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: 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.     

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.     

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.     

REM sleep latency and morbidity risk of affective disorders in depressive illness

The relationship between rapid eye movements (REM) sleep latency and morbidity risks for affective illness in first-degree relatives of affectively ill probands was investigated in 122 patients suffering from primary major depressive disorder (74 unipolars, 48 bipolars) according to the Research Diagnostic Criteria. Sleep EEG scoring was done blind to the clinical diagnosis of the probands and their relatives, and the evaluation of morbidity risks for affective illness in first-degree relatives was done using Str?mgren's method with age correction. A logistic regression analysis was performed to describe the proportion of affectively ill relatives as a function of variables recorded in 122 probands with primary major depression. Our analysis demonstrates an inverse relationship between REM sleep latency and the risk for depressive disorder in the families of affectively ill probands. These results suggest the possibility that common pathophysiological factors may be involved in the hereditary predisposition to affective illness and in the shortening of REM sleep latency in some depressed patients.     

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.     

Sleep EEG in bulimia

To evaluate the sleep electroencephalogram (EEG) characteristics of bulimia, all-night sleep EEGs were performed on 11 women meeting DSM-III criteria for bulimia. Comparison groups consisted of young women outpatients with major depression (n = 44) and young normal women (n = 20). The sleep EEGs of the bulimic patients were largely indistinguishable from those of the normal controls, except for a trend toward increased rapid eye movement (REM) density in the first REM period among the bulimic subjects. No differences in any sleep EEG measure were observed between bulimic patients with major depression and those without affective disorder. By contrast, the outpatients with major depression displayed marked sleep continuity disturbances, as well as significantly increased REM intensity and REM density, as compared to normal controls. Implications of these results with respect to the hypothesis that bulimia is related to major affective disorder are discussed.     

Lifetime prevalence of psychiatric disorders in patients with alopecia areata

Thirty-one patients with alopecia areata were administered a structured psychiatric interview (the Diagnostic Interview Schedule; DIS). Overall, 74% had one or more lifetime psychiatric diagnoses. Particularly noteworthy were the high lifetime prevalence rates of major depression (39%) and generalized anxiety disorder (39%). In addition, patients reported increased rates of psychiatric disorders in first-degree relatives: anxiety disorders (58%), affective disorders (35%), and substance use disorders (35%). Patients with patchy alopecia areata were more likely to have a diagnosis of generalized anxiety disorder. No relationships were found between major depression and any variable characterizing alopecia areata history. Possible interrelationships between psychiatric disorders and alopecia areata are discussed. The study suggests that patients with alopecia areata are at increased risk for psychiatric disorders, and calls attention to the need for psychiatric assessment in this population.     

Psychiatric disorders in the first-degree relatives of probands with bulimia nervosa

Data from a family study of psychiatric disorders showed higher rates of major affective disorders, eating disorders, and alcoholism in first-degree relatives of 40 bulimic probands than in first-degree relatives of 24 control subjects. More importantly, the data showed higher rates of major affective disorders in relatives of bulimic probands who themselves had no history of major affective disorders than in relatives of control subjects. This significant finding indicates a familial relationship between bulimia nervosa and major affective disorders, which suggests the possibility of a common diathesis.     

The CCC2000 Birth Cohort Study of Register-Based Family History of Mental Disorders and Psychotic Experiences in Offspring

