Sleep Medicine Reviews 14 (2010) 35–46

Contents lists available at ScienceDirect

Sleep Medicine Reviews

journal homepage: www.elsevier.com/locate/smrv

CLINICAL REVIEW

Comorbidity of insomnia and depression

Luc Staner
Sleep Laboratory, Forenap, Centre Hospitalier de Rouffach, 27 rue du 4ème R.S.M. F-68250 Rouffach, France

s u m m a r y

Keywords: During the last decade, several studies have shown that insomnia, rather than a symptom of depression,
Insomnia could be a medical condition on its own, showing high comorbidity with depression. Epidemiological
Depression research indicates that insomnia could lead to depression and/or that common causalities underlie the
Comorbidity
two disorders. Neurobiological and sleep EEG studies suggest that a heightened level of arousal may play
Non-REM sleep
a common role in both conditions and that signs of REM sleep disinhibition may appear in individuals
REM sleep
Antidepressant prone to depression. The effects of antidepressant drugs on non-REM and REM sleep are discussed in
relation to their use in insomnia comorbid with depression. Empirical treatment approaches are
behavioral management of sleep combined with prescription of a sedative antidepressant alone, co-
prescription of two antidepressants, or of an antidepressant with a hypnotic drug.
Ó 2009 Elsevier Ltd. All rights reserved.

Introduction reporting sufficient insomnia symptoms to warrant an additional

Insomnia symptoms appear to be one of the most frequent sleep
complaints in the general population with an estimated prevalence
varying from 10 to nearly 60% depending in part on the use of
varying definitions and data-collection methodologies.1 This esti-
mate falls below 10% when more stringent diagnostic criteria are
applied to define insomnia, including daytime consequence of
insomnia; for instance, the prevalence of insomnia diagnoses
according to the Diagnostic and Statistical Manual of Mental
Disorders 4th edition (DSM-IV) classification has been estimated at
6%.1 Individuals reporting disturbed sleep are more likely to report
emotional distress and recurrent health problems.2–4 This is not
surprising since it has been shown that sleep deprivation has great
impact on the daytime life of healthy subjects; alertness, attention,
concentration, cognitive abilities, memory, mood and pain
threshold have all been found impaired, even with a sleep depri-
vation of as little as 1–2 h per night.5–7
In this regard, studies have repeatedly emphasized the comor-
bid nature of insomnia and psychiatric disorders, especially
depression but also anxiety and substance use.8–10 Clinical and
epidemiological studies have shown that sleep disturbance is
tightly linked to major depression. In clinical samples, about three
quarters of all depressed patients complain of difficulty either in
initiation or in maintaining sleep.11–13 Epidemiological studies
showed a comparable prevalence of insomnia symptoms in
patients with depression,14,15 with 41% of depressed patients
DSM-IV diagnosis of insomnia.15
Other epidemiologic studies suggest that the link between
insomnia and depression is bidirectional. For instance, about 20% of
patients with insomnia exhibit some depressive symptoms8,16,17
whereas depression and depressive symptoms have been shown to
be the largest and most consistent risk factors for insomnia.4,10
During the last decade, several studies brought evidences that
insomnia could be more than a symptom of depression. For
instance, clinical efficacy of antidepressant drugs18,19 or of cognitive
behavioral therapy for depression*20 is unrelated to the effects on
insomnia complaints. Moreover continued insomnia has been
shown either to pre-exist the onset of depression14,21–*23 or to
become chronic despite successful resolution of depressive symp-
toms.24–27
Accordingly, it has been suggested that depression and insomnia
could be comorbid conditions having a clinical course different
from the index diseases and requiring specific treatment proce-
dure.28–30 In the present paper, theoretical and methodological
aspects of comorbidity studies will be first discussed with a special
emphasis on the notion of causality. The sleep EEG profiles of
antidepressant drugs are then discussed in relation to their use in
insomnia comorbid with depression and different other treatment
approaches for insomnia comorbid with depression are presented.
Definition and significance of comorbidity

Strictly speaking, comorbidity is defined as the occurrence of at

least two distinct diseases or disorders in a same patient. The term
E-mail address: luc.staner@forenap.com was introduced by Feinstein31 in general medicine to denote ‘‘any

1087-0792/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.smrv.2009.09.003
36 L. Staner / Sleep Medicine Reviews 14 (2010) 35–46
distinct additional clinical entity that has coexisted or that may
occur during the clinical course of a patient who has the index
disease under study’’. Comorbidity raises several important
research questions such as: are the disorders A and B distinct or do
they reflect an arbitrary division of a single syndrome? Might the
comorbid condition be a third disorder independent of disorders A
and B? Do risk factors correlate with disorder A because of
comorbidity with disorder B? Is it appropriate to give the same
treatment for the two disorders on the basis of their comorbidity?
Do comorbid conditions tell us something about the etiology of the
disorders?32
On a clinical point of view, comorbidity is often considered as an
aggravating factor of the index disease; patients with comorbid
conditions generally have a more pejorative clinical course and
often need specific treatment procedure. In the field of physical
diseases, the different co-existing clinical entities are generally
defined in terms of their underlying cause, such as a particular
pathophysiological process or a specific microorganism. Comor-
bidity within mental health more often applies to the co-
occurrence of two or more different mental disorder that are not
defined in terms of their underlying causes but rather on basis of
a characteristic symptomatic profile. Indeed, as far as insomnia and
depression are concerned, there are more evidences for common
rather than for different underlying causes, for instance both clin-
ical entities are thought to relate to adversity and life stress.33,34
Comorbid mental disorders have also been distinguished as
‘‘homotypic’’ or ‘‘heterotypic’’35 according to whether they belong
to the same general class of mental disorder. The co-existence of
both alcohol and sedative dependence is known as homotypic
comorbidity whereas the association of alcohol dependence and an
anxiety disorder is heterotypic comorbidity. Another distinction
relates to the period of time in which the disorders occur.
