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Psychiatry and Clinical Psychopharmacology
ISSN: 2475-0573 (Print) 2475-0581 (Online) Journal homepage: http://www.tandfonline.com/loi/tbcp21
The effect of cholinesterase inhibitors on sleep
in the patients with Alzheimer’s disease: an
observational prospective study
Osman Korucu, Bekir Enes Demiryürek, Gülin Morkavuk & Aysu Akbaş
Korucu
To cite this article: Osman Korucu, Bekir Enes Demiryürek, Gülin Morkavuk & Aysu Akbaş
Korucu (2017): The effect of cholinesterase inhibitors on sleep in the patients with Alzheimer’s
disease: an observational prospective study, Psychiatry and Clinical Psychopharmacology, DOI:
10.1080/24750573.2017.1368856
To link to this article: http://dx.doi.org/10.1080/24750573.2017.1368856
© 2017 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group
Published online: 07 Sep 2017.
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The effect of cholinesterase inhibitors on sleep in the patients with Alzheimer’s
disease: an observational prospective study
Osman Korucu
a
, Bekir Enes Demiryürek
b
, Gülin Morkavuk
c
and Aysu AkbaşKorucu
d
a
Neurology Department, Kecioren Training and Research Hospital, Unıversity of Health Sciences, Ankara, Turkey;
b
Neurology Department,
Sakarya Education and Research Hospital, Unıversity of Health Sciences, Ankara, Turkey;
c
Neurology Department, Ufuk University Hospital,
Ankara, Turkey;
d
Turkish Drug & Medical Device Institution, Ankara, Turkey
ABSTRACT
Introduction: The aim of this study was to evaluate the essential effects of cholinesterase
inhibitors between the first days of the medication and after 1 month in the patients have
not the history of disease, the patients not used the medicines which effect the sleep or the
patients started new medication.
Methods: Patients diagnosed with mild to moderate stage Alzheimer’s disease according to
DSM-IV criteria (age: 55–85) were admitted in this multi-centred study between December
2014 and January 2017. Thirty five patients with mini mental test score between 14 and 24
were included in the study. Pittsburgh Sleep Quality Index (PSQI), Cornell Scale for
Depression in Dementia (CSDD), Beck Anxiety Scale (BAS) and Standardized Mini Mental Test
(SMMT) were given to all patients were used in first days of treatment and at least after 1 month.
Results:Twenty patients (57%) were using Donepezil and 15 patients (43%) were using
Rivastigmine. Gender, marital status, educational status and family history of dementia were
not statistically significant difference for both of the groups. There was no statistically
significant difference between the first and second evaluation for two treatment groups in
SMMT, CSDD and BAS scores (pvalues .748, .232 and .611, respectively). In both groups,
positive effect were observed in PSQI scores after 1 month of treatment, but this positive
effect was not found to be statistically significant (p: .558).
Discussion:When donepezil and rivastigmine were compared in this study, it was observed
that they had similar positive effects on sleeping quality, but there was not statistically
significant difference.
ARTICLE HISTORY
Received 22 May 2017
Accepted 14 August 2017
KEYWORDS
Alzheimer; sleep; donepezil;
rivastigmine; dementia;
Pittsburgh
Introduction
As well as social problems associated with forgetful-
ness, sleep disorder can also create serious problems
for the patients with Alzheimer’s disease (AD) and
their relatives. Sleep disorder is observed in 40% of
dementia patients [1,2]. Several studies showed that
sleep disorder was observed more often in advancing
stages of dementia and sleeping disorder showed a lin-
ear correlation with the intensity of the disease [3]. AD
patients may experience insomnia symptoms such as
REM sleep behaviour disorder, sleeping difficulty,
intermittent sleeping, early morning awakening, and
sleep apnoea or excessive daytime sleepiness which
emerges as a result of insomnia. These sleep disorders
are important as risk factors in the development of psy-
chiatric symptoms as well as their effects on life quality,
functional and cognitive capabilities [4]. All these fac-
tors increase the burden on the caregiver. Acetylcholine
has an active role in regulating normal sleep patency
and strengthening the memory [5]. Cholinesterase
inhibitors used in AD patients contribute to clinical
improvement by providing natural circadian rhythm
of central cholinergic conduction [6]. The majority of
acetylcholine is released in REM sleep. According to
previous studies, cholinesterase inhibitors have been
reported to increase the amount of acetylcholine by
prolonging the REM sleep period and consequently
they caused sleep disorders [7–9]. Cholinesterase
inhibitors used in AD treatment today are rivastigmine,
donepezil and galantamine. There are studies in the lit-
erature that examine the effects of donepezil, rivastig-
mine and galantamine on sleeping behaviour. These
studies have reported that donepezil disrupts sleep
quality, rivastigmine has a negative effect and galanta-
mine has no effect on sleep quality [8,11–13]. However,
in these studies, the population of the patients are seen
to use the medicines affecting sleep.
