I.A. Antonijevic

Elevated nocturnal profiles of serum leptin in patients with depression

Leptin, the protein product of the obese (ob) gene, has been suggested to play a role in the regulation of food intake. As depressive episodes are frequently characterized by loss of appetite, reduced food intake and weight loss, altered leptin secretion might also be expected in patients with depression. Therefore, we examined nocturnal (10.00 p.m. to 7.00 a.m.) secretion of leptin, cortisol, ACTH and growth hormone (GH) in a group of 15 patients with depression and age- and sex-matched controls (age range 23-71 years). In addition, the effects of pulsatile administration of growth hormone-releasing hormone (GHRH), thought to be an endogenous antagonist of corticotropin-releasing hormone (CRH), which in turn is believed to play a critical role for the pathophysiology of depression, on nocturnal hormone secretion were assessed. Patients with depression showed a trend towards elevated nocturnal cortisol secretion (F = 3.8, p < 0.05). Nocturnal serum leptin was significantly higher in patients, despite a reported weight loss (F = 8, p < 0.05), but showed the same sexual dimorphism as in controls (F = 20.9, p < 0.01). No significant differences were seen between patients and controls with regard to plasma GH and ACTH. GHRH treatment increased GH secretion in both patients and controls, while the other hormones were not affected. Furthermore, serum leptin was correlated with body mass index (BMI) in controls, but not in patients with depression, supporting an altered regulation of leptin secretion in depressive illness. Finally, we provide some evidence that in young female patients the normal nocturnal leptin surge is blunted. As glucocorticoids can prevent the fasting-induced decline in serum leptin, we propose that hypercortisolism in depression might counteract the reduction in leptin secretion caused by decreased food intake and weight loss. Elevated serum leptin in depression might in turn further promote CRH release, as shown in animals and, hence, contribute to HPA system hyperactivity seen in depression.

Modulation of the sleep electroencephalogram by estrogen replacement in postmenopausal women.

OBJECTIVE We performed an examination of the effects of estrogen replacement on the sleep electroencephalogram in postmenopausal women. STUDY DESIGN A sleep electroencephalogram was recorded in 11 postmenopausal women with and without estrogen administered by skin patch (50 microg of estradiol per day). RESULTS Estrogen enhanced rapid-eye-movement sleep (50 +/- 4 vs 39 +/- 5 minutes, P <.05) and reduced time awake (12 +/- 5 vs 20 +/- 6 minutes, P <.05) during the first 2 sleep cycles. The normal decrease in slow-wave sleep and delta activity from the first to the second cycle (in percentage from the first cycle) was restored by estrogen (-56% +/- 9% vs -5% +/- 14% and -20% +/- 6% vs -2% +/- 5%; P <.05, respectively). Sigma electroencephalographic activity was increased by estrogen from the first to the second half of the night but decreased during baseline. CONCLUSION Estrogen treatment after menopause can help to restore the normal sleep electroencephalogram pattern, which in turn might contribute to improved cognitive functioning.

Neuropeptide Y promotes sleep and inhibits ACTH and cortisol release in young men

Anxiolytic and sedative effects of neuropeptide Y (NPY) are thought to involve inhibition of corticotropin-releasing hormone (CRH). Enhanced secretion of CRH plays a critical role in the pathophysiology of major depression, characterized by sleep disturbances, anxiety and loss of appetite. We examined for the first time in young men effects of intravenous injections of NPY (4x50 or 100 microg, n = 9 and 11, respectively, at 22.00, 23.00, 24. 00 and 01.00 compared to saline) on the sleep electroencephalogram (EEG; recorded from 23.00 to 07.00) and nocturnal secretion of adrenocorticotrophic hormone (ACTH), cortisol, growth hormone (GH), prolactin and leptin. Repeated measures MANOVA showed that ACTH secretion during the first half of the night was reduced by the lower dose of NPY only (F = 8.7, p<0.05), while cortisol secretion during the second half of the night was reduced regardless of the dose (F = 7.9, p<0.05). Regardless of the dose, NPY enhanced sleep period time and stage 2 sleep (F = 12.8 and 5.4, each p<0.05), and also reduced sleep latency and time awake (F = 4.9 and 4.4, each p<0.05) and modulated REM sleep. In summary, NPY promotes sleep and inhibits the hypothalamo-pituitary-adrenocortical (HPA) axis in humans, pointing to a possible role of NPY agonists for the development of novel treatment strategies for affective disorders.

