Neuroendocrinological investigations during sleep deprivation in depression. I. Early morning levels of thyrotropin, TH, cortisol, prolactin, LH, FSH, estradiol, and testosterone

Measurements of 12 hormones were conducted in patients with major depressive disorder at 8 AM on the morning before and at 8 AM on the morning after total sleep deprivation (SD). Thyrotropin (TSH), thyroxine (T4), triiodothyronine (T3), and free T3 (fT3) were measured in 50 patients, free T4 in 39 patients, reverse T3, cortisol, prolactin, luteinizing hormone, and follicle-stimulating hormone in 21, estradiol in 20 (women), and testosterone in 14 (men). After SD, there was a significant rise in TSH, T4, T3, and fT3 concentrations and a significant fall in testosterone levels. The increases in TSH levels were significantly correlated to clinical response. Responders to SD had higher T4, fT4, rT3, and testosterone concentrations before SD. Neither age, gender, polarity, nor antidepressant medication had a clearly significant effect on the response to SD.     

Serum thyrotropin concentrations and bioactivity during sleep deprivation in depression

BACKGROUND: One night of sleep deprivation induces a brief remission in about half of depressed patients. Subclinical hypothyroidism may be associated with depression, and changes in hypothalamic-pituitary-thyroid function may affect the mood response to sleep deprivation. We wished to define precisely the status of the hypothalamic-pituitary-thyroid axis of depressed patients during sleep deprivation and the possible relationship of hypothalamic-pituitary-thyroid function to the mood response. METHODS: We studied 18 patients with major depressive disorder and 10 normal volunteers. We assessed mood before and after sleep. We measured serum thyrotropin every 15 minutes during the night of sleep deprivation, thyrotropin bioactivity, the thyrotropin response to protirelin the next afternoon, and other indexes of hypothalamic-pituitary-thyroid function. To determine if the changes were limited to the hypothalamic-pituitary-thyroid axis, we measured serum cortisol, which also has a circadian secretory pattern. RESULTS: Nocturnal serum thyrotropin concentrations were consistently higher in responders, entirely because of elevated levels in the women reponders. Responders had exaggerated responses to protirelin the next afternoon. The bioactivity of thyrotropin in nonresponders was significantly greater than in responders (F(1,8. 99) = 7.52; P =.02). Other thyroid indexes and serum cortisol concentrations were similar among groups. CONCLUSIONS: Depressed patients have mild compensated thyroid resistance to thyrotropin action, not subclinical autoimmune primary hypothyroidism. Sleep deprivation responders compensate by secreting more thyrotropin with normal bioactivity; nonresponders compensate by secreting thyrotropin with increased bioactivity.     

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.     

Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans

Ghrelin is an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor. It is hypothesised to play a key role in energy balance stimulating food intake and body weight. Besides GH-releasing hormone (GHRH) and somatostatin, it is thought to be a regulating factor of GH release. Ghrelin also appears to be involved in sleep regulation. We showed recently that ghrelin promotes slow-wave sleep and the nocturnal release of GH, cortisol and prolactin in humans. Similarly, promotion of non-rapid-eye-movement (NREM) sleep was reported in mice after systemic ghrelin. If ghrelin is a factor that induces and/or maintains sleep, it should be enhanced after a period of sleep deprivation (SD). To clarify this issue, nocturnal ghrelin, GH, ACTH and cortisol plasma concentrations were determined and simultaneously sleep electroencephalogram (EEG) was recorded (2300-0700 h) during sleep before and after 1 night of total SD in 8 healthy subjects. Compared to baseline, ghrelin levels increased earlier by a non-significant trend, already before the beginning of recovery sleep. Further a non-significant trend occurred, suggesting higher ghrelin secretion in the first half of the night. The ghrelin maximum was found significantly earlier after SD than at baseline. GH secretion during the first half of the night and total night after SD were elevated. ACTH and cortisol were also elevated, which was most pronounced during the second half of the night. No effects of SD on the time of the maximum were found for GH, ACTH and cortisol. The increase in ACTH after SD is a novel finding. Whereas the effects of SD on ghrelin levels were relatively weak, our findings are in line with the hypothesis that ghrelin is a sleep-promoting factor in humans. Ghrelin may be involved in sleep promotion after SD.     