Concurrent comorbidity characterizes disorders present at the
same time of assessment as opposed to sequential comorbidity in
which one disorder precedes the other in time. In this regard,
comorbid insomnia and depression can be viewed as either
concurrent or sequential and as definitively heterotypic for diag-
nostic systems such as DSM36 and International Classification of
Diseases (ICD).37
Is the insomnia–depression comorbidity artefactual?
Comorbidity in mental disorder may be artefactual and the
consequence of how diagnostic systems are designed.38 Indeed,
illnesses have been classified in discrete diagnostic categories
although no sharp discontinuities in symptom distributions are
observed across most mental disorders.39 Symptomatic criteria that
define one disorder may overlap with those defining a second
disorder and apparently discrete diagnostic entities may not be as
separate as they seem. The proliferation of diagnostic categories in
recent classification systems (up to 200 in the DSM-IV36) and the
limited number of hierarchical rules that would have excluded
diagnosis B when diagnosis A is present have contributed to the fact
that comorbidity has been found to be the rule rather than the
exception in psychiatry.40–42 Accordingly, some authors suggested
that the use of the term psychiatric comorbidity, considered as
a by-product of recent diagnostic systems, appears inappropriate
‘‘because in most cases it is unclear whether the concomitant
diagnosis actually reflect the presence of distinct clinical entities or
refer to multiple manifestations of a single clinical entity’’.43
However, as far as DSM or ICD systems are concerned, there are
little evidences that comorbid insomnia and depression is an arte-
factual construct because of hierarchical rules (at least for DSM) and
the limited overlap between depression and insomnia diagnostic
criteria. Indeed, although clinicians often used ‘‘depressive’’
symptoms such as fatigue or concentration difficulties to charac-
terize the daytime consequence of insomnia, strictly speaking, the
criteria overlap between insomnia and depression is restricted to
the symptom of insomnia itself (see Fig. 1). In DSM-IV-R (but not in
ICD-10), insomnia has to be sufficiently severe to warrant separate
clinical attention and hierarchical rules prevent the co-diagnosis of
both insomnia and depression when insomnia symptoms occur
exclusively during the course of depression (see DSM-IV-R criterion
D in Fig. 1). Accordingly, criteria overlap plays only a minor role in
the high level of comorbidity found in studies using these classifi-
cation systems. Sleep disorder classifications such as ICSD-244 and
Research Diagnostic Criteria (RDC) for Insomnia45 provide a specific
diagnostic category for patients having both depression and
insomnia (i.e., Insomnia due to a Mental Disorder). However, other
forms of insomnia can be diagnosed if there is a lack of temporal
relationship between insomnia and depression. It is worth
mentioning that RDC system for Insomnia Disorder comprises many
symptoms found in DSM or ICD major depression categories and
that it could theoretically favour artefactual comorbidity (see Fig. 1).
True comorbidity or pseudo-comorbidity?
The next point to be discussed is whether a non-artefactual
comorbidity observed between insomnia and depression is
a matter of chance (random comorbidity also known as pseudo-
comorbidity) or results from a non-random association between
the occurrences of the disorders (non-random comorbidity also
known as ‘‘true’’ comorbidity). In the latter situation, the comorbid
condition is supposed to be caused, to cause or to be otherwise
related to the index disease. It has to be emphasized that from
a clinical point of view, both pseudo-comorbidity and true comor-
bidity are important. Whatever randomly or not randomly associ-
ated, comorbid conditions will often require a specific clinical
attention due to their generally more pejorative outcome.
The distinction between true versus pseudo-comorbidity has
received increasing attention during the last decades, especially in
the field of mental disorder,41,46 because it may help to improve our
understanding of cause, diagnosis and treatment of illnesses. In this
context, Kraemer et al.47 have shown that cross-sectional comor-
bidity studies that use lifetime prevalence with mixed-age sample
to calculate odds ratio bias the assessment of epidemiologic
comorbidity and create the appearance of true comorbidity even
when disorders are randomly associated. The authors also do not
advocate the use of log-linear model that study occurrence of one
disorder as a function of the other disorder occurrence because of
model assumption violation. They suggest that the ideal way to take
into account the fact that two disorders can co-occur by chance
alone in epidemiologic studies is to perform birth-to-death follow-
up for a sample of subjects from a population and to assess the
strength of comorbidity among those who survive at that age.
