The study of human sleep is a remarkably young field. Until the 1930s, sleep was viewed as a passive state during which the brain was “turned off.” As such, there was little interest in further characterization of normal sleep or exploration of sleep disorders. In 1937, A. L. Loomis first described the characteristic electroencephalographic patterns of the stages of NREM sleep, challenging the notion of sleep as a homogeneous and passive state.¹ This was followed in 1951 by the discovery of REM sleep and its correlation with dreaming.² A schema of sleep architecture consisting of repeated cycles of NREM and REM sleep was formulated shortly thereafter, a concept that has persisted largely unchanged into the modern era of sleep medicine.

Discovery of the electroencephalographic substrate of sleep prompted increasing curiosity about sleep physiology. Overnight polysomnography—a technique of simultaneous recording of sleep EEG, respiratory parameters, and muscle activity—was developed and employed to describe normal and abnormal sleep patterns (Fig. 18-1). During the second half of the twentieth century, polysomnographic characterization of obstructive sleep apnea (OSA), insomnia, periodic leg movements of sleep (PLMS), REM behavior disorder (RBD), and narcolepsy facilitated improved understanding of the pathophysiology of these disorders and expanded treatment options.

In addition to its utility in primary sleep disorders, polysomnography was also applied to the study of a variety of neurological and psychiatric conditions. In patients with depression, consistent abnormalities of sleep architecture were identified.³ These included shortened REM latency (time from sleep onset to the first episode of REM), prolongation of the first REM period, and increased density of eye movements during REM. These observations led to the hypothesis that “disinhibition” of REM sleep may play a role in the pathophysiology of depression. Furthermore, REM abnormalities may constitute a biomarker that predicts the onset of new depression and increased vulnerability to relapse in remitted patients.⁴ Thus, the abnormalities in sleep seen in depressed patients may not be merely incidental but may be closely tied to the precipitation and perpetuation of the illness.

In light of these significant sleep abnormalities in depressed patients, primary sleep disorders may also be expected to affect mood. Indeed, a markedly increased risk for depression has been identified in a variety of sleep disorders, including insomnia, OSA, and restless legs syndrome (RLS), among others. Recognition of these epidemiologic links has spawned further research into the pathophysiologic and prognostic implications of sleep disorders in depressed patients, investigations that have improved understanding of both conditions. In this chapter, we discuss the bidirectional and complex relationships between sleep disorders and depression. Although much is known about the depression–sleep disorder relationship, much less is known about the additional influence of concurrent medical illness on this relationship. We first address epidemiologic associations between the various sleep disorders and depression. This is followed by an exploration of shared pathophysiology among these disorders. We then consider aspects of the presentation and management of depression that are particular to patients with sleep disorders. When applicable, the impact of depression and its treatment on sleep are also considered.

INSOMNIA

Insomnia encompasses difficulty initiating sleep, difficulty maintaining sleep, and/or unrefreshing sleep, coupled with daytime impairment. Although in the past insomnia was often viewed as a symptom of depression likely to resolve with treatment of the mood disorder, recent research has focused on insomnia and depression as two independent diagnostic entities with distinct (but interrelated) characteristics and courses.⁵

Insomnia is likely both a cause and a consequence of depression, so understanding their epidemiologic relationship requires longitudinal descriptions of comorbidity. Many studies have examined insomnia symptoms as a predictor of major depression disorder (MDD). In a recent meta-analysis, the overall odds ratio of new-onset depression in individuals with insomnia compared to those without insomnia was 2.60 (CI: 1.98–3.42).⁶ The incidence of new-onset depression during the follow-up period was 13.1% in the insomniacs compared to 4.0% in the group without sleep complaints.

