The Munich vulnerability study on affective disorders: premorbid polysomnographic profile of affected high-risk probands.

BACKGROUND: The most characteristic alterations in the sleep electroencephalogram (EEG) during major depression are a shortened latency to rapid eye movement (REM) sleep and an elevated REM density. Because these changes persist in remission, they might represent vulnerability markers. To identify vulnerability markers, we investigated premorbid sleep EEG parameters in healthy high-risk probands (HRPs) with a positive family history of affective disorders. METHODS: We identified 136 depressed inpatients from referrals to our hospital who had first-degree relatives with an affective disorder as well as first-degree relatives with no current or lifetime history of psychiatric disorders. The latter (the HRP group) were investigated by polysomnography. During the follow-up period, 20 HRPs developed an affective disorder. Their premorbid sleep data were analyzed. RESULTS: Premorbid sleep EEG of affected HRPs showed an increased REM density (total night and first REM period) compared with the control group without personal or family history of a psychiatric disorder. CONCLUSIONS: Increased REM density can be observed not only in patients with depression, but also in their healthy relatives. Moreover, it is predictive for the onset of a psychiatric disorder. Therefore, it can be recommended as a possible endophenotype of these diseases.     

Dex/CRH-test response and sleep in depressed patients and healthy controls with and without vulnerability for affective disorders

Sleep electroencephalographic (EEG) abnormalities and increased hypothalamo-pituitary-adrenal (HPA) axis activity are the most prominent neurobiological findings in depression and were suggested as potential biomarker for depression. In particular, increased rapid eye movement sleep (REM) density, deficit in slow wave sleep and excessive stress hormone response are associated with an unfavorable long-term outcome of depression. Recent studies indicate that the sleep and endocrine parameters are related to each other. This study investigated the association of sleep structure including a quantitative EEG analysis with the results of the combined dexamethasone (Dex)/corticotropin-releasing hormone (CRH)-test in 14 patients with a severe major depression, 21 healthy probands with a positive family history of depression (HRPs) and 12 healthy control subjects without personal and family history for psychiatric disorders. As expected patients with depression showed an overactivity of the HPA axis, disturbed sleep continuity and prolonged latency until slow wave sleep in the first sleep cycle. Differences in microarchitecture of sleep were less prominent and restricted to a higher NonREM sigma power in the HRP group. Dexamethasone suppressed cortisol levels were positively associated with higher NonREM sigma power after merging the three groups. We also observed an inverse association between the ACTH response to the Dex/CRH-test and rapid eye movement sleep (REM) density in HRPs, with suggestive evidence also in patients, but not in controls. This contra-intuitive finding might be a result of the subject selection (unaffected HRPs, severely depressed patients) and the complementarity of the two markers. HRPs and patients with high disease vulnerability, indicated by an elevated REM density, seem to have a lower threshold until an actual disease process affecting the HPA axis translates into depression, and vice versa. To summarize, our findings provide further evidence that the HPA axis is involved in the sleep regulation in depression. These associations, however, are not unidimensional, but dependent on the kind of sleep parameters as well as on the selection of the subjects.     

The Munich Vulnerability Study on Affective Disorders: stability of polysomnographic findings over time.

BACKGROUND: Some of the sleep abnormalities found in depression also persist in remission, suggesting that these parameters could represent trait or vulnerability markers. In a previous study, we found that about one third of a group of high-risk probands (HRPs) showed sleep patterns that were comparable to those of depressed patients. In the present study, we re-investigated a subsample of these HRPs to evaluate the stability of these findings over time. METHODS: We investigated the sleep-electroencephalograms of 82 healthy subjects with a high genetic load of affective disorders. We were able to re-investigate 26 of these HRPs after a mean interval of 3.5 years. Thirty-five unrelated control probands and 33 unrelated depressed inpatients that were recruited at the first investigation served as reference groups. RESULTS: At index investigation, we found that the HRPs showed a significantly increased rapid eye movement (REM) sleep density compared to control subjects. At the second examination, no changes of the polysomnographic observations over time could be observed; in particular, the REM density remained elevated. CONCLUSIONS: The increased REM density in high-risk subjects for an affective disorder at index investigation was stable over time, so that one of the requirements for a true vulnerability marker is fulfilled.     

