Growth Hormone-Releasing Hormone (GHRH)- induced effects on sleep EEG and nocturnal secretion of growth hormone, cortisol and ACTH in patients with major depression

doi:10.1016/0022-3956(94)90008-6

Journal of Psychiatric Research

Volume 28, Issue 3, May–June 1994, Pages 225-238

https://doi.org/10.1016/0022-3956(94)90008-6 Get rights and content

Abstract

Studies in normal human subjects and animals suggest that the neuropeptide growth hormone-releasing hormone (GHRH) is a common regulator of the sleep EEG and nocturnal hormone secretion. In healthy volunteers GHRH prompts an increase in the amount of slow wave sleep (SWS) and in growth hormone (GH) secretion and blunting of cortisol release. Inhibition of GHRH may contribute to sleep-endocrine aberrances during depression. We tested the effects of pulsatile application of 4 x 50 μg GHRH on the sleep EEG and simultaneously investigated nocturnal hormone secretion in 10 inpatients (four females, six males) with the acute episode of major depression. In contrast to the effects of placebo, GH secretion increased distinctly and rapid-eye- movement (REM) density decreased during the second half of night. No other significant changes in sleep-endocrine activity, including SWS, cortisol and ACTH secretion, could be observed. We assume that hypothalamic-pituitary-adrenocortical system activity and slow wave sleep are inert to the influence of GHRH during acute depression. Cortisol and ACTH remained unchanged even in a subsample of five younger (aged 19–28 years) patients. This observation is in contrast to our recent finding that cortisol secretion is blunted in young normal volunteers after GHRH. But on the other hand, GHRH is capable of stimulating GH and inducing a decrease in REM density in these subjects.