Although the data are fewer, depression also appears to be a risk factor for new-onset insomnia. In one large survey, participants with depression but without insomnia at baseline had an OR of 6.7 of developing insomnia at 10-year follow-up.⁷

Several studies have attempted to tease out the directionality of causation between insomnia and depression. Ohayon and Roth surveyed nearly 15,000 people from the general population about sleep and psychiatric symptoms. In a large survey of the general population, insomnia symptoms preceded a first episode of a mood disorder 41% of the time, while they occurred concurrently in 29% of cases, and followed the onset of the mood disorder in another 29% of cases.⁸ This study was limited by its cross-sectional nature and its reliance on subjects to recount the order of symptom appearance. Still, these findings highlight the strongly bidirectional relationship between the two disorders.

Although most patients with MDD report difficulty sleeping, a substantial minority report “hypersomnia,” and this descriptor is included in the DSM 5 as a symptom of MDD. Rates of hypersomnia in MDD vary widely across studies, likely due in part to variable definitions of the term.⁹ As with insomnia, hypersomnia predicts both new-onset MDD and relapse of MDD.¹⁰ Despite considerable literature about the prevalence of hypersomnia in MDD, few studies have established whether this subjective complaint corresponds to an objectively assessed increased propensity to sleep. Patients may have difficulty distinguishing between fatigue, avolition, and psychomotor retardation that compel them to spend excessive amounts of time in bed and true increased sleep pressure or excessive total sleep time.¹¹ It is incumbent on the clinician to do so, however, since true sleepiness should prompt investigation for a primary sleep disorder.

OBSTRUCTIVE SLEEP APNEA

Obstructive sleep apnea (OSA) is a syndrome of repetitive partial or complete airway collapse during sleep. The consequent airflow obstruction may cause oxygen desaturation and/or sleep disruption. OSA is commonly comorbid with MDD. Estimates of the prevalence of depression among OSA patients vary widely from 7% to 63%. In the National Health and Nutrition Examination Survey, snorting/stopping breathing ≥5 nights/week compared to never was strongly associated with probable major depression in men (OR = 3.1; CI: 1.8–5.2) and women (OR = 3.0; CI: 1.6–5.4).¹² Conversely, in one cross-sectional telephone survey, 18% of individuals with a diagnosis of MDD also reported symptoms consistent with probable OSA.¹³ After controlling for known shared risk factors, the odds of sleep-disordered breathing was 5.26 (CI: 4.29–6.47) for those with MDD compared to those without MDD.

RESTLESS LEGS SYNDROME

Restless legs syndrome is another common sleep disorder frequently associated with depression. RLS is characterized by a strong urge to move the legs that is provoked by rest, relieved with movement, and worst in the evening or at night. The lifetime prevalence of MDD or dysthymia has been reported to be 36.9% in RLS patients compared to 15.2% in a control group drawn from the general population.¹⁴ The majority (77%) reported that RLS symptoms preceded depression. Another cross-sectional analysis described increasing risk for RLS as the PHQ-9 score increased.¹⁵ The issue has also been examined longitudinally using data from a large, long-term, prospective study. Women with RLS but no depression at baseline were more likely to develop subsequent depression at 6-year follow-up (RR = 1.5; CI: 1.1–2.1).¹⁶ Conversely, depressive symptoms at baseline were a risk factor for incident RLS.¹⁷ As in the case of insomnia, RLS and depression appear to have a bidirectional relationship.

The majority of RLS patients experience periodic limb movements of sleep (PLMS). PLMS are repetitive (usually every 20–40 sec) episodes of stereotyped limb movements during sleep that are often associated with EEG arousals. Both nighttime RLS symptoms and PLMS may compromise sleep quality and quantity and account for a proportion of the association between RLS and depression.¹⁸ However, sleep disruption does not seem to be entirely explanatory. In a large cohort of patients with chronic kidney disease (CKD), Szentkiralyi and colleagues found that those with probable RLS had a higher prevalence of depressive symptoms than those without RLS (56% vs. 22%, p<0.001), and this relationship remained significant after accounting for insomnia, indicating that mechanisms independent of sleep disruption may also contribute to the association between RLS and depression.¹⁹

