The World Journal of Biological Psychiatry

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Sleep disturbances: Core symptoms of major

depressive disorder rather than associated or
comorbid disorders

Julien Mendlewicz

To cite this article: Julien Mendlewicz (2009) Sleep disturbances: Core symptoms of major
depressive disorder rather than associated or comorbid disorders, The World Journal of
Biological Psychiatry, 10:4, 269-275, DOI: 10.3109/15622970802503086

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The World Journal of Biological Psychiatry, 2009; 10: 269
275

REVIEW ARTICLE

Sleep disturbances: Core symptoms of major depressive disorder

rather than associated or comorbid disorders

JULIEN MENDLEWICZ

Department of Psychiatry, Free University of Brussels, Brussels, Belgium

Abstract
Depression is increasingly prevalent in Western countries. It has severe consequences and is associated with increased rates
of disability, morbidity, and mortality. Despite numerous therapeutic options, a great number of depressed patients do not
achieve full remission. In addition, despite good short-term outcomes, long-term therapeutic results remain disappointing
and associated with a poor prognosis, raising significant concern in terms of public health. Impaired sleep
especially
insomnia
may be at least partly responsible for this problem. Very close relationships between major depressive disorder
(MDD) and sleep disorders have been observed. In particular, residual symptoms of sleep disturbance in a remitted patient
may predict a relapse of the disease. However, most currently available antidepressants do not always take into consideration
the sleep disturbances of depressed patients; some agents long used in clinical practice even appear to worsen them by their
sleep-inhibiting properties. But some other new medications were shown to relieve early sleep disturbance in addition to
alleviating other depression-related symptoms. This positive impact should promote compliance with medication and
psychological treatments, and increase daytime performance and overall functioning. Complete remission of MDD appears
therefore to depend on the relief of sleep disturbances, a core symptom of MDD that should be taken into consideration and
treated early in depressed patients.

Key words: Major depressive disorder, sleep disturbances, management, antidepressants, residual symptoms

Introduction who begin treatment achieve full remission, defined

Depression is a severe condition that negatively
impacts on both patients and their families. Ranked
third among the most debilitating disorders, its
consequences are severe and it is associated with
increased rates of disability, mortality, and second-
ary morbidity. In Western Europe as in the US, the
1-year prevalence of major depressive disorder
(MDD) is 4
6% (Kessler et al. 2003; Alonso et al.
2004; Paykel et al. 2005). This is of great concern
and constitutes a major public health issue, since the
incidence of depression is expected to increase as a
result of prolonged life expectancy and social and
demographic changes.
Despite the availability of numerous therapeutic
options for MDD, and the wide variety of the
mechanisms of action that allow different possible
treatment strategies, hence ‘‘tailoring of treatment’’,
30
40% of patients fail to respond to treatment
(Kennedy and Emsley 2006; Douery et al. 2007).
No more than one-third of the depressed patients
as a virtually complete relief of symptoms, and
return to full functioning in all areas of life (Thase
2003; McIntyre and O’Donovan 2004; Rush et al.
2006; Trivedi et al. 2006). Besides, although good
short-term outcomes may be obtained, long-term
outcomes remain disappointing and depression con-
tinues to be missed or under-diagnosed and under-
treated (McIntyre and O’Donovan 2004), and
associated with a poor prognosis.
The vast majority of depressed patients, about
90% (Thase 1999; Tsuno and Besset 2005), report
dysfunctional sleep conditions such as insomnia,
hypersomnia, and excessive sleepiness, and sleep
disturbance is very frequently the symptom that
makes depressed patients seek medical help. The
longitudinal study of Breslau et al. (1996) observed
that by far the strongest lifetime association of
sleep disturbance was in major depression. ‘‘Insom-
nia or hypersomnia nearly every day’’ is one of
the nine criteria that define MDD in the Diagnostic

Correspondence: Professor Julien Mendlewicz, Department of Psychiatry, Free University of Brussels, Brussels, Belgium. Tel: 32 2 380
5907. Fax: 32 2 381 0964. E-mail: julien.mendlewicz@skynet.be

