© Springer Science+Business Media, LLC 2015
Sudhansu Chokroverty and Michel Billiard (eds.)Sleep Medicine10.1007/978-1-4939-2089-1_3838. Depression
(1)
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
(2)
VA MIRECC Fellowship Program, VA Palo Alto, Palo Alto, CA, USA
Keywords
InsomniaMajor depressive disorderBipolar disorderSleep-disordered breathingNarcolepsyRestless leg syndromeIntroduction
Sleep has long been recognized as an associated feature of psychiatric conditions. The Diagnostic and Statistical Manual of Mental Disorders [1] (DSM-IV) includes some form of disordered sleep in the diagnostic criteria of a variety of mood, anxiety, and cognitive disorders. Furthermore, on a subclinical level, most people can attest to the subjective mood and cognitive disturbance following even one night of sleep loss. Although conventional now, the connections between psychopathology and sleep were not explored until the 1900s. The first to brave the unchartered intersections of sleep and emotions was Sigmund Freud. He posited that dreaming was a vehicle for the expression of intolerable wishes that waking life could not entertain [2]. Despite its scientific limitations, Freud’s interpretation of dreams provided the foundation for both scientific and popular conceptions of sleep.
As a graduate student interested in psychiatry, a young William Dement worked in the lab of physiologist Nathaniel Kleitman, who had pioneered the empiric study of sleep. Dement’s hope was to apply the newly established objective measures of sleep to evaluate the speculations of psychoanalysis. With time, Dement’s interests became far more extensive, encapsulating many sleep avenues. With the help of Christian Guilleminault, Mary Carskadon, and Vincent Zarcone, Dement went on to found the first Sleep Clinic at Stanford University in the Department of Psychiatry, and he became an outspoken advocate for the recognition and treatment of sleep disorders [3].
Sleep Deprivation and Mood
Early investigations of sleep were descriptive, attempting to outline sleep fundamentals. Guilleminault et al. [4] noted a higher than expected prevalence of depression and anxiety in men presenting with sleep complaints. These symptoms were in part attributed to a “repetitive sleep deprivation syndrome,” and the physiologic consequences of sleep-disordered breathing [5]. Early sleep researchers expected that the psychological consequences of sleep loss were restricted to selective deprivation of REM sleep, following Freud’s theory [4]. However, patients who were awoken mid-non-REM (NREM) sleep displayed similar effects on mood, so it appeared sleep’s impact on mood was not specific to dysfunctional dream sleep [4]. One meta-analysis found that, overall, sleep deprivation appears to have the greatest impact on mood, followed by repercussions on cognitive tasks [5]. Motor performance was shown to be the least affected by sleep deprivation, though the effect size was still large (− 0.87) [5]. Furthermore, partial sleep deprivation (< 5 h/24 h period), rather than short- or long-term total sleep deprivation, exacted the most acute influences on mood and cognition [5].
The 1970s presented a shift in sleep deprivation research, as sleep deprivation revealed antidepressant effects when applied to people with endogenous depression [6, 7]. One study found significant improvements on multiple objective and subjective mood and cognition ratings in patients with endogenous depression after one night’s sleep deprivation, compared to controls [8]. Controls, however, did depict elevated “dysphoria” and “activation” scores under identical procedures [9]. Given the immense effort required to maintain the wakefulness required of sleep deprivation, it was not considered a practical treatment option [9]. Even partial sleep deprivation was found to be too difficult and not potent enough to institute [10]. Regardless, more than 50 % of individuals do achieve an antidepressant response to sleep deprivation [10]. The response is transient as 83 % will relapse after a night of recovery sleep [10], and as such, is little used today.
Sleep Architecture Changes with Depression
Sixty to ninety percent of individuals with major depressive disorder (MDD) report disrupted sleep [11]. The 1960s introduced clinical recognition of the link between sleep and psychiatric conditions, spurring researchers to investigate the relationship of sleep to the cardinal mood disorder, depression [12]. Initial attempts were unsuccessful in finding a unifying model of the interaction of depression and sleep [13]. Subjective ratings of sleep were not able to explain the cause of depressive symptomatology to a satisfactory degree [13]. Some depressed patients presented chronic insomnia, with increased sleep latency and decreased sleep efficiency. Others presented hypersomnia, sleeping 10–14 h in a 24-h period.
As the field of sleep medicine progressed within the scientific community and the technology became more refined, psychiatrists started to turn to the objective techniques of the burgeoning field in an attempt to understand why so many of their depressed patients complained of difficulties with sleep. Some hoped that sleep in itself would become a biomarker for the disease [14, 15]. With the use of polysomnography (PSG) and electroencephalography (EEG) to characterize sleep stages, shortened REM latency was discovered as a hallmark feature of endogenous depression, with the interval length correlating with the severity of depression [14, 15].
