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by Daniel J. Buysse INTRODUCTION
Examining these associations has led to an improved understanding of the neurobiology of psychiatric disorders, as well as to insights regarding the functions of sleep and circadian rhythms. This review will focus on the associations between depression and disturbed sleep and circadian rhythms because this disorder has been studied most extensively. SUBJECTIVE SLEEP COMPLAINTS
Conversely, a high percentage of individuals with sleep complaints also have a mood disorder. Epidemiologic and cohort studies indicate that 35-50% of individuals with insomnia or hypersomnia also met criteria for a current mood or anxiety disorder, compared to 15-20% of individuals with no sleep complaint.12 14 Among patients referred to sleep disorders centers for chronic insomnia, psychiatric disorders (and in particular, mood and anxiety disorders) are identified as the major cause in 35-46% of cases.15,16 Further evidence suggests that insomnia is actually a risk factor for the new onset of depression. Ford and Kamerow reported that persistent insomnia complaints were a significant risk factor for incident mood disorders during a one-year follow-up, with an odds ratio of 39.8.12 A subsequent study found that individuals with a prior history of insomnia had a fourfold increase in the relative risk for incident depression over a 3½-year follow-up interval, even after controlling for the presence of other depressive symptoms at baseline.17 POLYSOMNOGRAPHIC SLEEP FINDINGS
The above findings have been described using both visually-defined sleep stage scoring, as well as quantitative measures such as period-amplitude analysis and power spectral analysis. Although each of these findings are characteristic of major depression, most patients do not have each feature, and no single finding can be considered a sensitive or specific marker of depressive disorders. In a meta-analysis of polysomnographic findings in psychiatric disorders, Benca et al23 found that REM sleep measures were consistently more abnormal in patients with MDD compared to patients with other diagnoses (Table 1). A number of clinical and historical features may influence EEG sleep findings in depressed patients, including age,28-35 sex,36,37 severity of depression,10, 38-44 depression history and clinical characteristics,45-49 and depression subtype.50-58 Seasonal affective disorder (SAD) deserves special mention because of the hypothesized links between this form of depression and circadian/ sleep dysregulation. Typically, patients with SAD are described as having hypersomnolence during their winter depressions. Studies using self-report questionnaires and prospective sleep diaries have found a significant increase in sleep duration and difficulty awakening during winter months, at times when patients are symptomatic.59 61 However, sleep duration correlates poorly with overall symptom severity.59,61 Polysomnographic studies of symptomatic SAD patients show reduced sleep efficiency, reduced Stage 3/4 percentage, and increased REM density (as in other forms of depression), but less evidence of reduced REM sleep latency.61 Successful treatment with bright light does not reliably alter EEG sleep measures, even though patients report less hypersomnia following treatment.62,63 SLEEP DEPRIVATION STUDIES IN DEPRESSION
One of the vexing features about sleep deprivation as a therapeutic tool in depression is the fact that recovery sleep, whether taken as a nap or as the following night's sleep, leads to a complete relapse of symptoms. The sleep stage composition of nap sleep does not appear to influence this relapse, although afternoon naps are more often associated with relapse compared to morning naps.74,75 Consequently, various investigators have tried to maintain sleep deprivation's therapeutic effects by conducting serial partial sleep deprivations,76 79 combining sleep deprivation with antidepressant drugs,80 82 and combining sleep deprivation with a subsequent phase advance of the sleep cycle.83
One possible explanation for the subjective and polysomnographic sleep findings in depression is that they are part of a larger disturbance in the regulation of circadian rhythms. Unfortunately, most circadian rhythm studies in depression have not been as rigorous methodologically as studies in healthy adults.89 For instance, no constant routine studies have been reported in symptomatic depressed patients.