Afterwards, onset curves (odds of onset against age) can be drawn
for diagnosis A, diagnosis B, random (calculated) AB comorbidity,
and observed AB comorbidity. The curves are further compared
using Kaplan–Meier survival methods and strength of comorbidity
is obtained by computing odds ratio at each age.47
Two long-term prospective longitudinal studies in the field of
depression and insomnia come near to this methodology. Chang
et al.22 reported a study of 1053 male medical students over
a median period of 34 years with annual follow-up. Results, based
on survival and relative risk analyses showed that the relative risk
of developing clinical depression was doubled among those who
experienced insomnia in medical school compared with those who
did not have insomnia. The other study reported the current
analyses from the Zurich cohort-based study that includes
a representative population sample (i.e., 4547 subjects) and a 21
 L. Staner / Sleep Medicine Reviews 14 (2010) 35–46
Figure 1. Comparison of selective diagnostic criteria for insomnia and depression in Diagnostic and Statistical Manual of Mental Disorder, 4th edition (DSM-IV-R)36 and Research
Diagnostic Criteria (RDC).45
years follow-up interval.*23 Stability and longitudinal association
between cross-sectional diagnosis of pure insomnia, pure depres-
sion and insomnia comorbid with depression were examined
through log-linear models. Results revealed the high stability of
pure insomnia and of insomnia comorbid with depression whereas
pure depression was less consistent longitudinally. Bidirectional
associations were found between pure insomnia and insomnia
comorbid with depression and a unidirectional association was
shown from pure depression to insomnia comorbid with depres-
sion. There were no associations between pure insomnia and pure
depression. These two studies favour the idea that insomnia and
depression are not randomly associated, i.e., that they are truly
comorbid and either causally or otherwise related to each other.
Causal relationships between insomnia and depression
Knowing that one disorder co-occurs with another one well
beyond chance level provides clues for identifying common risk
37
factors, possibly causal risk factors. One disorder may directly
produce the other (direct causality) or indirectly increases the risk of
the other disorder (indirect causality). Direct or indirect causality
implicates sequential comorbidity, i.e., that there is a temporal rela-
tionship between the two comorbid conditions. Another possibility is
that insomnia and depression may relate to each other through
a similar cause, such as a common genetic predisposition or
comparable environmental circumstances (common causality).
These hypotheses are not mutually exclusive. For instance, a direct
causal relationship between alcoholism and depression can be found
in alcohol-induced depression in patients who are alcohol depen-
dent48 but an indirect relationship is shown by the fact that depressed
patients may begin to use alcohol in an effort to medicate their
distress and therefore may become dependent to alcohol.49 Finally,
there are genetic studies favoring the idea that alcohol dependence
and depression should have a common genetic background.50,51
According to this conceptual framework, the next sections will
review studies bringing arguments for and against these different
38 L. Staner / Sleep Medicine Reviews 14 (2010) 35–46
hypotheses, i.e., that insomnia is a direct or indirect by-product of
depression or vice-versa or that there is a common cause for both.
Insomnia is causally related to depression
Very few studies investigated whether insomnia could follow
a depressive episode and therefore could be causally related to
depression; it is possible that the modest attention given to this
issue is based on the historical assumption that insomnia is
a depressive symptom as opposed to a disorder per se. Several
studies evidenced persistence of chronic insomnia in major
depressed patients despite successful resolution of depressive
symptoms.24–27 However, these studies did not investigate the
temporal relationship between depressive and insomnia symptoms
and whether the incidence of insomnia precedes or not the inci-
dence of depressive symptoms. The few studies addressing this
issue agree with the idea that insomnia generally precedes or is
concomitant rather than subsequent to depression.
A large European telephone survey using the Sleep-EVAL system
in 14,915 subjects found that 71% of depressed patients reported that
insomnia symptoms occurred prior or during their first episode of
mood disorder meaning that 29% of them experienced insomnia
after the depressive episode.52 Examining the order of occurrence
without accounting for the base rate of the disorders does not
establish an association between the disorder and its direction.53
Three studies were properly designed to assess this issue, the above
mentioned Zurich study,23 a retrospective study by Johnson et al.54
who investigated the direction of risk between DSM-IV primary
insomnia and depressive disorder in a large community-based
sample of adolescents, and a longitudinal study of twins aged 8 and
10 years.55 In all of these studies prior onset of insomnia was asso-
ciated with subsequent onset of depression but prior depression was
not significantly associated with onset of subsequent insomnia.
Thus, these three studies bring no clear evidence for the
hypothesis that insomnia is causally related to depression and
support the idea that persistence of insomnia symptoms after
remission from a depressive episode either reveals the perpetua-
tion of pre-existing insomnia or partial depressive remission. The
latter assumption is intuitively supported by studies showing that
persistence of insomnia is related to incomplete depressive
remission20,56,57 or that residual insomnia predicts a higher rate of
relapse.24,25,58 However, these studies do not rule out the alterna-
tive hypothesis, i.e., that the perpetuation of pre-existing insomnia
could trigger a new depressive episode.
Depression is causally related to insomnia
Several longitudinal epidemiologic studies examined the
evolution of psychiatric disorder among insomniac patients during
follow-up periods ranging from 1 to 40 years, with the majority
using a 1- to 3-year follow-up period. The relative risk of a first
episode of depression in these patients was approximately 5 (range
2–40), and in all cases it was statistically significant.14,21–23,54,59,60
In depressed patients, insomnia has been shown to be a risk factor
for relapse24,25,58 and for recurrence.61 In the latter study the
authors were able to show that sleep disturbance reported by
remitted depressive patients is a prodromal symptom of recurrence
in the following five weeks.
While these studies provide strong evidences for a temporal
relationship between insomnia and depression, it leaves the
question of causality unanswered. A direct causal relationship
would implicate that insomnia by itself leads to depression. At first
glance, it seems counter-intuitive because sleep deprivation is
a form of antidepressive therapy.62 However, sleep disruption
experienced by depressed patients suffering from insomnia is more
similar to chronic partial sleep deprivation or chronic sleep
restriction than to total or selective sleep deprivation used as
antidepressive therapy. Chronic partial sleep deprivation proce-
dures have been proposed as a chronic stress model of depression
in rats.63,64 In humans, it has been shown that chronic partial sleep
deprivation experienced by caregivers of children with chronic
illnesses mediates caregiver depression symptoms and fatigue.*65
Moreover, a 6-day sleep restriction study in healthy volunteers was
shown to induce sleep EEG abnormalities and endocrine distur-
bances usually observed in depression.66 Thus there are some
evidences that chronic sleep disruption experienced by insomniac
patients could play a direct causal role in the emergence of
depressive symptoms.
