Drugs Aging (2015) 32:453467

DOI 10.1007/s40266-015-0266-9

SYSTEMATIC REVIEW

A Risk-Benefit Assessment of Dementia Medications: Systematic

Review of the Evidence
Jacob S. Buckley1 Shelley R. Salpeter2,3

Published online: 5 May 2015

Springer International Publishing Switzerland 2015

Abstract
Background There is no cure for dementia, and no
treatments exist to halt or reverse the course of the disease.
Treatments are aimed at improving cognitive and functional outcomes.
Objective Our objective was to review the basis of
pharmacological treatments for dementia and to summarize
the benefits and risks of dementia treatments.
Methods We performed a systematic literature search of
MEDLINE through November 2014, for English-language
trials and observational studies on treatment of dementia
and mild cognitive impairment. Additional references were
identified by searching bibliographies of relevant publications. Whenever possible, pooled data from meta-analyses
or systematic reviews were obtained. Studies were included
for review if they were randomized trials or observational
studies on dementia or mild cognitive impairment that
evaluated efficacy outcomes or adverse outcomes associated with treatment. Studies were excluded if they
evaluated non-FDA approved treatments, or if they
evaluated treatment in disorders other than dementia and
mild cognitive impairment.
Results The literature search found 540 potentially relevant studies, of which 257 were included in the systematic

& Shelley R. Salpeter

salpeter@stanford.edu
1

Brown University, Providence, RI, USA

Stanford University School of Medicine, Stanford, CA, USA

1670 Amphlett Blvd, Suite 300, San Mateo, CA 94402, USA

review. In pooled trial data, cholinesterase inhibitors

(ChEIs) produce small improvements in cognitive, functional, and global benefits in patients with mild to moderate
Alzheimers and Lewy body dementia, but the clinical
significance of these effects are unclear. There is no significant benefit seen for vascular dementia. The efficacy of
ChEI treatment appears to wane over time, with minimal
benefit seen after 1 year. There is no evidence for benefit
for those with advanced disease or those aged over
85 years. Adverse effects are significantly increased with
ChEIs, in a dose-dependent manner. A two- to fivefold
increased risk for gastrointestinal, neurological, and cardiovascular side effects is related to cholinergic stimulation, the most serious being weight loss, debility, and
syncope. Those aged over 85 years have double the risk of
adverse events compared with younger patients. Memantine monotherapy may provide some cognitive benefit for
patients with moderate to severe Alzheimers and vascular
dementia, but the benefit is small and may wane over the
course of several months. Memantine exhibits no significant benefit in mild dementia or Lewy body dementia or
as an add-on treatment with ChEIs. Memantine has a
relatively favorable side-effect profile, at least under controlled trial conditions.
Conclusions ChEIs produce small, short-lived improvements in cognitive function in mild to moderate dementia,
which may not translate into clinically meaningful effects.
Marginal benefits are seen with severe disease, long-term
treatment, and advanced age. Cholinergic side effects, including weight loss, debility, and syncope, are clinically
significant and could be especially detrimental in the frail
elderly population, in which the risks of treatment outweigh the benefits. Memantine monotherapy may have
minimal benefits in moderate to severe dementia, balanced
by minimal adverse effects.

454

Key Points
Cholinesterase inhibitors produce small
improvements in cognitive function in mild to
moderate dementia, with marginal effects seen in
severe disease, long-term treatment, and advanced
age.
Cholinesterase inhibitors are associated with
significant cholinergic side effects, including weight
loss, debility, and syncope, which can be detrimental
in the frail elderly population.
The available evidence indicates that memantine
monotherapy produces small benefits in cognitive
function in moderate to severe dementia, without
significant adverse effects.

1 Introduction
Dementia is a clinical syndrome characterized by acquired
global cognitive deficits that interfere with social and occupational functioning [1]. It typically presents in elderly
individuals and involves a progressive decline in memory,
reasoning, language, and executive function [2, 3]. The
estimates for dementia prevalence vary based on geographic location and diagnostic criteria used, but it is
thought that at least 5 % of people over the age of 60 years
live with dementia, and the total number of these cases is
expected to double every 20 years [4]. Incidence of dementia increases exponentially with advancing age, with
one population study observing it doubling every 5 years
[5]. Due to the rapid expansion of the elderly population,
dementia is a serious public health concern, with an estimated worldwide cost of US$600 billion in 2010 [6].
Currently, there is no cure for dementia, and no treatments exist to halt or reverse its progression, so therapeutic
interventions are targeted to treat symptoms or to improve
cognitive function [79]. The two treatments with marketing approval for dementia are the cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine,
and the low-affinity N-methyl-D-aspartate (NMDA) antagonist memantine [1, 10]. The vast majority of published
data available on dementia treatment are in short-term industry-sponsored trials of ChEIs [11]. The trials have
mostly been limited to patient populations with a mean age
of approximately 75 years, with relatively mild Alzheimers dementia and few to no comorbidities [11, 12]. This
significantly decreases the clinical applicability of the research to real-world cases of dementia, as the vast majority
of patients, such as those with severe disease, advanced

J. S. Buckley, S. R. Salpeter

age, or frailty, would have been ineligible for these trials,

and the benefit of long-term treatment is unclear [1318]. It
is also important to distinguish between statistical and
clinical significance, as a small change in cognitive status
may not translate into a meaningful change for the patient
[1, 2, 19]. In addition, a riskbenefit assessment must include quantification of adverse effects, especially in old
frail individuals in whom side effects may have serious
consequences for survival and quality of life [2, 11, 20].

2 Methods
We performed a literature search of MEDLINE through
November 2014 for English-language studies evaluating
the risks and benefits of ChEIs and memantine in the
treatment of dementia and mild cognitive impairment
(MCI). Additional references were identified by reviewing
the bibliographies of relevant papers. Whenever possible,
pooled trial data from meta-analyses or systematic reviews
were obtained. Search terms for cognitive disorders included dementia, mild cognitive impairment, cognition
disorder, Alzheimer, Parkinsons dementia, Lewy
body dementia, and vascular dementia. Search terms for
treatment included cholinesterase inhibitor, acetylcholinesterase inhibitor, donepezil, galantamine, rivastigmine, and memantine. Studies were included for review if
they were randomized trials or observational studies that
evaluated efficacy outcomes (cognitive, neuropsychiatric,
or global function, and disease progression) or adverse
outcomes associated with treatment. Studies were excluded
if they evaluated non-FDA approved treatments for dementia, such as ginkgo biloba, vitamin E, and hormonal
treatments [2, 10]. In addition, studies were excluded if
they evaluated ChEIs or memantine in disorders other than
dementia and MCI.
Two independent reviewers (JSB, SRS) completed data
abstraction and evaluated the quality and risk of bias of
included studies. The results were then presented in a
systematic review, following PRISMA (preferred reporting
items for systematic reviews and meta-analyses) guidelines. The primary scales used to measure cognition deficits
were the mini-mental state examination (MMSE), the
Alzheimers Disease Assessment Scale (ADAS) cognitive
subscale (ADAS-cog), and the severe impairment battery
(SIB). Other domains assessed included the activities of
daily living (ADL), instrumental activities of daily living
(IADL), and the neuropsychiatric inventory (NPI). Global
function and disease progression were also assessed. Adverse events assessed included abdominal pain, nausea,
vomiting, diarrhea, anorexia, headache, dizziness, insomnia, abnormal dreams, vertigo, agitation, muscle cramps,
tremor, bradycardia, syncope, pacemaker implantation,

Systematic Review of the Risks and Benefits of Dementia Medications

fatigue, asthenia, weight loss, falls, and drugdrug

interactions.
The search identified approximately 6800 potentially
relevant articles, of which 540 were retrieved and evaluated.
Of those, 257 studies were included in the systematic review.
Study inclusion is represented in a flow diagram (Fig. 1).

3 Results
3.1 Epidemiology and Assessment of Dementia
There are several types and causes of dementia, with
confusion related to variations in diagnostic criteria and the
fact that many forms of dementia exist concurrently [2, 21].
Alzheimers disease is the most common cause, accounting
for roughly 5070 % of all dementia cases [22]. Another
large subgroup is vascular dementia, which is often observed concurrently with other forms, resulting in prevalence estimates that vary considerably [2328]. Mixed
Alzheimers disease and vascular dementia is common,
accounting for approximately 25 % of all dementia cases
[29]. Vascular dementia becomes increasingly prevalent
with advanced age, with at least 70 % of those over the age
of 90 years having some degree of vascular pathology [13].
Finally, Parkinsons disease dementia and dementia with
Lewy bodies are two major types of dementia with similar
neuropathological presentations, indicating that they are
part of the same condition or exist within a spectrum of
Fig.1 Flow chart of studies
search

