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Donepezil Improves Obstructive Sleep
Apnea in Alzheimer Disease*
A Double-Blind, Placebo-Controlled Study
Walter Moraes, MD, PhD; Dalva Poyares, MD, PhD;
Lucia Sukys-Claudino, MD; Christian Guilleminault, MD, PhD;
and Sergio Tufik, MD, PhD
Background: There is an association between Alzheimer disease and sleep-disordered breathing.
Donepezil is the drug most frequently used to treat cognitive symptoms in Alzheimer disease.
This study evaluates the effects of donepezil on obstructive sleep apnea in patients with
Alzheimer disease.
Methods: Randomized, double-blind, placebo-controlled design. Twenty-three patients with
mild-to-moderate Alzheimer disease and apnea-hypopnea index (AHI) > 5/h were allocated to
two groups: donepezil treated (n ⴝ 11) and placebo treated (n ⴝ 12). Polysomnography and
cognitive evaluation using Alzheimer disease assessment scale-cognitive (ADAS-cog) subscale
were performed at baseline and after 3 months. Cognitive and sleep data were analyzed using
analysis of variance.
Results: AHI and oxygen saturation improved significantly after donepezil treatment compared to
baseline and placebo (p < 0.05). Rapid eye movement (REM) sleep duration increased after
donepezil treatment (p < 0.05). ADAS-cog scores improved after donepezil treatment, although
they did not correlate with REM sleep increase and sleep apnea improvement (p < 0.01).
Conclusions: Donepezil treatment improved AHI and oxygen saturation in patients with Alzhei-
mer disease. Treatment also increased REM sleep duration and reduced ADAS-cog scores.
Trial registration: ClinicalTrials.gov Identifier: NCT00480870. (CHEST 2008; 133:677– 683)
Key words: Alzheimer; donepezil; oxygen saturation; polysomnography; rapid eye movement sleep; sleep apnea
Abbreviations: AASM ⫽ American Academy of Sleep Medicine; ADAS-cog ⫽ Alzheimer disease assessment scale-
cognitive; AHI ⫽ apnea-hypopnea index; ANOVA ⫽ analysis of variance; BMI ⫽ body mass index; CDR ⫽ clinical dementia
rating; MMSE ⫽ mini-mental state examination; OSA ⫽ obstructive sleep apnea; OSA-AD ⫽ obstructive sleep apnea-
Alzheimer disease; REM ⫽ rapid eye movement; WASO ⫽ wake after sleep onset
T
he association between Alzheimer disease and
sleep-disordered breathing has been frequently
studied.
1–5
The presence of apolipoprotein E epsilon
4 seems to be linked to the occurrence of both
conditions, suggesting a genetic basis.
3,6
Central-
acting cholinesterase inhibitors are the first primary
pharmacologic treatments approved for Alzheimer
disease, for which donepezil is the most frequently
used.
7
Multicenter studies
7–10
have found little tox-
icity, and its side effects (diarrhea, nausea, vomiting,
nightmares, among others) are mild and transient.
Donepezil is a reversible inhibitor of the acetyl-
cholinesterase enzyme, thus enhancing cholinergic
transmission.
11
Its half-life is approximately 70 h.
11
It
is excreted intact in the urine and metabolized into
four major metabolites, two of which are known to
be active.
11
Cholinergic activity also influences the upper air-
way opening via central and peripheral mecha-
nisms.
12–15
Decreased thalamic pontine cholinergic
projections may affect respiratory drive, leading to
both central and obstructive apnea at least in certain
degenerative conditions.
14,15
Since impairment of
cholinergic transmission is a putative pathophysio-
logic mechanism for Alzheimer disease, it is ex-
pected that cholinergic-related respiratory distur-
bances may occur.
7,8,16
However, donepezil has been
shown to augment rapid eye movement (REM) sleep
Original Research
SLEEP MEDICINE
www.chestjournal.org CHEST / 133/3/MARCH, 2008 677
in patients with Alzheimer disease, a sleep stage
during which sleep apnea events are more fre-
quent.
7,17–19
Such conflicting effects make it difficult to
know a priori whether improvement of sleep apnea is
likely to occur during donepezil treatment.
