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Sleep Medicine Reviews 14 (2010) 35–46

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Sleep Medicine Reviews

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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
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

DSM-IV diagnosis of insomnia.15
Insomnia symptoms appear to be one of the most frequent sleep Other epidemiologic studies suggest that the link between
complaints in the general population with an estimated prevalence insomnia and depression is bidirectional. For instance, about 20% of
varying from 10 to nearly 60% depending in part on the use of patients with insomnia exhibit some depressive symptoms8,16,17
varying definitions and data-collection methodologies.1 This esti- whereas depression and depressive symptoms have been shown to
mate falls below 10% when more stringent diagnostic criteria are be the largest and most consistent risk factors for insomnia.4,10
applied to define insomnia, including daytime consequence of During the last decade, several studies brought evidences that
insomnia; for instance, the prevalence of insomnia diagnoses insomnia could be more than a symptom of depression. For
according to the Diagnostic and Statistical Manual of Mental instance, clinical efficacy of antidepressant drugs18,19 or of cognitive
Disorders 4th edition (DSM-IV) classification has been estimated at behavioral therapy for depression*20 is unrelated to the effects on
6%.1 Individuals reporting disturbed sleep are more likely to report insomnia complaints. Moreover continued insomnia has been
emotional distress and recurrent health problems.2–4 This is not shown either to pre-exist the onset of depression14,21–*23 or to
surprising since it has been shown that sleep deprivation has great become chronic despite successful resolution of depressive symp-
impact on the daytime life of healthy subjects; alertness, attention, toms.24–27
concentration, cognitive abilities, memory, mood and pain Accordingly, it has been suggested that depression and insomnia
threshold have all been found impaired, even with a sleep depri- could be comorbid conditions having a clinical course different
vation of as little as 1–2 h per night.5–7 from the index diseases and requiring specific treatment proce-
In this regard, studies have repeatedly emphasized the comor- dure.28–30 In the present paper, theoretical and methodological
bid nature of insomnia and psychiatric disorders, especially aspects of comorbidity studies will be first discussed with a special
depression but also anxiety and substance use.8–10 Clinical and emphasis on the notion of causality. The sleep EEG profiles of
epidemiological studies have shown that sleep disturbance is antidepressant drugs are then discussed in relation to their use in
tightly linked to major depression. In clinical samples, about three insomnia comorbid with depression and different other treatment
quarters of all depressed patients complain of difficulty either in approaches for insomnia comorbid with depression are presented.
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 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: was introduced by Feinstein31 in general medicine to denote ‘‘any

1087-0792/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
36 L. Staner / Sleep Medicine Reviews 14 (2010) 35–46