(Received 05 August 2008; accepted 13 September 2008)

ISSN 1562-2975 print/ISSN 1814-1412 online # 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)
DOI: 10.3109/15622970802503086
270 J. Mendlewicz
and statistical manual of mental disorders, 4th ed.
(DSM-IV) (American Psychiatric Association 1994).
Sleep disorders in depression should be reconsid-
ered and viewed not as an associated symptom or
comorbidity but rather as a core symptom of MDD
that must be identified and addressed, taking into
account how antidepressant agents influence sleep
patterns in depressed patients.
Sleep disturbance in major depressive disorder
Many symptoms of sleep disorders are reported by
depressed patients (Table I). Of all sleep-related
complaints, insomnia (and resultant daytime sleepi-
ness) is the most frequent (Ford and Kamero 1989;
Gallup Organization 1991; Breslau et al. 1996;
Armitage 2000; Fava 2004). Insomnia is defined as
a perception of inadequate, insufficient, or nonres-
torative sleep. Gender and age are the most im-
portant demographic variables related to the
prevalence of insomnia: specifically, women have a
higher rate of insomnia than men and complaints of
insomnia appear to increase with age (Breslau et al.
1996; Armitage 2001). Hypersomnia is also a
complaint commonly reported in depressive disor-
ders. As shown in the longitudinal study of Breslau
et al. (1996), lifetime associations with psychiatric
disorders is as high for insomnia as for hypersomnia,
and persons with history of both disturbances were
shown to have higher rates of psychiatric disorders
than those with either alone.
Disturbed sleep patterns in MDD
Sleep patterns are disturbed in depressed patients.
Specific abnormalities of sleep have been identified
in depressed patients, which may not be present in
other mental conditions (Berger and Riemann 1993;
Armitage 1995). Three types of disturbances have
been identified (Kupfer et al. 1990, 1991; Mendlewicz
1991; Berger and Riemann 1993; Armitage 1995,
2000; Nofzinger et al. 1999; Fava 2004):
1. Difficulties initiating and maintaining sleep:
prolonged sleep latency, intermittent wakeful-
ness and sleep fragmentation during the night,
early morning awakenings with inability to
return to sleep, reduced sleep efficiency, and
decreased total sleep time.
Table I. Symptoms of sleep disorders in the depressed patient
(from Lemoine and Nicolas 2007).
Too early awakening after a fragmented sleep
Fatigue and distress at awakening and during the day, lasting until
late afternoon
Insomnia, ineffectiveness of hypnotics, patient obsessed with sleep
Daytime sleepiness
2. Abnormal sleep architecture: abnormal amo-
unts and distribution of non-rapid eye move-
ment (NREM) sleep stages during the night:
compared with a healthy subject, the depressed
patient has increased light sleep (stage 1), and
reduced deep slow-wave sleep (SWS) (stages 3
and 4). Table II presents the alterations of sleep
architecture in the depressed patient.
3. Disruptions in the timing of paradoxical sleep.
Paradoxical sleep is the sleep phase during
which muscle tone is abolished despite brief
contractions of the extremities and rapid eye
movements, while the brain remains as active as
in sleep stage 1.
Relationships between psychiatric disorders and sleep
disturbance
Insomnia being the most commonly reported type of
sleep disturbance (Perlis et al. 1997; Fava 2004) it is
the subject of more studies and publications than
other types. Whether analyses of the relationships
between MDD and insomnia are applicable to
other types of sleep disorders should be specifically
explored.
Ohayon and Roth (2003) investigated the psy-
chiatric history of insomniacs in a population-based
sample of 14,915 adults and observed that ‘‘pure’’
insomnia was very infrequent: 2.4% of insomniacs
had no current or past mental disorders. In virtually
all cases, close relationships and interactions were
observed between psychiatric disorders and insom-
nia (Ohayon and Roth 2003).
Despite the fact that the causal relationship
between insomnia and psychopathology requires
further investigation, it appears obvious that these
two disorders are closely related. As shown by many
studies, insomnia is an important symptom in
various psychopathological disorders (mood disor-
der, affective disorder, depression, anxiety), and is
Table II. Altered patterns of sleep architecture in the depressed
patient (from Tsuno et al. 2005).
Impaired sleep continuity and duration
Decreased deep sleep (stages 3 and 4)
Reduced slow-wave sleep
Decreased REM sleep latency
Short REM sleep latency: shortened interval between sleep
onset and the occurrence of the first REM period, to 20
30 min
(90 min in normal subjects)
Increased proportion of REM sleep in the early part of the night
Increased amount of REM sleep
Prolonged first REM period
Increased number of ocular movements during the REM period
(REM density)
REM, rapid eye movement.