OTHER SLEEP DISORDERS

Shift-work sleep disorder (SWSD) occurs in patients who complain of insomnia or excessive sleepiness that is temporally related to work hours scheduled during the usual sleep period. Although such a schedule universally produces circadian misalignment, a minority of shift workers (8–15%) have extreme difficulty adapting, that is, SWSD.²⁰ In one cross-sectional analysis, nearly one-third of patients with SWSD also carried a diagnosis of MDD.²⁰ Notably, the increased risk for depression in this analysis was specific to those with symptoms of SWSD (insomnia and/or excessive sleepiness) and did not appear to be a consequence of shift work itself.

Nightmare disorder is another sleep disorder that is commonly comorbid with MDD. In one study, three-quarters of individuals with MDD reported having nightmares at least twice per week.²¹

Narcolepsy is a disorder of excessive daytime sleepiness with frequent psychiatric comorbidity, including increased rates of depressive symptoms.²² Prevalence using self-report scales in various studies ranges from 15% to 30%.²³ Using formal psychiatric interview, Fortuyn and colleagues did not find an over-representation of MDD but did find high rates of depressive mood (30%), pathological guilt (22%), crying (25%), and anhedonia (27%), suggesting that narcoleptic patients may experience a subsyndromal form of depression.^22,24

A complicating factor when quantifying the association between depression and sleep disorders is their myriad shared risk factors. Obesity, lack of physical activity, and low socioeconomic status are a few of the more obvious confounders. Many of the multivariate models described above have attempted to account for these. However, in consideration of the likelihood of residual confounding, these data should be interpreted with caution.

Several lines of evidence suggest common pathophysiological mechanisms underlying sleep disorders and depression (Box 18-1). Although the link has been most thoroughly explored in insomnia, some abnormalities are shared across a range of sleep disorders. These may reflect causal relationships and/or consequences of sleep disruption itself rather than markers of a specific illness. For the most part, the directionality of these relationships remains an open question.

AROUSAL AND STRESS

Hyperarousal is a crucial element in the development and perpetuation of insomnia. It is evident as autonomic activation (increased heart rate, decreased heart rate variability), elevated stress hormones (e.g., cortisol and norepinephrine), higher metabolic rate (increased VO₂ and brain metabolism), electroencephalographic arousal (increased high-frequency beta activity), and behavioral evidence of decreased sleep propensity (increased latency to sleep on the MSLT) (Fig. 18-2).^25–27 Although the data are fewer, recent research also points toward a pattern of hyperarousal in RLS.²⁸

Somatic arousal has also been classically postulated as a component of the tripartite model of depression.²⁹ Recently, novel EEG analysis techniques have demonstrated hyperstable vigilance in MDD, suggestive of tonic CNS arousal.^30,31 As further evidence of physiologic arousal, autonomic activation is evidenced by decreased heart rate variability, an abnormality that correlates with the severity of depression.³² Plasma norepinephrine levels are also increased in untreated MDD patients and normalize with treatment.³³ Dysfunctional HPA axis regulation is manifest as diminished amplitude of diurnal cortisol rhythms and impaired cortisol suppression following dexamethasone challenge.³⁴

Although other sleep disorders are more often marked by sleepiness rather than hyperarousal, the profile of prolonged stress response (sympathetic nervous system activation and HPA axis dysregulation) is also common to other sleep disorders. Both autonomic abnormalities and hormonal markers of stress have been examined in OSA. Abnormally decreased heart rate variability³⁵ and elevated cortisol levels³⁶ are both consistent features of OSA that improve with continuous positive airway pressure (CPAP) treatment. Muscle sympathetic nerve activity (MSNA) is another measure of sympathetic activation. OSA patients demonstrate elevation in MSNA that correlates with the degree of sleepiness and improves in parallel with reduction in sleepiness during treatment.^37,38 Similarly in MDD, elevated MSNA correlates with the severity of depression and improves with antidepressant treatment.³⁹ Finally, inflammatory cytokines, including IL-6 and TNF, are elevated in both MDD and OSA—an abnormality closely tied to the increased cardiovascular risk seen with both disorders.^40,41

