The link between sleep and depression: The effects of antidepressants on EEG sleep

The assumption that sleep dysregulation is more than a mere epiphenomenon of depression is based on several observations: sleep disturbances are strongly associated with the depressive state; a number of sleep manipulations can alleviate symptoms of depression in some patients; and the majority of antidepressants bring about remarkable changes in sleep polygraphic variables. An obvious question is whether changes in sleep physiological processes are intimately involved in the pathogenesis and recovery from depression. One way to elucidate the link between sleep and depression is to examine whether the influence of antidepressants on sleep is related to clinical improvement in depressives. For that purpose, the effects of antidepressants on EEG sleep and their importance for the treatment of depression are summarized against the background of two existing hypotheses concerning the link between sleep and depression: one hypothesis concerning the role of REM; the other concerning the role of non-REM sleep. EEG sleep studies on the use of antidepressants in depressives have not produced clear evidence of the involvement of REM sleep or non-REM sleep in the mechanisms underlying clinical change. Furthermore, the role of sleep physiological mechanisms during treatment with antidepressants is still unclear. To interpret the effects of antidepressants on EEG sleep in terms of sleep physiological processes more fundamental sleep research is necessary. Also, more comparative studies of antidepressants with similar therapeutic effects but different pharmacological profiles are needed in both healthy and depressed subjects to further quantify the impact of EEG sleep modification in the recovery from depression and to differentiate between pharmacological and sleep-related aspects.     

Sleep as a biomarker for depression

Abstract

Sleep is a complex biological process that involves cyclic changes of brain activity. The smooth transition between wakefulness and sleep and cyclic succession of sleep stages depend on the function of numerous neurotransmitters that reciprocally influence each other. For this reason sleep is a very sensitive biomarker of brain functioning. This article provides an overview of sleep changes in depression, mechanisms involved in sleep regulation and pathophysiology underlying depression, studies on sleep as a biomarker for depression, effects of antidepressants on sleep EEG, and studies in depression with the use of quantitative sleep EEG analysis. Research on sleep in depression has provided several valuable biomarkers that are related to increased risk for depression, show worsening during depressive episode, and are related to treatment outcome and relapse risk during remission phase. Among many sleep parameters, increased REM density and diminished delta sleep ratio deserve special interest. Sleep studies are also an important research tool for antidepressant drug development. However, due to sensitivity of sleep parameters to pharmacological interventions, the patients have to be investigated before the start of pharmacological treatment or after washout from the antidepressant drug, to obtain reliable data on disease-related biological processes from polysomnography.     

REM sleep in depression is influenced by ethnicity

The influence of ethnicity on the manifestation of EEG sleep changes in depression was studied in 95 patients (21 African-Americans [AA], 17 Asians [AS], 37 Caucasians [C] and 20 Hispanics [H]) with unipolar major depression. Subjects were studied twice for 2 consecutive nights. On the second night of each 2-night session, placebo or scopolamine (1.5 microg/kg, IM, at 23.00 h) was administered. On the baseline (placebo) night, sleep architecture, sleep continuity and rapid eye movement (REM) sleep variables were generally comparable among the groups. However, REM sleep was less in AA and AS subjects than in C and H subjects. Furthermore, the distribution of REM sleep over the course of the night in AA and AS subjects differed significantly from that in the C and H groups. Although scopolamine significantly affected sleep continuity and REM sleep measures, no significant differential effects of scopolamine were observed. Because many antidepressants suppress REM sleep, the differences in baseline REM sleep observed might be related to the greater sensitivity of some ethnic-minority depressed patients to pharmacotherapy.     

Electroencephalographic sleep in psychotic depression. A valid subtype?

Electroencephalographic (EEG) sleep patterns were examined in 27 psychotic and 79 nonpsychotic subjects with major depression to evaluate the validity of the psychotic-nonpsychotic subtype dichotomy. Sleep in psychotic depression was characterized by increased wakefulness, decreased rapid eye movement (REM) sleep percentage, and decreased REM activity even after controlling for clinical differences in age, severity, and agitation. Psychotic depressive subjects also were more likely to have extremely short sleep-onset REM latencies. In psychotic depression EEG sleep varied as a function of total illness duration. Patients with recent-onset syndromes had profiles characterized by marked initial insomnia, increased stage 1 sleep percentage, and long REM latency; patients with illnesses of longer duration had extremely short REM latencies. Demonstration of selected EEG sleep variables discriminating between psychotic and nonpsychotic depression further supports psychotic depression as a distinct subtype of major affective disorder.     

