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.

In quest of identifying vulnerability markers for psychiatric disorders by all-night polysomnography.

BACKGROUND: The persistence of a depressionlike sleep pattern in fully remitted depressed patients suggests that the pattern is a trait characteristic of sleep measurements. However, in the past, subjects have undergone investigation only after the onset of the disorder, and, therefore, the altered sleep pattern may merely represent a biological scar. METHODS: We polysomnographically investigated 54 healthy subjects who had no lifetime or current diagnosis of a psychiatric disorder but had at least one first-degree relative with major depression or a bipolar disorder and at least one further close relative with major depression, a bipolar disorder, or a schizophrenic disorder. Twenty unrelated control probands without a personal and family history of psychiatric disorders and 18 unrelated inpatients with major depression served as reference groups. Prior to investigation, all healthy subjects had been free of any prescription and nonprescription drug for at least 3 months. The depressed patients were free of drugs for at least 1 week. All subjects slept for 2 nights in the sleep research unit. The sleep of the second night was recorded and visually scored. RESULTS: Analysis of the individual sleep cycles in these subjects revealed both a reduced amount of slow wave sleep and increased rapid eye movement density in the first sleep cycle. Discriminant analysis showed that 10 subjects (18%) had sleep patterns similar to those of depressed patients. CONCLUSIONS: According to our observations, one fifth of the healthy subjects with a high genetic load for psychiatric disorders showed a conspicuous (depression-like) sleep pattern. The follow-up will determine whether this sleep pattern indeed represents a trait marker indicating vulnerability.

Slow-wave sleep and ventricular size: a comparative study in schizophrenia and major depression.

BACKGROUND: A slow-wave sleep (SWS) deficit and a shortened rapid eye movement (REM) sleep latency are commonly described in schizophrenia and depression. In addition, a close association between ventricular system measurements and SWS are reported in both disorders; however, a comparative, combined polysomnographic and computed tomographic investigation is lacking. METHODS: In the present post hoc study we analyzed the electroencephalographic sleep pattern and the ventricular brain ratio (VBR) of 14 drug-naive schizophrenic patients and of 14 depressed patients who were drug-free for a sufficient time period. RESULTS: Whereas the depressives showed the often described SWS and REM sleep changes, these measurements were quite normal in the schizophrenics. The VBR values were similar in both patient groups and exceeded in 71% of the schizophrenics and in 50% of the depressives the cutoff point of a "normal" VBR value. A close association between SWS and VBR was found in the depressives but not in the schizophrenics. CONCLUSIONS: The results of the present study of drug-naive schizophrenic patients and of depressed patients indicate only a minor overlap between the pathophysiological changes observed in both disorders. Therefore, the present investigation adds evidence for the assumption that schizophrenia and depression are etiopathogenetically distinct entities, rather than representing points on a continuum of liability.

REM sleep disinhibition at sleep onset: a comparison between narcolepsy and depression.

Shortened REM latency and increased REM density are frequently observed in both narcolepsy and depression, suggesting a common mechanism of REM sleep disinhibition in these disorders. We compared night sleep recordings of 24 depressive and 24 narcoleptic patients. The amount of REM sleep and REM density did not differ between the patient groups; however, REM latency distributions differed significantly. Whereas in narcoleptic patients REM episodes started either immediately at sleep onset or following at least 60 min of non-REM sleep, in depressives two thirds of REM latencies were in the range from 1 to 60 min. In narcoleptic patients, short as compared to long REM latencies were associated with longer total sleep time, greater sleep efficiency, reduced amounts of wakefulness, and increased amounts of slow-wave sleep. In depressive subjects the reverse pattern was seen. We conclude that a common mechanism of REM sleep disinhibition in narcolepsy and depression is very unlikely.

From early to late adulthood. Changes in EEG sleep of depressed patients and healthy volunteers.

In order to evaluate the impact of aging on EEG sleep patterns we investigated the polysomnograms of 74 patients with major depression and 51 healthy volunteers aged 18-65 years. In most of the EEG sleep parameters, age-related changes were obvious in both the depressives and the normals. In the patients, some of these alterations occurred earlier and were more pronounced. The amount of slow-wave sleep decreased with age, but no differences were found between the depressives and the healthy volunteers at any particular age. Rapid-eye-movement (REM) latency was clearly affected by age, but there were no significant differences between patients and controls until the middle of the fourth decade of life. On the other hand, REM density measures did not vary with age and were increased in the depressives. Therefore, REM density appears to be a more likely candidate for a biologic marker for major depression than is REM latency.