In our study, the effect of cholinesterase inhibitor
drugs on sleep behaviour, in addition to depression
and anxiety symptoms, were investigated and drug
effect on sleep quality was observed. Our aim in the
present study was to investigate the effect of the chol-
inesterase inhibitors by excluding the medicines and
© 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONTACT Osman Korucu osmankorucu2@gmail.com, tubersulf@yahoo.com Kecioren Egitim ve Arastirma Hastanesi, Pınarbaşı Mah. Sanatoryum
Cad. Ardahan Sok. No:25, 06380 Kecioren, Ankara, Turkey
PSYCHIATRY AND CLINICAL PSYCHOPHARMACOLOGY, 2017
https://doi.org/10.1080/24750573.2017.1368856
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disease which have the known influence on sleep, and
additionally, to observe the only effect of the medi-
cation on sleep quality interrogating depression and
anxiety disrupting the sleep quality.
Methods
This prospective observational medication study was
conducted at second- and third-level hospitals between
December 2014 and January 2017. The study protocol
was approved by the local ethics committee. This study
was registered as a Turkish Ministry of Health drug
and pharmacy trial (number 2014-PMS-66). All pro-
cedures performed in studies involving human partici-
pants were in accordance with the ethical standards of
the institutional and/or national research committee
and with the 1964 Helsinki declaration and its later
amendments or comparable ethical standards. Patients
who were started the medicines a few days ago and the
patients admitted again with any reason were invited to
study. Informed consent forms were obtained from all
patients and/or their relatives.
Patients treated and diagnosed with mild to moder-
ate stage AD according to DSM-IV criteria (age: 55–
85), and patients who were at least literate with mini
mental score between 14 and 24 were included in this
multi-centred study.
Patients, who used antipsychotic, antidepressant,
sedative, opioid, benzodiazepine derivative drugs and
who have another accompanying neurodegenerative
disease, cerebrovascular disease history, mild cognitive
impairment (MCI) diagnosis and another significant
neurological, psychiatric disease or medical condition
that may affect sleep quality, were excluded from the
study. Age, gender, marital status, education level,
family history of dementia, comorbid diseases, medi-
cations and cholinesterase inhibitor use of patients
were recorded in case report form. Beck Anxiety
Scale (BAS), Cornell Scale for Depression in Dementia
(CSDD), Standardized Mini Mental Test (SMMT) and
Pittsburgh Sleep Quality Index (PSQI) surveys were
administered on the first days of treatment, and at
least 1 month later, to the patients with AD, whose
treatment had already been started. Patients used the
drugs belonging to exclusion criteria between two
evaluation, patients had the any diseases causing exclu-
sion, and the patients did not admit to second test 1
month later were excluded.