The action of clenbuterol on sleep and symptomatology in depressives

Five female inpatients with major depression (melancholic type, DMS-III-R) were treated with the beta-adrenergic agonist clenbuterol for three weeks, with doses ranging from 100 micrograms to 150 micrograms. Remission of depressive symptomatology during treatment was observed in only one patient. All patients complained of side effects, especially tremor, agitation and restlessness. The sleep EEG showed no consistent effects on sleep parameters, including REM latency and percentage of REM sleep. Thus, the impact of clenbuterol on sleep clearly differs from that of most classical antidepressants. Regarding the lack of therapeutic efficacy, the data are compatible with the hypothesis of a relationship between REM sleep suppression and an antidepressant drug effect. Despite the small sample size, it can be concluded that clenbuterol is not likely to be a promising alternative to proven antidepressants in the treatment of major depression.     

The sleep EEG's microstructure in depression: alterations of the phase relations between EEG rhythms during REM and NREM sleep

OBJECTIVE: We investigated the microstructure of sleep electroencephalograms (EEGs) of 13 unmedicated depressive inpatients and 13 healthy controls matched in sex and age, hypothesizing that depressives depict an alteration of certain EEG oscillations across the night. METHODS: We digitized the sleep EEGs with a sampling rate of 100 Hz (bipolar derivation C(z)-P(z), 1440 single sweeps; 2048 data points each), calculated the time course of delta (1-3.5 Hz), theta (3.5-7.5 Hz), alpha (7.5-15 Hz), and beta (15-35 Hz) activity over the night, and determined the correlation coefficients of these different EEG rhythms separately for rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. RESULTS: For both groups we detected a clear difference between REM and NREM sleep cycles at certain frequency bands. The most impressive changes occurred for the delta/beta and theta/beta correlations, which change their signs between NREM (negatively correlated) and REM (positively correlated) sleep cycles. Following an analysis of variance model with repeated measurement design, a statistically significant group effect (P=0.024) between depressives and controls was observable during NREM sleep for the delta/beta (P=0.010) and theta/beta (P=0.018) interactions. CONCLUSION: We detected alterations of certain sleep EEG oscillations during the NREM sleep cycle, where the delta/beta as well as the theta/beta activities were higher (negatively) compared to healthy controls. Together with previous investigations on the influence of antidepressants on the microstructure of sleep EEGs, this is another hint that the NREM sleep cycle plays a major role in depression.     

Electroencephalographic sleep studies in depressed outpatients treated with interpersonal psychotherapy: II. Longitudinal studies at baseline and recovery.

Electroencephalographic (EEG) sleep studies may help to identify persistent versus episodic biological characteristics of major depressive disorder. This report examines longitudinal EEG sleep studies in depressed patients treated with psychotherapy alone. Nineteen patients were studied during a symptomatic baseline period and again during early remission after treatment with interpersonal psychotherapy (IPT). EEG sleep findings at baseline were not markedly abnormal, but they were similar to those in other published studies of young adult outpatients. No changes were found in visually scored EEG sleep measures between depression and early remission. Automated measures of delta sleep and rapid eye movement (REM) activity showed small state-related changes, with delta activity increasing from baseline to remission, and automated REM measures decreasing. Strong baseline-remission correlations were noted for most sleep measures, including slow wave sleep, phasic REM activity, and automated delta EEG counts; measures of sleep continuity and tonic REM sleep were not strongly correlated. Consistent adaptation effects across nights were observed for sleep continuity and REM measures during each clinical phase. These findings support the hypothesis that most visually scored EEG sleep measures, as well as the sleep adaptation process, are stable through the acute episode of depression, at least into early symptomatic remission. They also suggest that finer-grained automated analyses of delta and REM activity may provide more sensitive tools for examining state-related changes.     

REM latency: a psychobiologic marker for primary depressive disease.

Previous investigations have indicated that one of the most consistent EEG sleep findings in depressive patients has been a shortened REM latency. On the basis of these studies, we have concluded that with the exception of drug withdrawal states (such as CNS depressant or amphetamine withdrawal and narcolepsy) shortened REM latency points to a strong affective component in the patient's illness. Short REM latency has also been observed in patients suffering from schizo-affective illness as well as in certain schizophrenic patients who require tricyclic antidepressants in their management. Furthermore, this psychobiologic marker is a persistent, rather than a transient phenomenon, and can be observed over a period of several weeks unless a patient's condition becomes more favorable through clinical intervention. This present report indicates that short REM latency is found in virtually all primary depressive illness and is absent in secondary depression. Thus, REM latency appears to be a dependable, measurable marker for diagnosing primary depression, and we argue that the phenomenon is independent of age, drug effect and changes in other sleep parameters. It is expected that EEG sleep and motor measurements can yield further significant data and improve differential diagnosis in psychiatry, in much the same way that laboratory data support other medical specialities.     