Effect of morning and afternoon naps on mood after total sleep deprivation in patients with major depression.

In 30 depressed patients who had responded to total sleep deprivation therapy, morning naps led more frequently to relapses into depression than did afternoon naps. Longer naps were less detrimental than shorter ones, and there was no significant relationship between the effect of a nap on mood and its content of slow-wave-sleep. The amount of the rapid eye-movement sleep, too, was unrelated to clinical nap effects. Thus, some of the current theories on the relationship between sleep and depressive symptomatology are not supported by the data. Our results demonstrate the importance of nap timing, suggesting a circadian variation of propensity to relapse into depression.

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.

Effects of clozapine on sleep: a longitudinal study.

Polysomnographic studies on the effects of clozapine, an atypical antipsychotic agent with strong sedative properties, on night sleep report inconsistent results. Most of these studies did not include baseline recordings and were not controlled for clozapine-induced fever, which is known to alter nocturnal sleep. We conducted a 2-week longitudinal polysomnographic investigation in 10 long-term drug-free schizophrenic patients prior to and at the end of the first and second weeks of clozapine treatment. Rectal temperature was measured daily and patients with fever (> 37.9 degrees C) were excluded. Clozapine significantly improved sleep continuity. In addition, non-rapid eye movement (NREM) sleep and in particular stage 2 sleep increased significantly, while the amounts of stage 4 and slow-wave sleep decreased significantly. Clozapine increased significantly REM density, but it did not affect the amount of REM sleep. We conclude that in patients who do not experience clozapine-induced fever, clozapine has strong sleep consolidating effects resulting from an increase in stage 2 NREM sleep.

On the issue of drug washout prior to polysomnographic studies in depressed patients.

In psychoneurobiological studies it is a point of controversy how long psychoactive medication has to be withdrawn to exclude drug effects on the variables to be investigated. In order to answer the question of whether the generally assumed two-week washout of psychoactive medication is sufficient for polysomnographic studies, we computed a post hoc analysis of EEG sleep recordings in 61 newly admitted depressed patients. The results indicate that after a 2-week withdrawal of tricyclic antidepressants and/or benzodiazepines there are no major drug effects on visually scored polysomnograms. In addition, the observations raise the question of whether even a 1-week drug washout may be sufficient to exclude confounding effects of prior psychoactive medication on EEG sleep.

Sleep in schizophrenia: a polysomnographic study on drug-naive patients.

A slow wave sleep (SWS) deficit and a shortened rapid eye movement (REM) sleep latency are commonly reported in schizophrenic patients. However, most of these patients have been off neuroleptic medication for only a short period of time. Therefore, the reported sleep alterations may be due to residual drug effects. We polysomnographically investigated 22 drug-naive patients with a schizophrenic disorder, paranoid type, and 20 normal controls. In addition, we assessed the ventricular brain ratio (VBR) by means of computed assisted tomography. Except for a prolonged sleep onset latency, increased wake time and decreased stage 2 sleep, the patients showed a sleep pattern, i.e., of SWS and REM sleep, comparable with that of controls. The VBR was increased in 71% of the patients but was not associated with the patients' clinical characteristics or their SWS and REM sleep patterns. Our results indicate that the commonly reported SWS and REM sleep changes in schizophrenia reflect the remnant of prior neuroleptic treatment rather than the pathophysiology of the disorder itself.

Effects of 5HT3 receptor antagonism by tropisetron on the sleep EEG and on nocturnal hormone secretion.

Two dosages (5 mg and 25 mg) of the selective 5HT3 receptor antagonist tropisetron (ICS 205-930) were administered to healthy male controls, and the effects on the sleep EEG and nocturnal secretory activity of growth hormone (GH) and cortisol were evaluated. The lower dosage was administered to four subjects and the higher dosage to eight on 5 consecutive days, preceded and followed by 2 days of placebo treatment. After 25 mg of tropisetron, there was a slight increase in REM sleep in the first part of the sleep period, and stage 2 was decreased during the total night. In addition, plasma cortisol levels increased earlier than under placebo, and plasma GH levels were reduced in the second part of the night. Thus, only discrete effects of tropisetron upon sleep-endocrine activity were noted, making it unlikely that serotoninergic neurotransmission exerts its well-documented effects upon sleep through 5HT3 receptors.