Effects of Hormones on Sleep

Administration of hormones to humans and animals results in specific effects on the sleep electroencephalogram (EEG) and nocturnal hormone secretion. Studies with pulsatile administration of various neuropeptides in young and old normal controls and in patients with depression suggest they play a key role in sleep-endocrine regulation. Growth hormone (GH)-releasing hormone (GHRH) stimulates GH and slow wave sleep (SWS) and inhibits cortisol, whereas corticotropin-releasing hormone (CRH) exerts opposite effects. Changes in the GHRH:CRH ratio contribute to sleep-endocrine aberrations during normal ageing and acute depression. In addition, galanin and neuropeptide Y promote sleep, whereas, in the elderly, somatostatin impairs sleep. The rapid eye movement (REM)-nonREM cycle is modulated by vasoactive intestinal polypeptide. Cortisol stimulates SWS and GH, probably by feedback inhibition of CRH. Neuroactive steroids exert specific effects on the sleep EEG, which can be explained by γ-aminobutyric acidA receptor modulation.

On the Gender Differences in Sleep-Endocrine Regulation in Young Normal Humans

Sleep-endocrine regulation in humans involves high activity of the somatotropic axis at the beginning of the night and an increase in the hypothalamic-pituitary-adrenocortical (HPA) system during the night. Gender differences were examined with regard to sleep-endocrine regulation in young healthy controls (10 men, 9 women). The sleep EEG was recorded (23:00–07:00 h) and plasma samples were collected and analyzed for GH, cortisol and ACTH at 20-min intervals. Cortisol secretion was significantly higher in females during the first half of the night (F = 9.9, p < 0.05), while ACTH was not different. In women, sleep-EEG analysis showed less slow wave sleep (SWS) during the second half of the night (F = 4.5, p < 0.05) and a significantly greater decrease in SWS and delta activity from the first to the second half of the night (F = 3.7 and 7.4, respectively, p < 0.05). Sigma activity increased during the night in women only (F = 3.7, p < 0.05). Our data are compatible with the hypothesis that in women compared to men activity of hypothalamic CRH neurons and central CRH release is greater, but is not reflected by greater HPA activity.

Depression-like changes of the sleep-EEG during high dose corticosteroid treatment in patients with multiple sclerosis.

Acute exacerbations of multiple sclerosis (MS) are commonly treated with high doses of corticosteroids that can influence sleep regulation and hypothalamo-pituitary-adrenal (HPA) activity. We examined the sleep-EEG (including conventional and spectral EEG analysis) in 9 female patients with relapsing-remitting MS (and no psychiatric disorder) just prior to and on days 2 and 10 of high dose corticosteroid treatment (500 mg/day methylprednisolone given IV for 5 days, then PO taper down) and age-matched healthy female controls. Before treatment with corticosteroids, MS patients compared to controls showed few changes of the sleep EEG, namely a significant increase in slow wave sleep (SWS) and a decrease in stage 2 sleep. In contrast, on day 10, but not day 2 of treatment, MS patients showed a number of sleep-EEG changes typically observed in patients with depression, including a reduction in REM latency, an increase in REM density, a decrease in the SWS and delta sleep ratio and a decrease in sigma EEG activity. However, no concomitant effect of treatment on mood was noted. In summary, unlike acute treatment with methylprednisolone, prolonged treatment induces several changes of the sleep-EEG in MS patients, that are also observed in patients with an acute depressive episode. Further prospective studies with longer-term follow-up are needed to examine the clinical relevance of our preliminary data.

Neuropeptide Y (NPY) shortens sleep latency but does not suppress ACTH and cortisol in depressed patients and normal controls

Preclinical and clinical studies suggest that neuropeptide Y (NPY) exerts functional corticotropin-releasing hormone (CRH) antagonistic effects. NPY activity appears to be blunted in depression. Recently, we have found in young normal male controls after repetitive administration of NPY a shortened sleep latency and a decrease of time awake and, in the second half of the night, EEG delta-power; cortisol and ACTH levels were blunted. Since during depression there is an overactivity of CRH, we tested the capacity of NPY to affect sleep endocrine activity in patients with depression compared with controls. After one night of adaptation we administered hourly IV injections of placebo (PL) during the second night and of 50 microg NPY during the third night between 22:00 and 01:00 h. Throughout the night ACTH, cortisol and prolactin levels were measured, simultaneously the sleep electroencephalogram (EEG) was recorded. Depressed patients as well as healthy controls exhibited significant shortening of sleep onset latency (SOL) (mean+/-SD; controls: 41.9+/-48.2 min PL vs 22.1+/-17.3 min NPY; patients: 31.8+/-19.8 min PL vs 24.7+/-20.1 min NPY; P<0.06) and REM latency (controls: 79.3+/-27.5 min PL vs 69.0+/-19.4 min NPY; patients: 79.8+/-45.5 min PL vs 52.4+/-51.2 min NPY; P<0.05). Both patients and controls showed a trend to an increase of prolactin during the night. In contrast to our recent observation in young normal subjects time awake, ACTH and cortisol remained unchanged in patients and controls in response to NPY. Whereas also an adaptation effect may contribute to the shortening of SOL, this change and the prolactin elevation are in line with a CRH antagonistic and GABA(A) agonistic/benzodiazepine-like effect of NPY. The lack of effects on time awake and HPA hormones may be explained by the higher CRH activity due to age and depression in the investigated samples in comparison to our recent study in young subjects.

