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: 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.     

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.     

The Munich vulnerability study on affective disorders: microstructure of sleep in high-risk subjects

Vulnerability markers for affective disorders have focused on stress hormone regulation and sleep. Among rapid eye movement (REM) sleep, increased REM pressure and elevated REM density are promising candidates for vulnerability markers. Regarding nonREM sleep, a deficit in amount of and latency until slow wave sleep during the first half of the night is a characteristic for depression. To further elucidate whether changes in the microstructure of sleep may serve as vulnerability markers we investigated the premorbid sleep composition in 21 healthy high-risk proband (HRPs) with a positive family history for affective disorders and compared HRPs with a control group of healthy subjects (HCs) without personal and family history for psychiatric disorders. The sleep electroencephalogram (EEG) was conventionally scored and submitted to a quantitative EEG analysis. The main difference in sleep characteristics between HRPs and HCs was an abnormally increased REM density. Differences in the spectral composition of sleep EEG were restricted to an increased power in the sigma frequency range. Since the HRP group comprised six unrelated and 15 related subjects we controlled for sibling effects. We could replicate the increased REM density in the group of HRPs whereas elevated power in the low sigma frequencies persisted only with approaching significance. The present study further supports elevated REM density as putative vulnerability marker for affective disorders. However, sleep EEG in our group of HRPs did not show slow wave sleep abnormalities. Ongoing follow up investigations of HRPs will clarify whether the observed increase in sigma EEG activity during nonREM sleep is of clinical relevance with respect to the likelihood to develop an affective disorder.     

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.     

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.     

Sleep electroencephalographic coherence abnormalities in individuals at high risk for depression: a pilot study.

BACKGROUND: Sleep electroencephalographic (EEG) studies of individuals with major depressive disorder have identified several microarchitectural features associated with the illness. These abnormalities are also found in clinically remitted individuals, raising the question of whether they are vulnerability markers of depression. This study evaluated the sleep EEG in high-risk individuals to see if abnormalities are present in the sleep EEG prior to the onset of illness. METHODS: A total of 26 subjects (13 males and 13 females) were recruited for study on the basis of 1) having a parent or grandparent treated for major depressive or bipolar affective disorder and 2) having no history of personal psychiatric illness. Polysomnographic data were collected and compared with gender- and age-matched healthy control subjects with no personal or family history of psychiatric illness. The primary outcome measures were interhemispheric and intrahemispheric coherence. RESULTS: Period analysis of the sleep EEG showed that beta-delta coherence was lower bilaterally in male high-risk subjects. Right-hemispheric theta-delta coherence was also lower in male high-risk subjects, with female high-risk subjects evidencing lower beta coherence. CONCLUSIONS: Sleep-EEG abnormalities associated with major depressive disorder are present in never mentally ill individuals at high risk for the illness. These markers may be useful in the prediction of illness and in family genetic studies of mood disorders.     

Melatonin suppression by light in euthymic bipolar and unipolar patients

BACKGROUND: Previous studies have suggested that bipolar patients are supersensitive to light suppression of melatonin and that this may be a trait marker for genetic vulnerability. The present study was an attempt to replicate and extend this observation. Propranolol hydrochloride effects were compared with light effects because of the documented influence of beta-adrenergic receptors on melatonin production. Nighttime levels of corticotropin and cortisol were also examined as potential trait vulnerability markers. METHODS: Melatonin levels in euthymic bipolar patients (n= 29) were tested before and after 500-lux light was administered between 2 and 4 AM and on a separate night in the dark. Results were compared with those of a group of patients with unipolar depression (n= 24) and with those of a group of non-psychiatrically ill control subjects (n= 50). Lithium effects and propranolol effects were tested in subgroups. RESULTS: No group differences were seen in light suppression among bipolar patients, unipolar patients, and controls; an analysis of the whole group did not reveal differences in propranolol effect, differences in corticotropin or cortisol levels, or evidence for a lithium effect. However, patients with bipolar I affective disorder showed the following: (1) significantly lower melatonin levels on the light night, at baseline and following light exposure; and (2) a later peak time for melatonin on the dark night. CONCLUSIONS: The general hypothesis of increased light sensitivity in bipolar patients was not supported. However, melatonin secretion abnormalities were confirmed in the subgroup with bipolar I disorder. Further assessments of circadian rhythm disruption as a vulnerability marker in bipolar illness are indicated.     