sometimes the first manifestation of the mental
disorder. Most insomniacs have no concomitant
mental disorder (Ohayon and Roth 2003), but the
majority of subjects with mental disorders have sleep
disturbances. As for depression, according to Thase
(1999), insomnia is a particularly frequent com-
plaint, reported by more than 90% of depressed
patients. This author states that sleep disturbances
are an integral part of a depressive disorder and that
as such they are included in all contemporary sets of
diagnostic criteria for major depression and all major
symptom-based rating scales for depression (Thase
1999). The Montgomery
Asberg Depression Rating
Scale (MADRS) (Montgomery and Asberg 1979),
which is frequently used to monitor the therapeutic
response in pharmacologic trials in depression,
consists of 10 items one of which (item # 4) assesses
the reduced duration or depth of sleep. The Hamil-
ton Depression Rating Scale (HDRS) (Hamilton
1960) includes three items (out of 17) pertaining to
insomnia considered according to the time of onset
during the night, and the DSM-IV (American
Psychiatric Association 1994) considers insomnia
or hypersomnia nearly every day during a 2-week
period as one of the nine symptoms of major
depressive episode. All these considerations clearly
demonstrate that sleep disturbances are core symp-
toms of depression.
Management of patients with MDD and sleep
disturbances
The initial therapeutic management of patients with
MDD and sleep disturbance is monotherapy with an
antidepressant. The effects of antidepressant drugs
on sleep patterns are presented in Table III.
Antidepressant monotherapy
Tricyclic antidepressants (TCAs). Several TCAs tend
to reduce sleep efficiency and increase wake time
after sleep onset. Tertiary amine tricyclics have a
tendency to improve sleep onset and sleep continuity
(Armitage 2000; Fava 2004; Wilson and Argyropoulos
2005).
Monoamine oxidase inhibitors (MAOIs). This drug
class shows a propensity to reduce sleep efficiency
and increase sleep onset latency; it also suppresses
REM sleep, as do most tricyclics (Fava 2004).
Significant rebounds of REM sleep time (up to
250% above baseline) occur upon withdrawal of
MAOIs (Monti 1989). Reversible MAOIs increase
REM sleep during treatment while maintaining their
antidepressant activity (Fava 2004).
Sleep disturbance, a core symptom of MDD 271
Selective serotonin reuptake inhibitors (SSRIs) and
selective norepinephrine reuptake inhibitors (SNRIs).
SSRIs and SNRIs have greatly improved the treat-
ment of depression, in particular because of their
superior safety profile compared with older TCAs,
despite adverse effects of their own (Gruenberg and
Goldstein 2003). Regarding their effects on sleep,
SSRIs and SNRIs have been shown to decrease
REM sleep and tend to disrupt sleep maintenance by
prolonging sleep onset latency, reducing sleep effi-
ciency, and increasing wake time after sleep onset
(Fava 2004).
Therapeutic adjunctions
Augmentation of antidepressant therapy with hyp-
notics, anticonvulsants, antihistamines, or sedative
antidepressants is another option that may treat
the insomnia more rapidly than the antidepressant
alone and offers long-term efficacy for sleep main-
tenance (Fava 2004). However, these compounds
are not the ideal solution to correct sleep disturbance
in depression and must be given with much caution
since they are associated with sleep-related adverse
effects such as daytime sleepiness, early awakening,
residual effects on daytime vigilance, reduced con-
centration, excessive sedative effect, altered sleep
architecture, and nocturnal arousals with anxiety
feelings.
Other therapeutic approaches
In depressed patients with marked insomnia, anti-
depressants with preferential 5-HT2 blocking prop-
erties have been recommended as a good treatment
option (Thase 1999). Mirtazapine is an agent with
joint 5-HT1, 5-HT2, and 5-HT3 blocking proper-
ties and, as such, it has an important role today in
the treatment of depressed patients with sleep
disturbances. Mirtazapine alleviates insomnia and
improves sleep architecture via a significant short-
ening of sleep-onset latency, an increase in slow-
wave sleep, an increase in total sleep time, and
consequently a marked improvement in sleep effi-
ciency. Despite these advantages, mirtazapine dis-
plays side effects such as somnolence, explained by
its strong antihistamine effects (Biglia et al. 2007;
Hannan et al. 2007) and increased body mass index
(Hannan et al. 2007; Schüle et al. 2007; Mrakotsky
et al. 2008), often leading to treatment discontinua-
tion and therefore a lack of overall therapeutic
efficacy.
The melatonergic approach
Agomelatine is a potent agonist at melatonergic
MT1 and MT2 receptors and an antagonist at
 272
Table III. Effects of antidepressant drugs on the sleep patterns of depressed patients.