14,15
Mindful
of the above, the authors hypothesized the following:
(1) donepezil may influence respiratory variables dur-
ing sleep in patients with obstructive sleep apnea-
Alzheimer disease (OSA-AD), and (2) there is a corre-
lation between cognitive improvement and sleep
respiratory changes.
Materials and Methods
Population
Forty patients with mild-to-moderate Alzheimer disease were
consecutively recruited from geriatric and neurologic clinics at
the University Hospital of the Universidade Federal de Sa˜o
Paulo. Thirty of them had obstructive sleep apnea (OSA) and
presented with apnea-hypopnea index (AHI) ⬎ 5/h according to
American Academy of Sleep Medicine (AASM) criteria.
20
OSA
was not previously diagnosed or treated in these patients. There
were technical problems in the polysomnography of seven pa-
tients due to frequent patient-movement artifacts. The final
sample consisted of the remaining 23 patients who were ran-
domly allocated to two groups: donepezil treated (n ⫽ 11) and
placebo treated (n ⫽ 12).
The diagnosis of Alzheimer disease was based on the proba-
bility criteria of the Alzheimer’s Disease and Related Disorders
Association.
21
Patients were rated 1 and 2 (mild-to-moderate
level) on the Brazilian version of the clinical dementia rating
(CDR), and the more severe cases were excluded.
22
Potential
subjects were evaluated by history, physical examination, mini-
mental state examination (MMSE), Alzheimer disease assess-
ment scale-cognitive (ADAS-cog) subscale,
23
brain MRI, and
laboratory tests (hematologic evaluation, renal and liver func-
tions, vitamin B
12
, folic acid, thyroid hormones, fasting glycemia,
venereal disease research test, and urine sediment).
.
Exclusion
criteria were the presence of other causes of dementia; MRI
compatible with other etiology of dementia; and pulmonary, cardiac,
and other current severe medical or psychiatric diseases. No psy-
choactive drugs other than the experimental drug were taken during
the trial or the preceding 1-month period. Alcohol and sleep
medications were not permitted during the trial and the preceding
1-month period. Caregivers were instructed to take note of the use
of any nonpsychoactive drugs in daily sleep diaries.
Drugs and Administration
Tablets containing placebo were prepared and packed in the
same fashion as those with 5 mg of donepezil. Donepezil and
placebo were administered in a single dose at bedtime. The
dosage was one tablet per day in the first month and two tablets
per day for the next 2 months. After completion of the protocol,
patients were referred to our sleep clinic to have OSA treated.
Randomization
Each medication-containing box was packed by a standard
pharmacy service. Boxes were coded as A or B, indicating placebo
or donepezil (the signification of the codes was kept in a closed
envelope). A random number list with uniform distribution from
0 to 1 was generated using software (Statistica; Statsoft; Tulsa, OK).
Patients were consecutively allocated to two treatment groups
according to the random number list: ⱕ 0.5 to group A and ⬎ 0.5 to
group B. Researchers were blind to patient conditions when record-
ing and scoring parameters. Codes were opened and assigned to
each patient when statistical analysis was performed.
Polysomnography and Scoring
Patients were submitted to 2 nights of polysomnography for
habituation purposes, followed by a baseline recording before the
onset of treatment and a second recording after 3 months of
treatment. The minimum duration of polysomnography was 7 h.
Polysomnography was performed in the sleep laboratory of the
Psychobiology Department at Universidade Federal de Sa˜o Paulo
using a 32-channel device (Sonolab; Meditron; Sao Paulo, Brazil):
resolution, 256 Hz; 22 EEG; 2 electro-oculogram, 1 chin electro-
myogram, 1 leg electromyogram, 1 ECG, 1 tracheal microphone, 1
oronasal thermistor, 1 nasal pressure transducer (Pro-Tech Services;
Mukilteo, WI), 2 chest and abdominal effort sensors, and 1 pulse
oximeter (Nellcor; Pleasanton, CA). Two researchers scored the
recordings visually using Rechtshaffen and Kales and AASM criteria
for respiratory parameters and microarousals.
24–26
Apneas and hypopneas were scored according to AASM crite-
ria.