Psychotic experiences (PE) in individuals of the general population are hypothesized to mark the early expression of the pathology underlying psychosis. This notion of PE as an intermediate phenotype is based on the premise that PE share genetic liability with psychosis. We examined whether PE in childhood was predicted by a family history of mental disorder with psychosis rather than a family history of nonpsychotic mental disorder and whether this association differed by severity of PE. The study examined data on 1632 children from a general population birth cohort assessed at age 11–12 years by use of a semistructured interview covering 22 psychotic symptoms. The Danish national registers were linked to describe the complete family history of hospital-based psychiatric diagnoses. Uni- and multivariable logistic regressions were used to test whether a family history of any mental disorder with psychosis, or of nonpsychotic mental disorder, vs no diagnoses was associated with increased risk of PE in offspring (hierarchical exposure variable). The occurrence of PE in offspring was significantly associated with a history of psychosis among the first-degree relatives (adjusted relative risk [RR] = 3.29, 95% CI: 1.82–5.93). The risk increased for combined hallucinations and delusions (adjusted RR = 5.90, 95% CI: 2.64–13.16). A history of nonpsychotic mental disorders in first-degree relatives did not contribute to the risk of PE in offspring nor did any mental disorder among second-degree relatives. Our findings support the notion of PE as a vulnerability marker of transdiagnostic psychosis. The effect of psychosis in first-degree relatives may operate through shared genetic and environmental factors.Key words: psychosis, schizophrenia, epidemiology, family liability, general population, psychiatric family history     

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.     

First episode of depression in children at low and high familial risk for depression

OBJECTIVE: To examine the development of first-onset major depressive disorder (MDD) in children at high and low familial risk for depression in a prospective study. METHOD: High-risk children (n = 76) who were free of any lifetime affective disorder and had at least one first-degree and one second-degree relative with a lifetime history of childhood-onset, recurrent, bipolar, or psychotic depression were included. Low-risk children (n = 63) were included if they were free of any lifetime psychiatric disorder and had no first-degree relatives and fewer than 20% of their second-degree relatives with a lifetime affective disorder. Children and their parents were assessed in a prospective design using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version (K-SADS-E). The average interval between follow-up interviews was 18 months, and the average follow-up period was 6 years. RESULTS: High-risk children had approximately a threefold increased risk of developing first-onset MDD compared with low-risk children (odds ratio = 3.21). The average age of new-onset MDD was 14.0 +/- 2.9 years (range 9.5-19.5 years). Above and beyond the familial loading for MDD, mother's lifetime anxiety disorder (odds ratio = 2.84) and lifetime behavioral disorder (odds ratio = 3.25) in the child significantly added to the risk of developing a first-onset MDD. CONCLUSIONS: Having high familial loading for affective disorders, a mother with and anxiety disorder, and a behavioral disorder in the child all significantly contributed to the risk of developing depression.     

Sleep and depression

BACKGROUND: Of all the psychiatric disorders associated with insomnia, depression is the most common. It has been estimated that 90% of patients with depression complain about sleep quality. Since the first reports of short rapid eye movement (REM) latency in depressed patients and of the effect of sleep deprivation on depression in the 1970s, numerous sleep studies have provided extensive observations and theoretical hypotheses concerning the etiology and pathophysiology of depression. The aim of this review is to summarize knowledge regarding the relationships between sleep and depression. DATA SOURCES AND SELECTION: MEDLINE and PsycINFO searches of the literature published in English or French between 1964 and 2005 that examined the relationships between sleep disturbance and depression were conducted. Search terms used were depression, depressive disorder, affective disorder, mood disorders, seasonal affective disorder, sleep, sleep disorders, insomnia, REM, polysomnography, sleep deprivation, electroencephalography, PET, SPECT, and fMRI. DATA SYNTHESIS: Two hundred five papers were identified and selected and then integrated into the following categories: sleep architecture, antidepressive therapies, age- and gender-associated differences, functional imaging results, and sleep-related hypotheses explaining the pathophysiology of depression. CONCLUSION: Numerous studies provide findings indicating the remarkable relationship between sleep alterations and depression. Although the existing hypotheses are not likely to explain all aspects of the sleep alterations in depression, each may be worth being maintained for refinements of pathophysiologic models of depression as new data accumulate. Further research taking into account the heterogeneity of depressive disorder and linking the different areas of research is needed to develop more comprehensive theoretical models and new therapies for depression.     

Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder.

