Clinical manifestations

Presentation and course

	• Patients with depression commonly complain of sleep disturbances.
	• Depressed patients with evening circadian preference experience more severe depressive symptoms.
	• Patients with depression showed sleep abnormalities, including prolonged sleep latency and increased wake time during sleep, resulting in reduced sleep efficiency.

Patients with depression commonly complain of sleep disturbances, including difficulty falling asleep, frequent nocturnal awakenings, early morning awakening, nightmares, nonrestorative nocturnal sleep, and daytime fatigue or loss of energy and diminished concentration (03; 02).

As they investigate the risk of incident major depressive disorder in the Danish population, Byrne and colleagues found an increased risk of incident depression for all sleep disorders analyzed (13). Highest incidence rate ratios (IRRs) were found for circadian rhythm disorders (IRR = 7.06 [2.78-17.91]) and insomnia of inorganic origin (IRR = 6.76 [4.37-10.46]). Those diagnosed with a sleep disorder in the last 6 months were at highest risk of developing depression compared to those with at least 1 year since diagnosis (3.10 vs. 2.36).

When studied polysomnographically, patients with depression showed sleep abnormalities, including prolonged sleep latency and increased wake time during sleep, resulting in reduced sleep efficiency. The time spent in slow-wave sleep during the night is reduced; REM sleep latency is reduced, and REM density and REM sleep percentage are increased. Some authors studied slow-wave activity (SWA) in hypersomnolent patients with mild/moderate major depressive disorder (66). SWA is the power density of low-frequency delta activity during sleep; it more accurately reflects slow oscillations than traditional sleep staging and is a marker of sleep homeostasis, which is also associated with sleep restoration. Hypersomnolent patients with major depressive disorder demonstrate significantly reduced parieto-occipital all-night SWA, suggesting that decrements in slow waves during sleep may be related to subjective report of hypersomnolence in mood disorders (66).

Insomnia and depression do not follow a typical cause-and-effect relationship. Insomnia may precede or follow depression; sometimes depression and insomnia are unrelated, but in many cases depression and insomnia are comorbid. Different studies examined the relationship between insomnia and depression, showing that insomnia is a risk factor for onset and worsening of depression.

Insomnia may predict depression in various populations, including younger and older adults (79; 17; 36). Sleep duration has a significant negative impact on a range of mood states in healthy adolescents across all geographical regions. Many studies documented reciprocal effects for major depression and sleep deprivation among adolescents, suggesting that reduced duration of sleep increases risk for major depression, which in turn increases risk for decreased sleep. In a survey investigating quality of life and depressive symptoms among 1814 medical students undergoing postgraduate neurology specialty training in China, one-third of respondents had depressive symptoms (90). In a study examining the association between morningness-eveningness preferences, sleep duration, weekend catch-up sleep duration, and depression among 8655 Korean high-school students, eveningness preference and insufficient weekday sleep duration were associated with an increased risk of depression (45). These results highlight that sleep is a universal and modifiable risk factor for preventing mood deficits and for reducing depressive symptoms in this at-risk population, including children (45; 75; 52; 55). Persistence and worsening of poor sleep or insomnia, but not their full remission, are significant predictors of incident depression (39). Greater depressive symptom levels are associated with more subjective reporting of poor sleep and objective evidence of sleep fragmentation and napping in older women.

There are different hypotheses to explain how insomnia may cause depression: insomnia is related to decreased quality of life, with a negative impact on social and interpersonal performances that could trigger, maintain, or worsen depression; lying awake may facilitate depressive ruminations; loss of control of sleep may trigger thoughts of impotence and vulnerability and may cause alterations in neurobehavioral functions that may result in depression. Persistent insomnia also increased the risk of suicide in adults, both directly and indirectly, by affecting the risk of depression (32).