IMAGING DATA

Brain imaging provides further evidence of shared pathophysiology between depression and sleep disorders. Using structural MRI, the hippocampus is consistently smaller in patients with MDD compared to normal controls.⁴² Abnormalities in hippocampal volume have also been shown in several sleep disorders, including narcolepsy and insomnia.^43,44,45 Proton magnetic resonance spectroscopy (1 H-MRS) is a type of MRI developed to measure levels of neurotransmitters in vivo. Using this technique, decreased gamma aminobutyric acid (GABA) in the occipital and prefrontal cortices has been a consistent finding in MDD. Similar reductions in whole brain and regional GABA have been demonstrated in insomnia patients in some⁴⁶ but not all investigations⁴⁷ and may reflect common neurochemistry between insomnia and depression.⁴⁶

Obstructive sleep apnea patients also exhibit abnormalities by both structural and functional imaging. Changes in the cingulate, frontal cortex, hippocampus, insular cortex, cerebellum, and amygdala overlap with findings in MDD.^48–50 The hippocampus is of particular interest because there are data suggesting that hypoxia due to OSA plays a causative role in damaging this area.^48,51 These findings highlight the potential detrimental interactions between depression and OSA.

NEUROTROPHINS

The neurotrophic model of depression postulates that dysfunctional neuroplasticity and remodeling contribute to the pathophysiology of depression. Brain-derived neurotrophic factor (BDNF) has been the most extensively studied neurotrophin. BDNF levels measured in the serum are decreased in depressed subjects relative to controls,⁵² and a functional polymorphism in the pro-BDNF gene is associated with increased risk of MDD and may mediate hippocampal atrophy.^53,54 BDNF during sleep has been shown to play a role in the generation of slow wave oscillations that mediate neuronal plasticity.^55,56 Deficits in slow wave sleep have been reported in insomnia,^57,58 and a recent study demonstrated decreased serum BDNF in insomnia patients.⁵⁹ This deficit was proportional to the severity of sleep disturbance. It is possible that decreased BDNF reflects common pathophysiology underlying the disorders, or insomnia may mediate the abnormalities seen in depression. As the authors suggest, sleep abnormalities could explain inconsistency in reports of BDNF changes during depression treatment. These relationships illustrate the subtlety and complexity of the pathophysiologic links between depression and insomnia.

PRESENTATION OF COMORBID DEPRESSION AND INSOMNIA

Patients with insomnia may experience distress due to fears of sleeplessness, preoccupation with the daytime consequences of poor sleep, guilt about the use of hypnotics. People with chronic insomnia report lower SF-36 scores in each of eight domains compared with good sleepers (p<0.001).⁶⁰ Compared to those without insomnia, insomniacs report greater impairment in all areas (energy, mood, concentration, relationships, work, and ability to stay awake).⁶¹

Major depressive disorder occurring in insomniacs tends to be more severe compared to depression in those without sleep complaints. In a study by O’Brien et al., 1,057 patients with a principal diagnosis of MDD were evaluated using the Structured Clinical Interview for DSM-IV Disorders (SCID), Schedule for Affective Disorders (SADS), and self-report measures of mood and psychosocial functioning.⁶² One quarter of patients with MDD have been found to have severe insomnia. These severe insomniacs, in comparison to those without severe insomnia, were older at the time of presentation, less likely to be married, less educated, had poorer social functioning, and had more severe depressive symptoms.