These EEG distinctions presented an opportunity for predicting treatment response. Initially, in studies with patients with depression, it was found that taking tricyclic antidepressants (TCAs) lead to greater suppression of REM, which in turn lead to a greater response to treatment [16]. This finding was confirmed when persistent prolonged REM latency exhibited a sustained response to treatment [17]. Furthermore, the same group found that prolonged sleep latency and shorter REM latency together were best able to predict response to treatment [18].
Over time, further abnormalities of sleep architecture have been substantiated in depression, including decreased slow wave sleep (SWS), increased REM density, prolonged sleep latency, increased fragmentation, and decreased sleep efficiency [19]. For a period, there was an active debate as to which variable was central to depression—REM or SWS changes [18]. However, a groundbreaking meta-analysis by Benca et al. [20] later demonstrated that reduction in REM latency was not specific to depressive disorders. She showed that while no specific sleep finding was pathognomonic for a specific psychiatric condition, there were consistent differences seen, especially when patients with affective disorders are compared with control groups [20].
More recently, researchers have started evaluating sleep microarchitecture utilizing specialized technology. Such techniques allow a finer analysis of the waveforms present in the EEG; shapes that are unable to be appreciated or quantified using the naked eye, but can be distinguished using various computer techniques. Like studies of the sleep macroarchitecture in depression, the results have been mixed [18]. Some studies have found alterations in SWS [21], whereas some found significant SWS patterns are restricted to male depressed sleepers [22]. Others have noted patients with MDD have less beta frequency percentage relative to patients with insomnia or controls [23]. Indeed, distinct microarchitectural patterns were found among patients with insomnia and those with coexisting depression and insomnia [24].
Sleep Disorders and Mood Disorders
Insomnia
Previously, insomnia was considered secondary to either a medical condition or psychiatric condition, and classically it was taught that treatment of the primary condition would; therefore, improve the disordered sleep disturbance [25]. However, with time, research has illustrated a more bidirectional relationship [23], and treatment of disturbed sleep has been recognized as warranting independent clinical attention [10, 26, 27].
Epidemiologic studies have shown that those with insomnia are at an increased risk of developing depression. One prospective epidemiologic study demonstrated that patients with persistent insomnia had three times the risk of developing depression when compared to those whose insomnia resolved [28]. Another epidemiologic study confirmed a sustained, elevated risk for depression lasting 34 years, for those experiencing a bout of insomnia in medical school [29]. In addition, poor sleep quality was related to the development of depressive symptoms with interferon treatment [30], and some studies have suggested an overlap of the genetics of insomnia, depression, and anxiety [31]. Furthermore, sleep disturbance has been shown to be the most common residual symptom following remission of depression [32] and reoccurrence of insomnia may herald recurrence of depression [33].
More recently, a body of literature describing the relationship of sleep disruption to suicidality has emerged. Krakow et al. [34] noted elevated self-reported suicidality in young women with a history of sexual assault, with the greatest incidence in women with symptoms of sleep-disordered breathing or movement disorders. Similarly, in patients with MDD, both insomnia and hypersomnia predict suicide risk [35]. Subjective report of insomnia in particular has been related to increased risk for suicide [36], with one meta-analysis finding a relative risk of having suicidal behavior in the presence of sleep disturbance ranging from 1.95–2.95 [37].
Similar to MDD, sleep disturbance has been implicated in the pathology of bipolar disorder (BD) . One of the hallmark features of a manic episode is the “reduced need for sleep” [1], which has been described in 69–99 % of subjects while undergoing a manic episode [38]. Gruber et al. [39] found similar results when they analyzed sleep variables in 468 subjects in the National Institute of Mental Health’s Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). They found lower total sleep time (TST) and increased sleep variability were associated with more severe manic symptoms [39]. Research on BD has associated mania’s sleep disruption with an instable circadian rhythm due to genetic and social factors [38]. Beyond an emanation of mania, insomnia, and its resulting sleep disruption have been demonstrated to be one of the most robust prodromal symptoms of the onset of a manic episode. Jackson et al. [40] reviewed 73 publications on early signs of mania onset, and identified sleep disruption as the most common symptom of an impending episode. Conversely, just as sleep disruption is associated with the onset and occurrence of mania, improved sleep functioning has been associated with increased BD remission over the course of treatment [39]. One study by Nowlin-Finch et al. [41] used a blinded chart review protocol in an inpatient manic BD group to find that greater TST on the first night of hospitalization was associated with faster response to treatment and earlier discharge. As a result of this association between sleep disturbance and mania , many psychological treatments for BD incorporate components of psychological treatments for insomnia [38].
Beyond BD, there is consistent evidence that the circadian rhythm plays a role in mood disorders. Both depression and BD can manifest variation based on time, whether seasonal differences or diurnal waxing of symptoms [42]. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) allows for a seasonal pattern specifier on both MDD and BD [1]. For MDD, the seasonal pattern leads to symptoms in the winter season, with full remission during other times of the year [1]. The DSM-IV describes seasonally patterned MDD as usually characterized by hypersomnia [1]. Nevertheless, some studies have documented high reports of combined hypersomnia–insomnia or insomnia alone in subjects with seasonally patterned MDD [43−45] In one of the largest studies on this issue, Øyane, et al.’s [44] group of 8860 subjects found insomnia and fatigue to be the most frequent complaints in participants with high seasonal depressive fluctuations, relative to medium and low seasonal depressive fluctuations. As a result, the authors propose two clinical subgroups of seasonally patterned MDD, one presenting the traditional hypersomnia and one presenting insomnia [44].