Studies of body temperature rhythms in depressed patients have typically been conducted with subjects on a normal diurnal sleep-wake cycle. As a result, measurement of temperature rhythms in depression is influenced by the masking effects of sleep (or the sleep disruption characteristic of depression). Early studies suggested a phase advance of core body temperature in depression,90,91 but this finding has not been consistently replicated. Rather, most studies have found increased variability of temperature phase in depressed patients. The most consistent finding from temperature studies is reduced amplitude of core body temperature amplitude, which is primarily related to a reduced fall in temperature during sleep92 94 (Figure 3). Temperature rhythm amplitude is lower among patients with reduced REM sleep latency, compared to patients with longer REM latency.95,96 Patients with bipolar mood disorder may have more disruption of temperature rhythms than unipolar patients. Wehr and Goodwin demonstrated a phase advance of temperature before switches from mania to depression, and phase delays preceding switches in the opposite direction.97 Only one study has examined the free-running temperature rhythms of three depressed patients (two of whom had bipolar disorder) under temporal isolation conditions.98 Two of the three patients continued to have entrained temperature rhythms with period length in the range observed in healthy volunteers; the remaining patient showed internal desynchronization with a sleep-wake period of less than 24 hours and temperature rhythm period of greater than 24 hours. In our laboratory, depressed outpatients were studied during a constant routine procedure after they had recovered from depression. The period and amplitude of their core body temperature rhythms were indistinguishable from those in a healthy contrast group,99 suggesting that any changes in the temperature rhythm which may have been present during depression did not persist into the aymptomatic state. Constant routine studies have been conducted in a small sample of individuals with SAD.100 This study showed a significant phase delay of core body temperature in patients relative to controls, and an advance in the nadir of core body temperature of patients following successful bright light treatment. Thus, patients with bipolar disorder and SAD may represent more chronobiologically-disturbed groups of depressed patients.
Unlike temperature rhythms, melatonin concentrations are not affected by sleep or wakefulness, and may therefore serve as a more reliable marker of circadian phase when unmasking and free-running studies are difficult to conduct. A number of studies have reported reduced melatonin concentrations in depressed patients (e.g., 101 103), but most of these studies have included small numbers of subjects, poorly-matched controls, and infrequent melatonin sampling. The best-controlled studies of melatonin in depressed patients found neither reduced levels nor phase alterations in patients with endogenous depression.104,105 A phase delay in melatonin onset described in seasonal affective disorder with winter depression.106,107 The dim-light melatonin onset (DLMO) of patients with SAD advances with morning phototherapy, and the timing of DLMO is correlated with reduced depression ratings.108 However, other investigators have not consistently confirmed the finding of delayed melatonin rhythms in patients with SAD, nor the finding that morning bright light is superior to bright light at other times of day.109,110 Other Neuroendocrine Measures of Circadian Rhythms. A variety of other endocrine rhythms, including those of cortisol, growth hormone, thyroid hormone, and prolactin, have been measured in patients with major depression. Interest in cortisol rhythms was sparked not only by interest in circadian physiology in depression, but also by the observation that approximaely 50% of patients fail to suppress cortisol in response to dexamethasone administration.111 Dexamethasone non-suppression indicates faulty feedback mechanisms in the hypothalamic-pituitary-adrenal axis, probably related to tonically elevated circulating cortisol levels and hypersecretion of corticotropin releasing factor (CRF) in the hypothalamus and ACTH in the pituitary.112,113 Several reports have indicated that patients with depression have reduced cortisol rhythm amplitude, which is specifically related to higher nadir values during the first half of the sleep period.114,115 A phase advance in cortisol is suggested by reduced latency between sleep onset and the major circadian rise in cortisol.116 Findings of reduced amplitude and phase advance have been substantiated by an unpublished meta-analysis of cortisol rhythms in depression that combined data from several laboratories (Van Cauter, personal communication). Unlike most depressed patients, those with SAD have been reported to have a phase delay of cortisol in a constant routine study.100 Abnormal cortisol circadian rhythms may be part of a cascade of dysregulation in the HPA axis: Excessive cortisol production may damage corticoid receptors in the hippocampus, which impairs feedback inhibition of CRH, leading to further excessive secretion of ACTH and cortisol.117,118 Growth hormone secretion normally occurs in pulsatile fashion, with secretory peaks stimulated by food and exercise (see chapter 15). The secretion of growth hormone is also strongly masked by sleep, with the largest secretory episode typically occurring in conjunction with the first NREM sleep period. Thus, the endogenous circadian rhythm of GH is weak. In patients with major depression, the relative balance between GH secretion during sleep and wakefulness is altered, so that relatively more GH is secreted during wakefulness, and relatively less during sleep (e.g.,115,119, 121). In addition, patients with depression show impaired responses to stimuli which typically increase GH secretion, such as clonidine and GH releasing hormone.122,123 Therefore, abnormal GH secretory patterns in depression appear to indicate a more general dysfunction of the somatotropic axis and its integration with sleep-wake regulatory mechanisms.