The epidemic of a highly contagious coronavirus 2019 disease (COVID-19) that was identified in China at the end of 2019 is associated with anxiety, depression, distress, and sleep disturbances (57). In a systematic review and meta-analysis to estimate the pooled prevalence of depression, anxiety, insomnia, and psychological distress related to COVID-19 among affected populations, the prevalence of depression and insomnia was 15.97% and 23.87%, respectively. In an online assessment of 667 participants from the Netherlands, COVID-19 lockdown measures more often worsened sleep complaints in pre-pandemic good sleepers whereas a subset of people with pre-pandemic severe insomnia symptoms underwent a clinically meaningful alleviation of symptoms (44). The COVID-19 pandemic significantly affected the mental health of healthcare workers, who stand at the frontline of this crisis (14; 67). A systematic search of literature databases including 13 studies with a combined total of 33,062 participants suggested that a considerable proportion of healthcare workers experienced mood disturbances (23%) and insomnia (38.9%) during the outbreak (62). Reports of insomnia are significantly higher among adolescents, especially senior high school and college students, suggesting devotion of more attention to sleep disorders in this patient population while combating COVID-19 (92).

Even after COVID-19 recovery, patients are prone to a variety of mental health problems including a high rate of insomnia (86). Individuals reporting a previous mental health diagnosis had worse stress, anxiety, and depression than those without a previous mental health diagnosis (53).

In bipolar disorder, switches into mania may be preceded or precipitated by periods of reduced sleep. Sleep disturbances may frequently appear 1 year or more before the onset of bipolar disorder, often during childhood or adolescence. A decreased need for sleep may precede the onset of the illness, especially in a manic episode, whereas insomnia appears to anticipate either a manic or a depressive episode. Hypersomnia seems to precede bipolar depressive episodes (60).

Hypersomnia is considered to be one of the main symptoms of depressive disorder (07). Relationships between symptoms of hypersomnolence, psychiatric disorders, and hypersomnia disorders (ie, idiopathic hypersomnia) are complex and multidirectional (07). Hypersomnia increases the risk of incident depression, is a highly treatment-resistant symptom, increases the risk of depressive relapse, and increases the risk of suicide. Patients with depression often report daytime fatigue and daytime sleepiness, with extended nocturnal sleep periods, difficult morning awakening, and frequent daytime naps. Self-reported daytime sleepiness shows the highest utility as a marker for major depressive disorder among the youngest patients. These patients spend more time in bed and report “resting” more than “sleeping”; the multiple sleep latency test (MSLT) usually shows normal mean sleep latencies. Similarly, patients with a seasonal pattern of depression, who have depressive episodes recurrent in a particular time of year (depression occurs during the winter months and disappears in the spring), may also complain of increased daytime sleepiness. Most patients with bipolar disorders report symptoms of hypersomnia while depressed, but excessive daytime sleepiness as assessed by the MSLT is not usually present (41).

The prevalence of depressive symptoms is high in patients with excessive daytime somnolence and narcolepsy (81; 63; 49). In the CoLaus-PsyCoLaus population-based cohort (Lausanne, Switzerland), among the 2438 subjects without excessive daytime sleepiness (Epworth Sleepiness Scale ≤ 10) at baseline, the 5-year incidence of excessive daytime sleepiness was 5.1% (n = 124). Multivariate logistic regression revealed that male sex, depressive symptoms, reported poor sleep quality, and moderate to severe obstructive sleep apnea were independent predictors of incident excessive daytime sleepiness (08). A meta-analysis revealed that the overall pooled prevalence of depression or depressive symptoms in patients with narcolepsy was 32% (49). The scores of depression associated with the level of sleepiness are the main correlates of the subjectively perceived attention deficits of patients with narcolepsy (88).

Depression may be reactive to narcolepsy but, according to some authors, may be related to the pathophysiology of the disease. Moreover, stimulant drugs may worsen the depressive symptoms. A large observational French study of central hypersomnia showed that patients with cataplexy treated with antidepressant and stimulant drugs had a higher depression frequency than patients treated by stimulants alone.

