting, diarrhea, insomnia, asthenia, weight
loss, fatigue, and anorexia. Due to the cholinergic inner-
vations of parasympathetic nervous system, the gas-
trointestinal (GI) system is most frequently affected.
However, in general GI side effects have been transi-
tory in most patients and ­disappear during 3–4 weeks
of treatment. In pivotal trials ­nausea was reported in
21% and diarrhea in 16% of patients treated with 10 mg
per day, and in 6% vs. 4%, respectively in the placebo
group.80 Lengthening the period of time during which
the patients are receiving 5  mg before introduction of
higher 10 mg dose, could reduce AE.81
Clinical Medicine Insights: Therapeutics 2010:2 783
Donepezil in the management of Alzheimer disease
The discontinuation rate due to adverse events
in mild-to-moderate and severe-AD trials is around
10%, while rates are higher in MCI trials (22% in
the 24-week-terial and 18% in the 48-week-tri-
als) (Table  1). Probably a better cognitive status
in MCI make these subjects more likely to report
adverse events and less willing to tolerate side
effects in the absence of an established dementia
diagnosis.
Concerns about drug tolerability must also con-
sider patients with co-morbidity and those receiving
­polypharmacy, the type of patient not represented in
early pivotal clinical trials. Several post-­marketing
observational studies designed to evaluate both safety
and efficacy in “real-life” clinical or community-
based settings did not demonstrate higher occur-
rence of severe AE than in pivotal RCTs.71,82,83 Simi-
lar incidence of total adverse events despite the more
complex medical background of patients might be
partly due to the naturalistic character of these studies
where adverse events are not specifically monitored
as in RCTs.
In a large 255 site, nationwide US, open-label study
of 1035 patients with a high concomitant medication
and extensive co-morbidity, Relkin et al demonstrated
that the risk ratios for gastrointestinal side effects were
not significantly increased by the concomitant use of
aspirin or non-steroidal, anti-inflammatory drugs.83
Risk ratios for cardiac events, including bradycardia
were not significantly increased by concomitant use of
beta-blockers, nondihydropyridine calcium-channel
blockers or digoxin. One or more dose adjustments
during the study were however related to a higher
incidence of AEs. German observational study by
Hager et al showed similar low risk for cardiovascu-
lar events, but reported that patients on concomitant
treatment with SSRIs showed moderately increased
risk of experiencing any AEs during donepezil treat-
ment.71 In addition, a large double-blind, placebo-
controlled RCT on patients with vascular dementia
and cardiovascular co-morbidity receiving donepezil
and multiple concomitant ­medications, reported nei-
ther greater occurrence of AE in general nor brady-
cardia in particular.84,85
In summary, both RCTs and observational
­naturalistic studies have consistently shown a good
tolerability and maintained long-term safety profile
for donepezil.
Jelic and Darreh-Shori
Clinical Effectiveness
and Patient Preference
It has been proposed that a treatment is likely to be
clinically meaningful if the effect size is large enough
to be clinically detectable, if there is a dose response
to treatment in question and if measures from differ-
ent outcome domains converge both within and across
the trials.86 Main efficacy results in clinical trials are
based on differences in mean scores or mean change
scores in cognitive, behavioral or functional rating
scales. Therefore the clinical response in individual
patients is difficult to extrapolate from data obtained
from this group of highly representative patients.87
As a result many regulatory bodies also require a
responder analysis, which determines actual pro-
portion of patients who benefit from the treatment
according to some a priori set criteria. Furthermore,
due to progressive nature of the disease, benefits
should not only be seen as improvement in single
domains but also stabilization or reduced worsen-
ing of symptoms preferably analyzed as a combina-
tion of outcomes.61,88 This definition of outcome was
used in a pooled analysis of 3 pivotal clinical trials,
including a 24-week RCT and a one 1-year RCT in
mild-to-moderate AD, and a 24-week RCT sampling
patients with moderate-to-severe disease, altogether
including 906 patients.88 The odds of declining were
significantly reduced in donepezil-treated patients
as compared to placebo, and results suggested that
many patients initially characterized by improve-
ment on traditional outcomes from single domains as
non-responders could still benefit from treatment.
The treatment benefits favored by patients and care-
givers are not defined as outcomes of clinical trials.
This has been demonstrated in a large survey of careers
and patients.89 Secondary analysis of a 12-month open-
label study of 100 patients with mild-to-moderate AD
showed that while those donepezil-treated patients who
improved on ADAS-cog were less likely to decline on
clinical measures, 43% of patients who declined on
the ADAS-cog, ­nevertheless, improved on at least two
of clinical measures.90 Recent FDA guidelines pro-
mote ­patient-reported ­outcome (PRO) instruments as
effectiveness endpoints in clinical t­rials.91
Quality of life (QoL) is defined as a patient’s and/or
caregiver’s perception of the multidimensional effects
of treatment such as physical, emotional, cognitive
784 Clinical Medicine Insights: Therapeutics 2010:2
and social functioning, and it is not captured by typical
outcome measurements such as psychometric tools.