The circadian pattern of sleep-wake propensity may itself be affected in patients with mood disorders, but very few studies have examined this possibility directly. Reduced amplitude of the circadian pattern of sleep propensity was reported in depressed patients with continuous EEG monitoring,124 but not in a study of remitted depressed patients monitored during a constant routine study.125 Thus, if unipolar depression affects the circadian rhythm of sleep propensity, this effect does not appear to persist beyond the symptomatic phase. A series of observations reported by Wehr, Leibenluft and colleagues suggest that sleep-wake rhythms are more seriously affected in patients with the bipolar form of depression, particularly those with rapid cycling between depression and mania. Among a group of 11 rapid-cycling patients followed longitudinally for 18 months, decreased nocturnal sleep time and wake onset time were significant predictors of mania or hypomania the following day.126 This suggests that reduced sleep time and a phase advance of sleep are associated with elevated mood, and that decreased sleep may serve as a "final common pathway" to mania.127 Based on observations that an extended nocturnal dark period can significantly affect sleep duration and circadian rhythm profiles128, Wehr and colleagues have also observed the effect of an extended dark period on a patient with rapid-cycling bipolar disorder.129 On a 10:14 light-dark cycle, the rapidity and intensity of mood cycling markedly diminished. Thus, the pattern of light-dark exposure, can have a substantial impact on mood in bipolar patients, which may be mediated at least in part by changes in sleep-wake cycles. The pattern of daily activities and social contact which we experience can also be expressed as a type of rhythm.130 This "social rhythm" may be disrupted as either a cause or consequence of depression, with its attendant social isolation and anhedonia. In a preliminary test of this theory, Szuba and colleagues reported that depressed inpatients did in fact have lower scores for social rhythms than nondepressed control subjects.131 SLEEP AND CIRCADIAN RHYTHMS: LONGITUDINAL STUDIES IN MOOD DISORDERS
Patients who are treated successfully for MDD report improved sleep quality.142 With regard to EEG sleep measures, sleep-onset REM periods are less likely to be observed in recovered patients than those who are still symptomatic.35 Phasic and tonic REM activity tend to decrease over time during the symptomatic episode,143 145 and several comparisons of sleep during symptomatic and recovered periods have shown reductions in REM sleep measures after successful pharmacotherapy or psychotherapy.45,146,147 In addition, measures of sleep continuity such as early morning awakening and sleep efficiency show improvement during recovery.146,148 Measures of slow wave sleep do not change with clinical phase in most investigations, although a few reports have shown decreases slow wave sleep or delta activity after recovery.151,152 Circadian rhythms have also been examined as a function of phase of illness. The blunted amplitude of core body temperature observed in some depressed patients increases toward normal values during recovery160,161(Figure 3). In a similar way, the hypercortisolemia and altered feedback inhibition of cortisol tend to assume more "normal" profiles after the episode.161 These findings stand in contrast to those for the somatotropic axis. Growth hormone secretion and responses to various stimuli for growth hormone release continue to show altered regulation even after patients have recovered from an episode of depression.119 As previously noted, the abnormal phase of melatonin onset observed in some patients with SAD advances toward a more normal phase with morning bright light treatment.106 Sleep and clinical course. Sleep measures are associated with treatment response and clinical outcome in depression. Persistent complaints of insomnia are associated with nonresponse to antidepressant medication,162 chronic depression,163 and suicide.164 Poor subjective sleep quality is also a risk factor for recurrence of depression among elderly patients who are not treated with maintenance medication.165 EEG sleep characteristics are also associated with clinical outcomes. Among elderly depressed patients, elevated measures of tonic and phasic REM are associated with a slower response, or non-response, to acute treatment with combined medication and psychotherapy.166 Younger depressed patients with reduced REM latency at baseline and those who show prolongation of REM latency and improved sleep efficiency during initial treatment are more likely to respond to pharmacotherapy with tricyclic antidepressants.167,168 Although these features do not predict a favorable response to psychotherapy,150,169,170 other EEG sleep measures do. As mentioned earlier, Thase and colleagues used a multivariate classification based on REM latency, REM density, and sleep efficiency to distinguish outpatient depressives with a "normal" (i.e., like healthy controls) or "abnormal" (i.e., like depressed inpatients) sleep profile. In two independent samples, the "abnormal" sleep profile was associated with reduced likelihood of response to psychotherapy, but not to subsequent pharmacotherapy.171,172 Finally, a series of investigations have demonstrated that certain aspects of slow wave sleep, such as reduced total delta activity by period-amplitude analysis and the temporal distribution of delta activity, are associated with the likelihood of recurrence of depression during maintenance treatment.152,173,174 Reduced REM latency has also been associated with recurrences of depression.153 MODELS OF SLEEP AND CIRCADIAN DYSREGULATION IN MOOD DISORDERS
