Martin Hatzinger

Sleep deprivation and bright light as potential augmenters of antidepressant drug treatment—Neurobiological and psychometric assessment of course

The present study was designed to investigate the clinical efficacy of trimipramine with adjunct sleep deprivation (SD) or bright light (BL) and to evaluate psychometric and neurobiological variables that might be of predictive value for treatment response. We used (1) the combined dexamethasone-corticotropin releasing hormone test (DEX-CRH test) to characterize alterations of the hypothalamic-pituitary-adrenal (HPA) system; (2) polysomnography to evaluate sleep disturbances; and (3) a standardized test battery to assess cognitive psychomotor functions after study initiation and after 5 weeks of treatment. The overall response rate (> or = 50% decrease in score on Hamilton Rating Scale for Depression [HRS]) was 55% (N = 42). The response rate in the group with trimipramine monotherapy (N = 14) was 79%, whereas in the groups with adjunct SD (N = 14) and BL (N = 14), respectively, it was only 43%. All three groups showed significant improvement at the end of the third week of treatment. Neither of the adjunct treatments hastened the onset of antidepressant action as measured by HRS. A significantly higher proportion of nonresponders than responders (p < .05) had HPA dysregulation, disturbed rapid eye movement (REM) sleep (REM latency, REM% first third of night) and decreased non-REM sleep (% stage 2). The non-responders showed significantly more corticotropin (ACTH) secretion after CRH stimulation in the DEX-CRH test than the responders and a less rapid normalization of the neuroendocrine dysregulation (cortisol secretion) (p < .01). In addition, REM latency was significantly shorter in the BL group than in the monotherapy group and estimated duration of illness significantly longer in the SD group than in the monotherapy group. REM latency, percentage of REM sleep during the first third of the total sleep period, percentage of non-REM sleep stage 2 and ACTH release after a DEX-CRH challenge predicted response across all three treatment groups. The neurobiological symptoms were unevenly distributed, among the three groups, thus creating heterogeneity in these measures. This heterogeneity may have contributed to the different treatment response rates as defined by psychopathology (HRS). In contrast, the neuropsychological tests and some of the sleep-EEG investigations revealed different response patterns for different groups: The onset of improvement in simple cognitive functions and in sleep continuity was earlier in the adjunct treatment groups. This study underlines the need for a multidimensional approach including use of neurobiological and neuropsychological measures to identify the therapeutic profiles of different treatment strategies and predictors of outcome.

Neuroendocrine effects of a 20-mg citalopram infusion in healthy males: A placebo-controlled evaluation of citalopram as 5-HT function probe

Pharmacokinetic measurements, neuroendocrine responses, and side effect profiles of intravenous infusions of 20 mg citalopram over 30 minutes during the early afternoon have been studied. Eight healthy male volunteers were enrolled in a placebo- (saline) controlled, single-blind, cross-over protocol. Plasma concentrations of the parent compound showed a double exponential decay. Demethyl and didemethyl metabolites were not detectable, but low concentrations of the propionic acid derivative of citalopram were found. Determination of the citalopram enantiomers yielded a balanced S(+)/R(−) ratio of 0.9 to 1.2. The endocrine response to the drug was characterized by significant increases in plasma prolactin and cortisol. Except for one subject, who developed pronounced side effects, human growth hormone showed a surge following saline that was inhibited following citalopram. Rectal temperature and heart rate were not affected and tolerability was favorable. Because of citaloprams extremely high selectivity for the presynaptic 5-hydroxytryptamine nerve terminals, the present data suggest that it might be a promising tool for the investigation of serotonergic function in the human brain in vivo.

Facing depression with botulinum toxin: A randomized controlled trial

Positive effects on mood have been observed in subjects who underwent treatment of glabellar frown lines with botulinum toxin and, in an open case series, depression remitted or improved after such treatment. Using a randomized double-blind placebo-controlled trial design we assessed botulinum toxin injection to the glabellar region as an adjunctive treatment of major depression. Thirty patients were randomly assigned to a verum (onabotulinumtoxinA, n = 15) or placebo (saline, n = 15) group. The primary end point was change in the 17-item version of the Hamilton Depression Rating Scale six weeks after treatment compared to baseline. The verum and the placebo groups did not differ significantly in any of the collected baseline characteristics. Throughout the sixteen-week follow-up period there was a significant improvement in depressive symptoms in the verum group compared to the placebo group as measured by the Hamilton Depression Rating Scale (F((6,168)) = 5.76, p < 0.001, η(2) = 0.17). Six weeks after a single treatment scores of onabotulinumtoxinA recipients were reduced on average by 47.1% and by 9.2% in placebo-treated participants (F((1,28)) = 12.30, p = 0.002, η(2) = 0.31, d = 1.28). The effect size was even larger at the end of the study (d = 1.80). Treatment-dependent clinical improvement was also reflected in the Beck Depression Inventory, and in the Clinical Global Impressions Scale. This study shows that a single treatment of the glabellar region with botulinum toxin may shortly accomplish a strong and sustained alleviation of depression in patients, who did not improve sufficiently on previous medication. It supports the concept, that the facial musculature not only expresses, but also regulates mood states.