Blunted prolactin response to fentanyl in depression. Normalizing effect of partial sleep deprivation

There is some evidence that sleep deprivation (SD) might exert its antidepressant properties by involving endogenous opioid mechanisms. The authors investigated the effects of mu-receptor agonist administration on prolactin release in depressed patients before and after partial SD. Medication-free female depressed inpatients (N=18) were participating in two fentanyl challenge tests after partial SD and undisturbed sleep, 3 days apart in random order. Healthy volunteer women (N=10) were enrolled after full night sleep as comparison subjects. Five of them had placebo trials. Participants were given an intravenous injection of 0.1 mg/70 kg fentanyl at 9:00 AM. The prolactin secretory response to the opiate agonist was investigated for 1 h with serial blood sampling. After a night of undisturbed sleep, fentanyl administration prompted increases in plasma prolactin concentrations with blunted responses found in the depressed group. Following partial SD, the stimulated prolactin secretion of depressed patients increased significantly and was comparable to the response of comparison subjects. These findings suggest that SD acts via an opioid/dopamine-related mechanism. An alternative explanation, based on serotonin involvement is addressed in the discussion.     

Body core temperature and depression during total sleep deprivation in depressives

Endogenously depressed patients were subjected to a total sleep deprivation (TSD) schedule of sleep-TSD-sleep-TSD. They were simultaneously treated with the antidepressant drug clomipramine. Self- and observer-rated depression was measured daily. Continuously measured rectal temperature (RT) data were available for the second TSD. It was found that a higher nocturnal minimum RT during this TSD was associated with a positive clinical response.     

Dopaminergic augmentation of sleep deprivation effects in bipolar depression.

Total sleep deprivation (TSD) has been used in association with lithium salts and with serotonergic and noradrenergic antidepressants, leading to sustained improvements in patients affected by major depression. Current theories on the neurobiological mechanism of action of TSD propose a major role for enhanced dopamine activity. To test the clinical relevance of dopaminergic enhancement in TSD, we treated a homogeneous sample of 28 bipolar depressed patients with three cycles of TSD combined with placebo or with the dopaminergic antidepressant amineptine. Changes in mood over time were rated with self-administered visual analogue scales and with the Montgomery-Asberg Depression Rating Scale. Patients showed improved mean daily-mood scores after TSD, an effect that was highest at the first cycle and decreased with treatment repetition. Amineptine enhanced the effects of TSD on perceived mood during the first two TSD cycles, but patients in the placebo and amineptine groups showed comparable results at the end of the treatment. Despite its theoretical importance, the clinical usefulness of combining TSD with a dopaminergic agent must be questioned.     

Effect of hypoglycaemia,TRH and levodopa on plasma growth hormone,prolactin, thyrotropin and cortisol in Parkinson's disease before and during therapy

Summary Thirteen drug-free and not severely affected patients with idiopathic Parkinson's disease underwent an insulin-hypoglycaemia test, a TRH test and a levodopa test. The responses of growth hormone, prolactin, cortisol and thyrotropin were measured, and retested under stable therapy with levodopa and benserazide. Mean basal and stimulated hormonal concentrations were in the normal range before and during therapy. Minor abnormalities were observed in individual cases, but did not indicate a hypothalamic dopamine deficit.     