20
Variables analyzed were total sleep time, sleep efficiency
(sleep time/recording time ⫻ 100), sleep latency (time from
lights off to sleep onset), REM sleep latency (time from sleep
onset to REM sleep onset), wake after sleep onset (WASO),
REM and non-REM sleep percentage, microarousal index (mi-
croarousals per hour), overall AHI, obstructive AHI, central AHI,
mixed AHI, REM AHI, non-REM AHI, average oxygen satura-
tion, and percentage of sleep time with oxygen saturation ⬍ 90%.
Apnea-hypopnea improvement ratio was calculated was calcu-
lated as follows: AHI improvement ⫽ initial AHI ⫺ final AHI/
initial AHI. Caregivers answered a Portuguese language-modified
version of Stanford Sleep Disorders Questionnaire after polysom-
nography to rule out other major sleep disorders.
27
Psychometric Testing
The ADAS-cog subscale evaluates multiple cognitive functions
including word evocation, verbal fluency, understanding of sim-
ple commands, constructive praxis, ideational praxis, temporo-
spatial orientation, word recognition, verbal fluency, vocabulary,
and understanding. Scores range from 0 to 70, with higher scores
indicating more cognitive deterioration. The Brazilian version of
ADAS-cog
22
was applied before donepezil treatment and again
after 3 months.
*From the Psychobiology Department (Drs. Moraes, Poyares,
Sukys-Claudino, and Tufik), Universidade Federal de Sa˜o Paulo,
Sa˜o Paulo, Brazil; and Human Sleep Research Center (Dr.
Guilleminault), Department of Psychiatry and Behavioral Sci-
ence, School of Medicine, Stanford University, Palo Alto, CA.
This work was supported by Fundac¸a˜o de Amparo a` Pesquisa do
Estado de Sa˜o Paulo and Associac¸a˜o Fundo de Incentivo a`
Psicofarmacologia.
The authors have no conflicts of interest to disclose.
Manuscript received June 22, 2007; revision accepted December
1, 2007.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Walter Moraes, MD, PhD, R. Manuel de
Paiva, 313-Sa˜o Paulo-SP, 04106-020, Brazil; e-mail: waltermoraes@
giro.com.br
DOI: 10.1378/chest.07-1446
678 Original Research
Ethics
Subjects or caregivers signed informed consent forms that ex-
plained possible side effects of donepezil and assured them that they
could leave the trial at any moment. All subjects were assured that
they would receive clinical treatment. The Ethics Committee at
Universidade Federal de Sa˜o Paulo authorized the study.
Statistical Analysis
One-way analysis of variance (ANOVA) was used to compare
all variables for donepezil and placebo groups during the baseline
recording night. Polysomnographic and cognitive data at baseline
and after 3 months of treatment were analyzed using two-way
ANOVA for repeated measures with treatment group and treat-
ment time as the main factors and time/treatment interaction
effect followed by Bonferroni test, with p ⱕ 0.01 comparing data.
The Spearman correlation test was used to assess possible
correlations between cognitive, body mass index (BMI) and sleep
respiratory parameters in the donepezil-treated group.
Results
General
Table 1 shows that there were no significant
differences in age, gender, BMI, MMSE, and CDR
scores between the donepezil and placebo groups
before treatment. There was no significant correla-
tion between AHI improvement ratio and BMI. MRI
scan showed brain atrophy. Results of other labora-
tory tests were within normal range.
Adverse Effects
Mild and transitory side effects involving nausea
and headache occurred in three patients receiving
donepezil. There were no reports of nightmares or
worsening of sleep when caregivers were questioned.