Galanin has REM-sleep deprivation-like effects on the sleep eeg in healthy young men

Rapid eye movement (REM) sleep deprivation leads to an induction of galanin gene expression in the rat brain, especially in the hypothalamus. Galanin affects neuroendocrine systems that are involved in sleep regulation, i.e. the growth hormone-releasing hormone-dependent system of the hypothalamus and the locus coeruleus. In the study reported here we investigated the effects of 4 x 50 microg galanin (n = 10) and of 4 x 150 microg galanin (n = 8) administered hourly between 22.00 and 01.00 h as intravenous boluses on the sleep EEG and nocturnal hormone secretion in healthy young men. Galanin administration significantly increased REM sleep in the third sleep cycle with no difference between the two doses. Spectral analysis revealed a significant increase in the EEG power in the delta and theta frequency range for the total night after the lower dose of galanin, but not after the higher dose. The secretion of growth hormone, cortisol and prolactin remained unchanged during sleep in both cases. Our data are consistent with the assumption of a functional resemblance between the effect of galanin and that of REM sleep deprivation, which is known to have antidepressive efficacy.

On the role of menopause for sleep-endocrine alterations associated with major depression

Aging and menopause are associated with alterations of the sleep EEG, while age-related changes of the hypothalamo-pituitary-adrenal (HPA) axis remain controversial. Major depression is also associated with typical sleep-endocrine changes, including enhanced activity of the HPA axis, while an influence of age and gender on these alterations is less clear. To test the hypothesis that after menopause sleep-endocrine alterations associated with major depression are accentuated, we examined the sleep EEG and nocturnal hormone secretion (ACTH, cortisol, GH, estradiol, LH, FSH, and leptin) in 16 drug-free female patients, mostly with the first episode of a major depressive disorder (seven pre- and nine postmenopausal subjects) and 19 female controls (10 subjects in the early follicular phase and nine postmenopausal subjects). Nocturnal cortisol secretion was increased in postmenopausal patients with depression, while a decrease was noted in postmenopausal controls. Sleep alterations typically associated with depression, namely a reduction in sleep continuity and slow wave sleep (SWS) and an increase in REM density, were prominent in post- but not in premenopausal patients. An inverse correlation was noted between the decline in SWS and sleep continuity and FSH secretion in patients with depression, suggesting a role of menopause for these sleep-endocrine alterations typically associated with major depression. In contrast, in premenopausal patients we noted primarily a shift in SWS and delta-EEG activity from the first to the second non-REM period, which was not related to age or hormone secretion. Though the relatively small number of subjects per group precludes a definitive conclusion, our data open up the possibility that the sleep-endocrine changes typically associated with major depression are most prominent in postmenopausal patients. Whether the predominant alteration of the distribution of SWS and delta EEG activity in younger patients with a first episode of major depression has a predictive value for the future course of the disease remains to be investigated.

Hexarelin decreases slow-wave sleep and stimulates the secretion of GH, ACTH, cortisol and prolactin during sleep in healthy volunteers

Ghrelin, the endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor and some GHSs exert different effects on sleep electroencephalogram (EEG) and sleep-related hormone secretion in humans. Similar to GH-releasing hormone (GHRH) ghrelin promotes slow-wave sleep in humans, whereas GH-releasing peptide-6 (GHRP-6) enhances stage 2 nonrapid-eye movement sleep (NREMS). As GHRP-6, hexarelin is a synthetic GHS. Hexarelin is superior to GHRH and GHRP-6 in stimulating GH release. The influence of hexarelin on sleep-endocrine activity and the immune system is unknown. We investigated simultaneously the sleep EEG and nocturnal profiles of GH, ACTH, cortisol, prolactin, leptin, tumor necrosis factor (TNF)-alpha, and soluble TNF-alpha receptors in seven young normal volunteers after repetitive administration of 4 x 50 microg hexarelin or placebo at 22.00, 23.00, 24.00 and 01.00 h. Following hexarelin, stage 4 sleep during the first half of the night, and EEG delta power during the total night decreased significantly. Significant increases of the concentrations of GH and prolactin during the total night, and of ACTH and of cortisol during the first half of the night were found. Leptin levels, TNF-alpha and soluble TNF receptors remained unchanged. We hypothesize that sleep is impaired after hexarelin since the GHRH/corticotropin-releasing hormone (CRH) ratio is changed in favour of CRH. There are no hints for an interaction of hexarelin and the immune system.