In short-term pivotal studies on donepezil treatment
by Rogers et al the QoL assessment scale was used
as secondary outcome with variable results.22,92 In
contrast, an open-label societal study from ­Germany
reported increased QoL of patients and/or their ­family
in 70% of cases during a 3-months observational
period.93
Cost-Effectiveness
Analyses of “cost-effectiveness” consider treatments
in terms of health outcomes in nonmonetary units,
such as progression on cognitive measures, decline
in functional abilities or institutionalization.94 While
this type of analysis cannot determine whether ben-
efits of treatment exceed costs, it takes into consider-
ation quality of life measures. Cost-benefit analyses
measure costs and health benefits of interventions in
monetary units. Both aspects of treatment, cost-effec-
tiveness and cost-benefit, are of particular interest for
health care financing systems and regulatory bodies
who stand behind treatment guidelines.
Two earlier studies reported on reduction in time
that patients spend in the severe-AD stage: A UK
study reported treatment to be cost neutral for both
treatment doses of 5 and 10 mg of donepezil,95 and a
Canadian study reported cost-saving over 5-years.96
An industry-sponsored Swedish study reported a
lengthening of time spent in non-severe AD and
cost-saving over 5-year period.97 A study from Japan
showed quality-adjusted life-year (QUALY) gains
and savings over 2 years.98
A majority of studies on cost-effectiveness of
AChEI treatment in AD, as well as economic model-
ing studies, utilize MMSE as measurement of cogni-
tive performance while tracking disease progression
and costs related to increased health care system utili-
zation.8,99 However cognitive function alone is not an
accurate predictor of disease progression, dementia
severity and costs of care.100 In a 24-month, prospec-
tive, multicenter, double-blind, ­community-based RCT
secondary analyses of efficacy, safety and tolerability
of donepezil and rivastigmine used survival analysis
to predict time to nursing home placement.101 In Cox
regression models, older age, female gender, lower
ADL at baseline and deterioration in ADL increased

risk of nursing home placement. Risk of nursing home
placement increased by 3% for each 1-point deterio-
ration in ADL as measured by ADCD-ADL, and was
independent of cognition since addition of MMSE to
the regression model did not significantly change the
outcome. Approximately 6% of patients with AD who
show a mean total decline of 15 points in ADL will be
institutionalized in 1 year time.
The AD 2000 Collaborative Group, a non-industry
sponsored, societal study from UK,51 reported that
improvements in functional ability with donepezil
treatment as observed in the study would not delay
institutionalization sufficiently to justify the costs of
the drug. The Health Technology Assessment Program
reported (2006) after extensive review that donepezil
treatment has QUALY in excess of £80 000, and that
it reduces time spent in full-time care or progression
to disease by 1.42–1.59 months.8 Cost-savings that are
gained by this reduction do not sufficiently overcome
treatment costs to satisfy cost-effectiveness required
by policy-makers in UK.
Place in Therapy, General Summary
Based on the current evidence donepezil is a symptom-
atic treatment for patients with mild to moderate AD. It
is safe and well tolerated even by elderly patients with
multiple co-morbidities and polypharmacies when
escalation of daily dose from 5–10 mg is titrated over
4–6 weeks. Donepezil-treated patients may improve
cognitively and show global clinical improvement in
all disease stages, with possible improvement in over-
all functioning reported even in severe AD. Effect on
behavioral and psychiatric symptoms of the disease is
more controversial. In moderate-to-severe ­dementia
larger clinical benefit could possibly be achieved in
combination with memantine. Cost-benefit data are
limited and impact of donepezil on patient-relevant
outcomes remains poorly understood. There is a need
for further research on clinically meaningful outcomes
and treatments benefits, which are favored by patients
and caregivers, but which have traditionally not been
considered as measurements of outcome in clinical tri-
als. Likewise, we need to know how to select respond-
ers, what is an optimal AChE inhibition appropriate in
long-term settings, which patients respond to increased
dosing for a sustained benefit, what is the optimal dura-
tion of treatment and when is meaningful to stop the
Clinical Medicine Insights: Therapeutics 2010:2 785
Donepezil in the management of Alzheimer disease
treatment. After almost two decades of routine clinical
use of donepezil these issues are still unresolved.
Disclosure
This manuscript has been read and approved by all
authors. This paper is unique and is not under consid-
eration by any other publication and has not been pub-
lished elsewhere. The authors and peer reviewers of
this paper report no conflicts of interest. The authors
confirm that they have permission to reproduce any
copyrighted material.
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