The Munich vulnerability study on affective disorders: premorbid psychometric profile of affected individuals

OBJECTIVE: We conducted a longitudinal high-risk study to identify psychometric vulnerability markers for affective disorders. METHOD: We examined 82 healthy subjects [high-risk probands (HRPs)] with at least one first-degree relative suffering from an affective disorder. The premorbid psychometric profile of 20 HRPs who developed a psychiatric disorder during follow-up was compared with the profile of control subjects without personal and family history of psychiatric disorders matched for age and gender. RESULTS: Somatization, complaints (vegetative lability), and perception of strain are increased in HRPs who developed a psychiatric disorder. These alterations were not influenced by the time interval until the onset of the disorder. CONCLUSION: The premorbid psychometric profile in subjects at high risk for affective disorders is characterized by somatization, complaints, and elevated perception of strain. Together with previous findings our results suggest that these alterations can be regarded as potential vulnerability markers for affective disorders.     

The Munich vulnerability study on affective disorders: overview of the cross-sectional observations at index investigation

Background: An altered nocturnal sleep pattern and a dysfunction of the hypothalamic–pituitary–adrenocortical system are neurobiological abnormalities typical for depression. A persistence of these neurobiological alterations during remission has been shown to be associated with an increased risk for a relapse. However, it remains unclear whether these persisting abnormalities are trait markers indicative of an increased vulnerability for affective disorders or only represent biological scars acquired during past episodes. Thus, respective examinations need to be performed in the premorbid state in order to answer this open question. Methods: In the present article we have summarized the various results of the index investigation of a prospectively designed study in which we investigated 54 healthy first-degree relatives (high-risk probands; HRPs) of patients with an affective disorder using polysomnography, the combined dexamethasone corticotropine-releasing hormone (DEX-CRH) test and psychometric measurements. Results: In the cross-sectional part of this study the HRPs, as a group, exhibited a depression-like sleep EEG profile and DEX-CRH test result, while their psychometric profile was characterized by elevated scores on the measures Rigidity and Autonomic lability. On an individual level, 35% of the HRPs were identified as conspicuous in at least two of the three areas under investigation. Conclusions: The question of whether these abnormalities do indeed reflect trait markers indicative of an increased vulnerability for depression will be answered by the longitudinal part of the study that allows for the retrospective identification of the premorbid status of those HRPs who develop an affective disorder during the follow-up period.     

Sleep in depression: the influence of age,gender and diagnostic subtype on baseline sleep and the cholinergic REM induction test with RS 86

Summary One hundred and eight healthy controls and 178 patients with a major depressive disorder according to DSM-III were investigated in the sleep laboratory after a 7-day drug wash-out period. Subsamples of 36 healthy controls and 56 patients additionally took part in the cholinergic rapid eye movement (REM) sleep induction test with RS 86. Data analysis revealed that age exerted powerful influences on sleep in control subjects and depressed patients. Sleep efficiency and amount of slow wave sleep (SWS) decreased with age, whereas the number of awakenings, early morning awakening, and amounts of wake time and stage 1 increased with age. REM latency was negatively correlated with age only in the group of patients with a major depression. Statistical analysis revealed group differences for almost all parameters of sleep continuity with disturbed indices in the depressed group. Differences in SWS were not detected. REM latency and REM density were altered in depression compared to healthy subjects. Sex differences existed for the amounts of stage 1 and SWS. The cholinergic REM induction test resulted in a significantly more pronounced induction of REM sleep in depressed patients compared with healthy controls, provoking sleep onset REM periods as well in those depressed patients showing baseline REM latencies in the normal range. Depressed patients with or without melancholia (according to DSM-III) did not differ from each other, either concerning baseline sleep or with respect to the results of the cholinergic REM induction test. The results stress the importance of age when comparing sleep patterns of healthy controls with those of depressed patients. Furthermore they underline the usefulness of the cholinergic REM induction test for differentiating depressed patients from healthy controls and support the reciprocal interaction model of nonREM-REM regulation and the cholinergic-aminergic imbalance hypothesis of affective disorders.     