An indirect causal relationship could also play a role. For
instance, lying in bed awake in the dark may intensify depresso-
genic feelings of failure or worries about the future in insomniac
patients. The daytime consequence of insomnia may diminish
ability to cope with interpersonal and social challenges, thereby
increasing the likelihood of stressful life events or poor response to
such events that could precipitate a depressive episode. Some
authors have recently suggested that depressed mood as a conse-
quence of chronic insomnia might be explained with the model of
‘‘learned helplessness’’.67 The chronic use of benzodiazepine
hypnotic drugs could play a role since long-term use of high doses
of benzodiazepines has been associated with significant risk of
causing depression.68–70 There is one prospective study in patients
with chronic insomnia showing that the use of hypnotic or tran-
quilizers is associated with subsequent depression.71
Common causalities relate insomnia to depression
A sequential comorbidity suggests a causal relationship whose
direction is indicated by the temporal link between the two
disorders: depression is supposed to be causally related to
insomnia because insomnia precedes depression. However,
sequential comorbidity does not preclude common causalities for
the disorders. For instance, the pure and the comorbid conditions
can be alternate forms of a same disorder that might be expressed
at the same time in the same individual or that might alternate.
Neale and Kendler32 have developed several formal threshold
models for comorbidity between multifactorial disorders such as
insomnia and depression (Fig. 2). A threshold model is based on the
assumption that disease liability arises from the independent
action of a large number of risk factors, each of small effect, which
give rise to a normal distribution of liability. Risk factors are of
genetic and environmental origins including those related to gene–
environment interactions. Timing, nature and frequency of expo-
sure to environmental stressors could also play a role. The
threshold model postulates that individuals above an abrupt
liability threshold are prone to express the disorder, whereas those
below are not.72
According to this scheme, a correlated liabilities model accounts
for the appearance of pure or comorbid conditions as alternate
forms of a same disorder. In this particular case liability of condition
A is perfectly correlated (r ¼ 1) with the liability of condition B, and
the causalities of both disorders are confounded. On the opposite
the correlated liabilities model predicts that if the liabilities of the
two conditions are uncorrelated (r ¼ 0), the comorbid condition
arises only by chance. Thus, under correlated liabilities models, the
liability of the two pure conditions are correlated at some level
between zero and one, and comorbid cases reflect the strength of
the correlation between these two liabilities.73 However, even
when liabilities of conditions A and B are not correlated (r ¼ 0),
comorbid AB condition can still occur beyond chance level if
liability factors for condition A are also liability factors for condition
 L. Staner / Sleep Medicine Reviews 14 (2010) 35–46
Correlated Liabilities Model
r
Liability Liability
for for
insomnia depression
Insomnia
Depression
Insomnia
Figure 2. Multifactorial threshold models for comorbidity between insomnia and depression according to Neale and Kendler.32
B (see Fig. 2). This is known as the multiformity model under which
individuals who are elevated on one of the two liabilities might
meet criteria for two disorders. A last model is the independence
model that does not relate to common causalities because it
assumes that the pure and the comorbid conditions are influenced
by their own liability factors. Under the independence model,
comorbidity does not represent the combined presence of two
disorders, but rather a third distinct disorder.
We are not aware of insomnia–depression comorbidity studies
that would have compared these different threshold models in
a sufficiently large sample and with an appropriate design such as
longitudinal, family or twin studies. For instance, many models are
indistinguishable in simple phenotypic cross-sectional designs.72
What model best fits for insomnia and depression is thus a matter of
speculation. However, the independence model is probably the least
appropriate, because it would have implicated that insomnia
comorbid with depression, pure insomnia and pure depression have
different risk factors. On the opposite, insomnia and depression have
many overlapping risk factors such as ageing, gender (to be a women),
marital status (to be divorced/separated or widowed), work status (to
be unemployed), stress, and lack of social support.74,75 The fact that
insomnia generally precedes or is concomitant rather than subse-
quent to depression argues against the alternate form or the inde-
pendence model that do not account for a temporal relationship
between the conditions; accordingly correlated liabilities or multi-
formity models are probably more appropriate.
What does neurobiological and sleep EEG studies tell us about the
causal relationships between insomnia and depression?