455

disorders, often collectively called Lewy body dementia

[30]. Lewy body dementia may account for 1020 % of
global dementia cases, with the risk increasing with age
and years since Parkinsons disease onset [3134]. Many
other forms of clinically relevant dementia exist, but this
review focusses on these three main subgroups.
MCI is classified as a cognitive decline that exceeds the
typical aging process yet does not meet the diagnostic
criteria of dementia [35]. This cognitive decline usually
manifests as a loss in memory that is not significant enough
to alter ADL [35]. The prevalence estimates for MCI range
from 5 to 20 % in older individuals, with up to one-third of
MCI cases progressing to dementia within 2 years [7].
Although MCI is a distinct entity, it is often considered to
be a pre-clinical stage of dementia [7]. Studies have
evaluated whether pharmacological interventions are capable of delaying the progression to dementia or improving
the quality of life of individuals with MCI.
Various assessment tools are available to measure cognitive function, which have been used to determine the
presence and severity of dementia as well as the progression of the disease [36]. One standard measurement is the
MMSE, which is easy to administer in the clinical setting
and measures cognitive function on a 30-point scale, with
higher scores corresponding to higher cognitive function
[37, 38]. Although the MMSE has its limitations, including
decreased utility for detecting dementia in patients with
minimal cognitive deficits or those with low education
levels, it has been widely used and validated globally, and

Literature search of studies on

treatment of dementia (n = 6800)

Studies excluded: Not potentially

relevant (n = 6260)

Potentially relevant studies of

benefits or risks of medications
for cognition disorders (n = 540)

Studies excluded from systematic review:

On non-FDA approved dementia
treatments (n = 52)
Not on treatments for dementia or mild
cognitive impairment (n = 72)
No relevant information provided
(n = 159)
Randomized trials or observational
studies on acetylcholinesterase
inhibitors or memantine for dementia
or mild cognitive impairment (n = 257)

456

is quite accurate for diagnosing and tracking mild to

moderate dementia [3942]. Another common tool is the
ADAS-cog, a 70-question scale with higher scores indicating worse cognitive performance, which was designed
to detect and follow clinical changes in cognition [43, 44].
The ADAS-cog is most sensitive to changes in mild to
moderate dementia [4448]. Another cognitive assessment
tool is the SIB, which is most helpful for those with severe
dementia [49].
Other tests are commonly used to measure outcomes
other than cognition in patients with dementia. An important measure in the determination of quality of life and
degree of disability is the assessment of ADL, such as
feeding and dressing, and IADL, such as handling money,
preparing food, or using the telephone [36, 50, 51]. In
addition, behavioral and psychological symptoms can be
assessed with the NPI, which focuses on behavioral disturbances such as delusions, anxiety, and disinhibition [51,
52]. Another research tool is the measurement of global
dementia status, which integrates in-depth clinical assessments of patients with caregiver input to derive a basic
quantitative measure of change [53].
There are no universally accepted cut-offs for defining
dementia severity, but it is reasonable to use MMSE scores to
divide dementia severity into mild (2023), moderate
(1019), severe (19), and end-stage (0) [40, 41, 5459].
MCI corresponds to an MMSE score of 2427, although this
is not sufficient as a sole diagnostic criterion [58, 6062].
Mild dementia can be detected by basic clinical assessment
and is characterized by decreased memory of personal and
current events and slightly diminished executive function
[41]. In moderate dementia, the individual begins to lose
independence and conversational skills and may forget significant personal information [56, 63]. By the stage of severe
dementia, there is a complete loss of independence in performing ADLs associated with lack of orientation, but with
some maintained ambulatory and verbal functioning [63,
64]. End-stage dementia, in which the individual no longer
has the ability to walk or speak, is an important clinical stage
that may persist for years before death [63, 64].
3.2 Pathophysiological Basis of Dementia
with Rationale for Treatment
Cognitive decline in dementia is due in part to deficient
cholinergic activity in the basal ganglia and neocortex
caused by destruction of cholinergic neurons. ChEIs
function by inhibiting acetylcholinesterase, thereby increasing available acetylcholine [6567]. Another cause of
cognitive decline common to various types of dementia is
excitatory neurotoxicity caused by overstimulation of
NMDA-glutamate receptors, and memantine could serve
by blocking NMDA activity at a low enough affinity to

J. S. Buckley, S. R. Salpeter

prevent excitotoxicity without interfering with necessary

functions of glutamate in learning and memory [6871].
Despite very different pathogenic mechanisms, there are
key similarities in the pathophysiology of Alzheimers
dementia, Lewy body dementia, and vascular dementia that
result in cognitive decline, and these may indicate ChEIs
and memantine as possible treatment options.
In Alzheimers disease, the initiating event is thought to
be the accumulation of amyloid beta-protein (Ab) plaques,
which in turn trigger hyperphosphorylation of tau protein
and neuronal degeneration [72]. The Ab plaques cause a
decrease in acetylcholine release and synthesis, along with
increased activity of acetylcholinesterase, impaired muscarinic acetylcholine signaling pathways, and a decrease in
cholinergic signaling and function; these changes in turn
indirectly result in disrupted NMDA-receptor activity and
glutamate neurotoxicity [73, 74]. Since the plaques are
concentrated in areas related to memory and executive
function, such as the basal ganglia and parts of the temporal lobe and neocortex, the neural damage caused by
cholinergic impairment and glutamate neurotoxicity is related to a loss of these cognitive functions [65].
Vascular dementia results from varied cerebrovascular
events such as ischemia, infarct, or hemorrhage, so its
pathogenesis is multifactorial and poorly defined [75]. The
cognitive deficits involved resemble those found in Alzheimers disease and other dementia types, as they involve
cerebrovascular damage to similar neural regions, such as
the temporal lobe, basal ganglia, and neocortex [75]. These
vascular changes in the brain are associated with inflammation, atrophy, and decreased cerebral perfusion, as well
as decreased inhibition of NMDA channels, leading to
chronic overstimulation of glutamate receptors [71, 75].
There is also some evidence that these changes may result
in impaired cholinergic transmission [67, 76].
Lewy body dementia is a multisystem disease with
various presentations along a spectrum; if the parkinsonian
extrapyramidal symptoms precede dementia, it is considered to be Parkinsons disease dementia, but if the order of
presentation is reversed it is typically diagnosed as dementia with Lewy bodies [77]. Both disorders eventually
involve the production of proteinaceous cytoplasmic inclusions throughout the brain, called Lewy bodies, with
neurodegeneration of dopaminergic neurons in the substantia nigra and denervation of cholinergic neurons in the
basal forebrain and cerebral cortex [7779]. There is some
evidence that these conditions may also induce glutamate
hyperactivity by altering the expression of glutamate receptors, and this is often worsened by chronic L-dopa administration, which is commonly used in the treatment of
Parkinsons disease [69, 80, 81].
Ultimately, the use of ChEIs may serve to compensate
for decreased cholinergic activity by increasing the

Systematic Review of the Risks and Benefits of Dementia Medications

availability of acetylcholine released from limited cholinergic neurons, and memantine may offer neuroprotective
effects from excitotoxic stimulation of overexpressed
NMDA pathways, but neither medication can reverse or
slow the underlying pathophysiological progression of the
disease. Therefore, the target of these therapies is to attempt to reduce symptoms related to the disease, rather
than address the neurodegenerative processes themselves.
3.3 Cholinesterase Inhibitors
3.3.1 Benefits of Cholinesterase Inhibitors for Mild
Cognitive Impairment
No medication has marketing approval for the treatment of
MCI, but many investigators have evaluated whether
ChEIs could delay the progression to dementia or provide
clinically significant improvements in cognition for individuals with MCI. A few small studies have shown some
minimal cognitive benefits of ChEIs in the treatment of
MCI [56, 8284], but pooled data analyses of the trials
show that there is no significant difference in progression
to dementia, nor in global, cognitive, or neuropsychiatric
outcomes [7, 85, 86]. A significant increase in adverse
events was observed for MCI patients treated with ChEIs,
mainly gastrointestinal side effects such as nausea, diarrhea, and vomiting, as well as cardiac syncope and headaches [7, 54, 84, 85, 87, 88]. Therefore, ChEIs are not
recommended for the treatment of MCI [89, 90].
3.3.2 Benefits of Cholinesterase Inhibitors for Dementia
Numerous studies have investigated the efficacy of different treatments for cognitive function in dementia, and
several systematic reviews and meta-analyses have worked
to pool the data and summarize the results (Table 1) [1, 2,
11, 20, 30, 56, 9196]. The three commercially available
ChEIs, donepezil, galantamine, and rivastigmine, have
marketing approval for the treatment of mild to moderate
dementia in most countries [10, 56]. The first-generation
ChEI, tacrine, was removed from the US market due to
poor efficacy and high incidence of serious adverse events,
and is not evaluated here [2, 20]. The available ChEIs
differ slightly in their pharmacological properties, but they
share the main mechanism of acetylcholinesterase inhibition [2, 97]. Studies have shown similar efficacies with
these medications so the data will be pooled for this review
[2, 91, 98, 99]. A meta-analysis also concluded that results
in efficacy for low and high doses of ChEIs were comparable, so results from studies using different doses will also
be pooled [20].
Essentially all of the published trials on ChEI use in
dementia were industry sponsored, with the exception of