Cholinergic REM sleep induction test in subjects at high risk for psychiatric disorders.

The influence of the cholinergic agonist RS 86 on electroencephalographic (EEG) sleep was investigated in 21 healthy members of families identified as being at high risk for psychiatric disorders and in 17 healthy control subjects without any personal or family history of a psychiatric illness. In comparison to the placebo night, the administration of RS 86 led to a shortening of rapid eye movement (REM) latency in both groups. This effect, however, was much more pronounced in the high-risk group, whereas in the control subjects the arousal system and the slow-wave sleep during the first nonREM period were more affected. These observations suggest that the cholinergic action on sleep regulating mechanisms has differing preferential targets in high-risk probands and in control subjects.     

Wake and sleep EEG provide biomarkers in depression

Both wake and sleep electroencephalogram (EEG) provide biomarkers of depression and antidepressive therapy, respectively. For a long time it is known that EEG activity is altered by drugs. Quantitative EEG analysis helps to delineate effects of antidepressants on brain activity. Cordance is an EEG measure with a superior correlation with regional brain perfusion. Prefrontal quantitative EEG cordance appears to be a predictor of the response to antidepressants. Sleep EEG shows characteristic changes in depression as impaired sleep continuity, desinhibition of REM sleep and changes of nonREM sleep. Elevated REM density (a measure for frequency of rapid eye movements) characterizes an endophenotype in family studies of depression. REM-sleep changes including a more distinct REM rebound after sleep deprivation are found in animal models of depression. Most antidepressants suppress REM sleep in depressed patients, normal controls and laboratory animals. REM suppression appears to be a distinct, but not an absolute requirement for antidepressive effects of a compound. Sleep-EEG variables like REM latency or certain clusters of variables were shown to predict the response to the treatment with a certain antidepressant or even the course of the disorder for several years. Some of these predictive sleep-EEG markers of the longterm course of depression appear to be closely related to hypothalamo-pituitary-adrenocortical system activity.     

Changes in muscle sympathetic nerve activity during sleep in humans.

We microneurographically recorded muscle sympathetic nerve activity (MSA) during sleep in 12 healthy volunteers while simultaneously recording EEG, EOG, ECG, respiration, and blood pressure and determined the number of pulse-synchronous MSA bursts per minute (burst rate) for non-rapid eye movement (nonREM) sleep and rapid eye movement (REM) sleep. MSA decreased during nonREM sleep with progressively deeper sleep stages. During REM sleep, the burst rate of MSA increased and was associated with marked fluctuations in arterial blood pressure. During sleep stage 2, MSA bursts occurred approximately 1 second after spontaneous K-complexes. We conclude that (1) the decreases in MSA during nonREM sleep stages may indicate sleep-stage dependent central suppression of MSA activity; (2) increases in MSA during REM sleep suggest instability of the autonomic nervous system; and (3) a common pathway may exist for MSA bursts and K-complexes.     

EEG sleep in African-American patients with major depression: A historical case control study