distinct additional clinical entity that has coexisted or that may symptoms such as fatigue or concentration difficulties to charac-
occur during the clinical course of a patient who has the index terize the daytime consequence of insomnia, strictly speaking, the
disease under study’’. Comorbidity raises several important criteria overlap between insomnia and depression is restricted to
research questions such as: are the disorders A and B distinct or do the symptom of insomnia itself (see Fig. 1). In DSM-IV-R (but not in
they reflect an arbitrary division of a single syndrome? Might the ICD-10), insomnia has to be sufficiently severe to warrant separate
comorbid condition be a third disorder independent of disorders A clinical attention and hierarchical rules prevent the co-diagnosis of
and B? Do risk factors correlate with disorder A because of both insomnia and depression when insomnia symptoms occur
comorbidity with disorder B? Is it appropriate to give the same exclusively during the course of depression (see DSM-IV-R criterion
treatment for the two disorders on the basis of their comorbidity? D in Fig. 1). Accordingly, criteria overlap plays only a minor role in
Do comorbid conditions tell us something about the etiology of the the high level of comorbidity found in studies using these classifi-
disorders?32 cation systems. Sleep disorder classifications such as ICSD-244 and
On a clinical point of view, comorbidity is often considered as an Research Diagnostic Criteria (RDC) for Insomnia45 provide a specific
aggravating factor of the index disease; patients with comorbid diagnostic category for patients having both depression and
conditions generally have a more pejorative clinical course and insomnia (i.e., Insomnia due to a Mental Disorder). However, other
often need specific treatment procedure. In the field of physical forms of insomnia can be diagnosed if there is a lack of temporal
diseases, the different co-existing clinical entities are generally relationship between insomnia and depression. It is worth
defined in terms of their underlying cause, such as a particular mentioning that RDC system for Insomnia Disorder comprises many
pathophysiological process or a specific microorganism. Comor- symptoms found in DSM or ICD major depression categories and
bidity within mental health more often applies to the co- that it could theoretically favour artefactual comorbidity (see Fig. 1).
occurrence of two or more different mental disorder that are not
defined in terms of their underlying causes but rather on basis of True comorbidity or pseudo-comorbidity?
a characteristic symptomatic profile. Indeed, as far as insomnia and
depression are concerned, there are more evidences for common The next point to be discussed is whether a non-artefactual
rather than for different underlying causes, for instance both clin- comorbidity observed between insomnia and depression is
ical entities are thought to relate to adversity and life stress.33,34 a matter of chance (random comorbidity also known as pseudo-
Comorbid mental disorders have also been distinguished as comorbidity) or results from a non-random association between
‘‘homotypic’’ or ‘‘heterotypic’’35 according to whether they belong the occurrences of the disorders (non-random comorbidity also
to the same general class of mental disorder. The co-existence of known as ‘‘true’’ comorbidity). In the latter situation, the comorbid
both alcohol and sedative dependence is known as homotypic condition is supposed to be caused, to cause or to be otherwise
comorbidity whereas the association of alcohol dependence and an related to the index disease. It has to be emphasized that from
anxiety disorder is heterotypic comorbidity. Another distinction a clinical point of view, both pseudo-comorbidity and true comor-
relates to the period of time in which the disorders occur. bidity are important. Whatever randomly or not randomly associ-
Concurrent comorbidity characterizes disorders present at the ated, comorbid conditions will often require a specific clinical
same time of assessment as opposed to sequential comorbidity in attention due to their generally more pejorative outcome.
which one disorder precedes the other in time. In this regard, The distinction between true versus pseudo-comorbidity has
comorbid insomnia and depression can be viewed as either received increasing attention during the last decades, especially in
concurrent or sequential and as definitively heterotypic for diag- the field of mental disorder,41,46 because it may help to improve our
nostic systems such as DSM36 and International Classification of understanding of cause, diagnosis and treatment of illnesses. In this
Diseases (ICD).37 context, Kraemer et al.47 have shown that cross-sectional comor-
bidity studies that use lifetime prevalence with mixed-age sample
Is the insomnia–depression comorbidity artefactual? to calculate odds ratio bias the assessment of epidemiologic
comorbidity and create the appearance of true comorbidity even
Comorbidity in mental disorder may be artefactual and the when disorders are randomly associated. The authors also do not
consequence of how diagnostic systems are designed.38 Indeed, advocate the use of log-linear model that study occurrence of one
illnesses have been classified in discrete diagnostic categories disorder as a function of the other disorder occurrence because of
although no sharp discontinuities in symptom distributions are model assumption violation. They suggest that the ideal way to take
observed across most mental disorders.39 Symptomatic criteria that into account the fact that two disorders can co-occur by chance
define one disorder may overlap with those defining a second alone in epidemiologic studies is to perform birth-to-death follow-
disorder and apparently discrete diagnostic entities may not be as up for a sample of subjects from a population and to assess the
separate as they seem. The proliferation of diagnostic categories in strength of comorbidity among those who survive at that age.
recent classification systems (up to 200 in the DSM-IV36) and the Afterwards, onset curves (odds of onset against age) can be drawn
limited number of hierarchical rules that would have excluded for diagnosis A, diagnosis B, random (calculated) AB comorbidity,
diagnosis B when diagnosis A is present have contributed to the fact and observed AB comorbidity. The curves are further compared
that comorbidity has been found to be the rule rather than the using Kaplan–Meier survival methods and strength of comorbidity
exception in psychiatry.40–42 Accordingly, some authors suggested is obtained by computing odds ratio at each age.47
that the use of the term psychiatric comorbidity, considered as Two long-term prospective longitudinal studies in the field of
a by-product of recent diagnostic systems, appears inappropriate depression and insomnia come near to this methodology. Chang
‘‘because in most cases it is unclear whether the concomitant et al.22 reported a study of 1053 male medical students over
diagnosis actually reflect the presence of distinct clinical entities or a median period of 34 years with annual follow-up. Results, based
refer to multiple manifestations of a single clinical entity’’.43 on survival and relative risk analyses showed that the relative risk
However, as far as DSM or ICD systems are concerned, there are of developing clinical depression was doubled among those who
little evidences that comorbid insomnia and depression is an arte- experienced insomnia in medical school compared with those who
factual construct because of hierarchical rules (at least for DSM) and did not have insomnia. The other study reported the current
the limited overlap between depression and insomnia diagnostic analyses from the Zurich cohort-based study that includes
criteria. Indeed, although clinicians often used ‘‘depressive’’ a representative population sample (i.e., 4547 subjects) and a 21
L. Staner / Sleep Medicine Reviews 14 (2010) 35–46 37