Statistical analysis
Descriptive statistics of the categorical variables
included in the study were given by frequency, and
statistics which vary with the percentage were given
by mean, standard deviation, median, minimum and
maximum values. Conformity of continuous variables
with normal distribution was evaluated by Shapiro–
Wilk test. Mann–Whitney Utest was used for compari-
son of two groups of variables which do not exhibit
normal distribution, whereas, independent ttest was
used for comparison of two groups of variables which
exhibit normal distribution. Wilcoxon test was used
for in-group comparison of variables which do not
exhibit normal distribution, whereas, ttest was used
for in-group comparison of variables which exhibit
normal distribution. Among from all statistical ana-
lyses in the study, comparisons which are below 0.05
were considered statistically meaningful.
Results
Fifty eight patients were evaluated for the study. Five
women and one man patients were not included in
the study because they used cholinesterase inhibitors
along with antidepressants. Remaining six patients
did not come to first control in a month. Eleven
patients were excluded because eight of them started
to use antipsychotics and the other three patients
began to take antidepressants between two evaluations
(Figure 1).
Seventeen (49%) women, and 18 (51%) male
patients finished the study. Twenty patients (57%)
were using donepezil and 15 patients (%43) were
using rivastigmine. There were no patients using
galantamine. The patients were receiving donepezil
tablet in the morning. After being included in the
study, none of the patients used memantine, or medi-
cations which are known to affect sleep quality, during
the first 1 month period. The mean age of the donepe-
zil group was 73.50 ± 6.66, and 73.93 ± 7.62 in the riv-
astigmine group. During second evaluation of the
patients, one patient was treated with 4.6 mg and 14
patients were treated with 9.5 mg rivastigmine;
among the patients who received donepezil, 17
patients received 10 mg, 3 patients received 5 mg per
day. Gender, marital status, educational status and
family history of dementia were not statistically sig-
nificant for both of the groups (Table 1).
There was no statistically significant difference
between the first and second evaluation between the
two treatment groups in SMMT, CSDD and BAS
scores (pvalues .748, .232 and .611, respectively).
CSDD scores in the group of rivastigmine were higher
in first evaluation; however, there were not any differ-
ences in terms of score change comparing to donepezil
group. In both groups, a positive effect was observed
with PSQI after 1 month of treatment, but this positive
effect was not found to be statistically significant
(p: .558) (Table 2). PSQI scores 5 and above are
regarded as poor sleep quality. After using cholinester-
ase inhibitors, a significant decrease in PSQI scores
(mean ± SD) were detected (Table 2); however, this
reducing did not take the patients except one to the
level of good sleep quality at following period (Table 3).
2O. KORUCU ET AL.
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BAS score applied to patients suggests: 0–9 normal
anxiety, 10–18 mild anxiety, 19–29 moderate anxiety
and 30–63 severe anxiety. The CSDD score of 8 and
above suggests depression. The clinical significance
and pvalues of depression, anxiety and sleep quality
changes of patients are given in Table 3.
Discussion
Sleep disorders frequently accompany AD and impair
the patients’quality of life. In our study, we intended
to detect the exact influence of cholinesterase inhibitors
on sleep quality, which are frequently used in patients
with AD. AD patients are frequently treated with medi-
cations that influence quality of sleep negatively, due to
behavioural and psychiatric symptoms. Hence, by
means of exclusion criteria and timing of the tests,
we aimed to isolate the effect of cholinesterase inhibi-
tors on sleep quality at the beginning of the treatment
and after at least one-month period.
Unlike previous studies, patients had a lot of factors
that effect the sleep prior the study or in including
period were excluded. None of the patients included
in our study was using galantamine. Although we
have found similar positive effects in both groups of
the patients using donepezil and rivastigmine, on the
scores of quality of sleep, the difference was not statisti-
cally significant. However, this positive finding is
important for daily clinical practice. Although in pre-
vious studies, donepezil had negative effects on sleep,
our study showed that its effect on sleep was similar
in comparison with rivastigmine. Because the number
of the patients in the group of rivastigmine had
depression and poor sleep quality in first evaluation
is higher than that of donezepil group and with the
Figure 1. Patient flow chart.
Table 1. Sociodemographic characteristics and family history
of patients based on type of medication.
