CanJPsychiatry 2014;59(12):618–623

In Review

Long-Term Efficacy and Toxicity of Cholinesterase

Inhibitors in the Treatment of Alzheimer Disease

David B Hogan, MD, FACP, FRCPC1

Brenda Strafford Foundation Chair in Geriatric Medicine, University of Calgary, Calgary, Alberta.
1

Correspondence: HSC-3330 Hospital Drive NW, University of Calgary, Calgary, AB T2N 4N1; dhogan@ucalgary.ca.

Key Words: cholinesterase
inhibitors, Alzheimer disease,
drug therapy, long-term effects
Received June 2014, revised,
and accepted August 2014.
Though the symptoms of Alzheimer disease go on for years, the phase 3 trials of the
cholinesterase inhibitors (ChEIs), the current mainstay of symptomatic pharmacotherapy
for this condition, were typically of only 3- to 6-months’ duration. We have limited data on
long-term (that is, a year or more) therapy with these agents. In this review, we explore the
available information on the biological and clinical effects of long-term ChEI therapy, what
happens when these agents are discontinued, and examine what others have recommended.
An individualized approach to deciding on whether to carry on with a ChEI should be taken.
If continued, treatment goals should be clarified and patients monitored over time, for both
drug-related benefits and adverse effects.
WWW

Efficacité et toxicité à long terme des inhibiteurs de la cholinestérase

dans le traitement de la maladie d’Alzheimer
Bien que les symptômes de la maladie d’Alzheimer durent pendant des années, les essais
en 3 phases des inhibiteurs de la cholinestérase (ICh), le soutien principal actuel de la
pharmacothérapie symptomatique de cette affection, ne durent habituellement que de 3 à
6 mois. Nous disposons de données limitées sur la thérapie à long terme (soit un an ou plus)
avec ces agents. Dans cette revue, nous explorons l’information disponible sur les effets
biologiques et cliniques de la thérapie des ICh à long terme, et sur ce qui se produit lorsque
ces agents sont discontinués, et nous examinons ce que d’autres ont recommandé. Il faudrait
prendre une approche individualisée pour décider d’un traitement aux ICh. Le cas échéant, il
faudrait clarifier les buts du traitement et surveiller les patients au fil du temps, tant pour les
avantages liés aux médicaments que pour les effets indésirables.

C holinesterase inhibitors, such as donepezil, galanta-

mine, and rivastigmine, are the most commonly
used medications for the symptomatic treatment of AD
in Canada. In 2012, ChEIs were the seventh most costly
agent covered by publically funded drug benefit programs
for older Canadians, with $129.4 million spent on them.1
RCTs indicate that their use may lead to modest cognitive
and global benefits.2
AD is a progressive form of dementia that goes on for
years after the onset of symptoms.3 For this condition, as
with many other chronic diseases, it is not uncommon for
pharmacotherapy to be taken for a longer period of time
than the duration of the trials that led to marketing approval.
Most of the phase 3 RCTs of ChEIs were 6 months or less
in duration,2 which is shorter than the average time span
that these drugs are taken by patients with AD in Canada.4.5
The 2008 Clinical Practice Guidelines on the pharmacologic
treatment of dementia of the American College of Physicians
and the American Academy of Family Physicians concluded
there was insufficient evidence on which to determine the
optimal duration of therapy with ChEIs and that research
on this topic was needed.6 Likewise, the second list of
Five Things Physicians and Patients Should Question
developed by the American Geriatrics Society notes that
the risks and benefits of long-term therapy with ChEIs are
not well-established.7 Notwithstanding this uncertainty, we
have to advise our patients and their families on how long
treatment should persist and to respond when they ask about
the relative benefits and safety of long-term use of ChEIs.
While at times dubious about their clinical utility, family
members of people with a dementia often fear that stopping
them may be accompanied by deterioration in the clinical
status of their relative.8
To help address this issue, a qualitative review of the available
literature on the relative benefits and risks of long-term (for
this review, defined as 1 or more years) ChEI therapy was
performed. The main themes relevant to the topic were
identified followed by purposive (nonexhaustive) searches
of the relevant literature. The papers referred to in this review
were either previously known to the author or identified by

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 Long-Term Efficacy and Toxicity of Cholinesterase Inhibitors in the Treatment of Alzheimer Disease
a series of PubMed word searches. The focus was on the
biomedical effects of long-term use. A pharmacoeconomic
analysis, based on an examination of available data, was not
done, though it should be noted that their current availability
as generics has lessened (though not eliminated) concerns
about the cost-effectiveness of these agents.