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 factors, possibly causal risk factors. One disorder may directly
between cross-sectional diagnosis of pure insomnia, pure depres- produce the other (direct causality) or indirectly increases the risk of
sion and insomnia comorbid with depression were examined the other disorder (indirect causality). Direct or indirect causality
through log-linear models. Results revealed the high stability of implicates sequential comorbidity, i.e., that there is a temporal rela-
pure insomnia and of insomnia comorbid with depression whereas tionship between the two comorbid conditions. Another possibility is
pure depression was less consistent longitudinally. Bidirectional that insomnia and depression may relate to each other through
associations were found between pure insomnia and insomnia a similar cause, such as a common genetic predisposition or
comorbid with depression and a unidirectional association was comparable environmental circumstances (common causality).
shown from pure depression to insomnia comorbid with depres- These hypotheses are not mutually exclusive. For instance, a direct
sion. There were no associations between pure insomnia and pure causal relationship between alcoholism and depression can be found
depression. These two studies favour the idea that insomnia and in alcohol-induced depression in patients who are alcohol depen-
depression are not randomly associated, i.e., that they are truly dent48 but an indirect relationship is shown by the fact that depressed
comorbid and either causally or otherwise related to each other. patients may begin to use alcohol in an effort to medicate their
distress and therefore may become dependent to alcohol.49 Finally,
Causal relationships between insomnia and depression there are genetic studies favoring the idea that alcohol dependence
and depression should have a common genetic background.50,51
Knowing that one disorder co-occurs with another one well According to this conceptual framework, the next sections will
beyond chance level provides clues for identifying common risk 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 similar to chronic partial sleep deprivation or chronic sleep
depression or vice-versa or that there is a common cause for both. restriction than to total or selective sleep deprivation used as
antidepressive therapy. Chronic partial sleep deprivation proce-
Insomnia is causally related to depression 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
Very few studies investigated whether insomnia could follow deprivation experienced by caregivers of children with chronic
a depressive episode and therefore could be causally related to illnesses mediates caregiver depression symptoms and fatigue.*65
depression; it is possible that the modest attention given to this Moreover, a 6-day sleep restriction study in healthy volunteers was
issue is based on the historical assumption that insomnia is shown to induce sleep EEG abnormalities and endocrine distur-
a depressive symptom as opposed to a disorder per se. Several bances usually observed in depression.66 Thus there are some
studies evidenced persistence of chronic insomnia in major evidences that chronic sleep disruption experienced by insomniac
depressed patients despite successful resolution of depressive patients could play a direct causal role in the emergence of
symptoms.24–27 However, these studies did not investigate the depressive symptoms.
temporal relationship between depressive and insomnia symptoms An indirect causal relationship could also play a role. For
and whether the incidence of insomnia precedes or not the inci- instance, lying in bed awake in the dark may intensify depresso-
dence of depressive symptoms. The few studies addressing this genic feelings of failure or worries about the future in insomniac
issue agree with the idea that insomnia generally precedes or is patients. The daytime consequence of insomnia may diminish
concomitant rather than subsequent to depression. ability to cope with interpersonal and social challenges, thereby
A large European telephone survey using the Sleep-EVAL system increasing the likelihood of stressful life events or poor response to
in 14,915 subjects found that 71% of depressed patients reported that such events that could precipitate a depressive episode. Some
insomnia symptoms occurred prior or during their first episode of authors have recently suggested that depressed mood as a conse-
mood disorder meaning that 29% of them experienced insomnia quence of chronic insomnia might be explained with the model of
after the depressive episode.52 Examining the order of occurrence ‘‘learned helplessness’’.67 The chronic use of benzodiazepine
without accounting for the base rate of the disorders does not hypnotic drugs could play a role since long-term use of high doses
establish an association between the disorder and its direction.53 of benzodiazepines has been associated with significant risk of
Three studies were properly designed to assess this issue, the above causing depression.68–70 There is one prospective study in patients
mentioned Zurich study,23 a retrospective study by Johnson et al.54 with chronic insomnia showing that the use of hypnotic or tran-
who investigated the direction of risk between DSM-IV primary quilizers is associated with subsequent depression.71
insomnia and depressive disorder in a large community-based
sample of adolescents, and a longitudinal study of twins aged 8 and Common causalities relate insomnia to depression
10 years.55 In all of these studies prior onset of insomnia was asso-
ciated with subsequent onset of depression but prior depression was A sequential comorbidity suggests a causal relationship whose
not significantly associated with onset of subsequent insomnia. direction is indicated by the temporal link between the two
Thus, these three studies bring no clear evidence for the disorders: depression is supposed to be causally related to
hypothesis that insomnia is causally related to depression and insomnia because insomnia precedes depression. However,
support the idea that persistence of insomnia symptoms after sequential comorbidity does not preclude common causalities for
remission from a depressive episode either reveals the perpetua- the disorders. For instance, the pure and the comorbid conditions
tion of pre-existing insomnia or partial depressive remission. The can be alternate forms of a same disorder that might be expressed
latter assumption is intuitively supported by studies showing that at the same time in the same individual or that might alternate.
persistence of insomnia is related to incomplete depressive Neale and Kendler32 have developed several formal threshold
remission20,56,57 or that residual insomnia predicts a higher rate of models for comorbidity between multifactorial disorders such as
relapse.24,25,58 However, these studies do not rule out the alterna- insomnia and depression (Fig. 2). A threshold model is based on the
tive hypothesis, i.e., that the perpetuation of pre-existing insomnia assumption that disease liability arises from the independent
could trigger a new depressive episode. 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
Depression is causally related to insomnia genetic and environmental origins including those related to gene–
environment interactions. Timing, nature and frequency of expo-
Several longitudinal epidemiologic studies examined the sure to environmental stressors could also play a role. The
evolution of psychiatric disorder among insomniac patients during threshold model postulates that individuals above an abrupt
follow-up periods ranging from 1 to 40 years, with the majority liability threshold are prone to express the disorder, whereas those
using a 1- to 3-year follow-up period. The relative risk of a first below are not.72
episode of depression in these patients was approximately 5 (range According to this scheme, a correlated liabilities model accounts
2–40), and in all cases it was statistically significant.14,21–23,54,59,60 for the appearance of pure or comorbid conditions as alternate
In depressed patients, insomnia has been shown to be a risk factor forms of a same disorder. In this particular case liability of condition
for relapse24,25,58 and for recurrence.61 In the latter study the A is perfectly correlated (r ¼ 1) with the liability of condition B, and
authors were able to show that sleep disturbance reported by the causalities of both disorders are confounded. On the opposite
remitted depressive patients is a prodromal symptom of recurrence the correlated liabilities model predicts that if the liabilities of the
in the following five weeks. two conditions are uncorrelated (r ¼ 0), the comorbid condition
While these studies provide strong evidences for a temporal arises only by chance. Thus, under correlated liabilities models, the
relationship between insomnia and depression, it leaves the liability of the two pure conditions are correlated at some level
question of causality unanswered. A direct causal relationship between zero and one, and comorbid cases reflect the strength of
would implicate that insomnia by itself leads to depression. At first the correlation between these two liabilities.73 However, even
glance, it seems counter-intuitive because sleep deprivation is when liabilities of conditions A and B are not correlated (r ¼ 0),
a form of antidepressive therapy.62 However, sleep disruption comorbid AB condition can still occur beyond chance level if
experienced by depressed patients suffering from insomnia is more liability factors for condition A are also liability factors for condition
L. Staner / Sleep Medicine Reviews 14 (2010) 35–46 39