Donepezil
(n:20)
Rivastigmine
(n:15) p
Sex Female 10 (%50) 7 (%47)
.845Male 10 (%50) 8 (%53)
Marital status Married 15 7
.086Single 5 8
Educational
status
Literate 12 (%60) 8 (%53)
.342
Primary
school
8 (%40) 5 (%33)
High school –2 (%14)
Dementia in
family
Positive 6 8
.163Negative 14 7
Table 2. First and second SMMT, CSDD, BAS scores and PSQI values at least 1 month apart.
Donepezil (n:20) Rivastigmine (n:15) Total (n:35)
Mean ± SD Median (min –max) Mean ± SD Median (min –max) Mean ± SD Median (min –max)
SMMT 1 18.65 ± 2.92 18 (14–24) 20.06 ± 3.28 21 (14–24) 19.25 ± 3.11 19 (14–24)
SMMT 2 18.65 ± 3.29 18.5 (13–24) 20.4 ± 3.37 21 (15–26) 19.4 ± 3.39 20 (13–26)
CSDD 1 7.6 ± 4.71 7 (0–20) 11.2 ± 6.33 11 (0–26) 9.14 ± 5.67 9 (0–26)
CSDD 2 7.5 ± 4.57 7.5 (0–20) 10.53 ± 5.93 10 (1–24) 8.8 ± 5.34 8 (0–24)
BAS score 1 9.5 ± 7.25 8.5 (2–29) 12.86 ± 6.02 14(4–26) 10.94 ± 6.86 10 (2–29)
BAS score 2 9 ± 7.12 8 (0–29) 12.93 ± 9.07 11 (4–40) 10.68 ± 8.13 10 (0–40)
PSQI 1 8.35 ± 5.45 8 (0–18) 9.07 ± 4.21 9 (2–17) 8.66 ± 4.9 9 (0–18)
PSQI 2 7.9 ± 4.93 9 (0–17) 8.73 ± 4.06 10 (2–16) 8.26 ± 4.53 9 (0–17)
SMMT: Standardized Mini Mental Test; CSDD: Cornell Scale for Depression in Dementia; BAS: Beck Anxiety Scale; PSQI: Pittsburgh Sleep Quality Index.
PSYCHIATRY AND CLINICAL PSYCHOPHARMACOLOGY 3
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reason of sample size, any statistically significant differ-
ence could not be seen between two groups. Neverthe-
less, even results of our study is not statistical,
donepezil has positive effect on sleep clinically like riv-
astigmine. At first evaluation, 1 month later, both in
two patients groups the decrease was seen in PSQI
scores and this reduction shows a positive change in
sleep quality. As far as we know, this is the very first
study comparing the effects of rivastigmine and done-
pezil on sleep, including anxiety and depression scores
as well.
Song et al. showed that intake of donepezil in the
morning was preferable to evening, in order to prevent
the negative effect of cholinesterase inhibitors on the
quality of sleep [10]. In our study, as the patients
took donepezil in morning, negative effects of it on
sleep may not have been observed and a significant
difference may not has been found in comparison
with rivastigmine.
Effect of cholinesterase inhibitors using PSQI on
sleep was investigated in a study conducted by
Naharci et al. They found a superior decline in post-
treatment PSQI score in patients using galantamine,
although not statistically significant, in comparison
with other groups of patients (donepezil, rivastigmine
and controls) and they advised to use galantamine in
dementia as a first-option medication [14]. In a ran-
domized double-blind trial, donepezil and galanta-
mine did not have deleterious effects on sleep,
furthermore galantamine was found to be slightly
more beneficial than of donepezil in terms of sleep
quality [7]. In our study, although galantamine
group was not investigated, we think that cholinester-
ase inhibitors may influence sleep positively. Another
study found a positive effect of donepezil in only AD
patients with obstructive sleep apnea [15], whereas
another study found that donepezil raised apnea/
hypopnea, desaturation and the lowest saturation
indexes [16]. Another study showed that rivastigmine
transdermal patch ameliorated the symptoms of sleep
breathing disorders [17].
