Journal of Affective Disorders 134 (2011) 421–426
Contents lists available at ScienceDirect
Journal of Affective Disorders
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Preliminary communication
Excessive daytime sleepiness and fatigue in depressed patients and
therapeutic response of a sedating antidepressant
Jianhua Shen a,⁎, Naheed Hossain a, David L. Streiner b, Aruu V. Ravindran c, Xuehua Wang a,
Prativa Deb a, Xin Huang a, Frank Sun a, Colin M. Shapiro a, d
a
b
c
d
Sleep Research Laboratory, Department of Psychiatry, University Health Network, University of Toronto, Canada
Kunin-Lunenfeld Applied Research Unit, Baycrest Centre and University of Toronto, Canada
Center for Addiction & Mental Health, University of Toronto, Canada
Youthdale Child and Adolescent Sleep Clinic, Toronto, Canada
a r t i c l e
i n f o
Article history:
Received 17 December 2010
Accepted 27 April 2011
Available online 25 May 2011
Keywords:
Depression
Therapeutic effects
Mirtazapine
Sleepiness
Fatigue
a b s t r a c t
Background: Although sleepiness and fatigue are common symptoms in depressed patients, the
relationships among sleepiness, fatigue and treatment of depression have not been fully
elucidated. The main objective of this study was to investigate the therapeutic effects of a
sedating antidepressant on sleepiness and fatigue in patients with depression.
Methods: Forty-two depressed patients, who met DSM-IV diagnostic criteria, and 32 matched
healthy controls participated in the baseline measurements. Sixteen of the depressed patients were
treated with mirtazapine. At baseline, daytime sleepiness was assessed using the Epworth Sleepiness
Scale (ESS) and Stanford Sleepiness Scale (SSS), and fatigue was assessed using the Fatigue Severity
Scale (FSS) and Fatigue Impact Scale (FIS). During treatment, Multiple Sleep Latency Test (MSLT), ESS
and SSS were used to measure daytime sleepiness, and the FIS, FACES Checklist-Fatigue subscale
(FAF) and Fatigue Assessment Instrument (FAI) were used to measure fatigue.
Results: At baseline, there were significant group differences between the depressed and healthy
controls on the ESS (P=0.001), SSS (Pb 0.001), FSS (Pb 0.001) and FIS (Pb 0.001). Significant
improvement of sleepiness and fatigue measures was seen after treatment with mirtazapine on the
MSLT (P=0.011), ESS (P=0.021), SSS (P=0.001), FIS (P=0.002) and FAF (P=0.004).
Limitations: Open-label treatment and relatively small sample size.
Conclusion: Daytime sleepiness and fatigue are significant symptoms in depressed patients. Slightly
paradoxically, a sedating antidepressant may alleviate these symptoms.
© 2011 Elsevier B.V. All rights reserved.
1. Introduction
Sleepiness and fatigue are common complaints in both
clinical and non-clinical populations (Hickie et al., 2002; Shen
et al., 2006a). Excessive daytime sleepiness is frequently seen in
the depressed population. A study found that most (57.1%)
depressive disorder patients scored high on the Epworth
⁎ Corresponding author at: Sleep Research Laboratory, Department of
Psychiatry, University Health Network, University of Toronto, 399 Bathurst
Street, 7M-417, Toronto, Ontario, Canada M5T 2S8. Tel.: + 1 416 603
5800×2173; fax: + 1 416 603 5292.
E-mail address: [email protected] (J. Shen).
0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jad.2011.04.047
Sleepiness Scale (ESS) — a measure of daytime sleepiness
(Chellappa and Araujo, 2006). Some suggest that depression
may be even more relevant than sleep apnea as the most
common risk factor for excessive daytime sleepiness (Bixler et al.,
2005).