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Ghrelin alone or co-administered with GHRH or CRH increases non-REM sleep and decreases REM sleep in young males
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The order of the treatment conditions was chosen at random. Hormone doses were chosen considering previous studies showing a biological action (e.g. increase of hormones, sleep effects) but no relevant side effects (Holsboer et al., 1988; Steiger et al., 1994; Weikel et al., 2003). Hormones were administered in a pulsatile manner in order to optimize effects on sleep (Marshall et al., 1996).
Ghrelin activates the somatotropic and the hypothalamic–pituitary–adrenal axes, being crucially involved in sleep regulation. Simplified, growth hormone releasing hormone (GHRH) increases slow-wave sleep and REM sleep in males, whilst corticotropin-releasing hormone (CRH) increases wakefulness and decreases REM sleep. Ghrelin's role in sleep regulation and particularly its interactions with GHRH and CRH are not entirely clear. We aimed to elucidate the interactions between ghrelin, GHRH and CRH in sleep regulation and the secretion of cortisol and GH. Nocturnal GH and cortisol secretion and polysomnographies were determined in 10 healthy males (25.7±3.0 years) four times, receiving placebo (A), ghrelin (B), ghrelin and GHRH (C), or ghrelin and CRH (D) at 22:00, 23:00, 00:00, and 01:00 h, in this single-blind, randomized, cross-over study. Non-REM sleep was significantly (p<0.05) increased in all verum conditions (mean±SEM: B: 355.3±7.4; C: 365.4±8.1; D: 371.4±3.9 min) compared to placebo (336.3±6.8 min). REM sleep was decreased (B: 84.3±4.2 [p<0.1]; C: 74.2±7.0 [p<0.05]; D: 80.4±2.7 min [p<0.05]) compared to placebo (100.9±8.3). CRH+ghrelin decreased the time spent awake and enhanced the sleep efficiency; furthermore, the REM latency was decreased compared to the other treatment conditions. CRH enhanced the ghrelin-induced cortisol secretion but had no relevant effect on GH secretion. In turn, GHRH enhanced the ghrelin-induced GH secretion but had no effect on cortisol secretion. In conclusion, ghrelin exhibited distinct sleep effects, which tended to be enhanced by both GHRH and CRH. CRH had sleep-improving and REM permissive effects when co-administered with ghrelin, being in contrast to the effect of CRH alone in previous studies.
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Enhanced activity of the hypothalamic-pituitary-adrenal (HPA) axis, involving elevated secretion of corticotropin-releasing hormone (CRH), is considered a key neurobiological alteration in major depression. Enhanced CRH secretion is also believed to contribute to the typical sleep alterations and the clinical presentation of major depression.
While it is acknowledged that HPA overdrive and hypernoradrenergic function is associated with melancholic depression, there is growing evidence that hypoactivity of the HPA axis and afferent noradrenergic pathways is present in patients with atypical features of depression. The clinical relevance of such a differentiation is highlighted by findings which suggest distinct responses to pharmacological treatments. Moreover, it has been reported that female patients respond better to selective serotonin re-uptake inhibitors (SSRI) than tricyclic antidepressants. Interestingly, the female predominance among patients with depression seems to be restricted to the atypical subtype.
Besides HPA axis activity, distinct alterations of the serotonergic system may also play a critical role for the melancholic and atypical phenotypes, namely a reduced restrained via 5-HT_1A autoreceptors in the former and primarily reduced serotonin synthesis in the latter. Moreover, there is evidence for an immune activation in patients with depression, the extent and duration of which may be distinguishable for the melancholic and the atypical subtype. In this regard, lessons can be learned from depressive symptoms in patients with autoimmune disease, associated with different alterations of the HPA axis, and in patients undergoing cytokine therapy.
In conclusion, the available data today suggest that clinically relevant differences in the underlying pathophysiology in patients with depression exist. The identification of distinct endophenotypes for major depression will not only improve our understanding of the disease, but will also contribute to more specific treatment strategies.
Sleep and depression - Results from psychobiological studies: An overview
2001, Biological Psychology
Citation Excerpt :
A marked REM sleep suppression has also been reported for the MAO-inhibitors phenelzine, tranylcypromine, and brofaromine (Akindele et al., 1970; Hoff et al., 1986; Steiger et al., 1987). REM sleep suppression is less pronounced with the selective and reversible MAO-A inhibitor moclobemide (Steiger et al., 1994). Exceptions to this rule are trimipramine (Dunleavy et al., 1972; Wiegand et al., 1986) and trazodone (Ware and Pittard, 1990), where no REM sleep suppression seems to occur.
Disturbances of sleep are typical for most depressed patients and belong to the core symptoms of the disorder. Polysomnographic sleep research has demonstrated that besides disturbances of sleep continuity, in depression sleep is characterized by a reduction of slow wave sleep and a disinhibition of REM sleep, with a shortening of REM latency, a prolongation of the first REM period and increased REM density. These findings have stimulated many sleep studies in depressive patients and patients with other psychiatric disorders. In the meantime, several theoretical models, originating from basic research, have been developed to explain sleep abnormalities of depression, like the two-process-model of sleep and sleep regulation, the GRF/CRF imbalance model and the reciprocal interaction model of non-REM and REM sleep regulation. Interestingly, most of the effective antidepressant agents suppress REM sleep. Furthermore, manipulations of the sleep–wake cycle, like sleep deprivation or a phase advance of the sleep period, alleviate depressive symptoms. These data indicate a strong bi-directional relationship between sleep, sleep alterations and depression.
Effects of chronic ethanol exposure on sleep in rats
2000, Alcohol
Sleep disturbance is a common complaint in alcoholics. When polysomnographic studies are performed in alcoholics, reductions in slow wave sleep are a common finding; however, few studies have evaluated the effects of chronic alcohol exposure on sleep in animal models. In the present study, the sleep EEG was evaluated in 40 Wistar rats who were exposed to chronic alcohol or control conditions in vapor chambers. Rats were exposed to ethanol vapors or control chambers for 6 weeks and then withdrawn. Sleep EEG was recorded before exposure (baseline), immediately following exposure, and 5 weeks after withdrawal from the ethanol/control chambers. In the ethanol-exposed animals, blood ethanol levels averaged 192 mg/dL over 6 weeks of exposure. Chronic ethanol exposure and withdrawal was not found to affect either slow wave sleep latency or slow wave sleep duration; however, overall spectral power as well as power in the delta, theta, and beta frequencies were significantly reduced following chronic exposure (2–4 Hz, [F(1, 17) = 18.11, p = 0.001], 4–6 Hz, [F(1, 17) = 15.98, p = 0.001], 6–8 Hz [F(1, 17) = 15.52, p = 0.001], 8–16 Hz band [F(1, 17) = 18.73, p < 0.0001], 16–32 Hz [F(1, 17) = 10.13, p = 0.005], and 1–50 Hz [F(1, 17) = 17.03, p = 0.001]. After 5 weeks of withdrawal, significant decreases still persisted in the delta and theta frequencies (2–4 Hz [F(1, 16) = 6.21, 0.024], 4–6 Hz [F(1, 16) = 6.26, 0.024], and 6–8 Hz [F(1, 16) = 4.84, p = 0.043]). These findings suggest that spectral analysis of the EEG is a highly sensitive measure of the effects of ethanol on sleep. These findings additionally demonstrate that chronic ethanol exposure can produce persistent diminution in the systems that generate cortical slow waves in the rat and thus may provide a model for understanding the mechanisms underlying sleep disturbances associated with alcoholism.
Reduced efficacy of growth hormone-releasing hormone in modulating sleep endocrine activity in the elderly
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In aging, a decline in sleep continuity, a decreased slow wave sleep, an earlier nocturnal cortisol rise, and a blunted growth hormone (GH) secretion occur. Pulsatile administration of GH-releasing hormone (GHRH) in young controls enhanced slow wave sleep and suppressed cortisol release. We administered GHRH 4 × 50 μg or placebo i.v. to 13 healthy seniors (5 women, 8 men, mean age 69.3 y ± 8.3 SD). We observed significantly reduced nocturnal awakenings and an increased first non-rapid-eye-movement sleep period. In a subgroup (n = 9), we found a significant activation of GH secretion but unchanged cortisol secretion. Our data underscore that GHRH is capable of promoting sleep in the elderly, but much less than in young subjects. Contrasting to young subjects, the hypothalamic-pituitary-adrenocortical system remains unaffected by GHRH in the elderly. These results provide further evidence that a decrease in the efficacy of GHRH is involved in the biological mechanisms underlying aging.
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Growth Hormone-Releasing Hormone (GHRH)- induced effects on sleep EEG and nocturnal secretion of growth hormone, cortisol and ACTH in patients with major depression

Abstract

Brain Research

Biological Psychiatry

Progress in Brain Research

Psychoneuroendocrinology

Psychiatry Research

Biological Psychiatry

Biological Psychiatry

Brain Research

Psychiatry Research

Psychiatry Research

Peptides

Peptides

Journal of Affective Disorders

Hormones and Behavior

Journal of Affective Disorders

DSM-III-R: Diagnostic and statistical manual of mental disorders

Cortisol secretion in relation to age in major depression

Psychosomatic Medicine

Growth hormone effects on sleep and wakefulness in the rat

Neuroendocrinology

Effects of corticotropin-releasing factor and growth hormone-releasing factor on sleep and activity in rats

Neuroendocrinology

Sleep and affective illness

A rating scale for depression

Journal of Neurology, Neurosurgery and Psychiatry

Psychiatric implications of altered limbic-hypothalamic-pituitary-adrenocortical activity

European Archives of Psychiatry and Neurological Science