457

one long-term trial by the Alzheimers Disease Collaborative Group [100, 101]. This raises the possibility of
publication bias or selective reporting of the results. One
study evaluating the potential bias in reporting adverse
events found that most of the randomized trials stated that
they examined harm, but many did not report mortality
data or provide clear definitions and detailed analyses of
harm [102].
A recent clinical practice guideline by the American
College of Physicians and the American Academy of
Family Physicians presented the available evidence on
ChEI treatments based on systematic evidence reviews
sponsored by the Agency for Healthcare Research and
Quality [1, 11, 93]. They concluded that ChEI treatment for
dementia results in a small statistically significant improvement in cognitive function that was not considered to
be clinically important [1]. Pooled data from ChEI trials in
Alzheimers disease, Lewy body dementia, and vascular
dementia show average improvements in the MMSE
ranging from 0.8 to 1.6 points on a 30-point scale, while 3
points or more was generally considered to be clinically
significant [1, 12, 30, 93, 94, 103]. Pooled data also showed
an average improvement in ADAS-cog of approximately
1.42.7 points on a 70-point scale, while several studies
have used a change of 4 points or more to indicate clinical
relevance [1, 12, 93, 94, 103].
The majority of available data has been in mild to
moderate Alzheimers disease, with limited data on Lewy
body dementia and vascular dementia [11]. The pooled
data from meta-analyses on ChEIs have shown relatively
similar results for cognitive outcomes in Alzheimers dementia and Lewy body dementia, with improvements on
the order of 1.5 points in MMSE and 2.5 points in ADAScog compared with placebo [12, 30]. In comparison, trials
on vascular dementia show marginal cognitive effects of
ChEIs (0.8 points in MMSE and 1.5 points in ADAS-cog),
with some studies finding no improvements at all [94].
In addition to cognitive assessment, many studies also
assessed global and functional outcomes of ChEI treatment. The results from studies on global outcomes have
been mixed, with some studies concluding that there is no
significant change and others finding slight improvements
[12, 30, 93, 94]. Pooled data show a mean improvement of
0.40.5 for treatment in Alzheimers and Lewy body dementia in a 7-point interview-based global assessment of
change scale [30, 93, 104]. Functional measures of ADL
showed similarly mixed results for the treatment of Alzheimers and Lewy body dementia, with studies achieving
improvements on the order of 0.1 standard deviations
compared with placebo, which was not considered to be
clinically significant. [1, 28, 87, 89, 93] Studies on ChEIs
for vascular dementia have found negligible improvements
in global and functional measures [94]. A secondary

458

J. S. Buckley, S. R. Salpeter

Table 1 Benefit assessment of cholinesterase inhibitors for dementia by type

Condition

The evidence

Comments

Mild cognitive impairment

Mild cognitive
impairment

Minimal cognitive benefits and possible delay of

progression to dementia suggested by a few small studies

Pooled data show no significant delay in dementia

progression or in cognitive and global benefits

Mild-moderate
AD

Improvements on the order of 1.5 MMSE (30-point scale),

2.5 ADAS-cog (70-point scale), 0.5 in interview-based
global assessment of change (7-point scale), 2 points in
NPI (144-point scale), and 0.1 standard deviations of ADL
scales

The most evidence exists for otherwise relatively young and

healthy individuals with this dementia type. While these
improvements are statistically significant, they fall short
of many standards of clinical significance, and most do
not assess for longer than 1 year

Mildmoderate
Lewy body
dementia

Similar outcomes in cognitive, neuropsychiatric, and global

domains as with mildmoderate AD

While there is slightly less evidence available for Lewy

body dementia than AD, pooled evidence indicates the
benefit of ChEIs is similar for both conditions in the short
term

Mildmoderate
vascular
dementia

Some small studies have shown more marginal benefit than

for AD and Lewy body dementiaon the order of 0.8
MMSE, 1.5 ADAS-cog, and negligible improvements in
other domains

Fewer large and long-term studies have been conducted on

vascular dementia than on other dementia types, but
pooled evidence indicates that benefits are small or
nonexistent

Advanced and endstage dementia of

any type

What limited evidence exists is mostly for AD, and shows

only small benefits to cognition4 to 7 points SIB (133point scale) and little to no benefits in other domains

A huge paucity of evidence for severe dementia of any type

and separately for dementia patients with advanced age
makes assessing data difficult. Limited pooled data
indicate that the effectiveness of ChEIs decreases with
increasing dementia severity, age, and duration of
treatment

Dementia

AD Alzheimers dementia, ADAS-cog Alzheimers Disease Assessment Scale-cognitive subscale, ADL activities of daily living, ChEI cholinesterase inhibitors, MMSE mini-mental state examination, NPI neuropsychiatric inventory, SIB severe impairment battery

outcome often studied in dementia trials is the incidence

and severity of neuropsychiatric symptoms, including behavioral and psychiatric disturbances, common in patients
with dementia [104]. As with global and functional scores,
pooled data showed a marginal improvement of about 2 of
144 points in NPI for Alzheimers and Lewy body dementia, and no improvement for vascular dementia [91, 94,
103].
Very few studies have evaluated severe dementia
(MMSE 19), and none have looked at end-stage dementia
(MMSE 0). In fact, only one published study with 248
participants examined monotherapy of ChEIs in patients
with severe dementia (MMSE 110) [105]. If the criteria
were expanded to define severe dementia as MMSE 112,
and then post hoc subgroup analyses of larger studies were
included, that would allow for the inclusion of a few more
small trials of short duration [106109]. One other study
evaluated severe dementia but did not classify patients
according to MMSE [110]. These trials had variable results
using the SIB, with some showing minimal cognitive
benefit (47 points of the 133-point SIB compared with
placebo) and others showing a trend to worse scores
compared with placebo [105111]. Treatment of severe
dementia resulted in minimal to no benefit in ADLs or in
NPI scores [105109].

There is also limited evidence for efficacy of ChEIs in

long-term treatment, with most randomized trials lasting
only 36 months despite the fact that patients often continue therapy indefinitely [12, 112]. Only four trials have
lasted 1 year or longer, all in mild to moderate Alzheimers
disease, and they provide some evidence for a waning of
effect over time [100, 113115]. One 1-year trial of
donepezil found an improvement in MMSE of 1.5 points
by 1 year [113], while another trial showed improvement at
6 months but no significant effect by 1 year [114]. One
2-year trial of galantamine found an improvement in
MMSE of 0.7 points by 2 years [115]. However, another
2-year trial of donepezil, which had a complicated protocol
with two randomization periods, found an improvement in
MMSE of 0.9 points by 12 weeks that did not significantly
change in the second randomization period for the duration
of the trial [100]. The two primary outcomes of that trial,
time to institutionalization and loss of critical ADLs, did
not significantly differ between treatment and placebo by
2 years [100].
Finally, a paucity of data exist for the effectiveness of
ChEIs in the treatment of those with advanced age; in
pooled trial data, the mean age was approximately
75 years, with few participants included over the age of
85 years [11, 12, 94, 116, 117]. A single trial examined the

Systematic Review of the Risks and Benefits of Dementia Medications

effectiveness of donepezil in a population of nursing home

residents with a mean age of 85 years and found no significant improvement in MMSE or neuropsychiatric outcomes at 24 weeks [118].
3.3.3 Risks of Cholinesterase Inhibitors
ChEIs can cause adverse effects due to increased cholinergic stimulation, both centrally and peripherally [119,
120]. Acetylcholine-containing neurons exist in the brain,
mainly in the cerebral cortex, and in the periphery, both in
the autonomic parasympathetic nervous system and skeletal muscle [121]. The central effects result in gastrointestinal and neurological disturbances, while peripheral
cholinergic activity related to vagal stimulation results in
cardiovascular and gastrointestinal events, as well as general effects such as weakness or fatigue (Table 2). The
ChEIs donepezil, galantamine, and rivastigmine have
slightly different mechanisms of action but they share the
common effect of reversible acetylcholinesterase inhibition
with relative selectivity for central nervous system effects;
they have been found to have similar adverse effects, so the
data for these drugs will be reported together [2, 121, 122].
Table 2 Adverse effects of cholinesterase inhibitors compared with
placebo in Alzheimers disease
Adverse outcome

OR (95 % CI)

459

In addition, similar effects have been seen with Alzheimers disease, vascular dementia, Lewy body dementia,
and MCI [7, 11, 12, 30, 94].
Pooled data from dementia trials show that ChEI treatment is associated with a twofold increase in drop-outs due
to adverse events compared with placebo [12, 103]. The
absolute increase in risk is 10 %, indicating that the
number needed to treat over 36 months to cause one
significant drug reaction is 10 [12]. For patients with advanced age, frailty, and comorbidities, and those using
concomitant medications, there is heightened concern for
clinically relevant adverse effects associated with ChEIs.
These patients, in general, have not been included in the
trial data, as less than 10 % of patients treated in clinical
practice would have been eligible for the published trials
[15]. Therefore, the exact magnitude of risk for real-world
patients is uncertain. Another major difficulty in evaluating
the risks of treatment is that the vast majority of randomized trials are industry sponsored [102]. One study
evaluated 27 ChEI trials that stated they reported on the
safety and tolerability of the medication; however, 90 % of
these trials did not report standard regulatory agency-defined serious adverse events, making interpretation of the
data very difficult [102]. We provide best estimates from
randomized trial data as well as real-world experiences.
3.3.4 Risks of Cholinesterase Inhibitors: Gastrointestinal
Effects

Gastrointestinal
Abdominal pain

1.95 (1.462.61)

Anorexia

3.75 (2.894.87)

Diarrhea

1.91 (1.592.3)

Nausea

4.87 (4.135.74)

Vomiting

4.82 (3.915.94)

Neurological
Abnormal dreams

5.38 (1.3421.55)

Dizziness

1.99 (1.642.42)

Headache

1.56 (1.271.91)

Insomnia

1.49 (1.122.00)

Tremor

6.82 (1.9923.37)

Vertigo

3.95 (1.0814.46)

Cardiovascular
Syncope

1.90 (1.093.33)