Fatigue is a frequent and often a dominant symptom of
depressive disorders (Gaudiano et al., 2008). Co-occurring
fatigue and depressed moods are often associated with a
variety of neurological and psychiatric disorders (Chellappa
and Araujo, 2006; Williamson et al., 2005). For example, in
patients with multiple sclerosis, fatigue and depressed moods
are frequent complaints. In a study conducted by Chwastiak
et al. (2005), 76% of significantly fatigued multiple sclerosis
422
J. Shen et al. / Journal of Affective Disorders 134 (2011) 421–426
patients scored 16 or higher on the Center for Epidemiologic
Studies Depression Scale (CES-D), indicating that they had
many symptoms of depression. In contrast, in the multiple
sclerosis patients without significant fatigue, only 31% had
clear symptoms of depression (Chwastiak et al., 2005).
Sleepiness and fatigue are often considered as residual
symptoms among depressed patients who have partially
recovered following treatment with antidepressants (Baldwin
and Papakostas, 2006). Such residual symptoms are thought to
predict poor outcome and high risk of relapse (Fava, 2004).
While the relationship between depressed mood and fatigue
are complex, there is a significant overlap of the latter with
daytime drowsiness.
Despite the great importance of sleepiness and fatigue in
depression, few published studies have specifically attempted
to evaluate the relationship between these symptoms and
sleep function, and the effect of antidepressants on these
specific complaints (Baldwin and Papakostas, 2006).
The objectives of this study was to investigate the severity
of daytime sleepiness and fatigue in depressed patients
(compared to normal controls) and to observe therapeutic
effects of a sedating antidepressant, mirtazapine, on these
parameters. It was hypothesized that daytime sleepiness and
fatigue would be more frequent and severe in depressed
patients compared to normal controls and mirtazapine
treatment would significantly alleviate these symptoms in
patients with depression.
2. Methods
2.1. Procedure
The protocol was approved by the institutional Research
Ethics Board. The study was conducted in the Sleep and
Alertness Clinic, Toronto Western Hospital — a tertiary
university teaching center.
On admission to the study, potential subjects signed
informed consent. The depressed subjects fulfilled the criteria
of the Diagnostic and Statistical Manual of Mental Disorders, 4th
edition (DSM-IV) for depression (American Psychiatric Association, 1994). The age of the study population was 18 or older.
The subjects were free of psychotropic medications in the two
weeks prior to entry into the study (four weeks if previously on
fluoxetine). Patients with Axis I or II co-morbidity (including
substance abuse and dependence) and significant physical
illness were excluded.
At baseline, all the patients (N = 42) completed the CES-D
(Radloff, 1977) and the Beck Depression Inventory, version II
(BDI-II; Beck et al., 1997). To further observe therapeutic
effects on sleepiness and fatigue, 16 patients received
mirtazapine treatment. In addition to the CES-D and BDI-II,
these 16 patients completed an assessment with the 17-item
Hamilton Rating Scale for Depression (HRDS-17; Hamilton,
1967). The scores of the mood measurement tools were 17 or
higher on the HRSD-17, 16 or higher on the CES-D and/or 15
or higher on the BDI-II. At baseline, in addition to providing
mood state information, all the subjects, including 42
depressed patients and 32 normal controls, completed four
questionnaires: the ESS, Stanford Sleepiness Scale (SSS),
Fatigue Severity Scale (FSS) and Fatigue Impact Scale (FIS).
The ESS and SSS were used to measure sleepiness, and the FSS
and FIS were used to measure fatigue.
Inclusion criteria of the subjects in the control group were
the same as those in patient group, except that they were not
depressed. Subjects in the control group included normal
people from various populations, such as factory workers and
university students. Subjects in the control group were only
assessed at baseline.
The 16 patients who received mirtazapine treatment
completed a 58-day therapeutic regimen. They took mirtazapine (30 mg daily) 30 min prior to bedtime, while the rest
(N = 26) received treatments other than mirtazapine; they
were not included in the treatment limb of the data analysis
and report in this study.