Sleeping disorders are important co-factors for the
progression of psychiatric symptoms, as well as for
quality of life, functional and cognitive skills of the
patients [1,2,4].
In a previous study, sleep disorders of the dementia
patients using memantine, donepezil, rivastigmine and
galantamine were evaluated with CSDD. It was
observed that the patients with sleep disorders had
depressive symptoms; however, these four medications
were not statistically superior to one another in any
aspects [2]. In our study, patients in both medication
groups were given CSDD and BAS tests and statisti-
cally significant differences were not found between
first and second examination scores. Meanwhile,
CSDD and BAS scores in rivastigmine group were
higher, albeit non-significant. It is not clear whether
sleep disorders are connected with AD, and co-incident
depression, or whether secondary depressive symp-
toms arose due to sleep disorders. According to our
observation, donepezil and rivastigmine have no nega-
tive effect on sleep by any means.
In a review article evaluating the relation between
sleeping behaviour and AD, methods of sleeping behav-
iour were examined. It was stated that subjective sleep
surveys (PSQI, sleep sickness survey and Athens insom-
nia scale) had limited value for AD patients with mild to
moderate stage sleep disorders [18]. Therefore, new
methods are needed, considering that both polysomno-
graphy and sleep surveys are not sufficient for AD
patients to investigate sleep disorders. Wrist actigraphy
is a method used to measure inactivity versus activity, or
wakefulness versus sleep, over a period of 24 hours,
which can be a reliable alternative. Wrist activity in
dementia patients during sleep and wakefulness was
evaluated by Ancoli-Israel et al.; a correlation between
EEG recording and actigraphy was observed during
total sleep and wakefulness, and this method was
found to be highly sensitive and specific [19].
The present study has several limitations such as a
short follow-up period, and sleep status was evaluated
by the PSQI scale alone. Sleep quality of patients can be
determined more clearly by polysomnography. How-
ever, AD patients may not be eligible for this type of
examination. Other limitations of our study are:
anxiety and depression were evaluated only by scales,
and that mild to moderate stage AD patients were
included in the study. In spite of above-mentioned
limitations, the main superiority of our study com-
pared to previous studies is that, our patients had no
drug use and medical condition which are known to
affect the sleep quality. It is widely accepted that
sleep disorders correlate with the course of the illness.
In advanced stage AD patients, sleep disorders may be
more evident.
In conclusion, good sleep quality of AD patients is
important for both patients and caregivers. The choice
of medication in AD treatment may have additional
Table 3. The number of patients with normal and abnormal
scores during two successive evaluations.
Donepezil
(n:20)
Rivastigmine
(n:15) p
CSDD 1–
CSDD 2
Normal score 11–10 4–4 .094–.163
Depression 9–10 11–11
BAS 1–
BAS 2
Normal score 10–10 3–5 .176–.788
Mild anxiety 7–76–6
Moderate
anxiety
2–25–3
Severe
anxiety
1–11–1
PSQI 1–
PSQI 2
Good sleep
quality
7–83–2 .331–.084
Poor sleep
quality
13–12 12–13
CSDD: Cornell Scale for Depression in Dementia; BAS: Beck Anxiety Scale;
PSQI: Pittsburgh Sleep Quality Index.
4O. KORUCU ET AL.
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benefits in terms of quality of life and cognitive status
of the patient. In many studies carried out before, it
was stated that donepezil had adverse effects on sleep-
ing quality. Yet, in this study when donepezil and riv-
astigmine were compared with each other, it was
observed that they had similar positive effects on sleep-
ing quality but there was not a significant statistical
difference. We suggest that donepezil should be taken
early in the morning. Thereby circadian rhythmicity
would be preserved with the cholinergic treatment of
AD, and sleeping disorders may be prevented. Further
studies are needed to clarify the effect of AD medi-
cations on sleeping disorders.
Disclosure statement
No potential conflict of interest was reported by the authors.
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