Edema

2.08 (1.014.28)

General
Asthenia
Fatigue
Muscle cramps

2.47 (1.274.81)
4.39 (1.2115.85)
13.32 (1.71103.74)

Weight loss

2.99 (1.894.75)

At least one adverse event

2.51 (2.142.95)

Based on Birks [12]

CI confidence interval, OR odds ratio

Procholinergic drugs such as ChEIs significantly increase

gastrointestinal side effects, which can be attributed to both
central and peripheral cholinergic pathways [119, 122].
Abdominal pain, nausea, vomiting, diarrhea, and anorexia
are all increased by two- to fivefold compared with placebo
in pooled data of Alzheimers trials lasting at least
6 months (Table 2) [12]. These effects may be particularly
prominent in the initial dose escalation phase but can remain throughout long-term treatment, often resulting in
discontinuation of the drug [12, 119]. The degree of adverse gastrointestinal side effects appears to be dose dependent [122].
In a meta-analysis of ChEI treatment of Alzheimers
dementia, a threefold increase in clinically significant
weight loss compared with placebo was observed, related
at least in part to these gastrointestinal side effects [12].
Little inter-study heterogeneity was observed in the results,
indicating a consistent class effect on weight loss for all
ChEIs [12]. Evaluation of trial data indicates a dose dependence related to weight loss, with a loss of C7 % of
body weight occurring in 1025 % of patients receiving
high-dose ChEIs [122125]. In one randomized trial of
ChEI use in nursing home patients with dementia, a twofold increase in significant weight loss was observed for

460

treatment compared with placebo, with those aged over

85 years having almost twice the risk of those aged under
85 years [118]. Weight loss can be quite detrimental in the
frail elderly population and has been associated with decreased quality of life, functional decline, institutionalization, and increased mortality [126130]. Observational
studies have indicated that subsequent weight gain can
occur when ChEIs are discontinued [131, 132].
3.3.5 Risks of Cholinesterase Inhibitors: Neurological
Effects
Central nervous system effects are frequently reported with
ChEIs [119]. In pooled data from Alzheimers trials, a
statistically significant increase, on the order of two- to
fivefold, was observed for headache, dizziness, insomnia,
abnormal dreams, and vertigo (Table 2) [12]. Observational evidence also exists that agitation may be increased
with ChEI use [119, 133]. Muscle cramps with ChEI use,
which may be related to direct cholinergic stimulation at
the neuromuscular junction, is increased 13-fold for ChEIs
compared with placebo, and could result in muscle weakness or falls [12, 119].
Tremor and Parkinsonian symptoms are also significantly increased by ChEIs, in those with and without
Parkinsons disease, related to central cholinergic activation [12, 30, 103, 122]. Tremor is increased sevenfold with
ChEI treatment in patients with Alzheimers dementia,
while tremor and Parkinsonian symptoms increase two- to
threefold in patients with Parkinsons disease being treated
with dopamine antagonists compared with placebo [12,
103, 117].
3.3.6 Risks of Cholinesterase Inhibitors: Cardiovascular
Effects
Procholinergic medications such as ChEIs can produce
bradycardia through vagal stimulation of the heart [119].
The degree of bradycardia is not an outcome generally
measured in randomized trials of ChEIs. Only one trial
reported this outcome and found a statistically significant
50 % increase in bradycardia in patients with MCI [84].
Several large observational studies have assessed the risk
for bradycardia and found a significant association between
ChEI use and hospital visits for symptomatic bradycardia,
with higher doses of medication associated with higher risk
[134136]. Those with symptomatic bradycardia were
significantly more likely to fall, experience syncope, or
need a pacemaker implantation [134136].
Pooled data from randomized trials in dementia have
found a statistically significant increase, by approximately
twofold, in the risk of syncope for ChEI treatment compared with placebo (Table 2) [12, 54]. A meta-analysis of

J. S. Buckley, S. R. Salpeter

ChEIs in patients with MCI also found a twofold increase

in risk of syncope [7]. Inter-study heterogeneity in these
pooled analyses was low, indicating a consistent increased
risk for syncope associated with ChEIs [7, 12]. Similar
results have been found in a large population-based observational study of community-dwelling subjects with
dementia, which, after adjusting for potential confounding
variables, found that ChEI use was associated with a significantly increased risk for hospital visits for syncope and
for syncope-related events such as pacemaker insertion and
falls with hip fracture [136]. The absolute increase in risk
for syncope in the study was 13 per 1000 person-years,
indicating that the number needed to treat for 1 year to
cause one hospitalization for syncope was 76 [136]. The
absolute increase in hip fracture was 3 per 1000 personyears, indicating a number needed to treat of 333 patients
for 1 year to cause one hip fracture [136].
3.3.7 Risks of Cholinesterase Inhibitors: General Effects
Acetylcholinesterase inhibitors can also cause some general adverse effects through cholinergic stimulation of
central and peripheral pathways [122]. These include fatigue and asthenia, each of which have been shown to be
increased two- to fourfold compared with placebo. Weight
loss is also increased threefold; this is discussed above
under gastrointestinal effects but is probably also related to
general effects of ChEIs on fatigue and debility [12, 122].
In older patients with frailty, these effects can be quite
serious and may precipitate further decline. As mentioned
above, the risk for significant weight loss with ChEIs
essentially doubles for those aged over 85 years compared
with younger patients [118]. Data from pharmacovigilance
studies have also suggested the risk for adverse drug reactions related to ChEIs are twofold higher for those aged
over 85 years than for younger individuals with dementia
[137].
The effect of ChEIs on falls is unclear, as the definition
of what constitutes a fall varies considerably among studies
and fall-related events are significantly under-reported
[54]. As mentioned above, ChEIs are associated with an
increased risk for syncopal episodes, with some evidence
for an increase in syncope-related injuries such as hip
fractures [12, 54, 136]. However, most falls are not due to
syncope and many do not result in injury [138140]. One
meta-analysis of randomized ChEI trials found no significant effect on falls, despite a 50 % increase in syncopal
episodes compared with placebo [54]. Some observational
studies of dementia populations have found ChEIs to be
associated with an increased risk for syncope, falls, and
fall-related injuries such as hip fractures [136, 141], while
other studies have found no effect or reduced risk
[142144].

Systematic Review of the Risks and Benefits of Dementia Medications

3.3.8 Risks of Cholinesterase Inhibitors: DrugDrug

Interactions

461

Cholinesterase inhibitors could be involved in several

drugdrug interactions, both because of their complex
pharmacodynamic and pharmacokinetic properties, and
also because elderly patients with dementia are typically
receiving multiple concomitant medications [2, 119, 145
147]. The use of medications with anticholinergic properties, such as some antidepressants, antipsychotics, antihistamines, and bronchodilators, is quite common in the
elderly, and the action of either the ChEI or the anticholinergic agent could be inhibited [145, 146]. In addition,
medications with anticholinergic effects could cause cognitive worsening or delirium in patients with dementia
[147]. Observational studies indicate that over one-third of
patients on ChEIs also receive at least one anticholinergic
drug [148, 149]. Drugs with additional cholinesterase inhibitory activity, such as ranitidine, could theoretically
enhance cholinergic activity and cause greater adverse
toxicity [145, 146]. The use of ChEIs together with antiparkinsonian medications could limit the efficacy of either drug when treating Parkinsons disease and dementia
[147]. In addition, as mentioned above, ChEIs have been
shown to increase tremor in patients with Parkinsons
disease two- to threefold [12, 103, 119]. Medications with
bradycardic effects, such as beta-blockers, digoxin, amiodarone, and calcium-channel blockers, cause vagal
stimulation or sympathetic blockade, and may increase the
risk for syncope or heart block [145147, 150].

addition, no statistically significant gain from memantine

monotherapy on behavioral outcomes in moderate to severe dementia was observed as measured by the NPI at
2428 weeks [56]. When the meta-analysis pooled data on
combination therapy with memantine and ChEIs, no statistically significant benefit on cognitive, functional, behavioral, or global outcomes was observed when
memantine was added to ChEI treatment [56].
Data on the effect of memantine in the treatment of mild
to moderate Alzheimers dementia are minimal. Two metaanalyses found that memantine treatment for up to
6 months in moderate Alzheimers disease produced a
marginal benefit in cognitive function (1 point on the
70-point ADAS-cog scale) and in global outcomes (0.1
points on a 7-point global assessment of change scale) but
had no effect on mood and behavior [95, 153]. However,
when evaluating trials of mild Alzheimers disease, no
significant effect of memantine on any outcome was observed, either in any single trial or when the trial data were
pooled together [153].
Data on the effect of memantine on vascular and Lewy
body dementia are even more scarce [1, 30, 9395, 154
156]. Memantine treatment in vascular dementia for
6 months showed minimal improvement in cognitive status
(approximately 2 points on the ADAS-cog scale) without a
significant effect on global outcomes or neuropsychiatric
scores [94, 154, 155]. Pooled trial data of memantine
treatment in Lewy body dementia found no statistically
significant effect on cognition, global outcome, or behavioral symptoms [30, 156158].