Correlated Liabilities Model Multiformity Model Independence Model


Liability Liability Liability Liability Liability Liability Liability

for for for for for for for
insomnia depression insomnia depression insomnia comorbidity depression

Insomnia Insomnia Comorbidity


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 Hyperarousal
individuals who are elevated on one of the two liabilities might Non-REM sleep PET findings suggest that an increased activity
meet criteria for two disorders. A last model is the independence of wake-promoting mechanisms also known as ‘‘hyperarousal’’ is
model that does not relate to common causalities because it operating in both insomnia and depression. In primary insomnia,
assumes that the pure and the comorbid conditions are influenced an increased arousal level that is incompatible with the initiation or
by their own liability factors. Under the independence model, maintenance of sleep is supposed to occur in reaction to life stress
comorbidity does not represent the combined presence of two (acting alone or in combination with predisposing factors) and to
disorders, but rather a third distinct disorder. be perpetuated through dysfunctional neurocognitive schemes and
We are not aware of insomnia–depression comorbidity studies behavioral attitudes.33 Accordingly, findings in insomniac patients
that would have compared these different threshold models in such as increased metabolic activity,87 decreased heart rate vari-
a sufficiently large sample and with an appropriate design such as ability,88 or indications of corticotrophin-releasing hormone (CRH)
longitudinal, family or twin studies. For instance, many models are and hypothalamic–pituitary–adrenal (HPA) axis hyperactivity89–92
indistinguishable in simple phenotypic cross-sectional designs.72 have been reported as reflecting a chronically activated stress
What model best fits for insomnia and depression is thus a matter of system. Occasional studies have reported non-significant or trend
speculation. However, the independence model is probably the least changes in cortisol measures93,94 in insomniac patients. However,
appropriate, because it would have implicated that insomnia the facts that experimental sleep loss in healthy subjects stimulates
comorbid with depression, pure insomnia and pure depression have the HPA axis,66,95,96 that insomniac patients normalize their cortisol
different risk factors. On the opposite, insomnia and depression have secretion after successful treatment97 or that a glucocorticoid
many overlapping risk factors such as ageing, gender (to be a women), receptor antagonist seems effective in treating chronic insomnia98
marital status (to be divorced/separated or widowed), work status (to strongly suggest a positive relationship between arousal level and
be unemployed), stress, and lack of social support.74,75 The fact that HPA function. A similar pathophysiological mechanism has been
insomnia generally precedes or is concomitant rather than subse- proposed in major depression: due to maladaptative cognitive
quent to depression argues against the alternate form or the inde- functioning, an arousal reaction is maintained despite the removal
pendence model that do not account for a temporal relationship of the stressful situation.99–101 Indeed, stress-induced arousal
between the conditions; accordingly correlated liabilities or multi- responses that implicate the HPA axis,102,103 the locus coeruleus,
formity models are probably more appropriate. and the autonomous nervous system,107–109 have also been
clearly demonstrated in depressed patients. Other arguments for
What does neurobiological and sleep EEG studies tell us about the the hyperarousal theory of insomnia and depression lie on the
causal relationships between insomnia and depression? demonstration that HPA hyperactivity is related to sleep continuity
disturbances and SWS deficit in both disorders.110–113
Disruption of sleep continuity (lengthening of sleep latency and Recent studies suggest that the wake-promoting effect of
increased wake after sleep onset resulting in a decreased time spent CRH could be mediated through the orexinergic system.114
asleep), deficit of slow wave sleep (SWS), especially during the first Interestingly, an animal study has shown that a neonatal
sleep cycle, and indices of REM sleep disinhibition (such as increased stressor known to induce behavioral manifestation of stress in
REM density, shortened REM latency, and prolonged REM sleep adulthood such as maternal deprivation is able to produce sleep
time) are the hallmarks of sleep EEG disturbances in major EEG evidences of hyperarousal and of hyperfunctioning of the
depression.76,77 The sleep EEG profile of patients with primary orexinergic system in rats.115 Moreover, orexin overexpression
insomnia has generally been found comparable to those of major has been shown to induce an insomnia-like phenotype in
depressive patients in terms of sleep continuity disturbances and Zebrafish116 and the clinical efficacy of an orexin antagonist has
SWS deficit, but in sharp contrast, primary insomniacs have not been been demonstrated in a proof-of-concept study in primary
shown to have any consistent REM sleep abnormalities.78–82 Posi- insomnia.117 However, to our knowledge, published results of
tron Emission Tomography (PET) studies grossly corroborate sleep studies investigating the orexinergic function in primary
EEG findings since both primary insomniac and major depressed insomnia are still lacking. In depressed patients, two studies
patients show smaller indices of thalamo-cortical deactivation have found indications of a lower orexinergic tone, but these
during non-REM sleep83–85 while depressive patients had an results are difficult to interpret due to concomitant medication
increased activation of REM related structures during REM sleep.86 or absence of a control group.118,119
40 L. Staner / Sleep Medicine Reviews 14 (2010) 35–46