This study was designed to evaluate the effect of race, specifically African-American, on electroencephalographic (EEG) sleep and clinical symptom profile in unipolar major depression. A clinical research database was used to identify appropriate subjects and a double-matched historical case-control design was implemented. African-American depression patients were double matched within protocol to Euro-American depressed patients. Age, sex, and protocol of origin were matching variables. African-American depressed patients had less total sleep, less slow wave sleep, more stage 2 sleep, longer rapid eye movement (REM) sleep latency, less REM sleep, and lower REM density than Euro-American depressed patients. African-American depressed patients did not differ from Euro-American patients in symptom severity, age of onset, number of episodes, socio-economic status, and, as planned, did not differ in age and sex distribution. Depressive symptom constellation also did not distinguish the two groups. African-American depressed patients demonstrated differences in EEG sleep profile, with less total sleep, overall lighter nonREM sleep, and relatively preserved REM sleep, despite a clinical symptom profile that did not differ from Euro-American depressed patients. The sleep profile appeared to be consonant with the sleep findings in chronic insomnia. The pathological implications of these differences remained to be explored in careful prospective studies of African-American depressed patients and in well-characterized, racially matched normal control comparisons. Depression and Anxiety 8:58–64, 1998. © 1998 Wiley-Liss, Inc.     

Aspects of short REM latency in affective states: a revisit

Electroencephalographic (EEG) sleep changes in affective disorders have been characterized by sleep continuity, slow wave sleep, and rapid eye movement (REM) abnormalities. The most commonly cited feature, however, has been shortened REM latency. Because the diagnostic and prognostic significance of shortened REM latency has been debated, this issue was reexamined in a group of 186 psychotic and nonpsychotic depressed inpatients and outpatients. The analyses suggest an increased frequency of sleep onset REM periods in psychotic depression and in elderly depressed patients (psychotic or nonpsychotic).     

Heart rate variability and cordance in rapid eye movement sleep as biomarkers of depression and treatment response

ObjectivesThe relevance of rapid eye movement (REM) sleep in affective disorders originates from its well-known abnormalities in depressed patients, who display disinhibition of REM sleep reflected by increased frequency of rapid eye movements (REM density). In this study we examined whether heart rate variability (HRV) and prefrontal theta cordance, both derived from REM sleep, could represent biomarkers of antidepressant treatment response.MethodsIn an open-label, case-control design, thirty-three in-patients (21 females) with a depressive episode were treated with various antidepressants for four weeks. Response to treatment was defined as a ≥50% reduction of HAM-D score at the end of the fourth week. Sleep EEG was recorded after the first and the fourth week of medication. HRV was derived from 3-min artifact-free electrocardiogram segments during REM sleep. Cordance was computed for prefrontal EEG channels in the theta frequency band during tonic REM sleep.ResultsHRV during REM sleep was decreased in depressed patients at week four as compared to controls (high effect size; Cohen's d > 1), and showed a negative correlation with REM density in both, healthy subjects and patients at week four. Further, the fourteen responders had significantly higher prefrontal theta cordance as compared to the nineteen non-responders after the first week of antidepressant medication; in contrast, HRV at week one did not discriminate between responders and non-responders.ConclusionsOur data suggest that HRV in REM sleep categorizes healthy subjects and depressed patients, whereas REM sleep-derived prefrontal cordance may predict the response to antidepressant treatment in depressed patients.     

Sleep EEG of patients with obsessive-compulsive disorder

Summary Twenty-two patients suffering from an obsessive and compulsive disorder (OCD) according to DSM-III-R were investigated by polysomnographic sleep EEG recordings under drug-free conditions and compared to age- and sex-matched healthy controls. Sleep efficiency was significantly lower and wake % SPT was significantly increased in the patient group compared to healthy subjects. Sleep architecture did not differ among the two samples. Especially REM sleep measures, in particular, REM latency did not differ among the groups. No positive correlation was found between sleep variables and rating inventories for obsession and compulsions (Y-BOCS), depression (Hamilton) and anxiety (CAS). A secondary depression did not influence sleep EEG variables. The results of this study contradict the assumption that OCD patients show REM sleep and slow wave sleep abnormalities similar to those shown by patients with primary depression.     