Impact of sleep deprivation and subsequent recovery sleep on cortisol in unmedicated depressed patients

OBJECTIVE: One night of sleep deprivation induces a transient improvement in about 60% of depressed patients. Since depression is associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis, the authors measured cortisol secretion before, during, and after therapeutic sleep deprivation for 1 night. METHOD: Fifteen unmedicated depressed inpatients participated in a combined polysomnographic and endocrine study. Blood was sampled at 30-minute intervals during 3 consecutive nights before, during, and after sleep deprivation. Saliva samples were collected at 30-minute intervals during the daytime before and after the sleep deprivation night. RESULTS: During the night of sleep deprivation, cortisol levels were significantly higher than at baseline. During the daytime, cortisol levels during the first half of the day were higher than at baseline in the patients who responded to sleep deprivation but not in the nonresponders. During recovery sleep, cortisol secretion returned to baseline values. CONCLUSIONS: This study demonstrated a significant stimulatory effect of 1 night of sleep deprivation on the HPA axis in unmedicated depressed patients. The results suggest that the short-term effects of antidepressant treatments on the HPA axis may differ from their long-term effects. A higher cortisol level after sleep deprivation might transiently improve negative feedback to the hypothalamus or interact with other neurotransmitter systems, thus mediating or contributing to the clinical response. The fast return to baseline values coincides with the short clinical effect.     

Clinical and biological correlates of sleep deprivation in depression

Sleep deprivation is reported to have therapeutic effectiveness in depressive illness. Furthermore, the response to sleep deprivation has important research implications. Recent conceptual advances, resulting in increased understanding of the role of abnormal biological rhythms and neurotransmitter function of the pathophysiology of affective disorder, highlight the future role of sleep deprivation in the research and treatment of these disorders.     

Delta sleep ratio as a predictor of sleep deprivation response in major depression.

The fast but short-lasting improvement of depressive symptoms by sleep deprivation (SD) in about 60% of patients with a major depressive disorder is well established, but the mechanisms of action are still not clear. Recent studies suggest that changes in non rapid eye movement (NREM) sleep, especially in slow wave activity (SWA), could be associated with the therapeutic outcome of SD. In the current study, spectral analysis of NREM sleep EEG directly prior to SD was performed to determine if automatically derived sleep parameters predict SD response. Sixteen pair matched and drug free patients with a major depressive disorder, 8 SD responders and 8 non-responders (response criterion: 50% reduction on the 6-item HAMD score), were included. Average EEG spectral power was calculated for the whole night before SD and for single NREM episodes. While whole-night averages of spectral power did not differ significantly between subgroups, SD responders showed a steady decrease of SWA across successive NREM episodes, whereas in non-responders an increase from the first to the second episode was observed. The different distribution of SWA was significantly expressed in the delta sleep ratio (quotient of SWA in the first to the second NREM episode). In conclusion, a high delta sleep ratio is a positive predictor for SD response. Referred to psycho- and pharmacotherapeutic results it is hypothesized that low and high values of the delta sleep ratio characterize subgroups of depressed patients with different neurobiological alterations, which could be relevant for further scientific and therapeutic approaches.     

Effects of selective sleep deprivation on sleep-linked prolactin and growth hormone secretion.

1. The secretion of prolactin and growth-hormone (hGH) was investigated during sleep in 10 healthy volunteers (8 males and 2 females): The comparison of one baseline night, one night after daytime physical exercise, and one night with selective deprivation of sleep stages 3 and 4 and paradoxical sleep showed clear differences of prolactin and hGH secretion during sleep. 2. Prolactin secretion is entrained into the sleep cycle of Non-REM and REM periods. A maximum of plasma hormone elevations occurs during the first quarter of sleep cycles, i.e., during Non-REM periods and less frequent rises at the end of the cycles, mainly during REM periods. 3. In contrast to growth hormone, concentrations of prolactin remain high also during later cycles occurring toward morning. This shows that high prolactin, but not high concentrations of hGH, regularly occur during sleep cycles with small amounts of slow-wave sleep. 4. Maximal prolactin concentrations during sleep are affected neither by preceding daytime physical exercise nor by selective deprivation of slow sleep stages 3 and 4. This is further evidence that slow-wave sleep stages are not necessary for the development of high plasma prolactin concentrations. However, peak values of growth hormone in the first and second cycle are significantly diminished after selective deprivation of sleep stages 3 and 4. 5. In abnormally long sleep cycles with artificial delay of the first REM period, the cyclical rhythmicity of prolactin release seems disturbed. This is further evidence for the sleep-dependent rhythmicity in the secretion of this hormone.     