Disruption of sleep continuity (lengthening of sleep latency and
increased wake after sleep onset resulting in a decreased time spent
asleep), deficit of slow wave sleep (SWS), especially during the first
sleep cycle, and indices of REM sleep disinhibition (such as increased
REM density, shortened REM latency, and prolonged REM sleep
time) are the hallmarks of sleep EEG disturbances in major
depression.76,77 The sleep EEG profile of patients with primary
insomnia has generally been found comparable to those of major
depressive patients in terms of sleep continuity disturbances and
SWS deficit, but in sharp contrast, primary insomniacs have not been
shown to have any consistent REM sleep abnormalities.78–82 Posi-
tron Emission Tomography (PET) studies grossly corroborate sleep
EEG findings since both primary insomniac and major depressed
patients show smaller indices of thalamo-cortical deactivation
during non-REM sleep83–85 while depressive patients had an
increased activation of REM related structures during REM sleep.86
39
Multiformity Model Independence Model
Liability Liability Liability Liability Liability
for for for for for
insomnia depression insomnia comorbidity depression
Insomnia Comorbidity
Insomnia
Depression Insomnia
Depression
Hyperarousal
Non-REM sleep PET findings suggest that an increased activity
of wake-promoting mechanisms also known as ‘‘hyperarousal’’ is
operating in both insomnia and depression. In primary insomnia,
an increased arousal level that is incompatible with the initiation or
maintenance of sleep is supposed to occur in reaction to life stress
(acting alone or in combination with predisposing factors) and to
be perpetuated through dysfunctional neurocognitive schemes and
behavioral attitudes.33 Accordingly, findings in insomniac patients
such as increased metabolic activity,87 decreased heart rate vari-
ability,88 or indications of corticotrophin-releasing hormone (CRH)
and hypothalamic–pituitary–adrenal (HPA) axis hyperactivity89–92
have been reported as reflecting a chronically activated stress
system. Occasional studies have reported non-significant or trend
changes in cortisol measures93,94 in insomniac patients. However,
the facts that experimental sleep loss in healthy subjects stimulates
the HPA axis,66,95,96 that insomniac patients normalize their cortisol
secretion after successful treatment97 or that a glucocorticoid
receptor antagonist seems effective in treating chronic insomnia98
strongly suggest a positive relationship between arousal level and
HPA function. A similar pathophysiological mechanism has been
proposed in major depression: due to maladaptative cognitive
functioning, an arousal reaction is maintained despite the removal
of the stressful situation.99–101 Indeed, stress-induced arousal
responses that implicate the HPA axis,102,103 the locus coeruleus,
104–106
and the autonomous nervous system,107–109 have also been
clearly demonstrated in depressed patients. Other arguments for
the hyperarousal theory of insomnia and depression lie on the
demonstration that HPA hyperactivity is related to sleep continuity
disturbances and SWS deficit in both disorders.110–113
Recent studies suggest that the wake-promoting effect of
CRH could be mediated through the orexinergic system.114
Interestingly, an animal study has shown that a neonatal
stressor known to induce behavioral manifestation of stress in
adulthood such as maternal deprivation is able to produce sleep
EEG evidences of hyperarousal and of hyperfunctioning of the
orexinergic system in rats.115 Moreover, orexin overexpression
has been shown to induce an insomnia-like phenotype in
Zebrafish116 and the clinical efficacy of an orexin antagonist has
been demonstrated in a proof-of-concept study in primary
insomnia.117 However, to our knowledge, published results of
studies investigating the orexinergic function in primary
insomnia are still lacking. In depressed patients, two studies
have found indications of a lower orexinergic tone, but these
results are difficult to interpret due to concomitant medication
or absence of a control group.118,119
40 L. Staner / Sleep Medicine Reviews 14 (2010) 35–46
Homeostatic dysregulation
Another common physiopathological mechanism that could
underlie sleep continuity disturbances in both primary and
depressive insomnia is a dysregulation of the homeostatic process of
sleep. Perlis and Pigeon120 recently reviewed experimental
evidences supporting that sleep homeostasis could be altered in
primary insomnia. Indeed, the homeostatic SWS response that
generally follows transient sleep loss in healthy subjects is not
observed in patients with insomnia. For instance, SWS has been
found reduced in patients with primary insomnia despite their
chronic sleep debt,78,79,121–125 a finding that was not evidenced in all
studies.126–128 However, in one of these three negative studies it was
shown that SWS was normal but that there was a reduction in delta
power,126 in the other, analyses of delta power were not reported,127
and in the latter, patients with primary insomnia did not exhibit
reduced SWS nor reduced delta power.128 Other indications of
a homeostatic dysregulation in primary insomnia come from sleep
deprivation studies investigating daytime sleepiness, as measured
by multiple sleep latency test, and SWS response during the
recovery night.120 In depressed patients, a comparable hypothesis,
known as Process S deficiency theory, has been proposed to account
for the characteristic sleep EEG disturbances.129 The most
convincing supports for this hypothesis come from spectral EEG
studies of the first non-REM period showing decreased delta
activities in depressed patients (reviewed in Staner et al.130).
Preliminary data suggest that the sleep homeostasis could be
dysregulated in insomnia and depression because of alteration of
the adenosinergic transmission. Adenosine has been implicated in
sleep homeostasis because it both inhibits wake-promoting struc-
tures and activates sleep promoting structures while its concen-
tration increases with extended wakefulness and normalizes slowly
during sleep.131,132 It has recently been shown that a genetic variant
of the adenosine receptor A2A is associated with the individual
sensitivity to caffeine, and determines how closely the caffeine-
induced change in sleep EEG resembles the alterations observed in
patients with insomnia.133 Interestingly, this A2A polymorphism has
been associated with susceptibility to panic disorder134,135 and with
the anxiogenic response to caffeine in healthy volunteers.136 In
major depression, some evidences suggest a deficit in adenosinergic
transmission,137,138 and studies indicate that adenosine could be
implicated in mood regulation139–143 and in the antidepressant
effects of sleep deprivation or of electroconvulsive therapy.144
REM sleep disinhibition
REM sleep disinhibition observed in major depression but not in
insomnia may directly relate to the monoamine hypothesis of
depression that postulates a deficiency of noradrenaline (NA) and
serotonin (5-HT) neurotransmission, because there are strong
evidences that REM sleep generating neurons are under the
opposite influence of inhibitory NA and 5-HT input and of excit-
atory cholinergic input.145,146 For instance, it has been shown that
the administration of cholinergic enhancing drugs induces stronger
signs of REM sleep disinhibition in depressed patients compared to
healthy subjects as well as an increased rate of awakenings and
arousals.147 Prolonged hyperarousal could lead to REM disinhibition
through CRH hypersecretion since CRH inhibits dorsal raphe 5-HT
neurons.148,149 More specifically it was shown that CRH repress the
5-HT1a receptor gene,150,151 a gene coding for a receptor playing
a key role in REM sleep propensity.152,153 One study investigating
the effects of a 4-week treatment with a CRH receptor 1 antagonist
brings further support to the idea that REM sleep disinhibition in
major depression is mediated by an overactivity of the CRH system.