Hormonal response pattern in the combined DEX-CRH test is stable over time in subjects at high familial risk for affective disorders.

One of the major neurobiological alterations in depressive disorders consists in a disturbed regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. This is reflected by a pathological increase in the adrenocorticotropin (ACTH) and cortisol release after pretreatment with 1.5 mg dexamethasone (DEX) the previous night and a challenge with 100 micrograms corticotropin-releasing hormone (CRH) the next day. The changes evoked by this combined DEX-CRH test recede partially with an improvement of the psychopathological symptoms of depressed patients. It is still unclear, however, whether this long-lasting disturbance of the HPA system is due to acquired changes in the acute illness or whether it plays a causal role and could be considered as a trait or vulnerability marker for depression. In a previous study we have examined the HPA function of healthy probands with a high genetic load for affective disorders. We found that this group of high-risk probands (HRPs) showed abnormal DEX-CRH test results with a cortisol release that was between that of a control group and a group of patients with depression. In a follow-up study we now reexamined 14 of the 47 HRPs about 4 years after the index investigation and found surprisingly constant DEX-CRH test results, so that one of the requirements for a vulnerability marker is fulfilled.

Dysregulation of the hypothalamic-pituitary-adrenocortical system in panic disorder.

The responsiveness of the hypothalamic-pituitary-adrenocortical (HPA) system was investigated with the combined dexamethasone-corticotropin-releasing hormone (DEX-CRH) challenge test in 13 patients with "pure" panic disorder. After DEX pretreatment, this group of patients had higher CRH-induced adrenocorticotrophic hormone (ACTH) and cortisol levels than the control group, but lower than a reference group of depressed patients. The panic disorder patients were also in a middle position in the ratio of suppressors to nonsuppressors on the dexamethasone suppression test (DST) and in the ratio of normal to abnormal results on the DEX-CRH test. Our results using the combined DEX-CRH test, which is known to be much more sensitive than the original DST, support the hypothesis that HPA system functioning is altered in panic disorder patients and that this dysregulation is directly involved in the pathogenesis of the disorder.

Flumazenil exerts intrinsic activity on sleep EEG and nocturnal hormone secretion in normal controls.

The physiological function of benzodiazepine (BDZ) receptors includes regulation of sleep and neuroendocrine activity. Most of the pharmacological effects of BDZ are blocked by flumazenil. However, recent neurological and behavioral studies suggest that flumazenil has its own central intrinsic activity. This issue was addressed in a study of the sleep EEG and the nocturnal secretion of growth hormone and cortisol in ten normal male controls, who were given flumazenil either alone or in combination with the BDZ agonist midazolam, placebo and midazolam alone. Flumazenil prompted an increase in sleep onset latency, a decrease in slow wave sleep and an increase in wakefulness. Plasma cortisol concentrations after flumazenil administration were lower than after midazolam. Both flumazenil and midazolam decreased nocturnal growth hormone secretion. After simultaneous application of both BDZ receptor ligands the growth hormone blunting was amplified. Our study demonstrates that at the level of the sleep EEG and neuroendocrine activity flumazenil is capable of exerting both agonistic and inverse agonistic or antagonistic effects.

Effects of flumazenil on recovery sleep and hormonal secretion after sleep deprivation in male controls.

The effects of flumazenil, a benzodiazepine antagonist, on the sleep electroencephalogram (EEG) and neuroendocrine secretion in early morning recovery sleep (0500-0800 hours) following sleep deprivation (SD; 2300-0500 hours) were studied in seven healthy men. SD induced an increase in slow wave sleep (SWS), a decrease in sleep onset latency (SOL), an enhancement of EEG delta and theta power in non-rapid-eye-movement sleep, an increase in plasma human growth hormone (GH) concentration, and a decrease in plasma cortisol levels in recovery sleep (0500-0800 hours). Plasma GH, but neither plasma cortisol nor adrenocorticotrophic hormone (ACTH) concentration was attenuated during SD as compared to sleep (2300-0445 hours). The administration of flumazenil (3 x 1 mg intravenously) during recovery sleep resulted in an inhibition in SWS, an increase in stage 2 sleep, a selective reduction in delta and theta power, and a tendency to prolongation of SOL. Plasma GH concentration was decreased but plasma cortisol and ACTH remained unaffected. Since the SD-induced changes in sleep EEG and plasma GH secretion were antagonized by flumazenil, it is suggested that electrophysiological and hormonal effects of SD are mediated at least in part through GABAergic mechanisms.