The combined DEX-CRH test in treatment course and long-term outcome of major depression

Neuroendocrine studies strongly suggest that the hypothalamic-pituitary-adrenocortical (HPA) system plays a crucial role in the development and course of depression. The interaction between the disease process and HPA system function in long-term course, however, is unclear. Since improvement of HPA system deterioration has been demonstrated to be associated with treatment response, the question has arisen whether the course of therapy response as reflected by, for example, early improvement or response (after 1 or 2 weeks of therapy) is also based on HPA system dysfunction and whether the course of HPA regulation during treatment is only a state marker or has additional predictive implications for long-term outcome. In order to elucidate these questions a long-term study was carried out to investigate whether HPA system disturbance is associated (1) with the course of treatment response, predominantly early treatment response, during acute depression and (2) with the long-term course of depression, i.e. number of episodes. Twenty patients with affective disorders who participated in earlier controlled antidepressant treatment studies over 6 weeks were enrolled in an exploratory follow-up study. Using the combined DEX/CRH test it was demonstrated that (1) early improvement, early treatment response and beneficial treatment outcome after 6 weeks were associated with a lower HPA system activity and that (2) in long-term course of depression the HPA system deterioration increases in parallel with the number of previous episodes. These findings suggest that HPA system alterations are closely related to treatment response and long-term outcome of depression.

Exercising, sleep-EEG patterns, and psychological functioning are related among adolescents

Abstract Objectives. Lay and scientific opinion alike hold that physical activity is efficient as both remedy and preventative measure for poor sleep. There is evidence that strenuous exercising of adolescent elite athletes leads to favourable sleep patterns. However, research on this in non-elite athletes is limited. The aim of the present study was to compare sleep-EEG patterns of higher leisure time exercisers and controls. Methods. A total 38 adolescents (M = 18.59) took part in the study; 17 were high, and 21 were low exercisers. Mean weekly exercise duration was 8.5 h for high and 2 h for low exercisers. Sleep-EEG recordings were performed following a day without exercise. Participants also completed questionnaires regarding their psychological functioning. Results. Compared to low exercisers, high exercisers had more slow wave sleep, and less light and REM sleep, higher scores for positive coping and curiosity, and lower scores for depressive symptoms and somatosensory amplification. Multiple regression analyses showed that weekly exercise duration predicted shortened SOL, low number of awakenings, and increased slow wave sleep. Conclusion. Regular, though not necessarily vigorous, exercise is related to improvement in objective sleep patterns and better psychological functioning. Regular physical activity should be promoted and access to sports facilities should be facilitated.

Neuropeptides and the hypothalamic-pituitary-adrenocortical (HPA) system: review of recent research strategies in depression.

Summary: Depressed patients show a variety of alterations in hypothalamic-pituitary-adrenocortical (HPA) system regulation which is reflected by increased pituitary-adrenocortical hormone secretion at baseline and a number of aberrant neuroendocrine function tests. The latter include the combined deamethasone (DEX) suppression/corticotropin-releasing hormone (CRH) challenge test, in which CRH was able to override DEX induced suppression of ACTH and cortisol secretion. Whereas the abnormal HPA activation in these patients improved in parallel with clinical remission, persistent HPA dysregulation was associated with an increased risk of relapse. Moreover, healthy subjects at high genetic risk for depression also showed this phenomenon as a trait marker. In consequence, it has been concluded that HPA alteration and development as well as course of depression may be causally related. As evidenced from clinical and preclinical studies, underlying mechanisms of these abnormalities involve impairment of central corticosteroid receptor function which leads to enhanced activity of hypothalamic neurons synthesising and releasing vasopressin and CRH. These neuropeptides mediate not only neuroendocrine but also behavioural effects. Recent research provided evidence that CRH can induce depression-like symptoms in animals and that these signs are mediated through the CRH1 receptor subtype. Hence, therapeutical application of new compounds acting more specifically on the HPA system such as CRH1 receptor antagonists appear to be a promising approach for future treatment options of depression. In conclusion, research in neuro-endocrinology provided new insights into the underlying pathophysiology of depression and, in consequence, may lead to the development of new therapeutic tools. This paper was given on the occasion of the Young Investigator Award 1998, presented to Dr Hatzinger by the Swiss Society of Biological Psychiatry (SSBP)