In that study, the drug was an effective antidepressant and has
a normalizing influence on the sleep EEG by increasing SWS and by
decreasing REM density and the number of awakenings.154
Since recent studies suggested that the genetic susceptibility to
depression in the face of stress could involve abnormal HPA
response,155–159 one may speculate that only subjects with this
genetic susceptibility would develop indices of REM sleep dis-
inbition. This physiopathological mechanism could account for the
sequential comorbidity of insomnia and depression (insomnia
precedes depression) and for the causal relationship between the
two disorders (insomnia causes depression) because insomnia by
itself reinforces the hyperarousal state triggered by environmental
risk factors such as stress.
Another explanation would be that, in individuals prone to
depression, some degree of REM sleep disinhibition pre-exists
before the onset of illness, as suggested by studies of high-risk
probands, i.e., subjects who have no lifetime or current diagnosis of
a psychiatric disorder but who, owing to their family history, are at
high risk of development of one. These studies showed that some of
these probands demonstrated a faster REM sleep induction after
a cholinergic stimulation during sleep than healthy subjects160 and
that this finding identifies probands having a higher risk for
developing an affective disorder during a long-term follow up
period.161 Modell et al.162 observed in the same but somewhat
enlarged group of high-risk probands (n ¼ 82) that increased REM
density at initial polysomnography was also predictive for the onset
of an affective disorder during a 4 to 10 years follow-up period.
According to these results, it may be suggested that indices of REM
sleep disinhibition in high-risk probands reflect some degree of
aminergic/cholinergic imbalance that would also reveal a genetic
susceptibility to depression. One may speculate that depression is
concomitant rather than subsequent to insomnia in subjects with
this genetic susceptibility because there is no evidence of REM
sleep disinhibition in patients with primary insomnia.
Treatment approaches for insomnia comorbid with
depression
Our knowledge about the nature of the comorbid relationship
between insomnia and depression should influence the way
treatment approaches are designed. For instance, a sequential
comorbidity (insomnia precedes depression) and a possible causal
relationship between the two disorders (insomnia causes depres-
sion) would indicate that the successful treatment of insomnia has
a preventive effect on depression occurrence. On the other hand,
concomitant comorbidity suggests common causalities and would
indicate that effective treatment for one disorder will also be
effective on the other disorder. Finally, absence of common
causalities would suggest the implementation of two specific
therapeutical approaches, one for the treatment of insomnia and
the other for the treatment of depression. However, it has to be
stressed that, regardless of the specific pathway to the onset of
comorbidity, once both disorders are present, they may serve to
maintain one another or even exacerbate one another to create
a vicious cycle such that the presence of one disorder can impede
recovery from the other. Accordingly, a combined therapeutical
approach is generally advocated for comorbid insomnia.163,164
Both psychological/behavioral and pharmacological therapies
are effective in the treatment of insomnia and depression30,165 and
one may thus conceive three different treatment combinations for
insomnia comorbid with depression: pharmacotherapy alone
(i.e., hypnotic drug combined with antidepressant drug), psycho-
therapy alone (i.e., by combining specific therapeutical approach
for insomnia and for depression) or pharmacotherapy combined
with psychotherapy. The latter combination would not only include
pharmacology for one disorder and psychotherapy for the other
disorder, but also mixed therapeutical approach such as
 L. Staner / Sleep Medicine Reviews 14 (2010) 35–46
antidepressant for depression and cognitive behavioral therapy
(CBT) combined with an hypnotic drug for insomnia.
At the present time, there are very few studies that have investi-
gated and compared efficacy and safety of these different treatment
options. They have been recently reviewed28 and will be only
summarized hereafter. The use of antidepressant drug in insomnia
comorbid with depression will be more extensively discussed in the
next section. Before going further, it must be underlined that the first
step in the management of patients having both insomnia and
depression is to rule out any other sleep disorders such as sleep apnea
and periodic leg movement syndrome. First, treatment of sleep apnea
may improve mood in these patients.166 Second, antidepressants and
hypnotics are known to worsen periodic leg movements and sleep
apnea, respectively, although there are some exceptions.167–169
Psychotherapy alone may be considered for patients with mild
to moderate depression but pharmacotherapy is mandatory for
patients with severe depression.165 In contrast, for the treatment of
insomnia, psychotherapy (i.e., behavioral treatment management)
has been shown to have similar and even more durable benefit than
hypnotics.170,171 The American Academy of Sleep Medicine rated
stimulus control, relaxation training, and CBT as an accepted
patient care strategy with a high level of clinical certainty. Sleep
restriction, multicomponent therapy without cognitive therapy,
paradoxical intention, and biofeedback obtained moderate level of
clinical certainty.163 Applicability of these practice parameters to
insomnia comorbid with depression is uncertain but there are
some evidences that CBT of insomnia is effective for insomnia
symptoms172–174 and that it can augment antidepressant response
to escitalopram.174 Accordingly, recent clinical guidelines for the
management of chronic insomnia recommend psychological and
behavioral interventions in the treatment of comorbid insomnia,
including insomnia comorbid with depression.162,163
Interestingly, CBT for depression has been found to improve
sleep in major depression, apart patients showing indices of REM
sleep disinhibition.18,20 However, another form of CBT which is
more focused on the interpersonal domain, the cognitive behav-
ioral analysis system of psychotherapy, was found, despite
comparable antidepressant efficacy, less effective than nefazodone
in subjective early morning awakening and total sleep time.175 We
are not aware of studies combining CBT for depression with
hypnotic drug and/or with CBT for insomnia.