Sleep Slow-wave REM

J. Mendlewicz
Sleep latency continuity sleep latency REM sleep

Drug Ac Ac Chr Ac Chr Ac Chr Ac Chr REM sleep rebound Sedation/daytime functioning Subjective sleep quality Side effects

TCAs
Amitryptiline /


/    ¡ ¡¡  
1, 2, 3
Doxepin /

/¡    ¡ ¡¡  
1, 2, 3
Imipramine  ¡ ¡
/¡
  ¡¡ ¡¡   ¡ 1, 2, 3
Nortriptyline 



  ¡¡ ¡¡ na  na 1, 2, 3
Desimipramine na
na

na na ¡¡ ¡¡   na 1, 2, 3
Chlorimipramine / ¡ ¡

  ¡¡ ¡¡¡¡  /
1, 2, 3
MAOIs
Phenelzine na ¡ ¡ na na   ¡¡¡¡ ¡¡¡¡  na na 3
Trancylpromine  ¡ ¡ na na na na ¡¡¡¡ ¡¡¡¡ na na
3
Moclovemide na ¡ ¡ na na  
/ ¡   na ¡ 3
SSRIs
Fluoxetine
¡ ¡ ¡/ 

¡ ¡¡  / ¡ 1, 2, 3
Paroxetine
/ ¡/ ¡/
/    ¡¡ ¡¡  na ¡ 1, 2
Sertraline
¡/ ¡/     ¡¡ ¡¡  na
1, 2
Fluvoxamine
¡ ¡     ¡¡ ¡¡  na
1, 2
Citalopram 

    ¡¡ ¡¡  na
1, 2
Escitalopram na

na na na na na na na na
na
SNRIs
Venlafaxine na ¡ ¡     ¡¡  na 
3
Duloxetine na ¡/
na na na  na ¡¡ na na na na na
Other antidepressants
Agomelatine na



na na   na na
na
Reboxetine (NARI) na     
 ¡  na ¡ na
Bupropion na    

¡ ¡ na  na na
Mirtazapine (NaSSa) na




   na 
na
Mianserin 

 

¡/  ¡/  na
na
Trazodone na





¡ ¡  
na
Nefazodone na

  ¡ ¡

 
na
Tianeptine na


/
/    ¡/  ¡/ / na
na
Mood stabilizers
Valproate na na na /
/
na na /
/
na  ¡ na
Carbamazepine na

na na   / ¡  na 
/? na
Lithium na na na na
na
na ¡ na  na na
Lamotrigine na na na  / ¡ na na  /
na na na na
Gabapentin na


na na  /
/ ¡ na na
1(?)

improvement or increase; ¡ worsening or decrease;increase;  no significant change; na, no data available; Ac, acute administration; Chr, chronic administration; 1, periodic limb movement
disorder; 2, nightmaresl; 3, REM sleep behaviour disorder.