Shift work disorder,depression, and anxiety in the transition to rotating shifts: the role of sleep reactivity

AimThe aim of this study is to investigate premorbid sleep reactivity as a vulnerability to incident shift work disorder (SWD), and related changes in depression as well as anxiety following a transition to a rotating shifts work schedule.MethodsThis is a longitudinal study with two waves of data collection. The community-based sample included normal sleeping non-shift workers (N = 96; 62.5% female; 47.9 ± 13.3 years) without a lifetime history of insomnia or baseline excessive daytime sleepiness who transitioned to rotating shift work one year later. Participants reported demographic characteristics, trait sleep reactivity on the Ford Insomnia Response to Stress Test, depression symptoms on the Quick Inventory of Depression Symptomatology, and anxiety symptoms on the Beck Anxiety Inventory. SWD was determined based on significant sleep disturbance and/or excessive sleepiness in the context of working in a rotating-shift schedule.ResultsAnalyses revealed that the odds were over five times greater for highly sleep-reactive individuals to develop SWD after transitioning to rotating shifts (OR = 5.59, p = 0.04). Nearly 90% of participants who suffered from SWD were accurately identified as high risk at one year before disease onset. Furthermore, individuals who developed SWD reported greater increases in symptoms of depression and anxiety. Finally, analyses revealed significant indirect effects wherein high sleep reactivity increased risk for SWD, which led to greater severity of anxiety and depression symptoms.ConclusionsThe Ford Insomnia Response to Stress Test (FIRST) accurately identifies a focused target population in which the premorbid psychobiological processes complicit in SWD onset and progression, as well as shift work-related depression and anxiety changes, can be better investigated, thus improving future preventative efforts.     

Sleep in obsessive compulsive disorder

Several lines of evidence suggest that brain serotonergic systems may be disturbed in obsessive compulsive disorder (OCD). The serotonergic system strongly affects sleep and characteristic abnormalities of sleep are documented in depression. This study, therefore, aimed to investigate sleep structure of OCD patients in order to evaluate whether similar changes as in depression are present. Up to now, this issue has been addressed only in few studies with small numbers of patients. Sleep patterns of 62 unmedicated patients with primary OCD and 62 age- and sex-matched healthy controls were investigated by polysomnography. Additionally, the impact of tryptophan depletion on sleep was studied in a subgroup of 12 OCD patients and 12 controls. The OCD patients exhibited moderate, but significant disturbances of sleep continuity measures but no abnormalities of slow wave sleep or REM sleep, except a significant elevation of 1st REM density. Tryptophan depletion induced a worsening of sleep continuity, but no changes of REM sleep or slow wave sleep. Assuming that changes of sleep architecture indicate underlying neurobiological abnormalities, this study indicates that neurobiological disturbances are different in primary OCD as compared with primary depression.     

Increased waking salivary cortisol levels in young people at familial risk of depression