Biological Effects of Long-Term
Cholinesterase Inhibitor Therapy
In 1976, Davies and Maloney suggested that AD arose from
9
a “cholinergic system failure.”p 1403 This was based on finding
a marked reduction in the activity of enzymes involved in the
metabolism of ACh within the brains of patients dying with
AD. This observation, coupled with data from experimental
studies showing an important role for ACh in learning and
memory, led to the cholinergic hypothesis for age-associated
memory loss and AD.10 This proposes that degeneration of
cholinergic neurons in the basal forebrain leads to the loss of
cholinergic neurotransmission in the cortex, hippocampus,
and other areas of the brain that, in turn, contributes to the
impaired cognition seen. Just as Parkinson disease was
considered a dopaminergic deficiency condition, AD was
conceptualized as a cholinergic one.11 This had an important
influence on early AD drug development and led to the
identification, study, and eventual approval of ChEIs for
the treatment of AD.11,12 The beneficial effects of ChEIs
are still felt to arise primarily from their ability to improve
cholinergic neurotransmission by slowing the degradation
of ACh by the enzyme AChE.
While the ChEIs are approved as symptomatic forms of
therapy for AD, some feel that they may also have disease-
modifying (that is, exert an impact on the underlying
pathophysiology of the disorder) effects.13,14 Numerous
mechanisms have been proposed for how this may occur,
including the antiinflammatory properties of cholinergic
upregulation, effects of these agents on AChE isoform
and nicotinic receptor expression, reduced amyloid
precursor protein processing, attenuation of beta-amyloid
toxicity, and maintenance of ACh-mediated compensatory
pathways.15–17 Unfortunately, convincing proof that ChEIs
have a neuroprotective effect in patients with AD is lacking,
and it appears that these agents have limited, if any, disease-
modifying activity.18 In support of this is the lack of any
significant changes in CSF AD biomarkers (that is, amyloid
beta 1–42, total tau, and phosphorylated tau) among patients
Abbreviations
ACh acetylcholine
AChE acetylcholinesterase
AD Alzheimer disease
ChEI cholinesterase inhibitor
CSF cerebrospinal fluid
MMSE Mini-Mental State Examination
RCT randomized controlled trial
www.TheCJP.ca
Highlights
• Long-term therapy with ChEIs is associated with a small
but statistically significant increased risk of bradycardia
and syncope and their consequences (for example,
pacemaker implantation and hip fracture).
• Discontinuing these agents can lead to the loss of
beneficial cognitive and functional effects that may not
have been evident.
• Decisions about whether to continue therapy should
be individualized. There is general agreement that
consideration of stopping should take place when the
patient’s dementia has progressed to a severe stage.
with this form of dementia treated for 6 to 12 months with
ChEIs.19–21 An autopsy study suggested that, if anything, the
use of these agents may accelerate disease progression. There
was significantly greater accumulation of phosphorylated
tau in the cerebral cortex of patients treated with ChEIs,
compared with untreated ones.22 Though this finding
requires verification, the authors of the report speculated
this may help explain diminishing responsiveness to these
agents with long-term therapy.
Treatment with rapidly reversible ChEIs, such as donepezil
and galantamine, is associated with significant upregulation
of AChE activity in the CSF of patients with AD, while use of
rivastigmine, a pseudo-irreversible ChEI, is associated with a
significant decrease in both AChE and butyrylcholinesterase
activity.21,23 These differing effects have not been correlated
with either favourable or adverse clinical outcomes.
Clinical Effects of Long-Term
Cholinesterase Inhibitor Therapy
Data from the RCTs of ChEIs provide little information about
their long-term effects. As previously noted, most of these
studies were of short (3 or 6 months) duration.2 As these
results were considered sufficient for regulatory approval of
the ChEIs, there was little incentive for pharmaceutical firms
to do longer studies. While there are a handful of 1-year-or-
more, placebo-controlled trials of ChEIs for patients with
AD,24–28 their interpretation is complicated by restricted
inclusion criteria, not surprising relatively high (that is,
25% or more) discontinuation rates, and (or) questionable
statistical analyses (for example, using last observation
carried forward to deal with missing data). Even if funding
could be found, ethical and feasibility considerations now
mean it is unlikely that 1-year-or-longer RCTs of ChEIs
could be conducted in our country.