Antidepressant drugs for insomnia comorbid with depression
Studies that reviewed the different treatment options of
insomnia comorbid with depression generally consider sedative
antidepressant drugs as first-line agents.28,176–178 The present
section discusses the sleep EEG profiles of antidepressant drugs in
relation to their use in insomnia comorbid with depression.
Sedative or non-sedative antidepressants?
Sedative antidepressants are in fact drugs having non-REM
sleep promoting properties; they generally improve sleep mainte-
nance rather than sleep initiation, although some of them like
doxepin,179 nefazodone180,181 and mirtazapine182,183 have been
shown to shorten sleep onset latency. Tricyclic antidepressants
(TCA) such as trimipramine, doxepin, amitriptyline have often
sedative effects and increase non-REM sleep in depressed
patients184–187 because of their various antagonist profiles at
serotoninergic (5-HT2A/C), muscarinic (M1, M3), histaminergic (H1),
and adrenergic (a1) receptors. Indeed, cholinergic and mono-
aminergic transmissions are largely implicated in the wake-
promoting system.146,188–190
41
Other non-TCA antidepressant drugs with similar receptor
binding profiles also favour sleep continuity by increasing non-REM
sleep, including SWS. The non-REM sleep promoting effect of
trazodone, a 5-HT2A/C and H1 antagonist, is well documented in
major depressed patients.191–193 A 6- to 8-week administration of
nefazodone also improves sleep continuity by decreasing sleep
onset latency131,132 and wakefulness,180,181 and by increasing total
sleep time194 and sleep efficiency.180,181,194,195 Mianserin, a 5-HT2A/C,
H1, and a1 antagonist promotes stage 2 and increases total sleep
time and sleep efficiency of depressed patients.196 A very consistent
non-REM sleep promoting profile has been documented for mir-
tazapine, a 5-HT2A/C and H1 antagonist devoid of a1 antagonist
properties. In all but one study183 the drug increases SWS and
generally improves sleep efficiency183,197,198 in depressed patients
by decreasing wakefulness181,197,199 and/or by increasing total sleep
time.197,198 The new antidepressant drug agomelatine (that
agonises melatonin MT1 and MT2 receptors and antagonises 5-HT2C
receptors as well) has been shown to improve sleep efficiency, to
decrease wake after sleep onset and to increase SWS in major
depressed patients.200
Antidepressant drug efficacy does not relate to their effects on
sleep continuity because most antidepressants such as monoamine
oxydase inhibitors (MAOIs), selective serotonin reuptake inhibitors
(SSRIs), selective noradrenaline reuptake inhibitors and double
reuptake inhibitors are rather sleep disrupting drugs.201 At first
glance, it appears that drugs having a non-REM sleep promoting
profile are more helpful in insomnia comorbid with depression; an
alternative would be the co-prescription of a non-sedating anti-
depressant with a hypnotic agent. For instance, Fava et al.19 showed
that the addition of eszopiclone to fluoxetine in major depression
patients improves both objective and subjective sleep complaints
as well as depression. On the other hand, studies investigating the
sleep EEG effects of a prolonged administration (i.e., up to 12
weeks) of a sedative and a non-sedative antidepressant (i.e., nefa-
zodone and fluvoxamine) showed an attenuation of the sleep
promoting effects of nefazodone and of the sleep disrupting effects
of fluvoxamine.194,202
Significance of the REM suppressant effect of antidepressant drugs
Most currently marketed antidepressant drugs are designed to
facilitate at least one of the two neurotransmission system
supposed to be implicated in major depression, i.e., 5-HT and NA.
Since a mounting of evidences indicates that REM sleep generating
neurons are under the inhibitory influence of NA and 5-HT
input,151,152,188,189 no wonder that antidepressant drugs suppress
REM sleep. However, some antidepressant drugs such as trimipr-
amine, iprindole, nefazodone, trazodone, mianserin, mirtazapine,
agomelatine, tianeptine, bupropion, and nomifensine do not
demonstrate any clear REM suppressant effect.201 It could indicate
an inefficient boost of 5-HT or NA transmission at the level of REM
sleep generating neurons. Alternatively, the 5-HT/NA mediated
REM suppression could be confounded by opposite drug effects on
the REM sleep regulating system. For instance, some recent
evidences suggest that the dopaminergic (DA) system is implicated
in REM sleep generation.203–205 In this context, the lack of typical
REM suppressant effect of NA/DA reuptake blockers (bupropion and
nomifensine) could result from a balance between DA promoting
influence and NA inhibiting influence.