3.4 Memantine

3.4.2 Risks of Memantine

3.4.1 Benefits of Memantine

In pooled trial data of memantine, the most common side

effects seen were constipation, dizziness, headache, hypertension, and somnolence, but there was no statistically
significant difference in the number of withdrawals or patients with at least one adverse event between memantine
and placebo [93, 95, 159, 160]. A small reduction was
observed in the incidence of agitation recorded as an adverse event, with a number needed to treat of 17 patients
for 6 months to prevent one occurrence of agitation [95].
Agitation was not a primary outcome for efficacy of memantine in these trials, and there was no evidence that
agitation or other behavioral problems could be treated
with memantine [95]. Memantine had no significant effect
on falls, weight loss, or confusion [95, 159, 160]. One trial
found a threefold increase in hypertension for memantine
compared with placebo, but other studies did not evaluate
this effect [95].
Minimal drugdrug interactions have been seen with
memantine use [160]. However, little is known about the
use of memantine with other NMDA antagonists, such as

Memantine has marketing approval for the treatment of

moderate to severe Alzheimers dementia in most countries
[10, 56, 151, 152]. Studies that have assessed memantine,
either as monotherapy or combination therapy with ChEIs,
are limited and all are short-term (36 months) industrysponsored trials [56, 95]. A recent meta-analysis from the
UK National Institute for Health and Care Excellence
pooled data on trials of memantine monotherapy versus
placebo in moderate to severe Alzheimers dementia and
found a small benefit at 3 months of treatment (4 points on
the 133-point SIB scale), but no significant change was
seen by 6 months of treatment [56]. In addition, memantine
monotherapy was found to produce a small improvement
of 0.3 points in a 7-point global assessment of change scale
at 2428 weeks of treatment [56]. However, pooled data
from the meta-analysis showed no significant benefit in
functional outcomes as measured by ADL, or by the
Functional Assessment Staging instrument [56]. In

462

amantadine, ketamine, and dextromethorphan, so caution is

recommended [160, 161].

4 Conclusions
This systematic review summarizes the available data on
the risks and benefits of dementia treatments in the elderly.
Treatment with ChEIs for mild to moderate Alzheimers
and Lewy body dementia for durations of up to 1 year
produces small statistically-significant improvements in
cognitive, functional, and global outcomes, but whether
these improvements result in clinically relevant effects is
unclear. The three available ChEIs have similar efficacy,
with minimal differences seen between low and high doses
of these agents. Evidence exists that the beneficial effects
of ChEIs wane over the course of 12 years, and essentially no data is available to evaluate treatment beyond
2 years. No evidence exists for any beneficial effect of
ChEIs in the treatment of vascular dementia, and their use
is not recommended for this disease [94].
Trial data on ChEI treatment for severe Alzheimers
dementia are limited and have variable results, and no
studies have evaluated severe end-stage dementia. This
lack of data may indicate a publication bias on the part of
the pharmaceutical industry, with the assumption that patients with more severe dementia are less likely to benefit
from treatment [11]. Over half of community-dwelling and
roughly 90 % of institutionalized Alzheimers patients
have dementia rated as moderate to severe, so further research on this population is clearly needed [55, 162]. The
present evidence indicates that ChEIs have minimal benefit
in patients with severe dementia, and discontinuation of
treatment should be considered once the disease becomes
severe [163, 164].
The limited trial data indicate that ChEIs do not significantly improve cognitive or neuropsychiatric outcomes in
patients aged over 85 years. Of note, the prevalence of vascular dementia increases with advancing age, with 7090 %
of those aged over 90 years showing vascular pathology at
autopsy [13]. As ChEIs showed marginal efficacy for the
treatment of vascular dementia, this could explain why ChEIs
have decreased efficacy in older populations.
ChEIs produce side effects through increased cholinergic stimulation of central and peripheral neural pathways.
Pooled trial data show a twofold increase in withdrawals
due to adverse effects compared with placebo, with a
number needed to harm of ten. Individuals aged over
85 years have almost double the risk for an adverse event
compared with younger patients. For this older population,
with decreased efficacy of treatment and increased occurrence of adverse effects, we believe the risks of treatment
outweigh the benefits.

J. S. Buckley, S. R. Salpeter

Gastrointestinal effects are common with ChEI treatment, with a significant increased risk for abdominal
pain, nausea, vomiting, diarrhea, and anorexia, and
clinically significant weight loss. In addition, the rate of
headache, dizziness, tremor, insomnia, abnormal dreams,
fatigue, asthenia, vertigo, and muscle cramps are higher
than with placebo. Finally, hospitalization for bradycardia and syncope is doubled, and is associated with an
increased risk for syncope-related conditions such as hip
fracture. There appears to be a dose-dependence related
to adverse effects but not efficacy, so treatment with
lower doses may be preferable. It is clear that real-world
conditions are quite different from the controlled trial
environment, involving an older, frailer population with
more severe disease.
Memantine monotherapy in moderate to severe Alzheimers and vascular dementia has been shown to have
small beneficial effects on cognitive and global function
in trials of 36 months duration, with some waning of
effect by 6 months. In limited pooled trial data, memantine has not been shown to be effective in the
treatment of mild dementia or Lewy body dementia, or
as an add-on treatment to ChEIs. From the available
evidence, memantine seems to have a favorable sideeffect profile.
In summary, ChEIs may provide some cognitive, functional, and global benefits in mild to moderate Alzheimers
and Lewy body dementia, but at the risk of significant
cholinergic side effects, the most serious being weight loss,
debility, and syncope. These effects could be especially
detrimental in the frail elderly population, in which the
risks of treatment outweigh the benefits. The effectiveness
of ChEI treatment may be short lived, with minimal evidence for benefit over 1 year or in those with more advanced disease. No significant efficacy of treatment is seen
for those with vascular dementia or for those aged over
85 years. Memantine monotherapy may provide some
benefit for patients with moderate to severe Alzheimers
and vascular dementia, but the benefit is small and may
wane over the course of several months. Memantine has a
relatively favorable side-effect profile, at least under controlled trial conditions.
This systematic review provides the available evidence
on efficacy and risk of dementia treatments, but leaves a lot
of uncertainty on how to use these drugs in clinical practice. Good diagnostic criteria for identifying various dementia types are lacking, and no well-defined markers for
evaluating therapeutic response across the spectrum of
memory disorders exists. How efficacy should be assessed
for individual patients in order to understand whether
treatment is providing continued benefit or should be
stopped is unclear. These decisions will need to be made on
a case-by-case basis.

Systematic Review of the Risks and Benefits of Dementia Medications

Compliance with ethical standards No outside funding was used
to complete this research. The authors, Jacob Buckley and Shelley
Salpeter, have no conflicts of interest that are directly relevant to the
content of this study.

References
1. Qaseem A, Snow V, Cross JT Jr, et al. Current pharmacologic
treatment of dementia: a clinical practice guideline from the
American College of Physicians and the American Academy of
Family Physicians. Ann Intern Med. 2008;148(5):3708.
2. Evans JG, Wilcock G, Birks J. Evidence-based pharmacotherapy
of Alzheimers disease. Int J Neuropsychopharmacol. 2004;7(3):
35169.
3. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders: DSM-IV-TR. 4th ed. Washington,
DC; 2000.
4. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP.
The global prevalence of dementia: a systematic review and
metaanalysis. Alzheimers Dement. 2013;9(1):6375.e2.
5. Bachman DL, Wolf PA, Linn RT, et al. Incidence of dementia
and probable Alzheimers disease in a general population: the
Framingham Study. Neurology. 1993;43(3 Pt 1):5159.
6. Wimo A, Jonsson L, Bond J, Prince M, Winblad B, Alzheimer
Disease I. The worldwide economic impact of dementia 2010.
Alzheimers Dement. 2013;9(1):111.e3.
7. Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev. 2012;9:CD00
9132.
8. OBrien JT, Burns A, BAP Dementia Consensus Group. Clinical
practice with anti-dementia drugs: a revised (second) consensus
statement from the British Association for Psychopharmacology.
J Psychopharmacol. 2011;25(8):9971019.
9. Cummings JL. Challenges to demonstrating disease-modifying
effects in Alzheimers disease clinical trials. Alzheimers Dement. 2006;2(4):26371.
10. Drugs for cognitive loss and dementia. Treat Guidel Med Lett.
2013;11(134):95100.
11. Santaguida PS, Raina P, Booker L, et al. Pharmacological
treatment of dementia. Evid Rep Technol Assess (Summ). 2004;
97:116.
12. Birks J. Cholinesterase inhibitors for Alzheimers disease.
Cochrane Database Syst Rev. 2006;(1):CD005593.
13. Bullain SS, Corrada MM. Dementia in the oldest old. Continuum (Minneap Minn). 2013;19(2 Dementia):45769.
14. Gill SS, Bronskill SE, Mamdani M, et al. Representation of
patients with dementia in clinical trials of donepezil. Can J Clin
Pharmacol. 2004;11(2):e27485.
15. Schneider LS, Olin JT, Lyness SA, Chui HC. Eligibility of
Alzheimers disease clinic patients for clinical trials. J Am
Geriatr Soc. 1997;45(8):9238.
16. Asahina Y, Sugano H, Sugiyama E, Uyama Y. Representation of
older patients in clinical trials for drug approval in Japan. J Nutr
Health Aging. 2014;18(5):5203.
17. Killin LO, Russ TC, Starr JM, Abrahams S, Della Sala S. The
effect of funding sources on donepezil randomised controlled
trial outcome: a meta-analysis. BMJ Open. 2014;4(4):e004083.
18. Gilstad JR, Finucane TE. Results, rhetoric, and randomized
trials: the case of donepezil. J Am Geriatr Soc. 2008;56(8):
155662.
19. Rockwood K, MacKnight C. Assessing the clinical importance
of statistically significant improvement in anti-dementia drug
trials. Neuroepidemiology. 2001;20(2):516.