There are numerous open-label extension and observational
studies that have followed treated patients for often more than
a year. These studies have been used to look for evidence of
long-term efficacy and safety. The former would be assessed
by comparing the cognitive and (or) functional outcomes of
patients who have continuously taken a ChEI with historical
control subjects, predictions from mathematical models,29
or contemporaneous patients who had never been treated,
The Canadian Journal of Psychiatry, Vol 59, No 12, December 2014 W 619
In Review
used the drugs briefly, or stopped taking them. These so-
called real-world studies almost always report benefits and
good tolerability with prolonged therapy.30,31 Because these
reports are uncontrolled, with drop-out and survivor bias,
their results have to be interpreted with caution as there
is substantial risk that erroneous conclusions about both
efficacy and safety will be drawn.32–36 As an example of
the reduction that can be seen in the number of subjects
from enrolment to completion of an open-label study, 286
participants were randomized at the start of the double-blind
component of the Donepezil Nordic study, 157 (54.9% of
all those randomized) entered the open-label phase, and
114 (39.9%) completed the full 2 years of it.37 Open-label
extension and observational studies do have their defenders,
who feel they provide useful and otherwise unavailable
long-term information.30,31,38 As a minimum, they show that
some patients can safely take these drugs for a long period
of time.
In opposition to the generally favourable results reported with
observational studies, the Alzheimer’s Disease Neuoimaging
Initiative and the Australian Imaging, Biomarkers and
Lifestyle studies both showed greater cognitive decline
among participants with mild cognitive impairment or AD
taking a ChEI, compared with not receiving treatment.39,40
As with the favourable studies, the known and unknown
potential sources of biases undermine our ability to draw any
firm conclusions from these results. For example, clinicians
may have selectively prescribed ChEIs to patients with more
aggressive disease.39
While adverse effects from these agents generally arise
during initiation and upward drug titration, several studies
using administrative data have raised safety concerns
with long-term use. For example, the prescription of
ChEIs is associated with an increased risk of receiving an
anticholinergic drug to manage urinary incontinence.41 This
is felt to be an example of a prescribing cascade, where the
first agent causes an adverse drug effect (that is, urinary
incontinence) that is treated by the prescription of a second
medication to deal with the drug-induced problem. The
concurrent prescription of procholinergic and anticholinergic
agents, which could blunt each other’s therapeutic effects
leading to a pharmacological stalemate, is a particular
concern with this specific combination of drugs.42 Of greater
worry, though, is the finding that the prescription of ChEIs is
associated with a small absolute but statistically significant
increased risk of bradycardia leading to hospitalization,
syncope, pacemaker insertion, and hip fracture (presumably
from presyncopal and [or] syncopal falls).43–45 Adverse
cardiovascular effects are not unexpected, as ChEIs can
induce sinus bradycardia, sinoatrial block, and aggravate
preexisting sinus node disease and atrioventricular blocks.
A meta-analysis of RCT results found an increased risk
of syncope with their use.46 There have also been several
case reports of QT interval prolongation with torsades de
pointes ventricular tachycardia with ChEIs.47 Patients on
ChEIs should be routinely asked about presyncope and (or)
syncope and have their pulse checked for bradycardia.48 An
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electrocardiogram should be done if the patient has been
prescribed another drug that could prolong their QT interval
(for example, antiarrhythmic, antihistamine, amtimicrobial,
tricyclic antidepressant, and neuroleptic) or if some other
factor that may increase the time required for ventricular
repolarization (for example, organic heat disease and
metabolic abnormalities) is present.49,50
Cohort studies have allayed some of the worries about
ChEIs. These agents could theoretically lead to or aggravate
bronchoconstriction. While a small study of hospitalized
patients on a geriatric unit receiving ChEIs suggested an
increased risk for pulmonary disorders,51 a much larger
population-based one found no evidence of an increased
likelihood of serious pulmonary complications in older
people treated with a ChEI who had concomitant chronic
obstructive airway disease.52 These drugs also may increase
gastric acid production, but a recent report found that upper
gastrointestinal bleeding was not associated with the use of
ChEIs.53 Though reassuring at a population level, this does
not mean that individual patients will not encounter these
problems if treated with these agents.
Involuntary weight loss has attracted attention as a
potential adverse effect of long-term use of these agents.
While gastrointestinal side effects, including anorexia and
weight loss, were relatively common in the RCTs of ChEIs,
interpreting a change in weight during long-term therapy
with a ChEI is difficult because weight loss commonly
occurs in untreated AD.54 Though highlighted as a potential
concern in a case series,55 2 observational studies did not find
a greater risk for weight loss in patients with AD receiving
a ChEI.56,57 This is another area where individual patients
may be at risk. Weight should be monitored during long-
term therapy.