At baseline and on Days 2, 9, 16, 30 and 58, mirtazapine
treated patients performed the multiple sleep latency test
(MSLT) after a standard polysomnographic recording and
completed a battery of questionnaires. The questionnaires
measuring sleepiness and fatigue included the ESS, SSS, FIS,
FACES Checklist-Fatigue subscale (FAF; Shapiro et al., 2002)
and Fatigue Assessment Instrument (FAI; Schwartz et al.,
1993). Mood state of those patients in the treatment group
was monitored using the HRSD-17 and BDI-II at baseline and
on Days 9, 16, 30 and 58 (i.e. not on Day 2).
2.2. Measurements
As noted above, several tests and instruments were used
to evaluate mood, sleepiness and fatigue during the study.
Mood state was measured using the HRSD-17, CES-D and
BDI-II. The HRSD-17 is a commonly used instrument to
measure the severity of depression. The score range of the
HRSD-17 is between 0 and 54. The CES-D is a well-established
depression measurement instrument. This 20-item scale
measures the presence and severity of depressive symptoms
during the last week. Each item of the scale ranges from
0 (rarely or none of the time) to 3 (most or all of the time). The
CES-D has excellent internal consistency and sensitivity for
depression (Beekman et al., 1997; Paddison et al., 2006). The
BDI-II is a 21-item self-report questionnaire measuring
severity of depression. Items in the BDI-II are scored on a
four-point scale (0–3); the sum of the scores is between 0 and
63 (Beck et al., 1997; Hamilton, 1967).
In this study, there are both objective and subjective
measurements available for evaluating sleepiness. Considering
a weak or moderate correlation between the multiple sleep
latency test (MSLT) and those subjective sleepiness measurements (Johnson et al., 1990; Johns, 1994; Punjabi et al., 2003;
Shen et al., 2006a) we used the MSLT and two subjective
measurements (ESS and SSS) to measure sleepiness, trying to
avoid any potential bias induced by a single sleepiness
measurement.
The MSLT is a widely accepted objective assessment; it is
considered the “gold standard” for evaluating sleepiness. The
test consists of 4–5 nap opportunities during the day. While
being recorded, subjects reclined in bed in a quiet darkened
room are instructed to close their eyes and try to fall asleep.
The mean sleep onset latency is used to judge the level of
daytime sleepiness (Bailes et al., 2006; Shapiro et al., 2006;
Thorpy et al., 1992). Various authors view a mean score below
5 or 6 min as indicative of severe sleepiness and a score below
J. Shen et al. / Journal of Affective Disorders 134 (2011) 421–426
10 or 11 min as indicative of moderate sleepiness. The ESS is a
reliable subjective instrument measuring sleepiness. It retrospectively questions the behavioral aspects of sleepiness.
Participants rate the potential of dozing off or falling asleep in
eight different situations. Each item is scored with a fourpoint scale (0 = never doze, 3 = high chance of dozing). The
total scores are between 0 and 24 (Johns, 1991; Johns, 1992;
Johns, 1994). The SSS consists of a seven-point Guttman
scaled item. It ranges from 1 (Feeling active and vital; alert;
wide awake) to 7 (Almost in reverie; sleep onset soon; lost
struggle to remain awake). Respondents select the most
suitable option (Hoddes et al., 1973).
Currently, no reliable objective measurement is available
to evaluate fatigue. Therefore, fatigue was measured using
only subjective measurement tools. Because each such
measurement tool has its own measurement range and
distinct features, we used the FSS, FIS, FAF and FAI to
concurrently measure fatigue. In this way, these instruments
would compensate each other's limitation and would show a
relatively full picture of fatigue in the subjects.
The FSS was developed by Krupp et al. (1989). As described
by its title, it is mainly used to measure the severity of fatigue.
This nine-item scale has good internal consistency. It has been
successfully used in clinical research involving patients with
systematic lupus erythematosus, multiple sclerosis and
insomnia to differentiate patients and controls (Krupp et al.,
1989; Lichstein et al., 1994). The FIS is a 40-item self-report
instrument to assess the impact of fatigue on cognitive,
physical and psychosocial functions. The score range of the FIS
is between 0 and 160 (Fisk et al., 1994). The FAF is the Fatigue
subscale of the FACES Checklist (Shapiro et al., 2006). This
subscale includes 15 items with a score range between 0 and
3. The FAI was developed by Schwartz et al. (1993). This 29item scale was effectively used to measure the quantitative
and qualitative components of fatigue in patients and healthy
controls (Schwartz et al., 1993).