Homeostatic dysregulation Since recent studies suggested that the genetic susceptibility to
Another common physiopathological mechanism that could depression in the face of stress could involve abnormal HPA
underlie sleep continuity disturbances in both primary and response,155–159 one may speculate that only subjects with this
depressive insomnia is a dysregulation of the homeostatic process of genetic susceptibility would develop indices of REM sleep dis-
sleep. Perlis and Pigeon120 recently reviewed experimental inbition. This physiopathological mechanism could account for the
evidences supporting that sleep homeostasis could be altered in sequential comorbidity of insomnia and depression (insomnia
primary insomnia. Indeed, the homeostatic SWS response that precedes depression) and for the causal relationship between the
generally follows transient sleep loss in healthy subjects is not two disorders (insomnia causes depression) because insomnia by
observed in patients with insomnia. For instance, SWS has been itself reinforces the hyperarousal state triggered by environmental
found reduced in patients with primary insomnia despite their risk factors such as stress.
chronic sleep debt,78,79,121–125 a finding that was not evidenced in all Another explanation would be that, in individuals prone to
studies.126–128 However, in one of these three negative studies it was depression, some degree of REM sleep disinhibition pre-exists
shown that SWS was normal but that there was a reduction in delta before the onset of illness, as suggested by studies of high-risk
power,126 in the other, analyses of delta power were not reported,127 probands, i.e., subjects who have no lifetime or current diagnosis of
and in the latter, patients with primary insomnia did not exhibit a psychiatric disorder but who, owing to their family history, are at
reduced SWS nor reduced delta power.128 Other indications of high risk of development of one. These studies showed that some of
a homeostatic dysregulation in primary insomnia come from sleep these probands demonstrated a faster REM sleep induction after
deprivation studies investigating daytime sleepiness, as measured a cholinergic stimulation during sleep than healthy subjects160 and
by multiple sleep latency test, and SWS response during the that this finding identifies probands having a higher risk for
recovery night.120 In depressed patients, a comparable hypothesis, developing an affective disorder during a long-term follow up
known as Process S deficiency theory, has been proposed to account period.161 Modell et al.162 observed in the same but somewhat
for the characteristic sleep EEG disturbances.129 The most enlarged group of high-risk probands (n ¼ 82) that increased REM
convincing supports for this hypothesis come from spectral EEG density at initial polysomnography was also predictive for the onset
studies of the first non-REM period showing decreased delta of an affective disorder during a 4 to 10 years follow-up period.
activities in depressed patients (reviewed in Staner et al.130). According to these results, it may be suggested that indices of REM
Preliminary data suggest that the sleep homeostasis could be sleep disinhibition in high-risk probands reflect some degree of
dysregulated in insomnia and depression because of alteration of aminergic/cholinergic imbalance that would also reveal a genetic
the adenosinergic transmission. Adenosine has been implicated in susceptibility to depression. One may speculate that depression is
sleep homeostasis because it both inhibits wake-promoting struc- concomitant rather than subsequent to insomnia in subjects with
tures and activates sleep promoting structures while its concen- this genetic susceptibility because there is no evidence of REM
tration increases with extended wakefulness and normalizes slowly sleep disinhibition in patients with primary insomnia.
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- Treatment approaches for insomnia comorbid with
induced change in sleep EEG resembles the alterations observed in depression
patients with insomnia.133 Interestingly, this A2A polymorphism has
been associated with susceptibility to panic disorder134,135 and with Our knowledge about the nature of the comorbid relationship
the anxiogenic response to caffeine in healthy volunteers.136 In between insomnia and depression should influence the way
major depression, some evidences suggest a deficit in adenosinergic treatment approaches are designed. For instance, a sequential
transmission,137,138 and studies indicate that adenosine could be comorbidity (insomnia precedes depression) and a possible causal
implicated in mood regulation139–143 and in the antidepressant relationship between the two disorders (insomnia causes depres-
effects of sleep deprivation or of electroconvulsive therapy.144 sion) would indicate that the successful treatment of insomnia has
a preventive effect on depression occurrence. On the other hand,
REM sleep disinhibition concomitant comorbidity suggests common causalities and would
REM sleep disinhibition observed in major depression but not in indicate that effective treatment for one disorder will also be
insomnia may directly relate to the monoamine hypothesis of effective on the other disorder. Finally, absence of common
depression that postulates a deficiency of noradrenaline (NA) and causalities would suggest the implementation of two specific
serotonin (5-HT) neurotransmission, because there are strong therapeutical approaches, one for the treatment of insomnia and
evidences that REM sleep generating neurons are under the the other for the treatment of depression. However, it has to be
opposite influence of inhibitory NA and 5-HT input and of excit- stressed that, regardless of the specific pathway to the onset of
atory cholinergic input.145,146 For instance, it has been shown that comorbidity, once both disorders are present, they may serve to
the administration of cholinergic enhancing drugs induces stronger maintain one another or even exacerbate one another to create
signs of REM sleep disinhibition in depressed patients compared to a vicious cycle such that the presence of one disorder can impede
healthy subjects as well as an increased rate of awakenings and recovery from the other. Accordingly, a combined therapeutical
arousals.147 Prolonged hyperarousal could lead to REM disinhibition approach is generally advocated for comorbid insomnia.163,164
through CRH hypersecretion since CRH inhibits dorsal raphe 5-HT Both psychological/behavioral and pharmacological therapies
neurons.148,149 More specifically it was shown that CRH repress the are effective in the treatment of insomnia and depression30,165 and
5-HT1a receptor gene,150,151 a gene coding for a receptor playing one may thus conceive three different treatment combinations for
a key role in REM sleep propensity.152,153 One study investigating insomnia comorbid with depression: pharmacotherapy alone
the effects of a 4-week treatment with a CRH receptor 1 antagonist (i.e., hypnotic drug combined with antidepressant drug), psycho-
brings further support to the idea that REM sleep disinhibition in therapy alone (i.e., by combining specific therapeutical approach
major depression is mediated by an overactivity of the CRH system. for insomnia and for depression) or pharmacotherapy combined
In that study, the drug was an effective antidepressant and has with psychotherapy. The latter combination would not only include
a normalizing influence on the sleep EEG by increasing SWS and by pharmacology for one disorder and psychotherapy for the other
decreasing REM density and the number of awakenings.154 disorder, but also mixed therapeutical approach such as
L. Staner / Sleep Medicine Reviews 14 (2010) 35–46 41