Sleep Polysomnographic Variables
REM sleep percentage increased after 3 months
of donepezil treatment, as seen in Table 2. There was
a significant improvement in the following respira-
tory parameters after 3 months of donepezil treat-
ment: AHI, obstructive AHI, mixed AHI, lowest
oxygen saturation, and time spent with oxygen satu-
ration ⬍ 90% (Table 2). Central AHI did not im-
prove significantly after donepezil treatment (Table
2, Fig 1). There was also a significant reduction in
non-REM AHI after donepezil treatment (interac-
tion factor F[1,21] ⫽ 5.39, p ⫽ 0.03) [Table 2]. Al-
though there was a trend toward reduction of REM
AHI, it was not significant (interaction factor
F[1,21] ⫽ 3.47 p ⫽ 0.07) [Table 2]. Microarousal
index decreased significantly after donepezil treat-
ment due to a reduction in respiratory-related mi-
croarousals (Table 2). Nine donepezil-treated pa-
tients (81%) had improvement of AHI (Fig 1). Six
patients (54%) spent ⬎ 1% sleep time with oxygen
saturation ⬍ 90% before donepezil treatment (Fig
1). Five of these patients (83%) improved after
donepezil treatment (Fig 1). There were no signifi-
cant differences between donepezil and placebo
groups in the following polysomnographic parame-
ters: total sleep time, sleep efficiency, sleep latency,
REM sleep latency, WASO, and percentage of non-
REM sleep stages. There was no significant differ-
ence in percentage of time spent in supine position
within and between groups (Table 2).
Psychometric Variables
ADAS-cog scores significantly decreased after 3
months of donepezil treatment (Table 2). Correlations
between ADAS-cog scores, AHI, average oxygen satu-
ration, time of oxygen saturation spent ⬍ 90%, mi-
croarousal index, and other polysomnographic variables
did not reach statistical significance in the donepezil-
treated group before and after therapy.
Discussion
The main finding of the present study was the
significant improvement in AHI and oxygen satura-
tion of OSA-AD patients treated with donepezil. No
previous polysomnographic studies on the effect of
donepezil on sleep apnea in Alzheimer disease have
been undertaken. As expected, donepezil was well
tolerated and no major side effects occurred.
10,11
No
evidence of worsening of sleep or nightmares was
found in this study. This is in accordance with the
Table 1—Sociodemographic Data*
Variables Donepezil-Treated Group (n ⫽ 11) Placebo-Treated Group (n ⫽ 12) p Value†
Age, yr 76.8 ⫾ 6.2 (68 to 86) 72.6 ⫾ 11.0 (62 to 87) 0.27
Male/female gender 3/8 5/7 0.49
BMI, kg/m
2
26.3 ⫾ 4.8 (17.2 to 32.0) 26.6 ⫾ 4.1 (17.0 to 32.1) 0.85
MMSE 19 ⫾ 3.6 (13 to 26) 17.2 ⫾ 7.8 (6 to 27) 0.50
CDR 1.3 ⫾ 0.5 1.3 ⫾ 0.5 0.76
*Data are presented as mean ⫾ SD (range) or No.
†p ⬍ 0.05, ANOVA.
www.chestjournal.org CHEST / 133/3/MARCH, 2008 679
findings of other authors
11
who have studied larger
samples in general practice. Acetylcholinesterase
inhibitors elevate central and peripheral acetylcho-
line levels. However, the distribution of donepezil
varies between different brain and peripheral tis-
sues.
28
An increase in REM sleep proportion after
donepezil treatment was an expected finding.
7
In contrast to the prolific literature on physical
and surgical treatments for sleep apnea, there is a
dearth of effective pharmacologic approaches.
29–32
Most drugs previously tested for this purpose acted
on monoaminergic and adenosinergic systems and
showed unsuccessful or ambiguous results.
29–32
Hed-
ner and colleagues
12
published the only previous
report on a cholinergic pharmacologic treatment in
humans using an IV infusion of the anticholinester-
ase drug physostigmine in sleep-disordered breath-
ing patients, improving both obstructive and central
respiratory events mostly during REM sleep. How-
ever, that study
12
focused on the acute effect of a
drug that does not sustain plasma levels during the
entire night. We have selected a cholinergic drug
already approved by many regulatory agencies for
the treatment of Alzheimer disease and that has been
extensively studied and shown to be safe and phar-
macologically stable.