OBJECTIVE: Cortisol hypersecretion is one of the most reliable biological abnormalities in major depression, but it is uncertain if it represents an illness marker or a trait vulnerability to mood disorder. The present study sought to answer this question by measuring waking salivary cortisol levels in young people at familial risk of depression but with no personal history of mood disorder. METHOD: The authors studied 49 young people who had not been depressed themselves but who had a parent with a history of major depression (FH+) and a comparison group of 55 participants who had no personal history of depression and no reported depression in a first-degree relative. The authors measured the amount of cortisol secreted in saliva during the first 30 minutes after awakening on a workday and on a nonworkday. RESULTS: The amount of cortisol secreted by the FH+ subjects was greater than that of the comparison subjects on both workdays (mean=698 nmol x minutes/liter, SD=243, versus mean=550, SD=225) and nonworkdays (mean=633 nmol x minutes/liter, SD=216, versus mean=492, SD=166). The increase in cortisol secretion was not accounted for by differences in parental attachment, life events, personality, or current mental state. CONCLUSIONS: Hypersecretion of cortisol can be detected in asymptomatic individuals at genetic risk of depression and may represent an illness endophenotype. Further studies will be needed to find out if increased waking salivary cortisol levels can predict individual risk of illness and whether the increased cortisol secretion has implications for general health and cognitive function.     

Differences in the response to the combined DEX-CRH test between PTSD patients with and without co-morbid depressive disorder

BACKGROUND: Neuroendocrine studies have shown profound alterations in HPA-axis regulation in posttraumatic stress disorder (PTSD). Based on baseline assessments and the response to dexamethasone, a hypothalamic overdrive with enhanced glucocorticoid feedback inhibition has been suggested. The dexamethasone-corticotrophin releasing hormone (DEX-CRH) test has shown to be a more sensitive test to assess HPA-axis dysregulation in major depression and therefore may provide a useful test tool to probe HPA-axis regulation in PTSD. METHODS: To evaluate the effect of PTSD on HPA-axis regulation, we compared the response to a DEX-CRH test between male veterans with PTSD (n=26) and male veterans, who had been exposed to similar traumatic events during their deployment, without PTSD (n=23). Patients and controls were matched on age, year and region of deployment. Additionally, we compared the response of PTSD patients with (n=13) and without co-morbid major depressive disorder (MDD) (n=13). RESULTS: No significant differences were observed in ACTH and cortisol response to the DEX-CRH test between patients and controls. PTSD patients with co-morbid MDD showed a significantly lower ACTH response compared to patients without co-morbid MDD. The response to the DEX-CRH test did not correlate with PTSD or depressive symptoms. CONCLUSION: The DEX-CRH test did not reveal HPA-axis abnormalities in PTSD patients as compared to trauma controls. PTSD patients with a co-morbid MDD showed an attenuated ACTH response compared to PTSD patients without co-morbid MDD, suggesting the presence of subgroups with different HPA-axis regulation within the PTSD group. Altered sensitivity of the CRH receptors at the pituitary or differences in AVP secretion might explain these differences in response.     

Electroencephalographic sleep profiles in treatment course and long-term outcome of major depression: association with DEX/CRH-test response

Altered electroencephalographic (EEG) sleep patterns are among the most prominent neurobiological findings in depression. Several of these alterations have been suggested to be associated with an unfavorable long-term outcome. However, the impact of pathological sleep parameters on a more recurrent course of illness or vice versa still warrants clarification. Underlying mechanisms may involve systems known to be related to both sleep regulation and long-term course of depression such as the hypothalamic-pituitary-adrenocortical (HPA) axis. Thus, EEG sleep profiles of patients with depression were examined to determine whether (1) the retrospective clinical course of depression, and (2) the prospective long-term outcome in follow-up are associated with EEG sleep parameters. To elucidate related mechanisms HPA system functioning was evaluated by using the combined DEX/CRH test. Fifteen patients with affective disorders who participated in an earlier controlled antidepressant treatment study over 6 weeks were consecutively enrolled in an exploratory follow-up study. The retrospective analysis revealed that during the acute state of depression predominantly sleep continuity measures were associated with the number of previously experienced episodes. While this relation disappeared during treatment and did not correlate with the prospective course, decreased slow wave sleep variables especially in the first sleep period and increased rapid eye movement density were predictive for the occurrence of recurrences in follow-up and, hence, probably reflect more trait-like markers. Additionally, EEG sleep variables unfavorable for long-term outcome were related to excessive stress hormone response in the DEX/CRH-test. These disturbances may reflect important mechanisms responsible of causing and maintaining the disease process of depression.     