serotonin-2C (5-HT2C) receptors (Yous et al. 1992;
Audinot et al. 2003; Millan et al. 2005) that relieves
core symptoms of depression including sleep dis-
turbance by its ability to resynchronize the circadian
rhythms (Armstrong et al. 1993; Martinet et al.
1996; Krauchi et al. 1997; Leproult et al. 2005;
Quera Salva et al. 2005, 2007). In depression and in
adults of all ages including elderly patients, it
improves initial HAMD scores of patients with
MDD similarly to the reference drugs in this
indication (Storosum et al. 2001; Kirsch et al.
2002; Lôo et al. 2002; Guilleminault 2005). Ago-
melatine improves the quality of sleep and the
disrupted sleep patterns of depressed patients with-
out affecting daytime vigilance and alertness as do
other antidepressants with sedative effects (Quera
Salva et al. 2005, 2007; Guilleminault 2005; Wilson
and Argyropoulos 2005).
It appears therefore that the majority of currently
available antidepressants do not take into considera-
tion the sleep disturbances of depressed patients. In
depressed patients with sleep disturbance, the ther-
apeutic option of an antidepressant therapy is taken
assuming that as the depression improves, insomnia
and resultant daytime drowsiness improve in paral-
lel. However, while this is sometimes true, other
times the existing sleep disturbances appear to be
worsened by the sleep-inhibiting properties of some
agents (Fava 2004).
Sleep residual symptoms: Limitations for
complete remission and markers of a future
relapse of the depressive disorder
In a recent publication, McIntyre and O’Donovan
(2004) write: ‘‘Of particular concern is the low rate
of depression treated to full remission since treating
only to response leaves patients with residual de-
pressive symptoms and an increased risk of a
recurrent or chronic course’’. Among such residual
depressive symptoms, severe and chronic current
insomnia appears to be an important residual core
symptom of depression since it was shown to be
closely related to a history of mental disorder
(Ohayon and Roth 2003). Besides, there is evidence
that people with recurrent depression have more
pronounced abnormalities of sleep neurophysiology
than those experiencing a single or initial episode.
Such observations are in line with the results of
longitudinal studies of insomniacs in whom it was
shown that maintenance of sleep disturbance over
time increased the risk of developing a mental
disorder or a new onset of major depression (Ford
and Kamerow 1989; Breslau et al. 1996). Similarly,
clinical studies that investigated sleep changes in the
course of affective disorders found that persistent
Sleep disturbance, a core symptom of MDD 273
abnormalities in the sleep EEG of remitted de-
pressed subjects could be good indicators of a
relapse (Kupfer et al. 1990, 1991), and two studies
on self-reported sleep disturbances suggest that such
disorders could be a prodromal symptom of a first or
recurrent depressive episode (Fava et al. 1990; Perlis
et al. 1997).
Two explanations have been proposed (Breslau
et al. 1996) for the increased risk of major depres-
sion in persons with history of insomnia: (1)
insomnia might be an early symptom of a major
depressive episode with other characteristic symp-
toms appearing later on; (2) insomnia due to
exogenous factors such as psychoactive substance
use might play a causal role in major depression,
precipitating the onset of the disorder in predisposed
individuals.
Nevertheless, early relief of sleep disturbance in a
depressed patient, in addition to alleviating other
symptoms, should promote compliance with medi-
cation and psychological treatments, and increase
daytime performance and overall functioning. Re-
garding more specifically insomnia, some authors
assume that complete relief of insomnia is likely to
improve MDD prognosis (Thase 1999; Wilson and
Argyropoulos 2005). Thus, complete remission in
depression appears to be partially conditional upon
recovery from sleep disturbance.
Conclusions
All together, these observations on the close relation-
ships between MDD and sleep disturbances, and the
fact that complete remission of MDD also depends
on relief of sleep disturbances, may suggest that
sleep disturbance is a core symptom in depression,
which should be taken into consideration and
treated early enough in the long-term management
of depression.
Acknowledgements
None.
Statement of Interest
None.
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