10
Taking advantage of the char-
acteristics of this drug, we were able to show that the
beneficial respiratory effect is maintained after long-
term use, possibly adding to its therapeutic spec-
trum. In contrast to this previous report,
12
we found
that overall AHI improvement was due to a reduc-
tion in obstructive and mixed respiratory events. In
addition, we did not find a significant improvement
in AHI during REM sleep, although there was a
nonsignificant trend toward reduction. These results
suggest that AHI improvement after donepezil treat-
ment is related to cholinergic mechanisms involved
in obstructive and mixed apnea and is not specifically
dependent on REM AHI reduction. OSA-AD pa-
tients showed different individual responses to done-
pezil. We found no parameter that could predict
individual treatment outcome. Future studies are
needed to explain individual differences in response
to cholinergic drugs for OSA treatment. As expected,
there was a high degree of variability in respiratory
parameters of the control group and no clear ten-
dency to worsening.
33,34
Besides respiratory effects,
donepezil increased REM sleep, and decreased mi-
croarousal index and ADAS-cog scores after 3
months of donepezil treatment, confirming findings
of previous research.
7,17,18
Hedner et al
35
reported a
similar finding in non-Alzheimer OSA patients in
abstract form.
Table 2—Cognitive and Polysomnographic Findings*
Variables
Donepezil-Treated
Group (n ⫽ 11)
Placebo-Treated Group (n ⫽ 12)
Interaction
p ValueBaseline Third Month Baseline Third Month
Total sleep time, min 307.7 ⫾ 90.9 312.9 ⫾ 106.8 296.9 ⫾ 61.6 295.6 ⫾ 81.3 0.81
Sleep efficiency, % 76.6 ⫾ 18.0 73.4 ⫾ 23.4 74.2 ⫾ 12.7 74.0 ⫾ 17.0 0.56
Sleep latency, min 35.6 ⫾ 86.6 41.9 ⫾ 86.0 14.5 ⫾ 21.5 16.9 ⫾ 19.1 0.63
REM sleep latency, min 125.7 ⫾ 80.7 138.7 ⫾ 136.4 129.5 ⫾ 79.4 133.7 ⫾ 89.4 0.87
WASO, min 91.9 ⫾ 74.4 114.8 ⫾ 111.1 104.4 ⫾ 56.7 100.9 ⫾ 64.9 0.23
Stage 1, % 9.0 ⫾ 7.7 9.1 ⫾ 11.2 14.4 ⫾ 11.3 14.8 ⫾ 13.0 0.90
Stage 2, % 54.2 ⫾ 16.7 49.0 ⫾ 14.8 54.5 ⫾ 13.5 52.7 ⫾ 12.8 0.53
Slow-wave sleep, % 30.3 ⫾ 16.6 30.5 ⫾ 14.8 22.0 ⫾ 15.3 21.8 ⫾ 10.5 0.95
REM sleep % 7.2 ⫾ 4.3 15.9 ⫾ 11.1 11.8 ⫾ 6.6 9.7 ⫾ 5.9 0.022†
Time spent in supine position, % 42.7 ⫾ 17.1 41.7 ⫾ 17.2 39.2 ⫾ 24.7 36.1 ⫾ 26.4 0.63
Microarousal index 26.3 ⫾ 12.6 15.7 ⫾ 8.3 23.9 ⫾ 19.7 23.8 ⫾ 21.0 0.021†
Nonrespiratory microarousal index 15.5 ⫾ 14.8 10.9 ⫾ 4.7 12.3 ⫾ 10.8 11.8 ⫾ 8.8 0.33
Respiratory microarousal index 11.0 ⫾ 10.4 5.1 ⫾ 7.1 11.6 ⫾ 15.9 12.0 ⫾ 8.2 0.001†
AHI, /h 20.0 ⫾ 15.9 9.9 ⫾ 11.5 23.2 ⫾ 26.4 22.9 ⫾ 28.8 0.035†
REM AHI, /h 24.7 ⫾ 19.4 7.6 ⫾ 7.9 35.4 ⫾ 31.5 39.0 ⫾ 25.6 0.077
Obstructive AHI, /h 19.4 ⫾ 15.4 9.2 ⫾ 10.3 22.7 ⫾ 25.8 21.3 ⫾ 26.7 0.047†
Central AHI, /h 0.1 ⫾ 0.2 0.6 ⫾ 1.9 0.1 ⫾ 0.4 0.3 ⫾ 0.6 0.56
Mixed AHI, /h 0.4 ⫾ 0.8 0.1 ⫾ 0.2 0.3 ⫾ 0.8 1.3 ⫾ 2.3 0.033†
Average oxygen saturation, % 91.5 ⫾ 6.1 94.0 ⫾ 2.0 94.0 ⫾ 2.5 93.5 ⫾ 3.1 0.12
Lowest oxygen saturation, % 80.8 ⫾ 8.3 85.7 ⫾ 6.3 83.0 ⫾ 11.1 81.9 ⫾ 10.9 0.002†
Desaturation events, No. 15.4 ⫾ 18.2 5.8 ⫾ 8.7 31.7 ⫾ 44.3 30.4 ⫾ 61.3 0.36
Time with oxygen saturation ⬍ 90%, % 13.4 ⫾ 17.4 3.7 ⫾ 4.8 8.5 ⫾ 14.7 11.0 ⫾ 20.1 0.017†
ADAS-cog score 34.5 ⫾ 15.8 29.7 ⫾ 15.7 29.3 ⫾ 17.3 31.8 ⫾ 18.5 0.004†
*Data are presented as mean ⫾ SD.