Poor sleep quality was strongly associated with mood disturbance among extremely obese patients, and depression was often present in patients with obstructive sleep apnea syndrome, both in adults and adolescents (68). A literature search in Medline, PubMed, PsycInfo, Scopus, and Web of Science showed a pooled prevalence of depressive and anxious symptoms in patients with obstructive sleep apnea of 35% (95% CI, 28%-41%) and 32% (95% CI, 22%-42%), respectively (29). Severity of the disorder, obesity, and excessive daytime sleepiness are strong risk factors for prevalent and incident depression (10). Patients with obstructive sleep apnea showed more intense depressive and somatic symptoms than patients with only snoring. The association between obstructive sleep apnea, anxiety, and depression indicates the value of an early diagnosis and personalized treatment of obstructive sleep apnea to improve mental disorders conditioning compliance to therapy (29).

Although some studies do not support a causal link between obstructive sleep apnea and severe depression (43), the association between depression and obstructive sleep apnea syndrome may have different explanations. Depression may be coincidental but unrelated to obstructive sleep apnea (72); a depressed mood may be induced by the symptoms of the sleep disorder; obstructive sleep apnea syndrome and depression could be induced by the same biological mechanisms (ie, the serotoninergic systems play a central role in the regulation of upper airway muscle), and deficiency in serotoninergic activity is associated with depression.

Symptoms of depression are common in individuals with restless legs syndrome. The prevalence is variable among different studies (16% to 53%). Given the high prevalence of both depression and restless legs syndrome in the general population, it would not be surprising that some patients have both disorders. However, emerging data indicate that occurrence of depression symptoms with restless legs syndrome is not a simple coincidence and a common pathogenetic mechanism, such as dopaminergic abnormality, may underlie restless legs syndrome and depression (65).

Prognosis and complications

For a particular episode of depression, the prognosis is usually good, with response to treatment in about three fourths of patients. Although resolution of sleep disturbance associated with depression usually parallels that of other depressive symptoms, some patients may develop psychophysiological insomnia that persists for years after depression has remitted.

The most serious complication of depression is suicide, and sleep disturbance is predictive of a greater risk of suicidal behavior (27). In a large population of 297 patients with narcolepsy type 1 and 346 controls, depression, depressive symptoms, suicidal thoughts, and suicide risk were frequent in patients with narcolepsy type 1, especially those without treatment, and were associated with narcolepsy type 1 severity (06). Depressive symptoms and suicidal thoughts improved after narcolepsy type 1 management. The causal role of mechanism of sleep disturbances in suicidal behavior remains unclear. Sleep disturbances could exacerbate psychological distress, but future researches are necessary to examine the specific mechanism of vulnerability and whether there are specific sleep profiles (for example, nightmares, insomnia, early morning awakenings, morningness-eveningness chronotype) that may discriminate individuals who are at risk to suicide behaviors (55). According to the diathesis-stress model of insomnia, insomnia may develop in vulnerable individuals in response to stress. A low resilience, which is the psychobiological factor that determines an individual's capacity to adapt successfully to stressful events, increases vulnerability for development of mental disorders (59).

Sleep seems to also have a role in the association between depressive symptoms and cardiovascular mortality (05).

Prestroke short sleep duration may be an independent risk factor for poststroke depression. Comparing with participants reporting 7 to 8 hours of sleep prestroke, those with short sleep duration (less than 6 hours) had significantly increased risk for poststroke depression, after adjustments for covariates including prestroke depression and sleep apnea risk (23). Prestroke short sleep duration may be an independent risk factor for poststroke depression, which needs to be investigated; the simple rule of adding an antidepressant to all patients poststroke who declare less than 6 hours prestroke may improve rehabilitation outcomes (21).

Clinical vignette

A 36-year-old female executive assistant complained of weariness and excessive daytime sleepiness since the age of 28 years. She reported frequent daytime naps (several times a day) that were refreshing. The naptime sleepiness often occurred with little warning, but was not usually irresistible.