antidepressant for depression and cognitive behavioral therapy Other non-TCA antidepressant drugs with similar receptor
(CBT) combined with an hypnotic drug for insomnia. binding profiles also favour sleep continuity by increasing non-REM
At the present time, there are very few studies that have investi- sleep, including SWS. The non-REM sleep promoting effect of
gated and compared efficacy and safety of these different treatment trazodone, a 5-HT2A/C and H1 antagonist, is well documented in
options. They have been recently reviewed28 and will be only major depressed patients.191–193 A 6- to 8-week administration of
summarized hereafter. The use of antidepressant drug in insomnia nefazodone also improves sleep continuity by decreasing sleep
comorbid with depression will be more extensively discussed in the onset latency131,132 and wakefulness,180,181 and by increasing total
next section. Before going further, it must be underlined that the first sleep time194 and sleep efficiency.180,181,194,195 Mianserin, a 5-HT2A/C,
step in the management of patients having both insomnia and H1, and a1 antagonist promotes stage 2 and increases total sleep
depression is to rule out any other sleep disorders such as sleep apnea time and sleep efficiency of depressed patients.196 A very consistent
and periodic leg movement syndrome. First, treatment of sleep apnea non-REM sleep promoting profile has been documented for mir-
may improve mood in these patients.166 Second, antidepressants and tazapine, a 5-HT2A/C and H1 antagonist devoid of a1 antagonist
hypnotics are known to worsen periodic leg movements and sleep properties. In all but one study183 the drug increases SWS and
apnea, respectively, although there are some exceptions.167–169 generally improves sleep efficiency183,197,198 in depressed patients
Psychotherapy alone may be considered for patients with mild by decreasing wakefulness181,197,199 and/or by increasing total sleep
to moderate depression but pharmacotherapy is mandatory for time.197,198 The new antidepressant drug agomelatine (that
patients with severe depression.165 In contrast, for the treatment of agonises melatonin MT1 and MT2 receptors and antagonises 5-HT2C
insomnia, psychotherapy (i.e., behavioral treatment management) receptors as well) has been shown to improve sleep efficiency, to
has been shown to have similar and even more durable benefit than decrease wake after sleep onset and to increase SWS in major
hypnotics.170,171 The American Academy of Sleep Medicine rated depressed patients.200
stimulus control, relaxation training, and CBT as an accepted Antidepressant drug efficacy does not relate to their effects on
patient care strategy with a high level of clinical certainty. Sleep sleep continuity because most antidepressants such as monoamine
restriction, multicomponent therapy without cognitive therapy, oxydase inhibitors (MAOIs), selective serotonin reuptake inhibitors
paradoxical intention, and biofeedback obtained moderate level of (SSRIs), selective noradrenaline reuptake inhibitors and double
clinical certainty.163 Applicability of these practice parameters to reuptake inhibitors are rather sleep disrupting drugs.201 At first
insomnia comorbid with depression is uncertain but there are glance, it appears that drugs having a non-REM sleep promoting
some evidences that CBT of insomnia is effective for insomnia profile are more helpful in insomnia comorbid with depression; an
symptoms172–174 and that it can augment antidepressant response alternative would be the co-prescription of a non-sedating anti-
to escitalopram.174 Accordingly, recent clinical guidelines for the depressant with a hypnotic agent. For instance, Fava et al.19 showed
management of chronic insomnia recommend psychological and that the addition of eszopiclone to fluoxetine in major depression
behavioral interventions in the treatment of comorbid insomnia, patients improves both objective and subjective sleep complaints
including insomnia comorbid with depression.162,163 as well as depression. On the other hand, studies investigating the
Interestingly, CBT for depression has been found to improve sleep EEG effects of a prolonged administration (i.e., up to 12
sleep in major depression, apart patients showing indices of REM weeks) of a sedative and a non-sedative antidepressant (i.e., nefa-
sleep disinhibition.18,20 However, another form of CBT which is zodone and fluvoxamine) showed an attenuation of the sleep
more focused on the interpersonal domain, the cognitive behav- promoting effects of nefazodone and of the sleep disrupting effects
ioral analysis system of psychotherapy, was found, despite of fluvoxamine.194,202
comparable antidepressant efficacy, less effective than nefazodone
in subjective early morning awakening and total sleep time.175 We Significance of the REM suppressant effect of antidepressant drugs
are not aware of studies combining CBT for depression with
hypnotic drug and/or with CBT for insomnia. 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.
Antidepressant drugs for insomnia comorbid with depression
Since a mounting of evidences indicates that REM sleep generating
neurons are under the inhibitory influence of NA and 5-HT
Studies that reviewed the different treatment options of
input,151,152,188,189 no wonder that antidepressant drugs suppress
insomnia comorbid with depression generally consider sedative