The above adverse effects were predictable from the known
pharmacology of ChEIs. Postmarketing surveillance is
needed to help identify unpredictable and rare ones. Though
causality is not confirmed, one that has been suggested as
arising from ChEI use is the Pisa syndrome (that is, abnormal
flexion of the body and head to one side accompanied by
slight axial rotation of the trunk).58 This is felt to arise from
a dopaminergic–cholinergic imbalance.
An important factor influencing the tolerability of ChEIs is
the use of other drugs. Drug–drug interactions were present
in about one-third of spontaneous reports of adverse effects
with ChEIs in France.59 The most frequently encountered
interactions were with medications that, on their own,
can lead to bradycardia (for example, beta blockers) and
anticholinergics. In Canada, nearly two-thirds of people 65
and older are prescribed 5 or more medications during a year,
with one-quarter receiving 10 or more.1 Safe prescribing of
ChEIs requires being knowledgeable of all the medications
the patient may be taking and being circumspect about
prescribing additional drugs.
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 Long-Term Efficacy and Toxicity of Cholinesterase Inhibitors in the Treatment of Alzheimer Disease
Effects of Stopping Long-Term
Cholinesterase Inhibitor Therapy
There are a few case reports of patients with AD experiencing
withdrawal symptoms after stopping a ChEI.60,61 A small
open-label study of patients with either Lewy-body or
Parkinson disease dementia found that abrupt withdrawal of
donepezil produced acute cognitive and behavioural decline.62
A retrospective cohort study of nursing home residents who
discontinued a ChEI found they were significantly more likely
than those who carried on with therapy to show aggression
and (or) repetitive behaviour. They also spent significantly
less time on leisure activities.63
Two double-blind RCTs provide information on the effects
of discontinuing a ChEI after prolonged use in patients
with AD. One was a 24-month, double-blind, randomized,
placebo-controlled withdrawal trial that followed a 12-month,
open-label study of galantamine.64 Patients randomized to
placebo were more likely to discontinue the double-blind
phase prematurely (overall and specifically because of a
perceived lack of efficacy), but were no more likely to show
a 4+ decline on the Alzheimer Disease Assessment Scale—
cognitive subscale (commonly referred to as ADAS-cog).
As well, there was no significant difference in the Clinical
Interview Based Impression of Changes—Plus Caregiver
Input (commonly referred to as CIBIC-plus) scores of the
2 groups. In the Donepezil and Memantine in Moderate to
Severe Alzheimer’s Disease (commonly referred to as the
DOMINO-AD Trial) study,28 participants with moderate-
to-severe AD treated with donepezil for at least 3 months
(87% had been on donepezil for 12 or more months) were
randomly allocated to continuing donepezil, stopping it,
stopping it and starting memantine, or continuing donepezil
and starting memantine. After a year, participants who carried
on with donepezil scored, on average, 1.9 points higher on
a standardized MMSE, compared with those who stopped
it and did 3.0 points better on the Bristol Activities of Daily
Living Scale (commonly referred to as BADLS). There is
an ongoing discontinuation trial of ChEIs that should shed
further light on the issue.65
If therapy is discontinued, the dose should be tapered before
stopping, and the patient should be monitored during the next
1-to-3 months, with consideration given to reinstating therapy
if there is a significant deterioration in the their condition.66
An older open-label study suggested that ChEI treatment
effects that are lost after prolonged (6-week) discontinuation
are not fully recovered when drug treatment is restarted.67
The validity and clinical importance of this observation is
debatable and should not, in itself, dissuade the practitioner
from consideration of stopping therapy. Reassurance that
permanent harm is not being done to patients by temporarily
stopping ChEIs to see if they are benefiting from therapy
comes from a Québec population-based observational study
that found the occurrence of treatment gaps of 6 or more
weeks during the first year of therapy with a ChEI among
those who resumed treatment was not associated with an
increased risk of institutionalization or death.68
www.TheCJP.ca
Recommendations of Others
A few years ago, Canadian dementia experts were surveyed
about their perceptions on discontinuing ChEIs. There was
near unanimous (96% of respondents) agreement that these
agents should not be discontinued after a year because of
the lack of long-term data.69 Most felt that they could not
specify a length of time at which point these drugs should
be discontinued. In other words, duration of therapy was
not viewed as a stand-alone criterion for stopping.