At 29 years of age, the patient reported depressed mood, poor concentration and memory, withdrawal from social situations and activities, and apathy. Antidepressants (venlafaxine and reboxetine) improved depressed mood and weariness but had no effect on excessive daytime sleepiness.

Neurologic examination and routine laboratory tests were within normal limits. But 48-hour polysomnographic recording disclosed a reduced nocturnal sleep efficiency (68%; normal values: greater than 85%) and sleep onset rapid eye movement periods both in nighttime (REM sleep latency: 4 minutes) and in two daytime naps. The Multiple Sleep Latency Test showed a reduced sleep latency (3 minutes as a mean) and two sleep onset rapid eye movement periods.

After initiation of modafinil, excessive daytime sleepiness markedly improved.

Comment. This vignette illustrates a case of major depressive disorder in a patient with narcolepsy without cataplexy.

Biological basis

Etiology and pathogenesis

Relatively little is known about the etiology of mood disorders. There have been a number of hypotheses for the cause of altered sleep in depression, and many of them suggest that the sleep changes are not epiphenomena but, indeed, may be central to the genesis of the overall illness (82; 20). At this point, no single hypothesis is generally accepted as the most likely, and many are not mutually exclusive.

Sleep changes in depression may be the consequence of:

	• a phase advance or delay of the central pacemaker and related circadian rhythms that regulate sleep, wake, temperature, cortisol, and melatonin (38).
	• an imbalance of the opponent interaction between the circadian and homeostatic processes such that a weaker circadian output signal leads to an overexpression of sleep-wake homeostasis influences (34).
	• a deficiency of a sleep/waking-dependent process (Process S) involved in sleep regulation (11).
	• a cholinergic-aminergic imbalance. Enhanced cholinergic neurotransmission or reduced aminergic neurotransmission may explain the short REM sleep latency and elevated REM density in depression.
	• a dysregulation in the hypothalamic-pituitary-adrenal axis, present in many patients with depression, which may contribute to sleep changes in depression related to excessive daily amounts of cortisol (which reduces REM sleep latency) and corticotropin-releasing hormone (which increases arousal and contributes to reduced REM sleep latency) (78).
	• an alteration of clock genes that might lead to desynchronized and abnormal circadian rhythms impairing in turn the synchronization between external and internal rhythms and, therefore, the adaptation of the individual to his/her internal and external environment with the development of psychiatric disorders (16; 51).

Humans, like other living organisms, show cyclical physiological changes across the 24-hour day. Sleep and wake are the most overt manifestations of the circadian rhythm, but mood also exhibits changes throughout the day. In one study, patients with depression showed early morning awakenings, early occurrence of REM sleep, and melatonin secretion shift; these features were central to the “phase shift” hypothesis, according to which mood disturbances result from a phase shift in the circadian pacemaker. An alternative model was based on the shortened REM latency and REM sleep suppression, but these features are not specific for depression. Lastly, the social rhythms hypothesis of depression postulates a role of disrupted social rhythms and associated changes in physiological rhythms in the pathogenesis of depression.

Diurnal variations of mood and sleep disturbances are the classical symptoms linking depression to the circadian system. A bidirectional association between evening circadian preference and depression emerges from studies on adolescents stratified into either low-risk for depression, high-risk for depression, or experiencing current major depressive disorder (MDD). The high-risk adolescents shared sleep and rhythm alterations (ie, higher social jetlag, lower relative amplitude of activity, and higher exposure to artificial light) with the major depressive disorder group (55).

Seasonal affective disorder shows how an alteration between the external light-dark cycle and circadian rhythms may trigger a depressive episode (70). An interaction between the Epworth Sleepiness Scale and the work schedule and the short-term Center for Epidemiologic Studies-Depression scale and the work schedule was stronger in shift workers than non-shift workers (48). The depressive symptoms of shift workers are associated with sleep problems, and the effects of sleepiness on depression were more prominent in shift workers than non-shift workers (48), suggesting the urgent need for the development of public health interventions that promote healthy lifestyles aimed at improving the mental health of shift workers (87).