Insomnia and comorbid psychiatric disorders

Defining the relationship between sleep disturbances and psychiatric disorders is a thought-provoking task and is becoming even more challenging because it is apparent that insomnia is not simply a typical symptom of a psychiatric disorder but may actually be a predictor (or independent risk factor) for the development of such a condition. Studies have shown that depressed patients not only have disturbances in sleep continuity but have reduced slow wave sleep and disinhibited REM sleep. In particular, REM sleep regulation is characterized by shortened REM latency and increased REM density. It has been suggested that the reciprocal interaction between REM and nonREM sleep, driven by inhibitory aminergic and excitatory cholinergic activity, becomes unbalanced in depression. Exposure to cholinergic stimulants reduces REM latency, particularly in major depressive disorder. In fact, it has been shown that healthy individuals at high risk for developing depression have greater sensitivity to cholinergic stimulation than those not at high risk. While the causality of the insomnia-depression relationship is debated, epidemiological studies have indicated that insomnia is an independent risk factor for depression and other psychiatric disorders. As we learn more about the interplay between these pathophysiologies, we will be able to make better treatment decisions for our patients.     

Functional topography of the human nonREM sleep electroencephalogram

The sleep EEG of healthy young men was recorded during baseline and recovery sleep after 40 h of waking. To analyse the EEG topography, power spectra were computed from 27 derivations. Mean power maps of the nonREM sleep EEG were calculated for 1-Hz bins between 1.0 and 24.75 Hz. Cluster analysis revealed a topographic segregation into distinct frequency bands which were similar for baseline and recovery sleep, and corresponded closely to the traditional frequency bands. Hallmarks of the power maps were the frontal predominance in the delta and alpha band, the occipital predominance in the theta band, and the sharply delineated vertex maximum in the sigma band. The effect of sleep deprivation on EEG topography was determined by calculating the recovery/baseline ratio of the power spectra. Prolonged waking induced an increase in power in the low-frequency range (1-10.75 Hz) which was largest over the frontal region, and a decrease in power in the sigma band (13-15.75 Hz) which was most pronounced over the vertex. The topographic pattern of the recovery/baseline power ratio was similar to the power ratio between the first and second half of the baseline night. These results indicate that changes in sleep propensity are reflected by specific regional differences in EEG power. The predominant increase of low-frequency power in frontal areas may be due to a high 'recovery need' of the frontal heteromodal association areas of the cortex.     

Correlation dimension of the human sleep electroencephalogram

Sleep electroencephalogram (EEG) was analyzed by nonlinear analysis. Polysomnography of a healthy male subject was analyzed and the correlation dimension was calculated. The mean correlation dimensions decreased from stage 'awake' to stages 1, 2 and 3, and increased during rapid eye movement (REM) sleep. These results were also seen at every sleep cycle. During each sleep cycle the correlation dimensions decreased for slow wave sleep, then increased for REM sleep. The mean correlation dimension of the sleep EEG in the second half of the night was significantly higher than those in the first half of the night. A significant change was seen both during REM sleep as well as in sleep stage 2. Nonlinear analysis may be a useful method in the analysis of the entire sleep electroencephalogram.     

The Munich vulnerability study on affective disorders: premorbid neuroendocrine profile of affected high-risk probands

One of the most characteristic alterations in depression is a disturbed regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. A function test combining the pre-treatment of 1.5 mg dexamethasone (DEX) with a challenge of 100 microg corticotropin-releasing hormone (CRH) reveals a pathological increase in the adrenocorticotropin and cortisol release in patients with major depression. These changes partially persist after successful treatment with remission and therefore, might represent trait or vulnerability markers. To further address this question, we were investigating the premorbid neuroendocrine profile of 74 healthy high-risk probands (HRPs) with a positive family history for affective disorders. The aim was to identify premorbid vulnerability factors. During the observation period, 19 HRPs developed an affective disorder. Their premorbid DEX/CRH test results were compared with 19 age- and sex matched controls. No significant differences could be observed between these two groups. Our results suggest that a dysregulated HPA system indicated by this function test can rather be regarded as a neurobiological scar developing during the course of affective disorders.     