REM sleep. However, some antidepressant drugs such as trimipr-
antidepressant drugs as first-line agents.28,176–178 The present
amine, iprindole, nefazodone, trazodone, mianserin, mirtazapine,
section discusses the sleep EEG profiles of antidepressant drugs in
agomelatine, tianeptine, bupropion, and nomifensine do not
relation to their use in insomnia comorbid with depression.
demonstrate any clear REM suppressant effect.201 It could indicate
an inefficient boost of 5-HT or NA transmission at the level of REM
Sedative or non-sedative antidepressants? sleep generating neurons. Alternatively, the 5-HT/NA mediated
REM suppression could be confounded by opposite drug effects on
Sedative antidepressants are in fact drugs having non-REM the REM sleep regulating system. For instance, some recent
sleep promoting properties; they generally improve sleep mainte- evidences suggest that the dopaminergic (DA) system is implicated
nance rather than sleep initiation, although some of them like in REM sleep generation.203–205 In this context, the lack of typical
doxepin,179 nefazodone180,181 and mirtazapine182,183 have been REM suppressant effect of NA/DA reuptake blockers (bupropion and
shown to shorten sleep onset latency. Tricyclic antidepressants nomifensine) could result from a balance between DA promoting
(TCA) such as trimipramine, doxepin, amitriptyline have often influence and NA inhibiting influence.
sedative effects and increase non-REM sleep in depressed On a theoretical point of view, the amount of REM suppression
patients184–187 because of their various antagonist profiles at induced by an antidepressant should more or less relate to its
serotoninergic (5-HT2A/C), muscarinic (M1, M3), histaminergic (H1), clinical efficacy since antidepressant drugs are supposed to act on
and adrenergic (a1) receptors. Indeed, cholinergic and mono- abnormal brain 5-HT or/and NA systems in order to normalize their
aminergic transmissions are largely implicated in the wake- function. This view is supported by a recent meta-analytic study
promoting system.146,188–190 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 procedure. Epidemiological research indicates that insomnia and
trials. Results indicate that the 3 drugs with weak (mirtazapine) or depression are not randomly associated and that they are either
no (bupropion and nefazodone) REM suppressant effects are among causally related to each other and/or that common causalities
the 4 drugs for which the effect size has been mostly inflated by underlie the two disorders. There are some evidences that chronic
ignoring non-published trials. When considering published and sleep disruption experienced by insomniac patients could play
non-published trials together, the effect sizes of bupropion (0.17) a direct causal relationship in the emergence of depressive symptoms
and nefazodone (0.26) were among the 3 lowest observed.206 but studies examining the benefits of insomnia treatment in pre-
One may suggest that, if REM sleep disinhibition reflects the venting depression are warranted to validate this hypothesis.
aminergic deficit supposed to be implicated in major depression, Empirical evidences suggest that different treatment approaches
REM suppressant antidepressant drugs could be particularly (behavioral management of sleep combined with prescription of
effective in depressed patients with evidences of REM sleep a sedative antidepressants alone, co-prescription of two antidepres-
disinhibition. In other words indices of REM sleep disinhibition sants, or combination of an antidepressant with an hypnotic drug) are
should identify depressed patients responding well to therapies effective in the treatment of insomnia comorbid with depression but
increasing NA or 5-HT transmission and poorly to other forms of further studies are needed to standardize the treatment.
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 Practice points
density identify depressive patients that do not respond to non-
 Primary sleep disorders such as sleep apnea and peri-
pharmacological treatments such as placebo207,208 or psycho-
odic leg movements have to be ruled out.
therapy.209,210 Pre-treatment sleep EEG did not have any predictive  Consider behavioral management of sleep and non-TCA
value on the response rate of bupropion211 and tianeptine,212 two sedative antidepressant such as mirtazapine or agome-
antidepressant drugs having no or low potency to inhibit NA or 5- latine as the first-line intervention.
HT213 and devoid of REM sleep suppressant effect.214,215 On the  Consider REM suppressant antidepressant for patients
opposite, most studies found that a baseline reduced REM latency with severe forms of depression, and particularly TCA
has a predictive value on antidepressant response216–220 but there when safety and tolerability indicators are favourable;
are also negative reports.207,221 alternatives are SSRI or double 5-HT/NA reuptake
We do not know the exact incidence of REM sleep dysregulation inhibitors with concomitant prescription of an hypnotic
in insomnia comorbid with depression. Age and depression severity
 Reserve antidepressant co-prescription for patients
are clearly found associated with evidences of REM sleep disinhi-
having an inadequate response to a single
bition222 and there is a probable role of insomnia since depressed antidepressant.
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 Research agenda