The Addenbrooke's cognitive examination (ACE) in the differential diagnosis of early dementias versus affective disorder.

OBJECTIVE: The authors describe the profile of performance of patients whose cognitive complaint is due to dementia, affective disorder, or combinations thereof on the Addenbrooke's Cognitive Examination (ACE) test battery. METHODS: Authors tested 90 subjects with dementia (63 Alzheimer disease [AD]; 27 fronto-temporal dementia [FTD]), 60 subjects with "pure" affective disorder (23 major depression [MDD], 37 whose affective symptoms did not meet criteria for major depression [Affective]); 22 patients with symptoms of affective disorder and organic dementia (Mixed); and 127 healthy volunteers (NC). RESULTS: The total ACE scores for the AD, FTD, and Mixed groups were significantly lower than for the NC group. Likewise, on total score, the AD and FTD groups scored significantly lower than either of the "pure" affective-disorder groups. Within the dementia group, the AD group scored significantly lower than the fronto-temporal group. CONCLUSIONS: The profile of performance on the ACE of patients with dementia is different from that of patients suffering from affective illness. Mild impairment in the total ACE score, along with a low score on the memory domain tasks and letter fluency (in contrast to normal category fluency), are strongly indicative of an affective, as opposed to organic, pathology. A total score of <88 in suspected dementia patients with affective symptoms appears strongly predictive of an underlying organic disorder.     

Sleep EEG,depression and gender

Despite clear evidence of an intimate connection between sleep, major depressive disorders (MDD) and gender, few studies have explored gender differences in either sleep or in wakefulness in patients as a means of better understanding the psychogenic components of MDD. Indeed, few sleep studies focus on characterising gender differences in any population. This paper will present a review of the literature on gender differences in sleep and depression. The theoretical and clinical implications of the findings will also be discussed. The premise of the present review is that there is an inherent increased vulnerability to depression in women that arises out of basic gender differences in brain organisation and state regulation, particularly in response to a "biological challenge" during sleep. It is argued that the inherent properties of organisation and regulation of sleep EEG in healthy men and women, elicited under challenge conditions, show gender-specific vulnerability to organisational abnormalities that model homeostatic abnormalities in depressed men and women and contribute to the genesis of depression. 2001 Harcourt Publishers Ltd     

Increased delta power and discrepancies in objective and subjective sleep measurements in borderline personality disorder

BACKGROUND: Previous studies have shown depression-like sleep abnormalities in borderline personality disorder (BPD). However, findings in BPD are not unequivocal for REM dysregulation, as well as for a decrement of slow wave sleep and sleep continuity disturbances. Earlier findings in sleep EEG abnormalities in BPD may have been confounded by concomitant depressive symptoms. METHODS: Twenty unmedicated female BPD patients without current comorbid major depression and 20 sex- and age-matched control subjects entered the study. Conventional polysomnographic parameters and for the first time sleep EEG spectral power analysis was performed on two sleep laboratory nights. Subjective sleep parameters were collected by sleep questionnaires in order to assess the relationship between objective and subjective sleep measurements. RESULTS: BPD patients showed a tendency for shortened REM latency and significantly decreased NonREM sleep (stage 2). Spectral EEG analysis showed increased delta power in total NREM sleep as well as in REM sleep in BPD patients. Subjective ratings documented drastically impaired sleep quality in BPD patients for the two weeks before the study and during the two laboratory nights. CONCLUSION: Not-depressed BPD patients only showed tendencies for depression-like REM sleep abnormalities. Surprisingly, BPD patients displayed higher levels of delta power in the sleep EEG in NREM sleep than healthy control subjects. There was a marked discrepancy between objective and subjective sleep measurements, which indicates an altered perception of sleep in BPD. The underlying psychological and neurobiological mechanisms of these alterations are still unclear and need to be clarified in future studies including interventions on a pharmacological and cognitive-behavioral level.     