Disruption of the circadian rhythms has been found among patients with depression. These changes may contribute to depression (as suggested by the dysphoria triggered by jet-lag), but they may also be a consequence of depression. Some studies reported that in patients with depression, mean core temperature is increased, cortisol and norepinephrine secretion are phase advanced, and there is an abnormal melatonin secretion.

REM alterations in depression have been attributed to an imbalance between monoaminergic and cholinergic neurotransmission; enhanced cholinergic neurotransmission or reduced aminergic neurotransmission may explain the short REM sleep latency and elevated REM density in depression (58).

In patients with depression, a lower sleep pressure (low Process S) could be related to sleep initiation disturbances rather than to hyperarousal (as in primary insomnia).

Sleep deprivation and selective REM sleep deprivation have been shown to have antidepressant effects through a mechanism that probably involves the activity of limbic structures (84). Sleep deprivation can acutely reverse depressive symptoms in some patients with major depression; the mood-elevating effects of sleep deprivation have been demonstrated by reports that sleep deprivation can trigger mood episode switches in patients with bipolar disorder. REM sleep deprivation also improves depressive symptoms, but it is not clear if REM sleep deprivation is more effective than non-REM sleep deprivation.

Finally, among older adults, insomnia symptoms appear partially related to personality, with persons higher in neuroticism experiencing greater insomnia symptom severity and those higher in conscientiousness experiencing lower insomnia symptom severity (69).

Epidemiology

	• Major depressive disorder is one of the most common mental disorders.
	• Women are 70% more likely than men to experience depression during their lifetime.
	• Self-reported insomnia symptoms are present in more than 50% of individuals with a major depressive episode (76).
	• Hypersomnia occurs in roughly 30% of patients with major depressive disorder (41).

In the Canadian Longitudinal Study on Aging, 28,485 participants greater than 45 years of age completed questionnaires assessing sleep and underwent physical examinations and neuropsychological tests (19). Probable insomnia disorder was identified in 1068 participants (3.7% of the sample), whereas 7813 (27.5%) experienced insomnia symptoms only. Participants with probable insomnia disorder exhibited greater proportions of adverse medical and lifestyle features such as anxiety, depression, and diabetes than both other groups.

Different epidemiological studies documented that insomnia was associated with a higher risk for developing a new major depressive illness if it persisted in the years following the initial evaluation.

A large population-based study suggests that the association between depressive symptoms and sleep quality is modified by life satisfaction. Higher depressive symptoms are associated with substantially worse sleep quality, especially among individuals with lower life satisfaction, suggesting a joint effect of depressive symptoms and life satisfaction (46).

Prevention

	• Because of the relationship between depression and sleep disturbances, all patients with sleep complaints must be screened for depression.
	• Sleep problems can co-occur with, precede, or follow common psychiatric disorders (such as generalized anxiety disorder and depression), especially during childhood and adolescence.
	• Screening children for sleep problems could offer promising opportunities for reducing the burden of mental illness during the early life course.

Asking about total sleep time in a clinical setting may be more informative than only assessing for insomnia symptoms to more fully characterize the relationship of sleep to suicide (54; 89). Treating depression in patients who present with sleep difficulties may subsequently help mitigate suicide risk (22).

Treatment of insomnia with cognitive behavioral therapy for insomnia (CBT-I) has an overall benefit in the prevention of incident and recurrent major depression in older adults with insomnia disorder (37).

Untreated obstructive sleep apnea impacts affective disorders and often leads to decline of cognitive functions or even leads to permanent brain damage. Further studies are needed to analyze the connection between obstructive sleep apnea and affective disorders, anxiety disorders, and its effect on cognitive functions more thoroughly, especially in the context of CPAP treatment (80).