Of all above measurements, higher scores on any of the
subjective measurements (HRSD-17, CES-D, BDI, FSS, FIS, ESS,
SSS, FAF and FAI) indicate greater severity or higher impact of
Patient
Control
**
**
Score
8
**
6
**
4
2
0
ESS
SSS
FSS
depressed mood, sleepiness or fatigue. The MSLT is the only
one where lower values to indicate higher severity of
sleepiness.
2.3. Statistical analyses
Student's t-tests were used to compare age and the scores
of the ESS, SSS, FSS, and FIS between the patient group and the
control group at baseline. Repeated measures analysis of
variance (rMANOVA) was used to evaluate the possible linear
trend of each measure during the research procedure. The
Huynh–Feldt correction was applied for the factors that did
not meet the sphericity assumption. The data were analyzed
with Statistical Package for the Social Sciences (SPSS)
software, version 15.0, for Windows (SPSS Inc., 2007).
Significance cut point was set at 0.05.
3. Results
3.1. Participants
At baseline, subjects included patient group (N = 42;
M = 8; F = 34) and control group (N = 32; M = 14; F = 18).
There was no significant difference (t = 1.39; df = 72;
P = 0.17) between the mean ages of the patients (43.9) and
that of the normal controls (39.7). The mean scores of the
CES-D were 27.4 (standard deviation [SD] 9.2) for the patient
group and 6.2 (SD 4.3) for the control group, and those of the
BDI were 23.9 (SD 12.5) for the patient group and 4.6 (SD 3.5)
for the control group.
3.2. Sleepiness and fatigue at baseline
The mean scores of the ESS, SSS, FSS and FIS in the patient
group were significantly higher than those in the control
group (Fig. 1). These results indicated that the severity of
daytime sleepiness and fatigue in depression patients were
significantly higher than that reported by the normal
controls.
3.3. Treatment effects of mirtazapine
12
10
423
FIS (x 0.1)
Fig. 1. Mean scores ± 1.96 SE (standard errors) of the Epworth Sleepiness
Scale (ESS; 8.4 ± 1.6 vs. 4.8 ± 1.2), Stanford Sleepiness Scale (SSS; 4.1 ± 0.4
vs. 2.0 ± 0.3), Fatigue Severity Scale (FSS; 5.1 ± 0.6 vs. 2.5 ± 0.5) and Fatigue
Impact Scale (FIS; 82.2 ± 11.9 vs. 13.9 ± 4.9 in patient group and control
group at baseline. Note: score values (mean and SD) of the FIS are one tenth
of the raw scores for both patient and control groups. **P b 0.01.
Fig. 2 shows the effects of mirtazapine on sleepiness in the
depressed treated group. After taking the medication for
2 days, the mean sleep latency, as measured by the MSLT, of
the patients was shortened from 7.8 (SD 5.0) min to 5.5 (SD
3.2) min. On Day 9, the mean sleep latency was 6.9 (SD 3.9)
min, which was close to that at baseline. Subsequently, the
mean sleep latency increased continuously. On Day 58, it was
9.7 (SD 5.8) min, 1.9 min longer than that at the baseline. The
effects of mirtazapine on the scores of the ESS and SSS are
similar to each other. The mean score of the ESS increased
from 8.3 (SD 4.8) at baseline to 9.9 (SD 5.3) on Day 2, and that
of the SSS increased from 4.5 (SD 1.6) to 4.8 (SD 1.8). On Day
9, the mean scores of the ESS and SSS were lower than those
at baseline. Then, the scores of both the ESS and SSS decreased
continuously. On Day 58, the mean score of the ESS was 6.2
(SD 4.5), 33.9% lower than that at baseline, and the mean
score of the SSS was 3.5 (SD 1.3), 28.6% lower than that at
baseline.