Sleep-Disordered Breathing
Clinical studies over the past several decades suggest the existence of a relationship between depression and sleep-disordered breathing, particularly obstructive sleep apnea (OSA) . OSA is by far the most common form of sleep-disordered breathing . It is defined by frequent episodes of obstructed breathing during sleep and is characterized by sleep-related decreases (hypopneas) or pauses (apneas) in respiration. The diagnosis of OSA is confirmed when a PSG recording determines an apnea–hypopnea index (AHI) of > 5/h of sleep.
Among the first studies investigating the relation between OSA and depression, Guilleminault et al. [46] reported that 24 % patients with OSA had previously seen a psychiatrist for anxiety or depression. Reynolds et al. [47] also found approximately 40 % of OSA patients met the research diagnostic criteria for an affective disorder. While not all studies have observed a significant association between sleep apnea and depression [48], many investigations of OSA patients have been observed to have higher levels of depressive symptoms [49, 50]. OSA and depression share common risk factors, which may partly explain their high comorbidity in the general population, including obesity, cardiovascular disease , hypertension, and diabetes . Older adults have been observed to have higher rates of both OSA and depression, further underscoring the potential of comorbid medical disorders, so common in the elderly for explaining the association of OSA and depressive symptoms [50]. In a large epidemiological study of 18,980 subjects representative of the general population in their respective countries (UK, Germany, Italy, Portugal, and Spain) and assessed by telephone survey, Ohayon [51] found 17.6 % of subjects with a DSM-IV breathing-related sleep disorder diagnosis also presented with a MDD diagnosis , and vice versa, after controlling for obesity and hypertension.
In one of the most comprehensive investigations of this issue, Peppard et al. [52] conducted a population-based epidemiological study to examine if sleep-disordered breathing was a longitudinal predictor of subsequent depression. This study had a sample of 788 men and 620 women randomly selected and evaluated for sleep apnea with in-laboratory PSG and for depression with the Zung depression scale, assessed at 4-year intervals. The authors found an increase of one sleep-disordered breathing category, e.g., from minimal to mild OSA, to be associated with a 1.8-fold increased adjusted odds for developing depression. Their findings provide evidence for a dose–response association between sleep apnea and depression and suggest a potential causal link between these conditions .
Two factors hypothesized to be responsible for depressive symptoms in OSA are sleep fragmentation and oxygen desaturation during sleep, but systematic studies examining these components in OSA patients with depression are limited. Preliminary imaging data suggest that OSA-associated hypoxemia may result in cerebral white matter hyperintensities (WMH), which in turn have a negative impact on mood. Aloia et al. [53] found more subcortical WMH in the brain magnetic resonance imaging (MRI) of patients with severe OSA, and a tendency for a positive correlation between these subcortical hyperintensities and depression scores on the Hamilton Depression Scale. On the neurotransmitter level, the serotoninergic system has a central role as a neurobiological substrate of mood and sleep regulations, in addition to upper airway muscle tone control during sleep. More recently, in nondepressed subjects, the serotonin transporter polymorphism long allele has been found to be associated with increased levels of OSA, suggesting a potential common biological mechanism for OSA and depressive symptoms [54].
Molecules increasing 5-HT neurotransmission such as the serotonin reuptake inhibitors (SSRI) are widely prescribed and are suggested to improve OSA. However, serotoninergic drugs have already been tested for OSA, with limited success and numerous adverse effects [55]. Several 5-HT receptor ligands and bifunctional molecules are under development, which may in the future be able to target both—the depressive syndrome and OSA.
In sum, the extant literature underscores the existence of a complex relationship between OSA and depression with respect to clinical presentation, treatment, and underlying pathophysiology. Given that up to 20 % of all patients presenting with diagnosed OSA may also have depressive syndrome, sleep medicine practitioners should be careful to assess for depression in patients with OSA. Further, the relationship of OSA to depressive symptoms may vary, depending on age, gender, and health characteristics of OSA patients. Future clinical research and basic research studies are required to more fully characterize the relationship between depression and OSA, as well as the potential mechanisms by which both disorders may interact .
Narcolepsy
As a disease, narcolepsy has contributed much to the history of sleep medicine. After it was first described, narcolepsy was proposed to have both a primary and secondary etiology, which could include a psychosomatic component [56]. In 1960, Vogel [57] discovered short REM latencies in patients with narcolepsy, arising from an interest in validating psychoanalytic concepts of sleep and dreams. In fact, when Dement first started the Sleep Clinic at Stanford University, characterizing narcolepsy was one of his primary goals [3].
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