In a retrospective study on a total of 105,071 individuals diagnosed with cancer and 420,284 age- and sex-matched patients without a diagnosis of cancer, patients with both sleep disorders and depression are at a higher risk of cancer (35). Clinically, a meticulous cancer risk evaluation could be recommended for patients with both sleep disorders and depression.

Differential diagnosis

Confusing conditions

The diagnosis of depression in patients with sleep disturbances may be complicated by a failure of the patient to recognize the nature of the illness. Some patients with sleep disorder associated with depression may deny or minimize other depressive symptoms or attribute depression to the effects of poor sleep. In such cases, complaints of poor or nonrestorative sleep may suggest diagnoses of psychophysiological insomnia, inadequate sleep hygiene, or idiopathic insomnia. If anxiety is a prominent component of the depression, the sleep complaint and clinical presentation may suggest sleep disorders associated with anxiety disorder. If frequent awakenings are the major complaint, movement disorders, obstructive sleep apnea, or sleep disorders associated with medical disorders may be considered.

Sleep disorder associated with primary depression should be distinguished from that associated with secondary depression due to another disorder such as alcoholism or anorexia nervosa. In some cases, depressive symptomatology may be associated with a specific medical disease such as disorders that cause pain, breathing, or cardiovascular problems and limited motility. Depression in the elderly that is associated with symptoms of cognitive dysfunction may be difficult to differentiate from dementia.

Diagnostic considerations in persons with difficulty falling or staying asleep include sleep disorder associated with medical, neurologic, or other psychiatric illness; psychophysiological or idiopathic insomnia; an extrinsic sleep disorder such as inadequate sleep hygiene; and circadian rhythm disturbances. When early morning awakening is a prominent complaint, advanced sleep phase syndrome is a consideration.

Depression with complaints of hypersomnolence may suggest narcolepsy, idiopathic hypersomnia, or obstructive sleep apnea. The temporal association with other depressive symptoms, a multiple sleep latency test that is usually normal, and the absence of complaints of falling asleep in inappropriate circumstances (as opposed to a feeling of fatigue and a desire for sleep) help to distinguish hypersomnolent depression from these other disorders.

Diagnostic workup

	• Clinical history is mandatory to establish the diagnosis.
	• Polysomnography is neither specific nor sensitive enough to diagnose depression.
	• Actigraphy, a noninvasive method for monitoring motor activity, can be used to objectively assess circadian rest-activity rhythms and sleep patterns in patients with depression.

Patients with depression must be questioned about sleep disturbances suggestive of insomnia (such as difficulty falling asleep, frequent nocturnal awakenings, early morning awakening, nonrestorative sleep, disturbing dreams, and daytime fatigue) or hypersomnia (such as extended sleep period, difficulty awakening, and excessive daytime sleepiness) (74). A possible association with other primary sleep disorders, such as obstructive sleep apnea syndrome or restless legs syndrome must be recognized.

Depression has several characteristic polysomnographic features, including sleep fragmentation, prolonged sleep latency, increased wake time during sleep, decreased total sleep time and reduced sleep efficiency, less “deep” sleep with decreased amounts of slow wave sleep, reduced REM sleep latency, and increased percentage of REM sleep. Polysomnographic studies (Video-PSG, MSLT) should be considered only in patients with symptoms of other sleep disorders, namely daytime sleepiness.

Management

	• Sleep disturbances are modifiable risk factors in the development and maintenance of depression and may be treated with medications, psychotherapy, or both.
	• Treating sleep disturbance may prevent the future depressive episodes.
	• Patients with moderate to severe depression are usually treated with antidepressants that may have significant effects on sleep.
	• Hypnotics can usually be combined with antidepressant drugs (or treatments).
	• Cognitive behavioral therapy was effective at reducing insomnia and depression severity.