†p ⬍ 0.05, ANOVA.
680
Original Research
As previously mentioned, it was expected that the
REM sleep increase would be associated to the
worsening of OSA because respiratory events are
more frequent during this sleep stage.
12,19
However,
cholinergic drugs display more complex effects on
respiration. Available evidence demonstrates that
cholinergic stimulation has potent excitatory effects
on medullary respiratory neurons and respiratory
motoneurones.
14
It also affects the central chemo-
sensitive drive of the respiratory control system.
14
Upper airway dilating muscle activity is characterized
by an early peaking pattern that serves to dilate the
upper airway at the time when the greatest negative
intraluminal pressure is generated by contraction of the
chest wall muscles and diaphragm.
36
An experimental
study
36
showed an increase in hypoglossus nerve activ-
ity with consequent opening of the upper airway fol-
lowing carbachol pontine injection in cats. Physostig-
mine administered to cholinergic neurons located in
the rostral ventrolateral medulla of anesthetized
vagotomized and artificially ventilated cats resulted
in elongation of the hypoglossal-to-phrenic nerve
firing interval resulting in improved oxygenation.
37
It
also antagonizes respiratory depression induced by
fentanyl in rats.
38
Furthermore, physostigmine stimu-
lates saliva production, resulting in reduced superficial
tension that increases upper airway stability, which may
represent another mechanism for improving OSA.
39,40
Figure 1. AHI before (1) and after (2) donepezil (top left, A) or placebo (top right, B) treatment, and
time spent with oxygen saturation ⬍ 90% before (1) and after (2) donepezil (bottom left, C) or placebo
(bottom right, D) treatment. An outlier (Subject 12) is not presented (top right, B) due to scale: AHI
was 81 events/h at entry and 87 events/h after placebo.
www.chestjournal.org CHEST / 133/3/MARCH, 2008 681
Cholinergic stimulation of the respiratory center and
the carotid body increases sensitivity to hypoxia improv-
ing the chemoreflex response.
12,14,15,41
Such effects
may contribute to the cholinergic-induced improve-
ment of the peripheral and central components of
respiratory regulation during sleep.
12,14,15,37–42
In our
study, most of the reduction of the microarousal index
in the donepezil group was attributable to a significant
decrease in respiratory-related microarousals, even
though cholinergic drugs may elicit arousal.
43,44
Donepezil-related cognitive improvement measured
by ADAS-cog subscale did not correlate with respira-
tory parameters, suggesting independence between
cognition and sleep respiratory symptoms in patients
with Alzheimer disease.
1
However, further clarification
is required as to whether or not OSA contributes to
cognitive deterioration in Alzheimer disease.
3–5
In summary our results support the concept that
cholinergic transmission is involved in the patho-
genesis of OSA in Alzheimer disease, suggesting a
possible target for pharmacologic intervention.
Larger placebo-controlled studies are needed to
confirm these results.
ACKNOWLEDGMENT: The authors thank Dr. Robert Skomro
for his comments.
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