Sleep-wake mechanisms and drug discovery: sleep EEG as a tool for the development of CNS-acting drugs

Sleep laboratory investigations constitute a unique noninvasive tool to analyze brain functioning, Polysomnographic recordings, even in the very early phase of development in humans, are mandatory in a developmental plan of a new sleep-acting compound. Sleep is also an interesting tool for the development of other drugs acting on the central nervous system (CNS), Indeed, changes in sleep electroencephalographic (EEG) characteristics are a very sensitive indication of the objective central effects of psychoactive drugs, and these changes are specific to the way the drug acts on the brain neurotransmitter systems. Moreover, new compounds can be compared with reference drugs in terms of the sleep EEG profile they induce. For instance, cognitive enhancers involving cholinergic mechanism have been consistently demonstrated to increase rapid eye movement (REM) sleep pressure, and studying drug-induced slow wave sleep (SWS) alteration is a particularly useful tool for the development of CNS compounds acting at the 5-HT(2A/C) receptor, such as most atypical antipsychotics and some antidepressant drugs. The sleep EEG profile of antidepressants, and particularly their effects on REM sleep, are specific to their ability to enhance noradrenergic or serotonergic transmission, it is suggested that the effects of noradrenergic versus serotonergic reuptake inhibition could be disentangled using specific monoamine depletion tests and by studying drug effects on sleep microsiructure.     

Depression and insomnia: questions of cause and effect

Chronic insomnia is a risk factor for the development of psychiatric disorders, including depression, as well as a prodrome of major depressive episodes, a consequence or complication of depression that often persists beyond the clinical episode, and a prognostic indicator of long-term illness course and treatment response. In addition, sleep is physiologically abnormal in persons at risk for depression; for example, shortened REM sleep latency is present not only during clinical episodes of depression, but also before the clinical episode in subjects at risk for depressive illness. Although insomnia usually disappears as depression is treated, it may persist, indicating heightened vulnerability to depressive relapse or recurrence. Physiological changes in sleep related to depression correlate with the likelihood of response to psychotherapy alone and may also identify which patients are unlikely to do well with psychosocial treatment and, therefore, to need somatic therapy in order to preserve recovery. Electroencephalographic (EEG) sleep changes also correlate with the speed of response and with the brittleness or durability of response (i.eprobability of relapse or recurrence). These observations suggest a close relationship between the regulation of sleep and the regulation of mood. The importance of this relationship is further underscored by recent brain imaging studies of sleep and sleep deprivation in patients with major depression. For example, therapeutic sleep deprivation (TSD) may serve as both a catalyst of rapid antidepressant activity and as a probe of treatment resistance. TSD's effects on brain metabolic rates, especially in limbic areas, may correlate with a therapeutic response to a night of sleep loss and to antidepressant medication. Finally, treating chronic insomnia with newer selective serotonin reuptake inhibitor (SSRI) antidepressant medication may represent an opportunity for preventing complications of insomnia, including depressive illness.     

Multivariate study of sleep EEG in depression

The effects of four subtypes of major depressive disorder on four sleep EEG variables obtained in 153 depressed inpatients were analyzed taking into account the effects of age, gender, DST response and severity of depression. We have found that age significantly affected slow wave sleep. Sleep efficiency and total sleep time were shown to vary with age and severity of depression. Such effects were not detected for REM latency which was influenced by the endogenous subtype and the gender. Our data indicate that in depressed patients sleep EEG measures are influenced by multiple factors.     