The presentation of insomnia is also influenced by depression. Insomnia symptoms can be divided into difficulty initiating sleep, middle-of-the-night insomnia, early morning waking, and/or nonrestorative sleep. Although it is commonly held that MDD is characterized particularly by early morning awakenings, this has not been the case in research samples. In a large study of patients with MDD, the most common presentation was the simultaneous presence of sleep onset, middle-of-the-night, and early morning insomnia symptoms (27.1%). Of these three types of insomnia symptoms, mid-nocturnal insomnia symptoms were the most commonly found alone (13.5%) and in combination with one or more other types (82.3%) (Fig. 18-3).⁶³ Another study found shorter sleep duration in depressed compared to nondepressed insomniacs.⁶⁴ These findings indicate that depression is associated with increased severity of insomnia.

PRESENTATION OF COMORBID DEPRESSION AND OSA

As in insomnia, patients with sleep apnea frequently experience distressing emotional consequences and reduced quality of life. Fear of dying as well as the physical effects of sleep deprivation, oxygen desaturation, and hypercarbia may all play a role. The severity of hypoxia and the degree of excessive daytime sleepiness are independent predictors of reduced quality of life in patients with severe OSA.⁶⁵

The presence of depression affects the presentation of OSA. Depressed OSA patients tend to present with more prominent sleepiness than those without depression.⁶⁶ Indeed, one study found that the presence of depression correlated more strongly with sleepiness than did the severity of sleep apnea. OSA severity explained 4.2% of variance in sleepiness while depressive symptoms explained an additional 42.3%. In another cross-sectional evaluation of patients with REM-related OSA (in which the severity of sleep apnea does not correlate well with sleepiness), depressive symptoms were associated with worse quality of life and elevated sleepiness scores.⁶⁷

Patients with RLS also report poorer health-related quality of life in all physical domains as well as in the Mental Health and Vitality domain.⁶⁸ In RLS patients with MDD, the frequency of RLS symptoms has been associated with depression severity.¹⁶

Given the association between various sleep problems and the severity of depression at presentation, it is not surprising that sleep disturbance also predicts a more prolonged course of the mood disorder with more negative consequences. Suicidal thoughts and behaviors have been the focus of much attention. Sleep disturbances (in particular insomnia and nightmares) consistently predict both suicidal ideation and suicide attempts. This association persists after adjustment for depression severity and other psychiatric comorbidity. One meta-analysis found that the presence of any sleep disturbance increased the risk of suicidal ideation (RR = 1.86), suicide attempts (RR = 2.01), and completed suicide (RR = 1.96).⁶⁹ There were insufficient data to draw definitive conclusions about the differential risk associated with specific sleep disorders. Not all participants carried a diagnosis of MDD, but the lack of a modifying effect of depressive symptoms indicates that this association is likely to hold in both depressed and nondepressed patients.

The course of both depression and sleep disorders is often marked by absenteeism from work or school and short- and long-term disability. Thus, both insomnia and OSA are independent predictors of subsequent long-term sick leave.⁷⁰ Insomnia is also a risk factor for days out-of-role⁷¹ and delay in returning to work among those on sick leave.⁷² Depression is also a major cause of disability.^73,74 Most evidence suggests that insomnia and depression independently increase the risk of absenteeism-related outcomes, with the highest risk occurring in those with both conditions.^71,72 In addition to the lost productivity, the absence of a regular daily schedule is likely to perpetuate sleep problems, and lack of structure and social stimulation may perpetuate depression. Thus, depression, insomnia, and disability status are mutually exacerbating conditions that likely prolong the course of all three.

Sleep problems often persist in patients whose depression has remitted. In a large sample of patients whose depression was in remission, insomnia was found in 19.3% and nightmares in 9.3%.⁷⁵ Those with residual sleep disturbance were also more likely to have persistent anxiety (Box 18-2) symptoms. Another study found a significantly higher rate of insomnia (53%) among remitters when any positive response on the HAM-D insomnia items was included. Among this group, residual insomnia was associated with persistent social and occupational functional impairment.⁷⁶

Given the association between insomnia and new-onset depression, several investigators have examined the effect of residual insomnia symptoms on the risk of relapse to MDD. In two studies of patients with late-life depression,^77,78 insomnia increased the risk of relapse, but another study did not replicate this finding in younger patients.⁷⁹