As AD is a progressive illness, over time patients treated
with symptomatic drugs, such as ChEIs, will unfortunately
continue to decline. In deciding whether to discontinue
because of a perceived lack of efficacy, a challenge is trying
to estimate the expected rate of decline on cognitive and (or)
functional measures if the patient was untreated. Focusing
on the MMSE as an example of a cognitive measure that
may be used to try and make this determination, a meta-
analysis reported that the overall annual rate of change
in the MMSE among untreated patients with AD was 3.3
(95% CI 2.9 to 3.7).70 Declines on even brief cognitive
measures, such as the MMSE, though, are not linear. In
general, faster deterioration is seen at a moderate degree of
cognitive impairment, compared with milder or more severe
deficits, and the rate of change is influenced by various other
factors.29 There is even evidence of a secular trend. Subjects
assigned to the placebo arm in more recent RCTs of AD
showed slower rates of cognitive decline, compared with
older studies.71 Finally, it has to be noted that the overall
annual rate of change in the MMSE is close to the standard
deviation of the measurement error for the test.72 These
factors make it difficult to come up with an accurate estimate
of expected MMSE decline, to compare it with what was
seen, and to decide if there are meaningful differences at
the level of an individual patient. While uncertainty on how
best to determine greater-than-expected decline was evident
in the survey, most respondents agreed that progression to
a severe stage (that is, Global Deterioration Scale stage
7, development of swallowing difficulties) should trigger
consideration of stopping.69
Recently published consensus recommendations and
clinical practice guidelines66,73–75 have advocated for an
individualized approach,75 with a search for evidence that
continued therapy is having a worthwhile effect.74 There was
support for stopping when the patient has progressed to a
severely impaired stage (for example, to profound disease
or Global Deterioration Scale stage 7).66,73
Conclusions
Decisions about whether to continue a ChEI should be
individualized and not arbitrarily based on factors such as a
MMSE score, length of treatment, or being institutionalized.
It goes without saying that deliberations about when to start,
continue, and stop these agents must not detract from other
aspects of the care that should be provided to a patient with
dementia and their family.76 At this stage in the life cycle
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In Review
of ChEIs, it is unlikely that additional long-term controlled
trials will be conducted.
Though this can be seen in untreated patients,77 we often
ascribe beneficial effects to ChEI therapy if the patient’s
dementia appears to be progressing slowly (however
defined) while on long-term therapy. In this situation,
treatment is generally continued as long as the patient (or
their proxy decision maker, if they lack capacity to consent
to health care) is willing to continue with the agent, remains
reasonably adherent, does not have comorbidities that
would make continued therapy unacceptably risky or futile,
is not having intolerable adverse drug effects, and has not
progressed to a severely impaired stage.66 If one persists
with the ChEI, treatment goals should be agreed on with
the patient and their family. Patients would then be seen
periodically to monitor for both perceived benefits and
adverse effects.7
Acknowledgements
Dr Hogan holds and is supported by the Brenda Strafford
Foundation Chair in Geriatric Medicine, University of
Calgary.
The Canadian Psychiatric Association proudly supports the
In Review series by providing an honorarium to the authors.
References
1. Canadian Institute for Health Information (CIHI). Drug use among
seniors on public drug programs in Canada, 2012. Ottawa (ON):
CIHI; 2014.
2. 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;148:379–397.
3. Wolfson C, Wolfson DB, Asgharian M, et al; on behalf of the
Clinical Progression of Dementia Study Group. A reevaluation of
the duration of survival after the onset of dementia. N Engl J Med.
2001;344:1111–1116.
4. Herrmann N, Gill SS, Bell CM, et al. A population-based study
of cholinesterase inhibitor use for dementia. J Am Geriatr Soc.
2007;55:1517–1523.
5. Amuah JE, Hogan DB, Eliasziw M, et al. Persistence with
cholinesterase inhibitor therapy in a population-based cohort of
patients with Alzheimer’s disease. Pharmacoepidemiol Drug Saf.
2010;19:670–679.
6. Qaseem A, Snow V, Cross JT, 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;148:370–378.
7. American Geriatrics Society. Choosing wisely—five things
physicians and patients should question: part 2 [Internet]. New
York (NY): American Geriatrics Society; 2014 [cited 2014 Jun
23]. Available from: http://www.americangeriatrics.org/files/
documents/5things_list_PART.pdf.
8. Smith A, Kobayashi K, Chappell N, et al. The controversial
promises of cholinesterase inhibitors for Alzheimer’s disease and
related dementias: a qualitative study of caregivers’ experiences.
J Aging Stud. 2011;25:397–406.
9. Davies P, Maloney AJ. Selective loss of central cholinergic neurons
in Alzheimer’s disease. Lancet. 1976;2(8000):1403.
10. Bartus RT, Dean RL 3rd, Beer B, et al. The cholinergic hypothesis of
geriatric memory dysfunction. Science. 1982;217:408–417.
11. Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials
and late-stage drug development for Alzheimer’s disease:
an appraisal from 1984 to 2014. J Intern Med. 2014;275:251–283.