463
20. Lanctot KL, Herrmann N, Yau KK, et al. Efficacy and safety of
cholinesterase inhibitors in Alzheimers disease: a meta-analysis. CMAJ. 2003;169(6):55764.
21. Chui HC, Mack W, Jackson JE, et al. Clinical criteria for the
diagnosis of vascular dementia: a multicenter study of comparability and interrater reliability. Arch Neurol. 2000;57(2):1916.
22. Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimers disease: occurrence, determinants, and strategies toward
intervention. Dialogues Clin Neurosci. 2009;11(2):11128.
23. Hebert R, Brayne C. Epidemiology of vascular dementia. Neuroepidemiology. 1995;14(5):24057.
24. Rocca WA, Kokmen E. Frequency and distribution of vascular
dementia. Alzheimer Dis Assoc Disord. 1999;13(Suppl
3):S914.
25. Knopman DS, Parisi JE, Boeve BF, et al. Vascular dementia in a
population-based autopsy study. Arch Neurol. 2003;60(4):569
75.
26. Skoog I, Nilsson L, Palmertz B, Andreasson LA, Svanborg A. A
population-based study of dementia in 85-year-olds. N Engl J
Med. 1993;328(3):1538.
27. Lobo A, Launer LJ, Fratiglioni L, et al. Prevalence of dementia
and major subtypes in Europe: a collaborative study of
population-based cohorts. Neurologic Diseases in the Elderly
Research Group. Neurology. 2000;54(11 Suppl 5):S49.
28. Fitzpatrick AL, Kuller LH, Ives DG, et al. Incidence and
prevalence of dementia in the Cardiovascular Health Study.
J Am Geriatr Soc. 2004;52(2):195204.
29. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain
pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69(24):2197204.
30. Wang HF, Yu JT, Tang SW, et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in
Parkinsons disease, Parkinsons disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and
trial sequential analysis. J Neurol Neurosurg Psychiatry.
2015;86(2):13543. doi:10.1136/jnnp-2014-307659.
31. Aarsland D, Zaccai J, Brayne C. A systematic review of
prevalence studies of dementia in Parkinsons disease. Mov
Disord. 2005;20(10):125563.
32. Mayeux R, Stern Y, Rosenstein R, et al. An estimate of the
prevalence of dementia in idiopathic Parkinsons disease. Arch
Neurol. 1988;45(3):2602.
33. Shergil S, Mullan E, Dath P, Katona C. What is the clinical
prevalence of Lewy body dementia? Int J Geriatr Psychiatry.
1994;9:90712.
34. Vann Jones SA, OBrien JT. The prevalence and incidence of
dementia with Lewy bodies: a systematic review of population
and clinical studies. Psychol Med. 2014;44(4):67383.
35. Chertkow H, Massoud F, Nasreddine Z, et al. Diagnosis and
treatment of dementia: 3. Mild cognitive impairment and cognitive
impairment without dementia. CMAJ. 2008;178(10):127385.
36. Sheehan B. Assessment scales in dementia. Ther Adv Neurol
Disord. 2012;5(6):34958.
37. Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A
practical method for grading the cognitive state of patients for
the clinician. J Psychiatr Res. 1975;12(3):18998.
38. Crutch S. The mini mental state examination (MMSE). Fact
sheet. 2013. http://www.alzheimers.org.uk/site/scripts/download_
info.php?downloadID=1116. Accessed 12 Apr 2015.
39. Tombaugh TN, Hubley AM, McDowell I, Kristjansson B. Minimental state examination (MMSE) and the modified MMSE
(3MS): a psychometric comparison and normative data. Psychol
Assess. 1996;8(1):4859.
40. Kahle-Wrobleski K, Corrada MM, Li B, Kawas CH. Sensitivity
and specificity of the mini-mental state examination for

464

41.
42.

43.
44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

J. S. Buckley, S. R. Salpeter
identifying dementia in the oldest-old: the 90? study. J Am
Geriatr Soc. 2007;55(2):2849.
Galea M, Woodward M. Mini-mental state examination
(MMSE). Aust J Physiother. 2005;51(3):198.
Lourenco RA, Veras RP. Mini-mental state examination: psychometric characteristics in elderly outpatients. Rev Saude
Publica. 2006;40(4):7129.
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimers disease. Am J Psychiatry. 1984;141(11):135664.
Doraiswamy PM, Kaiser L, Bieber F, Garman RL. The Alzheimers Disease Assessment Scale: evaluation of psychometric
properties and patterns of cognitive decline in multicenter
clinical trials of mild to moderate Alzheimers disease. Alzheimer Dis Assoc Disord. 2001;15(4):17483.
Skinner J, Carvalho JO, Potter GG, et al. The Alzheimers disease assessment scale-cognitive-plus (ADAS-Cog-Plus): an expansion of the ADAS-Cog to improve responsiveness in MCI.
Brain Imaging Behav. 2012;6(4):489501.
Khan A, Yavorsky C, DiClemente G, et al. Reliability of the
Alzheimers disease assessment scale (ADAS-Cog) in longitudinal studies. Curr Alzheimer Res. 2013;10(9):95263.
Weyer G, Erzigkeit H, Kanowski S, Ihl R, Hadler D. Alzheimers Disease Assessment Scale: reliability and validity
in a multicenter clinical trial. Int Psychogeriatr. 1997;9(2):
12338.
Mohs RC, Knopman D, Petersen RC, et al. Development of
cognitive instruments for use in clinical trials of antidementia
drugs: additions to the Alzheimers Disease Assessment Scale
that broaden its scope. The Alzheimers Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):
S1321.
Panisset M, Roudier M, Saxton J, Boller F. Severe impairment
battery. A neuropsychological test for severely demented patients. Arch Neurol. 1994;51(1):415.
Lawton MP, Brody EM. Assessment of older people: selfmaintaining and instrumental activities of daily living. Gerontologist. 1969;9(3):17986.
Robert P, Ferris S, Gauthier S, Ihl R, Winblad B, Tennigkeit F.
Review of Alzheimers disease scales: is there a need for a new
multi-domain scale for therapy evaluation in medical practice?
Alzheimers Res Ther. 2010;2(4):24.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S,
Carusi DA, Gornbein J. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44(12):230814.
Reisberg B. Global measures: utility in defining and measuring
treatment response in dementia. Int Psychogeriatr. 2007;19(3):
42156.
Kim DH, Brown RT, Ding EL, Kiel DP, Berry SD. Dementia
medications and risk of falls, syncope, and related adverse
events: meta-analysis of randomized controlled trials. J Am
Geriatr Soc. 2011;59(6):101931.
Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA.
Alzheimer disease in the US population: prevalence estimates
using the 2000 census. Arch Neurol. 2003;60(8):111922.
National Institute for Health and Care Excellence. Donepezil,
galantamine, rivastigmine and memantine for the treatment of
Alzheimers disease. NICE technology appraisal guidance 217.
NICE; London; 2011.
Anthony JC, LeResche L, Niaz U, von Korff MR, Folstein MF.
Limits of the Mini-Mental State as a screening test for dementia and delirium among hospital patients. Psychol Med.
1982;12(2):397408.
OBryant SE, Humphreys JD, Smith GE, et al. Detecting dementia with the mini-mental state examination in highly
educated individuals. Arch Neurol. 2008;65(7):9637.