Abnormal phase relationships among circadian rhythms. Papousek 175, and later Wehr and Goodwin 97 and Kripke 176 proposed that mood disorders may result from a phase advance of the circadian rhythm governing temperature, cortisol, and REM sleep relative to other circadian rhythms such as sleep-wakefulness. This theory was later refined as the "internal phase coincidence" model,177 which posits that depressed mood occurs when awakening occurs at an abnormally early or "sensitive" phase of circadian rhythms. Phase advance theories may explain findings such as short REM latency and increased REM sleep early in the night, phase advance of cortisol and temperature rhythms. A limited amount of experimental data in non-depressed subjects and from computer simulations also support these theories: Abruptly delaying the major sleep period under these circumstances produces reduced REM latency and increased amounts of REM sleep early in the sleep period, as well as (in some cases) depressed mood.178 Furthermore, a small number of studies have demonstrated that advancing the phase of sleep (thereby "normalizing" phase relationships between sleep-wake and other rhythms) can improve symptoms of depression. 83,179,180 Longitudinal studies in patients with rapid-cycling bipolar disorder show lengthening of sleep and relative advances of REM sleep prior to depressive episodes, and short sleep with relative delays of REM sleep in mania, further supporting the concept of abnormal phase relationships in mood disorders. 97
The "Social Zeitgeber" hypothesis of depression proposes a cascade of rhythm disruptions which lead to
depression in vulnerable individuals.181 Initially, a stressful life event precipitates a change in
social prompts for daily activities (social zeitgebers), and day-to-day instability in those social and
activity rhythms results. This instability in turn destabilizes biological rhythms, which, in
vulnerable individuals, can lead to pathological entrainment (or nonentrainment) of biological rhythms.
This pathological entrainment produces depressed mood. However, several lines of evidence also suggest
the limitations of abnormal phase models in depression. Significant phase advances are not present in
the majority of depressed patients. Moreover, the magnitude of phase shifts required to make normal
sleep look "depressed" is very large-- approximately 6 hours. Finally, there have been very few
studies of circadian rhythms in depression which account for the masking effects of sleep and activity
with paradigms such as constant routine studies or forced desynchrony. It seems likely that phase
advances or delays are present only in a subset of patients with depression, including those with
bipolar mood disorder. Reduced amplitude of circadian rhythms. Although reduced amplitude of rhythms is the most consistent
observation in depressed patients, this observation alone has limited explanatory power. Reduced
amplitude could be due to a number of factors, including masking effects of sleep disturbance,
intra-subject dyssynchrony of various circadian rhythm phases, inter-subject differences in phase, or
impaired expression of circadian rhythmicity in organs which express circadian rhythms "downstream"
from the central pacemaker(s). The "S-deficiency hypothesis." This theory, based on the "two process" model of sleep
regulation182,183 proposes that depressed patients have deficient build-up of Process S, the
homeostatic sleep regulatory process, which could result in decreased slow wave sleep, exaggerated
expression of REM sleep, and (through undefined mechanms), depressed mood.184 According to this
hypothesis, interventions such as sleep deprivation permit greater build-up of Process S, more slow
wave sleep (during recovery sleep), and antidepressant effect. However, the antidepressant effects of
sleep deprivation occur before recovery sleep and increased slow-wave sleep expression. An alternative
explanation of the effects of total and REM sleep deprivation is that they decrease slow wave sleep
expression during the therapeutic interval. Many antidepressant drugs decrease the amount of slow wave
sleep, which is also apparently inconsistent with predictions of the S-deficiency hypothesis. These
observations led Beersma and van den Hoofdakker185 and Wu and Bunney66 to propose that NREM sleep, or
some process associated with sleep, is actually depressogenic. The two types of theories relating to