622 W La Revue canadienne de psychiatrie, vol 59, no 12, décembre 2014
12. Francis PT, Palmer AM, Snape M, et al. The cholinergic hypothesis
of Alzheimer’s disease: a review of progress. J Neurol Neurosurg
Psychiatry. 1999;66:137–147.
13. Seltzer B. Is long-term treatment of Alzheimer’s disease
with cholinesterase inhibitor therapy justified? Drugs Aging.
2007;24:881–890.
14. Shanks M, Kivipelto M, Bullock R, et al. Cholinesterase inhibition:
is there evidence for disease-modifying effects? Curr Med Res Opin.
2009;25:2439–2446.
15. Nizri E, Hamra-Amitay Y, Sicsic C, et al. Anti-inflammatory
properties of cholinergic up-regulation: a new role for
acetylcholinesterase inhibitors. Neuropharmacology.
2006;50:540–547.
16. Nordberg A. Mechanisms behind the neuroprotective actions of
cholinesterase inhibitors in Alzheimer disease. Alzheimer Dis Assoc
Disord. 2006;20(Suppl 1):S12–S18.
17. Craig LA, Hong NS, McDonald RJ. Revisiting the cholinergic
hypothesis in the development of Alzheimer’s disease. Neurosci
Biobehav Rev. 2011;35:1397–1409.
18. Salloway S, Mintzer J, Weiner MF, et al. Disease-modifying
therapies in Alzheimer’s disease. Alzheimers Dement.
2008;4:65–79.
19. Parnetti L, Amici S, Lanari A, et al. Cerebrospinal fluid levels
of biomarkers and activity of acetylcholinesterase (AChE) and
butyrylcholinesterase in AD patients before and after treatment with
different AChE inhibitors. Neurol Sci. 2002;23(Suppl 2):S95–S96.
20. Blennow K, Zetterberg H, Minthon L, et al. Longitudinal stability
of CSF biomarkers in Alzheimer’s disease. Neurosci Lett.
2007;419:18–22.
21. Parnetti L, Chiasserini D, Andreasson U, et al. Changes in CSF
acetyl- and butyrylcholinesterase activity after long-term treatment
with AChE inhibitors in Alzheimer’s disease. Acta Neurol Scand.
2011;124:122–129.
22. Chalmers KA, Wilcock GK, Vinters HV, et al. Cholinesterase
inhibitors may increase phosphorylated tau in Alzheimer’s disease.
J Neurol. 2009;256:717–720.
23. Darreh-Shori T, Soininen H. Effects of cholinesterase inhibitors
on the activities and protein levels of cholinesterases in the
cerebrospinal fluid of patients with Alzheimer’s disease:
a review of recent clinical studies. Curr Alzheimer Res.
2010;7:67–73.
24. 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;57:481–488.
25. 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;57:489–495.
26. Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment
in 565 patients with Alzheimer’s disease (AD2000): randomized
double-blind trial. Lancet. 2004;363:2105–2115.
27. Suh G-H, Jung HY, Lee CU, et al; for the Korean Galantamine
Study Group. Economic and clinical benefits of galantamine in
the treatment of mild to moderate Alzheimer’s disease in a Korean
population: a 52-week prospective Study. J Korean Med Sci.
2008;23:10–17.
28. Howard R, McShane R, Lindesay J, et al. Donepezil and memantine
for moderate-to-severe Alzheimer’s disease. N Engl J Med.
2012;366:893–903.
29. Wattmo C. Prediction models for assessing long-term outcome in
Alzheimer’s disease: a review. Am J Alzheimers Dis Other Dement.
2013;28:440–449.
30. Rountree SD, Chan W, Pavlik VN, et al. Persistent treatment
with cholinesterase inhibitors and/or memantine slows clinical
progression of Alzheimer disease. Alzheimers Res Ther. 2009;1:7.
31. Rountree SD, Atri A, Lopez OL, et al. Effectiveness of antidementia
drugs in delaying Alzheimer’s disease progression. Alzheimers
Dement. 2013;9:338–345.
32. Finucane TE. Another advertisement for donepezil. J Am Geriatr
Soc. 2004;52:843.
33. Royall DR. Donepezil’s effects remain uncertain. J Am Geriatr Soc.
2004;52:843–845.
34. Karawish JHT. Donepezil delay to nursing home placement study is
flawed. J Am Geriatr Soc. 2004;52:845.
www.LaRCP.ca
 Long-Term Efficacy and Toxicity of Cholinesterase Inhibitors in the Treatment of Alzheimer Disease
35. Schneider LS. Open-label extension studies and misinformation.
Arch Neurol. 2006;63:1036.