Selective serotonin reuptake inhibitors (SSRIs) are the class of drug most commonly used for depression. The adverse effects of SSRIs include REM sleep suppression (reduction in the amount of REM sleep and delayed onset of REM sleep). These effects are dose-related and are probably due to an increased level of synaptic serotonin.

Although the use of tricyclic antidepressants has diminished because of the associated side effects, the sedative effects of these drugs may be helpful in depressed patients with insomnia. In clinical practice, low doses of amitriptyline have been commonly prescribed for insomnia although there are no controlled studies on the use of tricyclic antidepressants as hypnotics in nondepressed patients. Tricyclic antidepressants and SSRIs have a similar effect on REM sleep. REM sleep rebound after withdrawal has been described and may be due to a rebound increase in cholinergic function. Trimipramine is the only tricyclic antidepressant that does not affect REM sleep. Insomnia may, however, be exacerbated by antidepressants (both SSRIs and tricyclic antidepressants) and may directly or indirectly precipitate or exacerbate sleep disorders such as restless legs syndrome and periodic limb movements.

Mirtazapine has a robust and sustained effect in improving sleep continuity in patients with depression and has been polysomnographically shown to increase total sleep time, sleep efficiency, and slow-wave sleep both acutely and after 1 to 2 months of treatment when administered to depressed subjects. Mirtazapine has been reported to induce or exacerbate restless legs syndrome in some patients; venlafaxine can increase periodic limb movements.

Trazodone (50 to 200 mg) is particularly useful in the treatment of patients with depression and insomnia (42). Side effects of trazodone include priapism, orthostatic hypotension, and induction of cardiac arrhythmias in subjects with preexisting cardiac disease. Daytime sedation can be a side effect of the use of trazodone as a hypnotic, but tolerance of this adverse effect usually develops within several weeks.

Agomelatine is an antidepressant acting as an agonist at melatoninergic MT1 and MT2 receptors and as an antagonist at 5-HT2c serotoninergic receptors. This dual mechanism is the basis of the drug’s antidepressant efficacy as well as its capacity to improve sleep-wake rhythm disorders.

Modafinil is a wake-promoting agent that is indicated for the treatment of excessive sleepiness in patients with narcolepsy, obstructive sleep apnea (as an adjunct to standard treatment aimed at the underlying obstruction), and shift-work sleep disorder. In an open-label study, Schwartz and colleagues found that adding modafinil at a dose of 100 to 400 mg daily to the medication regimen of patients on stable treatment with selective serotonin reuptake inhibitors led to significant improvement in overall depressive symptoms, fatigue, and sleepiness (as measured by the Epworth Sleepiness Scale) (71). The authors concluded that adjunctive modafinil improves wakefulness and reduces fatigue in patients who experience sedation as a side effect of serotonergic antidepressant therapy. Modafinil induces cytochrome p450 3A4 activity and inhibits the activity of cytochrome p450 2C19. Through cytochrome p450 3A4 induction, modafinil can decrease the effectiveness of oral contraceptives.

Cognitive behavior therapy for insomnia (CBT-I) is an effective treatment for patients with insomnia and a comorbid mental disorder, especially depression, post-traumatic stress disorder, and alcohol dependency (04). CBT-I is also an effective add-on treatment for improving mental health in patients with depression (33). Treatment options in patients with depression and insomnia include:

	• Basic sleep hygiene education should include general guidelines about lifestyle (eg, diet, exercise, drug use) and environmental factors (eg, light, noise, temperature) that may promote or interfere with sleep (12).
	• Sleep restriction therapy consists of curtailing time in bed and creating mild sleep deprivation, although using a methodologically rigorous approach, a meta-analysis did not find evidence that the addition of sleep deprivation to treatment packages leads to favorable depressive outcomes (56).
	• Stimulus control therapy can help patients to reassociate the bed and bedroom with sleep (ie, go to bed only when sleepy, get out of bed when unable to sleep, use the bed for sleep only--no eating, reading, watching TV).
	• Relaxation training (eg, progressive muscle relaxation, autogenic training, biofeedback) is important, and clinical procedures to reduce somatic tension or intrusive thoughts can be helpful.
	• Cognitive therapy can teach patients coping skills to prevent excessive preoccupation with sleep and their daytime consequences, which often exacerbate insomnia and depression, and to control intrusive thoughts interfering with sleep. All chronotypes benefited from sleep improvement, but those with greater eveningness or less sleep improvement experienced less reduction in depressive symptom severity.
	• Light therapy is an effective treatment for seasonal affective disorders and delayed sleep phase disorders (28; 31). Morning and evening light exposure is associated with a 50% decrease in depression severity scores and reduced suicidal ideation. Adults with unipolar depression and evening preference who experienced a change in eveningness by week 5 of treatment with bright light therapy were twice as likely to experience remission of depression at follow-up than those who did not experience a change (15).
	• In a randomized, double-blind study involving 90 patients with major depression and insomnia, transcranial direct current stimulation of the dorsolateral prefrontal cortex improved symptoms of depression and anxiety and had a positive effect on sleep quality (91).

For patients with mood disorders and significant insomnia or hypersomnia that does not respond to appropriate pharmacotherapy or for those with known comorbidities such as restless legs syndrome or obstructive sleep apnea syndrome, it is necessary to treat the concomitant primary sleep disorders.

Repetitive transcranial magnetic stimulation (rTMS) seems to exert direct effects on both mood and sleep in patients with major depressive disorder, regardless of age, sex, sedative-hypnotic use, number of rTMS treatments, depression severity, and changes in depressive symptoms (18).

Outcomes

Stress and depression symptoms should be considered risk factors that play an important role in the long-term outcome of cognitive behavioral therapy (73). Patients with insomnia who had stress and depression symptoms maintained the highest percentage of clinical depression at the end of treatment and insomnia at follow-up in comparison with others classes.

A depressive mood disorder in patients with moderate/severe obstructive sleep apnea impairs the rate of initial acceptance of CPAP treatment (24) and many authors reported a decrease in symptoms of anxiety and depression from baseline to follow-up of CPAP treatment. The improvement in symptoms of depression was depending on CPAP adherence (50), with a trend toward greater reduction in those with high CPAP adherence (83).

Special considerations

Very few studies have examined the directionality of the sleep-depression link in children. In a large ongoing population-based longitudinal study, the Norwegian Mother, Father and Child Cohort Study, a total of 35,075 children were included. Short sleep duration (≤10 hr) and frequent (≥3) nightly awakenings at 1.5 years predicted the development of depressive symptoms at 8 years of age. Also, internalizing problems at 1.5 years predicted onset of later short sleep duration after accounting for early sleep problems (77).

Pregnancy

Insomnia during the perinatal period associated with depressive symptoms warrants screening pregnant mothers for insomnia and depression (25).

Poor sleep quality and depression are prevalent during pregnancy and may negatively impact maternal and fetal outcomes, including perinatal depression, gestational diabetes, preeclampsia, and preterm birth (30). In addition, in a study on 267 pregnant women, high rumination and insomnia were associated with depression and suicidal ideation (40). Different BMI status and gestational age impact sleep habits, depression, and anxiety/stress levels (64).

The use of antidepressant or mood-stabilizing medications during pregnancy depends on a careful risk-benefit analysis of treatment, addressing the potential risk to the fetus from teratogenic effects (including neurobehavioral teratogenesis) as well as untreated depression in the mother. Limited data suggest that appropriately timed bright light therapy may be an effective treatment of depression during pregnancy.

Depression can occur in the postpartum period, with symptomatology similar to non-postpartum depressive episodes. A systematic review found a strong relationship between postpartum sleep disturbance and postpartum depression, especially in educated, middle class females older than 30 years of age (09).

Preliminary evidences suggest that digital cognitive behavior therapy for insomnia use during pregnancy may prevent postpartum depression and anxiety (26).