424
J. Shen et al. / Journal of Affective Disorders 134 (2011) 421–426
MSLT
ESS
D61
D03
SSS
12
10
Score
8
6
4
2
0
BL
D2
D9
D85
Fig. 2. Treatment effects of mirtazapine on sleepiness measurements
Abbreviations: MSLT = Multiple Sleep Latency Test; ESS = Epworth Sleepiness Scale SSS = Stanford Sleepiness Scale; D = Day.
Fig. 3 shows the effects of mirtazapine on the scores of the
fatigue measurements. On Day 2, the mean score of the FIS
increased from 90.2 (SD 36.5) to 95.3 (SD 38.6). On Day 9, the
mean score of the FIS was 86.0 (SD 45.4), which was lower
than at baseline. On Day 58, the FIS mean score was 64.4 (SD
49.4), 28.6% lower than at baseline. The change patterns of
the FAI and FAF are similar to that of the FIS, excepting that
the highest increment of FAI score was on Day 9, instead of
Day 2. No significant increment of FAF score was seen after
the patients took the medication.
Results of rMANOVA from the data at 6 time points
(baseline and Days 2, 9, 16, 30 and 58) showed that 5 (MSLT,
ESS, SSS, FIS and FAF) of the 6 sleepiness and fatigue
measurements showed a statistically significant change. For
the data following Day 2, the trend was linear and significant
for all 6 measurements (Table 1). This indicates that a “longterm” (58 days) administration of mirtazapine effectively
reduced the severity and impact of both daytime sleepiness
and fatigue in patients with depression.
4. Discussion
In this study, we found that the severity of daytime
sleepiness and fatigue is significantly higher in patients with
depression than that in normal controls, as shown by the
greater mean scores on the ESS, SSS, FSS and FIS. This finding
is consistent with those of previous studies (Baldwin and
FAI (x 0.1)
FIS (x 0.1)
FAF
18
16
14
Score
12
10
8
6
4
2
0
BL
D2
D9
D16
D30
D58
Fig. 3. Treatment effects of mirtazapine on subjective fatigue measurements
Abbreviations: FAI = Fatigue Assessment Instrument; FIS = Fatigue Impact
Scale FAF = FACES Checklist-Fatigue subscale; D = Day. Note: mean scores of
the FAI and FIS are 10 times diminished values.
Papakostas, 2006; Zifko, 2004), confirming that both excessive daytime sleepiness and fatigue are common in depression (Martin and Menza, 2005). Posternak and Zimmerman
(2002) found that 36.2% of their patients (N = 130) with
atypical MDD had excessive daytime sleepiness. An epidemiological investigation (Tylee et al., 1999) of depressed
patients has further confirmed high frequency of fatigue
with 73% of those being surveyed having significant fatigue.
This symptom frequency is only second to depressed mood
(76%). Other research suggests that the presence of fatigue
may be a vulnerability factor that predicts the later onset of
major depression (Addington et al., 2001).
The mechanism underlying the relationship between
depression, daytime sleepiness and fatigue has not been
fully elucidated. A correlation between sleep disorder and
depression and the associations of depressed mood with
increased daytime sleepiness and fatigue suggest that sleep
symptoms, especially insomnia, and depressed mood may be
key features in the daytime sleepiness and fatigue in patients
with depression (Samborski et al., 2004; Shen et al., 2005;
Shen et al., 2006b). It has been proposed that increased
serotonin activity in certain brain areas may contribute to
fatigue and daytime sleepiness (Martin and Menza, 2005).
This proposition is certainly worthy of further study to clarify
the possible underlying mechanisms. Current established
theory and clinical evidence indicate that depressed patients
have a decrease, rather than an increase, in serotonin level
and activity (Baldwin and Papakostas, 2006).