36. Schneider LS. Could cholinesterase inhibitors be harmful over the
long term? Int Psychogeriatr. 2012;24:171–174.
37. Winblad B, Wimo A, Engedal K, et al. 3-year study of donepezil
therapy in Alzheimer’s disease: effects of early and continuous
therapy. Dement Geriatr Cogn Disord. 2006;21:353–363.
38. Cummings JL. What we can learn from open-label extensions of
randomized clinical trials. Arch Neurol. 2006;63:18–19.
39. Schneider LS, Insel PS, Weiner MW; for the Alzheimer’s Disease
Neuroimaging Initiative. Treatment with cholinesterase inhibitors
and memantine of patients in the Alzheimer’s Disease Neuroimaging
Initiative. Arch Neurol. 2011;68:58–66.
40. Sona A, Zhang P, Ames D, et al. Predictors of rapid cognitive
decline in Alzheimer’s disease: results from the Australian Imaging,
Biomarkers and Lifestyle (AIBL) study of Ageing. Int Psychogeriatr.
2012;24:197–204.
41. Gill SS, Mamdani M, Naglie G, et al. A prescribing cascade
involving cholinesterase inhibitors and anticholinergic drugs.
Arch Intern Med. 2005;165:808–813.
42. Sink KM, Thomas J 3rd, Xu H, et al. Dual use of bladder
anticholinergics and cholinesterase inhibitors: long-term functional
and cognitive outcomes. J Am Geriatr Soc. 2008;56:847–853.
43. 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;169:867–873.
44. Hernandez RK, Farwell W, Cantor MD, et al. Cholinesterase
inhibitors and hospitalizations for bradycardia. J Am Geriatr Soc.
2009;57:1997–2003.
45. Park-Wylie LY, Mamdani MM, Li P, et al. Cholinesterase inhibitors
and hospitalizations for bradycardia. PLoS Med. 2009;6:e1000157.
doi: 10.1371/journal.pmed.1000157. Epub 2009 Sep 29.
46. Kim DH, Brown RT, Ding EL, et al. Dementia medications and
risk of falls, syncope, and related adverse events meta-analysis
of randomized controlled trials. J Am Geriatr Soc.
2011;59:1019–1031.
47. Howes LG. Cardiovascular effects of drugs used to treat Alzheimer’s
disease. Drug Saf. 2014;37:391–395.
48. Rowland JP, Rigby J, Harper AC, et al. Cardiovascular monitoring
with acetylcholinesterase inhibitors: a clinical protocol. Adv
Psychiatr Treat. 2007;13:178–184.
49. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de
pointes. Heart. 2003;89:1363–1372.
50. Leitch A, McGinness P, Wallbridge D. Calculate the QT interval in
patients taking drugs for dementia. BMJ. 2007;335:557.
51. Helou R, Rhalimi M. Cholinesterase inhibitors and the risk of
pulmonary disorders in hospitalized dementia patients. J Popul Ther
Clin Pharmacol. 2010;17:e379–e389. Epub 2010 Oct 26.
52. Stephenson A, Seitz DP, Fischer HD, et al. Cholinesterase inhibitors
and adverse pulmonary events in older people with chronic
obstructive pulmonary disease and concomitant dementia:
a population-based, cohort study. Drugs Aging. 2012;29:213–223.
53. Thavorn K, Gomes T, Camacho X, et al. Upper gastrointestinal
bleeding in elderly adults with dementia receiving cholinesterase
inhibitors: a population-based cohort study. J Am Geriatr Soc.
2014;62:382–384.
54. Tamura BK, Masaki KH, Blanchette P. Weight loss in patients with
Alzheimer’s disease. J Nutr Elder. 2007;26:21–38.
55. Stewart JT, Gorelik AR. Involuntary weight loss associated
with cholinesterase inhibitors in dementia. J Am Geriatr Soc.
2006;54:1013–1014.
56. Gillette-Guyonnet S, Cortes F, Cantet C, et al; on behalf of the
REAL.FR Group. Long-term cholinergic treatment is not associated
with greater risk of weight loss during Alzheimer’s disease:
data from the French REAL.FR cohort. J Nutr Health Aging.
2005;9:69–73.
57. Droogsma E, van Asselt DZ, van Steijn JH, et al. Effect of long-term
treatment with galantamine on weight of patients with Alzheimer’s
dementia. J Nutr Health Aging. 2013;17:461–465.
www.TheCJP.ca
58. Zannas AS, Okuno Y, Doraiswamy PM. Cholinesterase inhibitors
and Pisa syndrome: a pharmacovigilence study. Pharmacotherapy.