Effects of the Novel Acetylcholinesterase Inhibitor SDZ ENA 713 on Sleep in Man

A novel brain-selective acetylcholinesterase inhibitor, SDZ ENA 713, is under development for the treatment of dementia of the Alzheimer type. To determine the threshold dose for central activity, single doses of the compound were administered to 20 young male volunteers in a double-blind cross-over design and the effects on the sleep electroencephalography studied. The first group of eight volunteers received in random order: placebo, 0.5 mg; and 1 mg SDZ ENA 713. The second gup of 12 volunteers received: placebo, 1.3 mg; and 2 mg SDZ ENA 713. Sleep quality was not affected by the study medication, which was well tolerated by all subjects. A statistically significant increase in rapid-eye movement sleep density was observed after doses of 1 mg, 1.3 mg, and 2 mg. Rapid-eye movement latency and slow-wave sleep were not altered. The results demonstrate that SDZ ENA 713 is centrally active in man at well-tolerated doses.

Sleep actigraphy pattern and behavioral/emotional difficulties in kindergarten children : association with hypothalamic-pituitary-adrenocortical (HPA) activity

BACKGROUND Various studies of adult endocrinology and sleep show close connections between poor sleep quality, deterioration of the HPA axis and negative psychological characteristics. However, the extent to which these associations may have already emerged and developed in childhood remains unclear. METHODS A total of 82 preschoolers (age 4.91+/-0.48) underwent activity monitoring for seven consecutive days and nights, wearing a digital movement-measuring instrument. Additionally, on the first and on the last morning of sleep registration, the activity of the HPA axis was assessed via the amount of cortisol in the saliva. Psychological and behavioral assessments were also made. RESULTS Three sub-groups of good (22%), normal (58.5%) and poor (19.5%) sleepers were distinguished. Poor sleep patterns were associated with higher HPA activity and with behavioral/emotional difficulties. CONCLUSIONS The interplay between unfavorable sleep patterns, deterioration of the HPA axis and behavioral/emotional difficulties is already apparent in pre-school children.

'Football is good for your sleep': favorable sleep patterns and psychological functioning of adolescent male intense football players compared to controls.

It is commonly assumed that physical activity exerts a favorable impact on sleep, although scientific evidence is lacking. This study investigated the impact of football sports on the sleep patterns of 36 male chronic and intense football players and 34 controls. Participants completed a sleep log for seven consecutive days. Compared to controls, football players reported shorter sleep onset latency, fewer awakenings, higher scores of sleep quality and a lower variability of sleep from weekdays to weekends. The findings suggest that football sports activity is positively associated with both quantitative and qualitative dimensions of sleep.

Associations between satisfaction with life, burnout-related emotional and physical exhaustion, and sleep complaints

Abstract Objectives. Burnout is a state of work-related emotional and physical exhaustion. Burnout is related to sleep complaints. By contrast, people with optimistic attitude seem to be less vulnerable to stress and burnout. Therefore, the present study aimed at investigating the relation between burnout, depressive symptoms, satisfaction with life, and sleep complaints. Methods. A total of 2231 participants (age [years]: M=40.8; 1183 females and 1048 males) took part in the study. Participants completed a series of questionnaires such as the Tedium Measure, the Insomnia Severity Index, and the Satisfaction with Life-questionnaire. For statistical analyses, a Structural Equation Model (SEM) was applied. Results. Pessimism, emotional and physical exhaustion, depressive symptoms, and low satisfaction with life were interrelated. Emotional and physical exhaustion was related to sleep complaints, whereas sleep complaints were not related to depressive symptoms and pessimism. Satisfaction with life was related to low sleep complaints, though mediated via low emotional and physical exhaustion, and low pessimism. Conclusions. Results suggest that among burnout symptoms emotional and physical exhaustion, but not depressive symptoms, are related to sleep complaints. Satisfaction with life, via low emotional and physical exhaustion, and low pessimism, further contributes to favourable sleep.