Sleep in depression and sleep deprivation: a brief conceptual review.

Risk factors for somnipathies are psychological stress or psychiatric illness. More severe sleep difficulties have been found to be clearly related to psychiatric illness such as depression and phobias, as well as to addiction. Somnipathies can objectively be identified by means of polygraphy. Overall, polysomnographic measures in patients with affective disorders differ most frequently and significantly from those in normal control subjects. Persistent sleep disturbances are associated with significant risk of both relapse and recurrence in mood disorders and an increased risk of suicide. In addition to changes in sleep architecture, patients with major depression show profoundly altered patterns of nocturnal hormone secretion, possibly through mechanisms that link regulation of sleep with neuroendocrine activity. Basic and clinical approaches of sleep research established neurobiological models into the underlying pathophysiology associated with psychiatric disorders.     

Oxytocin does not modify GH, ACTH, cortisol and prolactin responses to Ghrelin in normal men

Background

In order to test the possible effect of Oxytocin (OT) on Ghrelin-stimulated GH, PRL, ACTH and cortisol, ten healthy normal men were studied.

Methods

Tests: Ghrelin (0.2 μg/kg body weight (BW)) as an iv bolus; Ghrelin plus OT (2 IU as bolus plus 0.07 IU/min administered for 90 min).

Results

The administration of OT did not change GH, PRL, ACTH and cortisol release induced by Ghrelin.

Conclusions

The data suggests that in humans OT did not modulate the GH, PRL, ACTH and cortisol response to Ghrelin.     

The timing and duration of sleep in partial sleep deprivation therapy of depression

The antidepressant response to partial sleep deprivation early in the night (PSD-E) was compared with the response to partial sleep deprivation late in the night (PSD-L) in 16 drug-free depressed inpatients using a balanced order crossover design. PSD-L had a significantly greater antidepressant effect that PSD-E. The response to PSD-L was sustained and enhanced by a second night of treatment. Patients had significantly shorter sleep durations and reduced REM sleep on PSD-L that did not occur in the PSD-E situation. There was a significant negative correlation between response to PSD and sleep duration, and in particular, REM sleep duration, in the late sleep deprivation situation. Thus, the amount and timing of sleep appear to be factors in the response to PSD, but additional studies are needed to evaluate the relative importance of these parameters.     

Rate of switch from depression into mania after therapeutic sleep deprivation in bipolar depression.

Sleep deprivation is a potentially useful non-pharmacological treatment for depression. A relationship between sleep loss and the onset of mania has been reported, so it is possible that a switch from depression into mania after sleep deprivation might be expected in bipolar depressed patients who are treated with sleep deprivation. In a sample of 206 bipolar depressed treated with three cycles of sleep deprivation, alone or in combination with heterogeneous medications, we observed a 4.85% switch rate into mania and a 5.83% switch rate into hypomania. These percentages are comparable to those observed with antidepressant drug treatments.     

Clinical effects of sleep deprivation and clomipramine in endogenous depression

Three groups of ten hospitalized endogenously depressed patients were treated with clomipramine alone (CL), a combination of sleep deprivation and clomipramine (CL/SD), and a combination of sleep deprivation and placebo (PL/SD), respectively. The sleep deprivation (SD) regime consisted of two deprivations per week. Measurements by self, blind and nurse ratings were taken twice daily during the experimental period of 15 days. Self and blind ratings indicate that, on average, over the entire experimental period, CL/SD was the most effective treatment in alleviating depression. The results of the PL/SD treatment were not significantly different from those of CL. In contrast, the nurse ratings did not differentiate significantly between the CL/SD and CL groups. Hamilton depression ratings indicated significantly less depression after one week of treatment with CL/SD relative to the treatment with CL alone. After the second week, however, no such differential clinical gain was found for the CL/SD group. It is concluded that SD in combination with clomipramine as compared with CL alone induces a faster onset of improvement in depression.