The most important findings of this study are that the
effect of mirtazapine on sleepiness and fatigue has two
phases. After taking the medication for 2 days, the patients
seemed to feel sleepier and more fatigued than they were
prior to taking the medication at baseline. However, after the
patients took mirtazapine for 9 to 16 days, their sleepiness
and fatigue returned to close baseline level. Subsequently, the
level of sleepiness and fatigue decreased progressively. Scores
on five instruments at 6 time points showed significant linear
time effects. This indicates that during an 8-week treatment
with mirtazapine, a decrease in severity of both daytime
sleepiness and fatigue occurs. These findings have important
clinical implications. For example, at the onset of using a
sedating antidepressant, patients should be advised to avoid
potentially dangerous activities, such as driving a car or
operating machinery.
The reported treatment effects of mirtazapine on sleepiness and fatigue are not consistent. In short-term (≤1 week)
and/or non-quantitative studies (Bremener, 1995), sleepiness
and fatigue are usually regarded as side effects of mirtazapine
(Baldwin and Papakostas, 2006). However, in Samborski's
study, after taking mirtazapine 15–30 mg daily for 6 weeks,
both depression and fatigue symptoms of the 26 patients with
fibromyalgia syndrome were significantly improved. These
results are similar to ours, although the subjects in the study
were fibromyalgia sufferers, rather than depressed patients
(Samborski et al., 2004).
Mirtazapine is a clinically established antidepressant. Via
the blockade of adrenergic alpha-2 receptors, it enhances
central noradrenergic and serotonergic neurotransmission.
As well, mirtazapine blockades postsynaptic 5-HT2 and 5-HT3
receptors. In addition, it has a high affinity to histamine H1
receptors (Lee et al., 2009; Rawlings et al., 2010). This may
J. Shen et al. / Journal of Affective Disorders 134 (2011) 421–426
Table 1
Treatment effects of mirtazapine on sleepiness and fatigue at 6 time points
and at 5 time points in patients with depression.
6 time points
(with baseline)
5 time points
(without baseline)
Measurement
F (df)
P
F (df)
P
MSLT
ESS
SSS
FIS
FAF
FAI
3.22
3.68
4.55
5.80
4.73
1.99
0.011
0.021
0.001
0.002
0.004
0.089
4.06
3.75
5.35
6.78
3.72
2.64
0.006
0.024
0.001
0.001
0.010
0.043
(5, 75)
(2.8, 42.3)
(5, 75)
(3.0, 45.3)
(3.6, 43.2)
(5, 75)
(4, 60)
(2.5, 38.0)
(4, 60)
(2.9, 43.3)
(4, 60)
(4, 60)
Abbreviations: MSLT = Multiple Sleep Latency Test; ESS = Epworth
Sleepiness Scale; SSS = Stanford Sleepiness Scale; FIS = Fatigue Impact
Scale; FAF = Fatigue subscale, FACES; FAI = Fatigue Assessment Instrument.
account for the reduction in sleepiness and fatigue. The
effects may be detected only short-term, as benefits from
antidepressants may be not sustained, as demonstrated by
Bockting et al. (2008).
The major limitation of this study is its open-label
treatment, leading to a lack of comparison. To compensate
for this limitation, we applied the MSLT to objectively
measure sleepiness. It has been reported in previous studies
that polysomnographic measurements, including MSLT, are
not significantly affected by a placebo response (Aslan et al.,
2002; Dorsey et al., 1996). However, because no reliable
objective measurements of fatigue are available, it is possible
that the results of those related variables are negatively
affected on their explanation. Another limitation is that the
study sample size is relatively small.
In conclusion, sleepiness and fatigue are more common in
depressed patients than in normal individuals. The effects of
mirtazapine on sleepiness and fatigue appear to have two
phases. There is a short-term (less than 1 week) tendency of
increasing sleepiness and fatigue, but subsequently a decrease in the severity of sleepiness and fatigue in depressed
patients. Alerting patients to this pattern will improve both
compliance with treatment (“riding through” a sleepy first
week) and safety (avoiding driving or operating dangerous
machinery in the first week of treatment).
Role of funding source
This study did not receive any financial support.
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgments
We appreciate Ms. Nancy MacFarlane's excellent work in assisting with
the organization of the research subjects.
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