slow wave sleep may be reconciled by the possibility that increased "drive" or "pressure" for slow wave
sleep, rather than its actual expression, may be associated with a therapeutic response. "Depressogenic REM sleep." Based on the observation that selective REM sleep deprivation has
antidepressant effects, and that most efficacious antidepressant medications suppress REM sleep, Vogel
has proposed and modified the hypothesis that REM sleep (or its neurobiological substrate) is
depressogenic.71,186 More specifically, effective antidepressant interventions are generally
characterized by "arousal type REM suppression," i.e., the reduced expression of REM sleep during the
intervention, followed by a REM sleep rebound upon discontinuation of the intervention. Indeed, REM
suppression followed by REM rebound are characteristic of total sleep deprivation, REM sleep
deprivation, and antidepressant drugs in the tricyclic, monoamine oxidase inhibitor, and selective
serotonin reuptake inhibitor classes. However, newer data indicate that some atypical antidepressants,
such as bupropion, trazodone, and nefazodone are associated with little REM sleep suppression, or even
increased REM. The exact mechanism underlying the "REM depressogenic" theory is not entirely clear,
but may relate to alterations in sensitivity of serotonergic and noradrenergic receptors which may
normally occur during REM sleep. Neurochemical theories. These theories often focus on a functional cholinergic "overdrive" relative to monoaminergic neurotransmission (serotonin and norepinephrine).187 Evidence in support of this theory comes from studies showing more rapid induction of REM sleep when cholinomimetic agents are infused during NREM sleep in depressed patients, as compared to healthy control subjects.188 190 Although the acute dietary depletion of the serotonin precursor L-tryptophan leads to acute worsening of depression in patients treated with serotonergic antidepressants,113 depressed patients do not have differential EEG sleep responses to this intervention compared to healthy control subjects.191 The main difficulty with neurochemical theories of sleep and depression is that they must remain rather general. While it is true that most efficacious antidepressants enhance serotonergic and/or noradrenergic neurotransmission, they do not all have anticholinergic effects. Furthermore, the specific mechanisms by which different antidepressants act, and their effects on sleep, are quite different. For instance, effective antidepressants include those which inhibit serotonin reuptake into presynaptic neurons, those which antagonize post-synaptic 5-HT2 receptors, and those which are 5-HT1A receptor agonists. Functional neuroanatomical models are currently being developed from observations using PET and other neuroimaging modalities. One model suggests a globally increased metabolic rate during NREM sleep in depressed patients compared to controls.135 This hypermetabolism could relate to other findings such as reduced slow wave sleep, increased nocturnal core body temperature, and reduced sleep-related growth hormone secretion. Neuroimaging studies of REM sleep suggest a different pattern of control-depressed differences, with greater regional specificity. REM sleep is associated with robust limbic and paralimbic system activation relative to wakefulness in healthy control subjects.137,138 Depressed patients show waking hypermetabolism relative to controls in these areas, with a lesser degree of activation during REM sleep.139 Thus, heightened measures of REM sleep in depressed patients may be an indicator of limbic and paralimbic system "overdrive" during both wakefulness and REM sleep. Taken together with studies of sleep and treatment outcome, functional neuroimaging studies suggest the possibility of two different types of arousal which may affect depressed patients. One type of arousal may be indicated by reduced slow wave sleep, global hypermetabolism during NREM, and greater likelihood of recurrences during long-term outcome. A second type of arousal, indicated by increased REM sleep and reduced activation of limbic structures during REM sleep, may be associated with worse short-term response to treatment. These two types of arousal can also be understood within the context of the "Type 1/ Type 2" schema of reduced latency proposed by Kupfer and Ehlers,192 in which physiological abnormalities may be related to either a persistent, genetic dysregulation (Type 1, exemplified by reduced slow wave sleep), an acute symptom-related dysregulation (Type 2, exemplified by increased REM sleep), or some combination. Future neuroimaging studies can add to this model by examining specific receptor distributions and binding capacities, which will lend neurochemical specificity to the regional metabolic data currently being generated. SUMMARY
FUTURE NEEDS
RECOMMENDATIONS
Polysomnographic Sleep Findings in Depression and Other Disorders
Arrows indicate consensus findings from a majority of studies, and indicate direction of change relative to healthy control subjects.  = increase;  = no change;  = decrease.
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