On a theoretical point of view, the amount of REM suppression
induced by an antidepressant should more or less relate to its
clinical efficacy since antidepressant drugs are supposed to act on
abnormal brain 5-HT or/and NA systems in order to normalize their
function. This view is supported by a recent meta-analytic study
regarding the 12 more recently launched antidepressant drugs and
42 L. Staner / Sleep Medicine Reviews 14 (2010) 35–46
that compared effect sizes of published and non-published clinical
trials. Results indicate that the 3 drugs with weak (mirtazapine) or
no (bupropion and nefazodone) REM suppressant effects are among
the 4 drugs for which the effect size has been mostly inflated by
ignoring non-published trials. When considering published and
non-published trials together, the effect sizes of bupropion (0.17)
and nefazodone (0.26) were among the 3 lowest observed.206
One may suggest that, if REM sleep disinhibition reflects the
aminergic deficit supposed to be implicated in major depression,
REM suppressant antidepressant drugs could be particularly
effective in depressed patients with evidences of REM sleep
disinhibition. In other words indices of REM sleep disinhibition
should identify depressed patients responding well to therapies
increasing NA or 5-HT transmission and poorly to other forms of
treatment. To our knowledge, no studies have directly addressed
these issues. Indirect evidences supporting this view come from
studies showing that shorter REM latency and increased REM
density identify depressive patients that do not respond to non-
pharmacological treatments such as placebo207,208 or psycho-
therapy.209,210 Pre-treatment sleep EEG did not have any predictive
value on the response rate of bupropion211 and tianeptine,212 two
antidepressant drugs having no or low potency to inhibit NA or 5-
HT213 and devoid of REM sleep suppressant effect.214,215 On the
opposite, most studies found that a baseline reduced REM latency
has a predictive value on antidepressant response216–220 but there
are also negative reports.207,221
We do not know the exact incidence of REM sleep dysregulation
in insomnia comorbid with depression. Age and depression severity
are clearly found associated with evidences of REM sleep disinhi-
bition222 and there is a probable role of insomnia since depressed
patients with complaints of hypersomnia rather than of insomnia,
do not show any evidence of REM sleep dishinbition.130,147,222
Combined antidepressant drug treatment
Co-prescription of antidepressant drugs is a commonly used
strategy to treat persistent insomnia during antidepressant treat-
ment. Typically, a low dose of a sedative antidepressant (such as
amitiptyline, trimipramine, doxepin, trazodone, nefazodone,
mianserine or mirtazapine) is added to a therapeutical dose of
a non-sedative antidepressant. This practice has gained in attrac-
tiveness because of potential synergistic antidepressant effects and
avoidance of concerns of drug misuse associated with other
hypnotic drugs. Concerns are safety issues and lack of proof of the
effectiveness of this strategy.28
Another alternative therapy is to combine a classical benzodi-
azepine (BDZ) or a BDZ-like drug such as zolpidem, zaleplon or
eszopiclone. It has been shown that up to 40% of depressed patients
treated with SSRIs receive concomitant BDZ.223 Controlled studies
have documented the benefit of adding triazolam, lormetazepam,
and chlordiazepoxide in patients treated with TCA224–226 or of
adding zolpidem to SSRI.227 Some studies also suggest that the co-
prescription is more effective than the antidepressant drug alone
on both insomnia and depressive symptoms; this was observed
when clonazepam228 or eszopiclone19 was added to a fluoxetine
treatment. Although abuse, dependence and tolerance are not
frequently observed, it is suggested to shift to intermittent hypnotic
doses within the first weeks of therapy given the usual length of
a successful antidepressant therapy.28
Conclusions
The present review supports the idea that depression and
insomnia could be comorbid conditions having a different clinical
course than the index diseases and that require specific treatment
procedure. Epidemiological research indicates that insomnia and
depression are not randomly associated and that they are either
causally related to each other and/or that common causalities
underlie the two disorders. There are some evidences that chronic
sleep disruption experienced by insomniac patients could play
a direct causal relationship in the emergence of depressive symptoms
but studies examining the benefits of insomnia treatment in pre-
venting depression are warranted to validate this hypothesis.
Empirical evidences suggest that different treatment approaches
(behavioral management of sleep combined with prescription of
a sedative antidepressants alone, co-prescription of two antidepres-
sants, or combination of an antidepressant with an hypnotic drug) are
effective in the treatment of insomnia comorbid with depression but
further studies are needed to standardize the treatment.
Practice points
 Primary sleep disorders such as sleep apnea and peri-
odic leg movements have to be ruled out.
 Consider behavioral management of sleep and non-TCA
sedative antidepressant such as mirtazapine or agome-
latine as the first-line intervention.
 Consider REM suppressant antidepressant for patients
with severe forms of depression, and particularly TCA
when safety and tolerability indicators are favourable;
alternatives are SSRI or double 5-HT/NA reuptake
inhibitors with concomitant prescription of an hypnotic
medication.
 Reserve antidepressant co-prescription for patients
having an inadequate response to a single
antidepressant.
Research agenda
 Long-term prospective longitudinal studies in the
general population or in patient samples would be
helpful to determine neurobiological and psychosocial
risk factors for developing either insomnia, depression,
and insomnia comorbid with depression.
 Genetically informative data coming from pairs of rela-
tives or of twin studies would designate the appropriate
model explaining the comorbidity between insomnia
and depression, and therefore would bring valuable
information on the nature of the causal relationship
between the two conditions.
 Intervention trials (both pharmacologic and behavioral)
treating persistent insomnia in remitted depression or
insomnia comorbid with depression in order to assess:
B whether curing insomnia prevents further
depression;
B different treatment approaches in the comorbid
condition; and
B the predictive value on outcome of particular
clinical or neurobiological characteristics
including sleep EEG.
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