OBJECTIVE: Panic attacks are a common complication of affective disorder, although the etiologic relationship of panic and affective symptoms has not been determined. Evidence from a family study suggests that panic attacks and panic disorder may be related genetically to bipolar disorder. This study used diagnostic data from the NIMH Bipolar Disorder Genetics Initiative to assess in a separate, larger family set the familiality of panic combined with bipolar disorder. METHOD: First-degree relatives (N=966) of probands with bipolar I disorder (N=192) and schizoaffective disorder, bipolar type, (N=11) were included in the study. All subjects were interviewed directly and were assigned best-estimate diagnoses for major affective and other psychiatric disorders. The risk of a family member being diagnosed with panic disorder if the proband with bipolar disorder had panic attacks or panic disorder was calculated with logistic regression analysis with generalized estimating equations that controlled for sex and affective disorder subdiagnosis. RESULTS: More than 90% of the probands and first-degree relatives with panic disorder also had an affective disorder diagnosis. Panic disorder was present in 17% of the relatives with recurrent major affective disorder and in 3% of the relatives without recurrent major affective disorder. Risk of panic disorder in relatives with bipolar disorder was increased significantly if the proband had panic attacks or panic disorder. CONCLUSIONS: Risk for panic disorder with familial bipolar disorder appears to be inherited. Inherited risk for panic disorder with bipolar disorder may indicate a shared genetic etiology for both disorders in some families. The patterns of bipolar disorder and panic disorder comorbidity observed in families imply a complex genetic etiology, which may be elucidated by using endophenotypes.     

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.     

Affective and impulsive personality disorder traits in the relatives of patients with borderline personality disorder

OBJECTIVE: This study tested the hypothesis that the risk for affective and impulsive personality disorder traits commonly found in patients with borderline personality disorder would be greater in the first-degree relatives of probands with borderline personality disorder than in two comparison groups. METHOD: Blind family history interviews were conducted with family informants to assess the extent to which first-degree relatives of 29 probands with borderline personality disorder, 22 probands with other personality disorders who met three or fewer of the criteria for borderline personality disorder, and 43 probands with schizophrenia fulfilled operationalized criteria for the two kinds of personality disorder traits and for other diagnostic categories. The crude proportions of adult relatives with each diagnosis, as well as the age-adjusted morbid risks, were assessed in the three groups of relatives. RESULTS: The risks for affective and impulsive personality disorder traits were independently greater in the 129 relatives of the borderline probands than in the 105 relatives of the probands with other personality disorders and the 218 relatives of the schizophrenic probands. There was no similarly greater risk for any other psychiatric disorder assessed, including major affective disorder. In addition, the relatives of borderline probands with current or past major depressive disorder showed a greater risk for major affective disorders than the relatives of never-depressed probands with other personality disorders but not the relatives of never-depressed borderline probands. CONCLUSIONS: These results suggest familial transmission of the hallmark borderline-related personality characteristics and raise the possibility that these familial traits may be partially independent.     

Childhood-onset bipolar disorder: Evidence for increased familial loading of psychiatric illness

OBJECTIVE: To determine whether childhood-onset bipolar disorder (BP) is associated with an increased psychiatric family history compared with adolescent-onset BP. METHOD: Semistructured psychiatric interviews were conducted for 438 youth with BP spectrum disorders. To evaluate the effects of age at onset and psychiatric family history, the sample was divided into childhood-onset BP (age and BP onset <12 years; n = 192), adolescents with early-onset BP (age > or =12 years and BP onset <12 years; n = 136), and adolescents with late-onset BP (age and BP onset > or =12 years; n = 110). Lifetime family history of psychiatric illness was ascertained for first- and second-degree relatives through both direct interview of caretakers and the Family History Screen. RESULTS: After significant demographic and clinical factors were controlled for, children and adolescents with childhood-onset BP showed higher percentages of positive first-degree family history for depression, anxiety, attention-deficit/hyperactivity, conduct, and substance dependence disorders and suicidal behaviors compared with adolescents with late onset. Subjects with childhood-onset BP also showed elevated familial loading for depression and attention-deficit/hyperactive disorder in second-degree relatives. CONCLUSIONS: These data support a model that postulates a higher density of familial risk for a broad range of psychopathology in childhood-onset BP.     

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.