2014;34:272–278.
59. Tavassoli N, Sommet A, Lapeyre-Mestre M, et al. Drug interactions
with cholinesterase inhibitors: an analysis of the French
pharmacovigilence database and a comparison of two national
drug formularies (Vidal, British National Formulary). Drug Saf.
2007;30:1063–1071.
60. Singh S, Dudley C. Discontinuation syndrome following donepezil
discontinuation. Int J Geriatr Psychiatry. 2003;18:282–284.
61. Bidzan L, Bidzan M. Withdrawal syndrome after donepezil cessation
in a patient with dementia. Neurol Sci. 2012;33:1459–1461.
62. Minett TS, Thomas A, Wilkinson LM, et al. What happens when
donepezil is suddenly withdrawn? An open label trial in dementia
with Lewy bodies and Parkinson’s disease with dementia. Int J
Geriatr Psychiatry. 2003;18:988–993.
63. Daiello LA, Ott BR, Lapane KL, et al. Effect of discontinuing
cholinesterase inhibitor therapy on behavioral and mood symptoms
in nursing home patients with dementia. Am J Geriatr Pharmacother.
2009;7:74–83.
64. Scarpini E, Bruno G, Zappalà G, et al. Cessation versus continuation
of galantamine treatment after 12 months of therapy in patients with
Alzheimer’s disease: a randomized, double blind, placebo controlled
withdrawal trial. J Alzheimers Dis. 2011;26:211–220.
65. ClinicalTrials.gov. Discontinuation of cholinesterase inhibitors for
the treatment of severe Alzheimer’s disease [Internet]. Bethesda
(MD): National Institutes of Health; 2013 Nov 25 [updated 2014
Jan 13; cited 2014 Jun 9]. Available from: http://clinicaltrails.gov/
show/NCT02035982.
66. Herrmann N, Lanctôt KL, Hogan DB. Pharmacological
recommendations for the symptomatic treatment of dementia: the
Canadian Consensus Conference on the Diagnosis and Treatment of
Dementia 2012. Alzheimer Res Ther. 2013;5(Suppl 1):S5.
67. Doody RS, Geldmacher DS, Gordon B, et al; for the Donepezil
Study Group. Open-label, multicenter, phase 3 extension study of
the safety and efficacy of donepezil in patients with Alzheimer’s
disease. Arch Neurol. 2001;58:427–433.
68. Pariente A, Fourrier-Réglat A, Bazin F, et al. Effect of treatment
gaps in elderly patients with dementia treated with cholinesterase
inhibitors. Neurology. 2012;78:957–963.
69. Herrmann N, Black SE, Li A, et al. Discontinuing cholinesterase
inhibitors: results of a survey of Canadian dementia experts. Int
Psychogertiatr. 2011;23:539–545.
70. Han L, Cole M, Bellavance F, et al. Tracking cognitive decline in
Alzheimer’s disease using the mini-mental state examination:
a meta-analysis. Int Psychogeriatr. 2000;12:231–247.
71. Jones RW, Schwam E, Wilkinson D, et al. Rates of cognitive change
in Alzheimer disease—observations across a decade of placebo-
controlled clinical trials with donepezil. Alzheimer Dis Assoc
Disord. 2009;23:357–364.
72. Clark CM, Sheppard L, Fillenbaum GG, et al. Variability in annual
Mini-Mental State Examination score in patients with probable
Alzheimer’s disease. Arch Neurol. 1999;56:857–862.
73. Fillit HM, Doody RS, Binaso K, et al. Recommendations for best
practices in the treatment of Alzheimer’s disease in managed care.
Am J Geriatr Pharmacother. 2006;4(Suppl A):S9–S24.
74. National Institute for Health and Clinical Excellence (NICE).
Donepezil, galantamine, rivastigmine and memantine for the
treatment of Alzheimer’s disease. NICE technology appraisal
guidance 217. London (GB): NICE; 2011.
75. Ihl R, Frölich L, Winblad B, et al. World Federation of Societies
of Biological Psychiatry (WFSBP) guidelines for the biological
treatment of Alzheimer’s disease and other dementias. World J Biol
Psychiatry. 2011;12:2–32.
76. Hogan DB, Bailey P, Black S, et al. Diagnosis and treatment
of dementia: 4. Approach to management of mild to moderate
dementia. CMAJ. 2008;179:787–793.
77. Perrault A, Wolfson C, Egan M, et al. Prognostic factors for
functional independence in older adults with mild dementia: results
from the Canadian study of health and aging. Alzheimer Dis Assoc
Disord. 2002;16:239–247.
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