59. Schmitt FA, Wichems CH. A systematic review of assessment

and treatment of moderate to severe Alzheimers disease. Prim
Care Companion J Clin Psychiatry. 2006;8(3):1589.
60. Benson AD, Slavin MJ, Tran TT, Petrella JR, Doraiswamy PM.
Screening for early Alzheimers disease: is there still a role for
the mini-mental state examination? Prim Care Companion J Clin
Psychiatry. 2005;7(2):629.
61. Petersen RC. Mild cognitive impairment as a diagnostic entity.
J Intern Med. 2004;256(3):18394.
62. Pozueta A, Rodriguez-Rodriguez E, Vazquez-Higuera JL, et al.
Detection of early Alzheimers disease in MCI patients by the
combination of MMSE and an episodic memory test. BMC
Neurol. 2011;11:78.
63. Voisin T, Vellas B. Diagnosis and treatment of patients with
severe Alzheimers disease. Drugs Aging. 2009;26(2):13544.
64. Reisberg B, Jamil IA, Khan S, et al. Staging dementia. In: AbouSaleh MT, Katona CLE, Kumar A, editors. Principles and
practice of geriatric psychiatry. 3rd ed. Chichester, Hoboken:
Wiley; 2011. p. 162169.
65. Frolich L. The cholinergic pathology in Alzheimers disease:
discrepancies between clinical experience and pathophysiological findings. J Neural Transm. 2002;109(78):100313.
66. Francis PT, Perry EK. Cholinergic and other neurotransmitter
mechanisms in Parkinsons disease, Parkinsons disease dementia, and dementia with Lewy bodies. Mov Disord.
2007;22(Suppl 17):S3517.
67. Grantham C, Geerts H. The rationale behind cholinergic drug
treatment for dementia related to cerebrovascular disease.
J Neurol Sci. 2002;203204:1316.
68. Molinuevo JL, Llado A, Rami L. Memantine: targeting glutamate excitotoxicity in Alzheimers disease and other dementias.
Am J Alzheimers Dis Other Demen. 2005;20(2):7785.
69. Ahmed I, Bose SK, Pavese N, et al. Glutamate NMDA receptor
dysregulation in Parkinsons disease with dyskinesias. Brain.
2011;134(Pt 4):97986.
70. Sabbagh MN, Hake AM, Ahmed S, Farlow MR. The use of
memantine in dementia with Lewy bodies. J Alzheimers Dis.
2005;7(4):2859.
71. Mobius HJ. Pharmacologic rationale for memantine in chronic
cerebral hypoperfusion, especially vascular dementia. Alzheimer Dis Assoc Disord. 1999;13(Suppl 3):S1728.
72. Blennow K, de Leon MJ, Zetterberg H. Alzheimers disease.
Lancet. 2006;368(9533):387403.
73. Nyakas C, Granic I, Halmy LG, Banerjee P, Luiten PG. The
basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-beta42 with
memantine. Behav Brain Res. 2011;221(2):594603.
74. Danysz W, Parsons CG. Alzheimers disease, beta-amyloid,
glutamate, NMDA receptors and memantinesearching for the
connections. Br J Pharmacol. 2012;167(2):32452.
75. Iemolo F, Duro G, Rizzo C, Castiglia L, Hachinski V, Caruso C.
Pathophysiology of vascular dementia. Immun Ageing. 2009;6:13.
76. Ni JW, Matsumoto K, Li HB, Murakami Y, Watanabe H.
Neuronal damage and decrease of central acetylcholine level
following permanent occlusion of bilateral common carotid arteries in rat. Brain Res. 1995;673(2):2906.
77. Tsuboi Y, Uchikado H, Dickson DW. Neuropathology of
Parkinsons disease dementia and dementia with Lewy bodies
with reference to striatal pathology. Parkinsonism Relat Disord.
2007;13(Suppl 3):S2214.
78. Bohnen NI, Albin RL. The cholinergic system and Parkinson
disease. Behav Brain Res. 2011;221(2):56473.
79. Grothe MJ, Schuster C, Bauer F, Heinsen H, Prudlo J, Teipel SJ.
Atrophy of the cholinergic basal forebrain in dementia with
Lewy bodies and Alzheimers disease dementia. J Neurol.
2014;261(10):193948.

Systematic Review of the Risks and Benefits of Dementia Medications

80. Dalfo E, Albasanz JL, Martin M, Ferrer I. Abnormal
metabotropic glutamate receptor expression and signaling in the
cerebral cortex in diffuse Lewy body disease is associated with
irregular alpha-synuclein/phospholipase C (PLCbeta1) interactions. Brain Pathol. 2004;14(4):38898.
81. Starr MS. Glutamate/dopamine D1/D2 balance in the basal
ganglia and its relevance to Parkinsons disease. Synapse.
1995;19(4):26493.
82. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and
donepezil for the treatment of mild cognitive impairment.
N Engl J Med. 2005;352(23):237988.
83. Lu PH, Edland SD, Teng E, et al. Donepezil delays progression
to AD in MCI subjects with depressive symptoms. Neurology.
2009;72(24):211521.
84. Winblad B, Gauthier S, Scinto L, et al. Safety and efficacy of
galantamine in subjects with mild cognitive impairment. Neurology. 2008;70(22):202435.
85. Tricco AC, Soobiah C, Berliner S, et al. Efficacy and safety of
cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis. CMAJ. 2013;185
(16):1393401.
86. Cooper C, Li R, Lyketsos C, Livingston G. Treatment for mild
cognitive impairment: systematic review. Br J Psychiatry.
2013;203(3):25564.
87. Doody RS, Ferris S, Salloway S, et al. Safety and tolerability of
donepezil in mild cognitive impairment: open-label extension
study. Am J Alzheimers Dis Other Demen. 2010;25(2):1559.
88. Feldman HH, Ferris S, Winblad B, et al. Effect of rivastigmine
on delay to diagnosis of Alzheimers disease from mild cognitive impairment: the InDDEx study. Lancet Neurol. 2007;6(6):
50112.
89. Russ TC. Cholinesterase inhibitors should not be prescribed for
mild cognitive impairment. Evid Based Med. 2014;19(3):101.
90. Gauthier S, Touchon J. Mild cognitive impairment is not a
clinical entity and should not be treated. Arch Neurol.
2005;62(7):11646 (discussion 1167).
91. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a metaanalysis. JAMA. 2003;289(2):2106.
92. Takeda A, Loveman E, Clegg A, et al. A systematic review of
the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimers disease. Int J Geriatr Psychiatry. 2006;21(1):1728.
93. Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia:
evidence review for a clinical practice guideline. Ann Intern
Med. 2008;148(5):37997.
94. Kavirajan H, Schneider LS. Efficacy and adverse effects of
cholinesterase inhibitors and memantine in vascular dementia: a
meta-analysis of randomised controlled trials. Lancet Neurol.
2007;6(9):78292.
95. McShane R, Areosa Sastre A, Minakaran N. Memantine for
dementia. Cochrane Database Syst Rev. 2006;(2):CD003154.
96. Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG,
Jonas DE. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimers disease: a systematic
review and meta-analysis. Clin Interv Aging. 2008;3(2):21125.
97. Ellis JM. Cholinesterase inhibitors in the treatment of dementia.
J Am Osteopath Assoc. 2005;105(3):14558.
98. Hogan DB, Goldlist B, Naglie G, Patterson C. Comparison
studies of cholinesterase inhibitors for Alzheimers disease.
Lancet Neurol. 2004;3(10):6226.
99. Nordberg A, Svensson AL. Cholinesterase inhibitors in the
treatment of Alzheimers disease: a comparison of tolerability
and pharmacology. Drug Saf. 1998;19(6):46580.

465
100. Courtney C, Farrell D, Gray R, et al. Long-term donepezil
treatment in 565 patients with Alzheimers disease (AD2000):
randomised double-blind trial. Lancet. 2004;363(9427):
210515.
101. Schneider LS, Sano M. Current Alzheimers disease clinical
trials: methods and placebo outcomes. Alzheimers Dement.
2009;5(5):38897.
102. Lee PE, Fischer HD, Rochon PA, et al. Published randomized
controlled trials of drug therapy for dementia often lack complete data on harm. J Clin Epidemiol. 2008;61(11):115260.
103. Rolinski M, Fox C, Maidment I, McShane R. Cholinesterase
inhibitors for dementia with Lewy bodies, Parkinsons disease
dementia and cognitive impairment in Parkinsons disease.
Cochrane Database Syst Rev. 2012;(3):CD006504.
104. Schneider LS. Assessing outcomes in Alzheimer disease. Alzheimer Dis Assoc Disord. 2001;15(Suppl 1):S818.
105. Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimers disease: double-blind, parallelgroup, placebo-controlled study. Lancet. 2006;367(9516):
105765.
106. Black SE, Doody R, Li H, et al. Donepezil preserves cognition
and global function in patients with severe Alzheimer disease.
Neurology. 2007;69(5):45969.
107. Homma A, Imai Y, Tago H, et al. Donepezil treatment of patients with severe Alzheimers disease in a Japanese population:
results from a 24-week, double-blind, placebo-controlled, randomized trial. Dement Geriatr Cogn Disord. 2008;25(5):
399407.
108. Burns A, Bernabei R, Bullock R, et al. Safety and efficacy of
galantamine (Reminyl) in severe Alzheimers disease (the
SERAD study): a randomised, placebo-controlled, double-blind
trial. Lancet Neurol. 2009;8(1):3947.
109. Feldman H, Gauthier S, Hecker J, et al. Efficacy and safety of
donepezil in patients with more severe Alzheimers disease: a
subgroup analysis from a randomized, placebo-controlled trial.
Int J Geriatr Psychiatry. 2005;20(6):55969.
110. Ballard C, Margallo-Lana M, Juszczak E, et al. Quetiapine and
rivastigmine and cognitive decline in Alzheimers disease:
randomised double blind placebo controlled trial. BMJ.
2005;330(7496):874.
111. Cummings J, Jones R, Wilkinson D, et al. Effect of donepezil on
cognition in severe Alzheimers disease: a pooled data analysis.
J Alzheimers Dis. 2010;21(3):84351.
112. Froelich L, Andreasen N, Tsolaki M, et al. Long-term treatment
of patients with Alzheimers disease in primary and secondary
care: results from an international survey. Curr Med Res Opin.
2009;25(12):305968.
113. Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized,
placebo-controlled study of donepezil in patients with mild to
moderate AD. Neurology. 2001;57(3):48995.
114. Mohs RC, Doody RS, Morris JC, et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in
AD patients. Neurology. 2001;57(3):4818.
115. Hager K, Baseman AS, Nye JS, et al. Effects of galantamine in a
2-year, randomized, placebo-controlled study in Alzheimers
disease. Neuropsychiatr Dis Treat. 2014;10:391401.
116. Birks J, McGuinness B, Craig D. Rivastigmine for vascular
cognitive impairment. Cochrane Database Syst Rev. 2013;5:
CD004744.
117. Pagano G, Rengo G, Pasqualetti G, et al. Cholinesterase inhibitors for Parkinsons disease: a systematic review and metaanalysis. J Neurol Neurosurg Psychiatry. 2014.
118. Tariot PN, Cummings JL, Katz IR, et al. A randomized, doubleblind, placebo-controlled study of the efficacy and safety of
donepezil in patients with Alzheimers disease in the nursing
home setting. J Am Geriatr Soc. 2001;49(12):15909.