The electroencephalographic sleep pattern in schizophrenic patients treated with clozapine or classical antipsychotic drugs.

The effects of antipsychotic agents on sleep were tested by examining the nocturnal electroencephalographic recordings of 14 drug-naïve schizophrenic patients and comparing these with recordings from 12 patients treated with clozapine and 10 treated with classical neuroleptics (haloperidol: n = 7; flupentixol: n = 3). In both of the treated groups, sleep continuity measures and rapid eye movement (REM) density were significantly higher than in the drug-naïve group. Clozapine-treated patients showed significantly more stage two sleep, more stable non-REM sleep (stages two, three and four) and less stage one than patients treated with haloperidol or flupentixol. Clozapine had no effect on the amount of REM sleep. Although mean REM latency was almost twice as long in the clozapine compared with the other two groups, this difference was not statistically significant. The present study suggests considerable differences between the influence of typical and atypical antipsychotic agents on sleep. However, the results of this cross-sectional study should be confirmed using a longitudinal intraindividual approach.

Neuropsychological assessments before and after treatment in patients with anorexia nervosa and bulimia nervosa.

In psychiatric patients the identification of cognitive deficits which predict a poor clinical outcome is important for the development of specific treatment strategies aimed at the amelioration of these impaired cognitive functions to increase the likelihood of full clinical remission. However, such attempts are absent in bulimia nervosa (BU), are scarce in anorexia nervosa (AN) and, furthermore, provide conflicting results. In the present prospective study we investigated the neuropsychological demands in 12 patients with AN and in 14 patients with BU before, during, and after a treatment period. At the initial testing session, both patients samples showed similar and impaired performance levels on tasks measuring attentional demands and problem solving abilities, while their mnemonic functions were preserved. At the final testing session, which took place 7 months thereafter, the impaired cognitive functions had improved to a similar degree in the AN and the BU subgroups. However, although the eating disorder symptomatology had ameliorated in parallel, no direct associations could be established with the initial neuropsychological demands and their rectification, respectively. On an individual level, 11 patients initially showed obvious cognitive deficits. However, the clinical characteristics of this subgroup differed not from that found in the 15 'good performers'. These findings indicate that the cognitive functions in the acute AN and BU are similarly impaired, but also ameliorate in a similar manner with clinical remission. Because no associations were obvious between cognitive and clinical rectifications, significant contributions of mediating factors (e.g., changes in metabolic brain turnover and in steroid hormones) are suggested.

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.

Nocturnal sleep in Huntington's disease.

Nocturnal sleep was studied in 16 inpatients with Huntington's disease. In comparison with healthy controls, patients exhibited a disturbed sleep pattern with increased sleep onset latency, reduced sleep efficiency, frequent nocturnal awakenings, more time spent awake and less slow wave sleep. These abnormalities correlated in part with duration of illness, severity of clinical symptoms, and degree of atrophy of the caudate nucleus. Patients showed an increased density of sleep spindles.

Patterns of response to repeated total sleep deprivations in depression.

BACKGROUND: Patterns of response and nonresponse in repeated sleep deprivation (SD) are of both clinical and scientific interest; as yet, studies have yielded inconsistent results. METHODS: Eighteen inpatients suffering from a major depression were subjected to a series of six scheduled total sleep deprivations within 3 weeks; 12 of them completed the whole protocol. All were under a constant antidepressant medication with amitriptyline. SD effects were measured using observer and self rating scales. RESULTS: Each single SD led to a significant improvement. Of the 12 patients who completed the protocol, seven were classified as responders at endpoint (i.e., 1 week after the sixth TSD). The majority of patients exhibited a pattern of responses and nonresponses randomly distributed over time. There was no temporal trend. The initial effect did not predict the average response to the following SDs. LIMITATIONS: One third of patients dropped out before completing the protocol which limits the scope of the study. CONCLUSIONS: Response to a single SD is not generalizable on a series of following SDs in an individual. The mechanism of action of SD does probably not involve mechanisms subjected to habituation or sensitization.