抑郁症及其亚型的睡眠脑电图研究

目的 探讨抑郁症患者睡眠脑电图的异常改变以及抑郁闰不同亚型之间的差异。方法 采用日本光电ＲＭ－６０００多导生理记录仪,对１８例抑郁症患者和１９名健康人进行睡眠脑电图检查。结果 与对照组比较,抑郁症组出现明显的醒觉时间增多、睡眠总时间减少、晒起时间增加、睡眠效率下降、睡眠维持率下降、第一阶段睡眠百分比增加、快速眼球运动（ＲＥＭ）潜代期缩短和ＲＥＭ密度增加,经统计学处理差异均有显著性（Ｐ〈０．０５）。     

Senior Vipassana Meditation practitioners exhibit distinct REM sleep organization from that of novice meditators and healthy controls

Abstract/Summary

The present study is aimed to ascertain whether differences in meditation proficiency alter rapid eye movement sleep (REM sleep) as well as the overall sleep-organization. Whole-night polysomnography was carried out using 32-channel digital EEG system. 20 senior Vipassana meditators, 16 novice Vipassana meditators and 19 non-meditating control subjects participated in the study. The REM sleep characteristics were analyzed from the sleep-architecture of participants with a sleep efficiency index?>85%. Senior meditators showed distinct changes in sleep-organization due to enhanced slow wave sleep and REM sleep, reduced number of intermittent awakenings and reduced duration of non-REM stage 2 sleep. The REM sleep-organization was significantly different in senior meditators with more number of REM episodes and increased duration of each episode, distinct changes in rapid eye movement activity (REMA) dynamics due to increased phasic and tonic activity and enhanced burst events (sharp and slow bursts) during the second and fourth REM episodes. No significant differences in REM sleep organization was observed between novice and control groups. Changes in REM sleep-organization among the senior practitioners of meditation could be attributed to the intense brain plasticity events associated with intense meditative practices on brain functions.     

MAO activity and EEG sleep in primary depression

Platelet monoamine oxidase (MAO) activity and electroencephalographic (EEG) sleep measures were examined in 56 drug-free hospitalized patients with primary depression as defined by the Research Diagnostic Criteria. The group included 35 females and 21 males with a mean age of 42.6 +/- 1.4 years. Platelet MAO and EEG sleep data were compared for the group as a whole and separately for the unipolar, bipolar, male, and female subgroups. No significant relationships could be demonstrated for the entire group or for the unipolar, male, or female subgroups. However, an inverse relationship between MAO activity and REM sleep percent was noted in the bipolar subgroup (p < 0.02). While changes in REM sleep have been relatively firmly established in primary depression, the relationship of MAO to depression and to REM sleep remains unclear.     

Effects of bupropion SR on anterior paralimbic function during waking and REM sleep in depression: preliminary findings using

This study sought to clarify the effects of bupropion SR on anterior paralimbic function in depressed patients by studying changes in the activation of these structures from waking to REM sleep both before and after treatment. Twelve depressed patients underwent concurrent EEG sleep studies and [18F]fluoro-2-deoxy-D-glucose ([18F]-FDG) positron emission tomography (PET) scans during waking and during their second REM period of sleep before and after treatment with bupropion SR. Nine subjects completed pre- and post-treatment waking PET studies. Five subjects completed pre- and post-treatment waking and REM sleep PET studies. Bupropion SR treatment did not suppress electrophysiologic measures of REM sleep, nor did it alter an indirect measure of global metabolism during either waking or REM sleep. Bupropion SR treatment reversed the previously observed deficit in anterior cingulate, medial prefrontal cortex and right anterior insula activation from waking to REM sleep. In secondary analyses, this effect was related to a reduction in waking relative metabolism in these structures following treatment in the absence of a significant effect on REM sleep relative metabolism. The implications of these findings for the relative importance of anterior paralimbic function in REM sleep in depression and for the differential effects of anti-depressant treatment on brain function during waking vs. REM sleep are discussed.     

Influence of sleep stage and wakefulness on spectral EEG activity and heart rate variations around periodic leg movements.

OBJECTIVE: Typical changes in spectral electroencephalographic (EEG) activity and heart rate (HR) have been described in periodic leg movements (PLM) associated with or without microarousals (MA). We aimed to determine the effects of sleep stage and wakefulness on these responses to ascertain whether a common pattern of EEG and HR activation takes place. METHODS: The time course of EEG spectral activity and HR variability associated with PLM was analysed in 13 patients during light NREM sleep, rapid-eye-movement (REM) sleep and wakefulness. The same analysis was also conducted for PLM without MA occurring in stage 2. RESULTS: A significant EEG and electrocardiogram (ECG) activation was found associated with PLM during sleep, but not during wakefulness. While in light NREM sleep, an increase in delta and theta bands was detected before the PLM onset, in REM sleep the EEG activation occurred simultaneously with the PLM onset. Moreover, during stage 1 and REM sleep, alpha and fast frequencies tended to remain sustained after the PLM onset. In contrast, during wakefulness, a small and not significant increase in cerebral activity was present, starting at the PLM onset and persisting in the post-movement period. A typical pattern of cardiac response was present during NREM and REM sleep, the autonomic activation being lesser and prolonged during wakefulness. CONCLUSIONS: We conclude that the EEG and HR responses to PLM differ between sleep stages and wakefulness with lesser changes found during wakefulness. SIGNIFICANCE: These findings suggest that specific sleep state-dependent mechanisms may underlie the occurrence of PLM.     