Is there a relationship between eating disorder and affective disorder? New evidence from sleep recordings

There is evidence that patients with anorexia nervosa (particularly those who also have bulimia) and patients with affective disorder share many features. The authors present sleep polygraph data from 20 young women with anorexia nervosa (17 also bulimic) and 10 age-matched normal women. Their urinary free cortisol levels were determined, and the subjects with eating disorders were also rated for depression. The findings suggest the existence of a subgroup of patients who show sleep abnormalities, in addition to clinical and possibly endocrine abnormalities, that indicate concurrent affective disorder. The authors present several models that could account for this relationship.     

Limbic abnormalities in affective processing by criminal psychopaths as revealed by functional magnetic resonance imaging.

BACKGROUND: Psychopathy is a complex personality disorder of unknown etiology. Central to the disorder are anomalies or difficulties in affective processing. METHODS: Functional magnetic resonance imaging was used to elucidate the neurobiological correlates of these anomalies in criminal psychopaths during performance of an affective memory task. RESULTS: Compared with criminal nonpsychopaths and noncriminal control participants, criminal psychopaths showed significantly less affect-related activity in the amygdala/hippocampal formation, parahippocampal gyrus, ventral striatum, and in the anterior and posterior cingulate gyri. Psychopathic criminals also showed evidence of overactivation in the bilateral fronto-temporal cortex for processing affective stimuli. CONCLUSIONS: These data suggest that the affective abnormalities so often observed in psychopathic offenders may be linked to deficient or weakened input from limbic structures.     

Sleep in eating disorders

Sleep research on eating disorders has addressed two major questions: (1) the effects of chronic starvation in anorexia nervosa and of rapidly fluctuating eating patterns in bulimia nervosa on the sleep regulating processes and (2) the search for a significant neurobiological relationship between eating disorders and major depression. At present, the latter question appears to be resolved, since most of the available evidences clearly underline the notion that eating disorders (such as anorexia and bulimia nervosa) and affective disorders are two distinct entities. Regarding the effects of starvation on sleep regulation, recent research in healthy humans and in animals demonstrates that such a condition results in a fragmentation of sleep and a reduction of slow wave sleep. Although several peptides are supposed to be involved in these regulatory processes (i.e. CCK, orexin, leptin), their mode of action is still poorly understood. In opposite to these experimentally induced sleep disturbances are the findings that the sleep patterns in eating disorder patients per se do not markedly differ from those in healthy subjects. However, when focusing on the so-called restricting anorexics, who maintain their chronic underweight by strictly dieting, the expected effects of malnutrition on sleep can be ascertained. Furthermore, at least partial weight restoration results in a 'deepening' of nocturnal sleep in the anorexic patients. However, our knowledge about the neurobiological systems (as well as their circadian pattern of activity) that transmit the effects of starvation and of weight restoration on sleep is still limited and should be extended to metabolic signals mediating sleep.     

Chronotherapeutics and psychiatry: setting the clock to relieve the symptoms

Circadian rhythms are near 24-h cycles in a number of physiological and behavioural parameters and the underpinning circadian timing systems is one of the key homeostatic regulatory systems in mammalian physiology. Many common psychiatric conditions are associated with disrupted sleep, including a common occurrence of delayed or advanced phase sleep syndromes, which in themselves may be indicative of dysregulated circadian timing in these disorders. In this article we discuss the evidence for abnormal circadian rhythms in seasonal affective disorder, bipolar disorder and attention deficit/hyperactivity disorder. Much of this evidence suggest that these conditions are associated with either phase delays or phase advances of core phase markers of the circadian clock such as melatonin or core body temperature, suggesting the presence of circadian desynchrony in these conditions. We also highlight findings that pharmacological and/or behavioural interventions that ameliorate circadian misalignments are efficacious in producing symptomatic relief, suggesting an intrinsic link between the circadian and affective systems that can be manipulated for clinical benefit.