Co-prescription of antidepressant drugs is a commonly used  Long-term prospective longitudinal studies in the
strategy to treat persistent insomnia during antidepressant treat- general population or in patient samples would be
ment. Typically, a low dose of a sedative antidepressant (such as helpful to determine neurobiological and psychosocial
amitiptyline, trimipramine, doxepin, trazodone, nefazodone, risk factors for developing either insomnia, depression,
mianserine or mirtazapine) is added to a therapeutical dose of and insomnia comorbid with depression.
a non-sedative antidepressant. This practice has gained in attrac-  Genetically informative data coming from pairs of rela-
tiveness because of potential synergistic antidepressant effects and tives or of twin studies would designate the appropriate
model explaining the comorbidity between insomnia
avoidance of concerns of drug misuse associated with other
and depression, and therefore would bring valuable
hypnotic drugs. Concerns are safety issues and lack of proof of the
information on the nature of the causal relationship
effectiveness of this strategy.28 between the two conditions.
Another alternative therapy is to combine a classical benzodi-  Intervention trials (both pharmacologic and behavioral)
azepine (BDZ) or a BDZ-like drug such as zolpidem, zaleplon or treating persistent insomnia in remitted depression or
eszopiclone. It has been shown that up to 40% of depressed patients insomnia comorbid with depression in order to assess:
treated with SSRIs receive concomitant BDZ.223 Controlled studies B whether curing insomnia prevents further
have documented the benefit of adding triazolam, lormetazepam, depression;
and chlordiazepoxide in patients treated with TCA224–226 or of B different treatment approaches in the comorbid

adding zolpidem to SSRI.227 Some studies also suggest that the co- condition; and
B the predictive value on outcome of particular
prescription is more effective than the antidepressant drug alone
clinical or neurobiological characteristics
on both insomnia and depressive symptoms; this was observed including sleep EEG.
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
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