Alpha activity in the human REM sleep EEG: topography and effect of REM sleep deprivation.

The topographical distribution of alpha activity (8.125-11.125 Hz) in the REM sleep EEG, its time course within and across REM sleep episodes, and the effects of selective REM sleep deprivation were investigated in 8 young males. Power spectra of bipolar derivations along the antero-posterior axis in the left (F3C3, C3P3, P301) and right (F4C4, C4P4, P402) hemisphere were calculated. Alpha activity increased along the antero-posterior axis in both hemispheres, and was dominant in the right hemisphere. It decreased within and across REM sleep episodes. Selective REM sleep deprivation resulted in a reduction of alpha activity in the REM sleep EEG. However, the topographical distribution and the time course were not affected. It is suggested that alpha activity in the REM sleep EEG is a marker of REM sleep homeostasis.     

REM-suppressing effects of amitriptyline and amitriptyline-N-oxide after acute medication in healthy volunteers: results of two uncontrolled pilot trials

Almost all tricyclic and tetracyclic antidepressants as well as the MAO (monoamineoxidase) inhibitors suppress REM sleep significantly and sustainedly. This does not seem to be an epiphenomenon of antidepressant pharmacotherapy, since initial REM sleep suppression during pharmacological treatment correlated positively with antidepressant effect after three weeks. Furthermore, selective REM-sleep deprivation (by waking patients) had a marked antidepressive effect in depressed patients. The present study used rapid eye movement (REM) sleep suppression in healthy volunteers as a marker to compare the central nervous effects of 150 mg amitriptylineoxide (AMINO) with those of 75 mg amitriptyline (AMI). Both compounds exerted comparable sleep-inducing effects; suppression of REM sleep tended to be more pronounced after application of AMI, despite the higher dose of AMINO used. While this result is evidence of the immediate central nervous effects of a single dose of AMINO, they seem less marked than those of AMI.     

EEG sleep in outpatients with generalized anxiety: A preliminary comparison with depressed outpatients

To develop further perspective on the psychophysiology of generalized anxiety disorder and primary depression, all-night electroencephalographic (EEG) sleep measures in outpatients with diagnoses of generalized anxiety disorder and primary (nondelusional) depression were compared. Both groups had difficulty initiating and maintaining sleep, and diminished amounts of slow-wave sleep. Compared to patients with generalized anxiety disorder, depressive had a shorter rapid eye movement (REM) latency, greater REM sleep percent and eye movement activity, and a different temporal distribution of REM sleep. Anxious patients showed few changes from first to second night, whereas depressives showed increases in several REM sleep indexes. The combination of REM sleep latency and REM percent correctly classified 86.7% of patients. These data may provide a more direct measure of central nervous system arousal and sleep / wake function than previous studies in the psychophysiology of anxiety. They also lend support to the clinical distinction between generalized anxiety disorder and primary depression and to the classification of anxiety states as disorders of initiating and maintaining sleep.     

Galanin has REM-sleep deprivation-like effects on the sleep EEG in healthy young men.

Rapid eye movement (REM) sleep deprivation leads to an induction of galanin gene expression in the rat brain, especially in the hypothalamus. Galanin affects neuroendocrine systems that are involved in sleep regulation, i.e. the growth hormone-releasing hormone-dependent system of the hypothalamus and the locus coeruleus. In the study reported here we investigated the effects of 4 x 50 microg galanin (n = 10) and of 4 x 150 microg galanin (n = 8) administered hourly between 22.00 and 01.00 h as intravenous boluses on the sleep EEG and nocturnal hormone secretion in healthy young men. Galanin administration significantly increased REM sleep in the third sleep cycle with no difference between the two doses. Spectral analysis revealed a significant increase in the EEG power in the delta and theta frequency range for the total night after the lower dose of galanin, but not after the higher dose. The secretion of growth hormone, cortisol and prolactin remained unchanged during sleep in both cases. Our data are consistent with the assumption of a functional resemblance between the effect of galanin and that of REM sleep deprivation, which is known to have antidepressive efficacy.