466
119. Thompson S, Lanctot KL, Herrmann N. The benefits and risks
associated with cholinesterase inhibitor therapy in Alzheimers
disease. Expert Opin Drug Saf. 2004;3(5):42540.
120. Inglis F. The tolerability and safety of cholinesterase inhibitors
in the treatment of dementia. Int J Clin Pract Suppl.
2002;127:4563.
121. Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimers disease: the relationship between pharmacological effects and
clinical efficacy. Drugs Aging. 2004;21(7):45378.
122. Gauthier S. Cholinergic adverse effects of cholinesterase inhibitors in Alzheimers disease: epidemiology and management.
Drugs Aging. 2001;18(11):85362.
123. Corey-Bloom J, Anand R, Veach J. A randomized trial
evaluating the efficacy and safety of ENA 713 (rivastigmine
tartrate), a new acetylcholinesterase inhibitor, in patients with
mild-to-moderately severe Alzheimers disease. Int J Geriatr
Psychopharmacol. 1998;1:5565.
124. Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of
rivastigmine in patients with Alzheimers disease: international
randomised controlled trial. BMJ. 1999;318(7184):6338.
125. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S,
Ding C. A, 5-month, randomized, placebo-controlled trial of
galantamine in AD. The Galantamine USA-10 Study Group.
Neurology. 2000;54(12):226976.
126. White H, Pieper C, Schmader K. The association of weight
change in Alzheimers disease with severity of disease and
mortality: a longitudinal analysis. J Am Geriatr Soc.
1998;46(10):12237.
127. Keller HH, Ostbye T, Goy R. Nutritional risk predicts quality of
life in elderly community-living Canadians. J Gerontol A Biol
Sci Med Sci. 2004;59(1):6874.
128. Crogan NL, Pasvogel A. The influence of protein-calorie malnutrition on quality of life in nursing homes. J Gerontol A Biol
Sci Med Sci. 2003;58(2):15964.
129. Payette H, Coulombe C, Boutier V, Gray-Donald K. Nutrition
risk factors for institutionalization in a free-living functionally
dependent
elderly
population.
J
Clin
Epidemiol.
2000;53(6):57987.
130. Sullivan DH, Morley JE, Johnson LE, et al. The GAIN (Geriatric Anorexia Nutrition) registry: the impact of appetite and
weight on mortality in a long-term care population. J Nutr
Health Aging. 2002;6(4):27581.
131. Stewart JT, Gorelik AR. Involuntary weight loss associated with
cholinesterase inhibitors in dementia. J Am Geriatr Soc.
2006;54(6):10134.
132. Gallini A, Sommet A, Salandini AM, Veyssiere P, Montastruc
JL, Montastruc JL. Weight-loss associated with anti-dementia
drugs in a patient with Parkinsons disease. Mov Disord.
2007;22(13):19801.
133. Dunn NR, Pearce GL, Shakir SA. Adverse effects associated
with the use of donepezil in general practice in England. J Psychopharmacol. 2000;14(4):4068.
134. Hernandez RK, Farwell W, Cantor MD, Lawler EV. Cholinesterase inhibitors and incidence of bradycardia in patients
with dementia in the veterans affairs New England healthcare
system. J Am Geriatr Soc. 2009;57(11):19972003.
135. Park-Wyllie LY, Mamdani MM, Li P, Gill SS, Laupacis A,
Juurlink DN. Cholinesterase inhibitors and hospitalization for
bradycardia: a population-based study. PLoS Med. 2009;6(9):
e1000157.
136. Gill SS, Anderson GM, Fischer HD, et al. Syncope and its
consequences in patients with dementia receiving cholinesterase
inhibitors: a population-based cohort study. Arch Intern Med.
2009;169(9):86773.

J. S. Buckley, S. R. Salpeter
137. Pariente A, Sanctussy DJ, Miremont-Salame G, et al. Factors
associated with serious adverse reactions to cholinesterase inhibitors: a study of spontaneous reporting. CNS Drugs.
2010;24(1):5563.
138. Brignole M. Distinguishing syncopal from non-syncopal causes
of fall in older people. Age Ageing. 2006;35(Suppl 2):ii4650.
139. McIntosh S, Da Costa D, Kenny RA. Outcome of an integrated
approach to the investigation of dizziness, falls and syncope in
elderly patients referred to a syncope clinic. Age Ageing.
1993;22(1):538.
140. Shaw FE, Kenny RA. The overlap between syncope and falls in
the elderly. Postgrad Med J. 1997;73(864):6359.
141. French DD, Campbell R, Spehar A, Cunningham F, Bulat T,
Luther SL. Drugs and falls in community-dwelling older people:
a national veterans study. Clin Ther. 2006;28(4):61930.
142. Tamimi I, Ojea T, Sanchez-Siles JM, et al. Acetylcholinesterase
inhibitors and the risk of hip fracture in Alzheimers disease
patients: a case-control study. J Bone Miner Res. 2012;27(7):
151827.
143. Chung KA, Lobb BM, Nutt JG, Horak FB. Effects of a central
cholinesterase inhibitor on reducing falls in Parkinson disease.
Neurology. 2010;75(14):12639.
144. Kallin K, Gustafson Y, Sandman PO, Karlsson S. Drugs and
falls in older people in geriatric care settings. Aging Clin Exp
Res. 2004;16(4):2706.
145. Tavassoli N, Sommet A, Lapeyre-Mestre M, Bagheri H, Montrastruc JL. Drug interactions with cholinesterase inhibitors: an
analysis of the French pharmacovigilance database and a comparison of two national drug formularies (Vidal, British National
Formulary). Drug Saf. 2007;30(11):106371.
146. Bentue-Ferrer D, Tribut O, Polard E, Allain H. Clinically significant drug interactions with cholinesterase inhibitors: a guide
for neurologists. CNS Drugs. 2003;17(13):94763.
147. Seritan AL. Prevent drug-drug interactions with cholinesterase
inhibitors: avoid adverse events when prescribing medications
for patients with dementia. Curr Psychiatry. 2008;7(2):5767.
148. Carnahan RM, Lund BC, Perry PJ, Chrischilles EA. The concurrent
use of anticholinergics and cholinesterase inhibitors: rare event or
common practice? J Am Geriatr Soc. 2004;52(12):20827.
149. Roe CM, Anderson MJ, Spivack B. Use of anticholinergic
medications by older adults with dementia. J Am Geriatr Soc.
2002;50(5):83642.
150. Paulison B, Leos CL. Potential cardiotoxic reaction involving
rivastigmine and beta-blockers: a case report and review of the
literature. Cardiovasc Toxicol. 2010;10(4):30610.
151. Agency EM. Ebixa. European Public Assessment Report.2004.
www.emea.eu.int/humandocs/Humans/EPAR/ebixa/ebixa.htm.
Accessed 12 Apr 2015.
152. FDA approves memantine drug for treating AD. Am J Alzheimers Dis Other Demen. 2003;18(6):32930.
153. Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of
evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 2011;68(8):9918.
154. Wilcock G, Mobius HJ, Stoffler A, Group MMM. A doubleblind, placebo-controlled multicentre study of memantine in
mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002;17(6):297305.
155. Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F.
Efficacy and safety of memantine in patients with mild to
moderate vascular dementia: a randomized, placebo-controlled
trial (MMM 300). Stroke. 2002;33(7):18349.
156. Emre M, Tsolaki M, Bonuccelli U, et al. Memantine for patients
with Parkinsons disease dementia or dementia with Lewy
bodies: a randomised, double-blind, placebo-controlled trial.
Lancet Neurol. 2010;9(10):96977.

Systematic Review of the Risks and Benefits of Dementia Medications

157. Leroi I, Overshott R, Byrne EJ, Daniel E, Burns A. Randomized
controlled trial of memantine in dementia associated with
Parkinsons disease. Mov Disord. 2009;24(8):121721.
158. Aarsland D, Ballard C, Walker Z, et al. Memantine in patients
with Parkinsons disease dementia or dementia with Lewy
bodies: a double-blind, placebo-controlled, multicentre trial.
Lancet Neurol. 2009;8(7):6138.
159. Jones RW. A review comparing the safety and tolerability of
memantine with the acetylcholinesterase inhibitors. Int J Geriatr
Psychiatry. 2010;25(6):54753.
160. Mimica N, Presecki P. Side effects of approved antidementives.
Psychiatr Danub. 2009;21(1):10813.

467
161. Stahl SM. Essential psychopharmacology: the prescribers
guide. Cambridge: Cambridge University Press; 2005.
162. Lindsay J. Patterns of caring for people with dementia in Canada. The
Canadian study of health and aging. Can J Aging. 1994;13:47087.
163. Molino I, Colucci L, Fasanaro AM, Traini E, Amenta F. Efficacy of memantine, donepezil, or their association in moderatesevere Alzheimers disease: a review of clinical trials. ScientificWorldJournal. 2013;2013:925702.
164. Shega JW, Ellner L, Lau DT, Maxwell TL. Cholinesterase inhibitor and N-methyl-D-aspartic acid receptor antagonist use in
older adults with end-stage dementia: a survey of hospice
medical directors. J Palliat Med. 2009;12(9):77983.