Effects of ECT on sleep and CSF biogenic amines in affective illness

The effects of electroconvulsive therapy (ECT) on sleep and cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) were studied in 11 male patients suffering from major depressive disorders severe enough to require ECT. Total sleep time and sleep efficiency index increased significantly after ECT, while the number of awakenings, the ratio wake/total sleep time, and the time of intermittent awake decreased, indicating that sleep continuity improved after treatment. Sleep architecture was also favorably influenced by ECT as shown by a significant increase in time of stage 2 and rapid eye movement (REM) sleep. REM latency and REM density also normalized after ECT. CSF 5HIAA increased significantly after ECT, but this was not the case for CSF HVA. These results demonstrate a positive effect of ECT on sleep EEG and CSF neurochemical markers for depressive illness.     

Polysomnographic comparison between patients with primary alcohol dependency during subacute withdrawal and patients with a major depression

Complex neurobiological models based on animal research have been formulated in an attempt to explain the cyclic pattern of nonREM and REM sleep. The "reciprocal interaction model" of nonREM and REM sleep regulation, which has been updated to incorporate new evidence is still the most convincing. Therefore it is reasonable to apply this model also to REM sleep abnormalities such as shortened REM latency and increased REM density, observed in patients with depression and alcohol dependency. In a retrospective analysis baseline data from 40 subjects with primary alcohol dependency are compared with a group of 40 patients diagnosed with major depression (diagnoses according to DSM-III-R) and healthy subjects. All alcohol dependent patients were examined in the sleep laboratory during subacute withdrawal at least 7 days off medication and after at least 14 days of abstinence. The patients with major depression (at least 7 days off psychoactive medication) and the healthy subjects had been examined previously by polysomnography during the last few years in the context of various studies and were assembled from our database to match the group of alcohol dependent patients with respect to age and sex.Alcohol dependent patients exhibited similar disturbances in sleep continuity and REM sleep as depressed patients in comparison to healthy controls while parameters of sleep architecture were even more strongly disturbed in alcohol dependence.While enhanced sensitivity of cholinergic receptors is the most likely explanation for the increase in "REM pressure" in depressives, this appears not to apply to alcoholics, who rather exhibit a decreased response to cholinergic stimulation. Thus, according to the reciprocal interaction model of nonREM- and REM sleep regulation and in contrast to the interpretation of the findings in depressed patients, an impaired aminergic rather than an increased cholinergic neurotransmission might be responsible for the increased REM sleep pressure in alcohol dependent patients. Alternatively or in addition the REM anomalies in alcoholic patients could also be due to adaptive regulatory processes during chronic alcohol consumption that lead to downregulation of GABA(A)- and upregulation of NMDA-receptors or their intracellular signalling and become apparent with alcohol withdrawal. Such adaptive counterregulation might also explain the alterations in slow wave sleep found in alcoholics that are even more pronounced in these patients than in patients with major depression.     

Band-specific electroencephalogram and brain cooling abnormalities during NREM sleep in patients with winter depression.

BACKGROUND: We previously reported that delta wave activity and facial skin temperatures, an index of brain cooling activity, were both abnormal during sleep in patients with winter depression (SAD). Because other electroencephalographic (EEG) frequencies may also convey relevant thermal, homeostatic, and circadian information, we sought to spectrally analyze delta, theta, alpha, and sigma frequencies during sleep from 23 patients with SAD and 23 healthy control subjects. METHODS: We computed means for delta, theta, alpha, and sigma power during both NREM and REM sleep. We also generated 22 cross-correlation functions for each group by crossing facial and rectal temperature with each other, as well as with delta, theta, alpha, and sigma frequencies. RESULTS: We found that delta, theta, and alpha frequency activities were all increased during NREM, but not REM sleep, in patients with SAD. In addition, there were significant and abnormal cross-correlations between facial temperatures and delta and theta frequencies during NREM sleep in patients with SAD. CONCLUSIONS: Patients with winter depression exhibit correlated abnormalities of sleep homeostasis and brain cooling during NREM sleep. Their EEG profiles during NREM sleep resemble the EEG profiles of subjects who have been sleep deprived. Further studies of NREM sleep homeostasis in patients with SAD seem warranted.