Today the most widely prescribed hypnotics do not induce physiological sleep.

Benzodiazepines suppress slow wave sleep [SWS], EEG delta activity and REM sleep and enhance sleep spindles. The newer hypnotics zolpidem and zopiclone exert similar effects, particularly d ê .

The best physiological stimulus for sleep is sleep deprivation.

After sleep deprivation: SWS é , d é , spindles ê .

Hypnotics of the future should share the effects of sleep deprivation.

This symposium summarizes latest results in basic and clinical research on sleep regulation. Substances which are leads for the development of novel hypnotics will be presented.

Hypothalamic growth hormone-releasing hormone (GHRH) stimulates growth hormone (GH) and sleep in various species including men. F. Obàl summarizes experimental preclinical findings on GHRH in sleep regulation.

Stimulation of Non-REM sleep and GH secretions are parallel, independent outputs of hypothalamic GHRH mediated by the preoptic region and the anterior pituitary, respectively.

Currently known stimuli that promote Non-REM sleep in part via GHRH include sleep deprivation, diurnal rhythm, and interleukin-1.

The negative feedback mechanisms in the somatotropic axis (somatostatin, and high concentrations of GH and IGF-1) also decrease non-REM sleep.

A. Steiger reports on sleep promotion by neuropeptides and neuroactive steroids. Clinical findings support a reciprocal interaction of GHRH and corticotropin-releasing hormone (CRH) in sleep regulation.

GHRH in young normal men: SWS é , GH é , cortisol ê

CRH in young normal men: SWS ê , GH ê , cortisol é

The efficiency of GHRH is reduced, when CRH is elevated: 2^nd half of night in young men, during aging, in depression, in females compared to males.

Also NPY, galanin and GHRP promote sleep. Somatostatin impairs sleep in the elderly.

Neuroactive steroids are ligands of the GABA_A receptor. After the neurosteroid pregnenolone: SWS é , sleep efficiency é .

M. Vitiello focuses on endocrine interventions for sleep disturbances in the elderly. During aging sleep quality ê and use of hypnotics é . Decline of endocrine function may contribute to shallow sleep in the elderly. GHRH and estrogen replacement therapy may be useful strategies to treat sleep disorders by counteracting age-related changes of endocrine activity.

E. Holsboer-Trachsler shows the impact of peptides in sleep promotion by the phytotherapeutic Ginkgo Biloba.

Most of the studies about phytotherapeutics and sleep confirmed only hypnotic effects on subjective sleep variables. For hypericum extract, valerian and kava-kava an induction of SWS was demonstrated in sleep-EEG studies. All three substances influence GABA-ergic neurotransmission, which may explain the effects on SWS.

Ginkgo Biloba extract has proved to be efficient in the improvement of cognitive abilities in healthy subjects and patients with diseases of the dementia spectrum. To date Ginkgo Biloba has not been applied in patients with major depression. In major depression both cognitive deficits and sleep disturbances are common features probably connected to a similar underlying pathophysiology of hypothalamic-pituitary-adrenal(HPA)-dysregulation. Animal studies demonstrated: complex modifications of the HPA-axis during chronic treatment with Ginkgo Biloba.

Studies protocol: open pilot study on the effects of Ginkgo Biloba LI 1370 on cognitive performance and sleep regulation in depressed patients (on a constant treatment with trimipramine 200 mg/d).

After one week Ginkgo Biloba: sleep efficiency é , awakenings ê , REM-density ê .

After four weeks SWS é .

Discontinuation (week 6) of Ginkgo after 1 week reversed these effects.

Based on the animal data these results surmise that Ginkgo Biloba increases SWS by tonic CRH-activity ê leading to GHRH/CRH ratio é .

In rats Ginkgo Biloba seems to have direct effects on the HPA-system at the level of the adrenal gland through diminution of the number of peripheral-type benzodiazepine-receptors (PBR) resulting in decreased corticosteroid synthesis and circulating glucocorticoid levels. In view that these receptors have been found in high concentrations within the hypothalamus as well, the precise mechanism of Ginkgo Biloba on hypothalamic CRH may involve PBR.

Taken together Ginkgo Biloba may exert its effects on sleep in depressed patients over variation of the GHRH/CRH-component which may involve PBR.

M. Wiegand reports on antidepressants in the treatment of insomnia.

The benzodiazepines and benzodiazepine receptor agonists continue to be the most widely prescribed hypnotics; in general, this is justified by a favourable risk-benefit ratio. Sometimes, however, the use of these compounds is risky or contraindicated, e.g., in certain patients with a history of substance dependence, or in chronic insomnia besides nonpharmacological interventions such as relaxation therapies, sleep hygiene education, and behavioral therapy.

Antidepressants play an important role as alternative hypnotic drugs. Some "classical", tricyclic antidepressants have pronounced sleep-promoting properties due to their antihistaminic action, e.g., amitriptyline, doxepine, and trimipramine (the latter compound being of special interest since in contrast to other tricyclics, it does not suppress REM sleep). In depressed patients, these compounds improve sleep even before the onset of the antidepressant action. The hypnotic efficacy of some tricyclic antidepressants in non-depressed patients with chronic, psychophysiological insomnia could be demonstrated in several studies. However, the incidence of (mostly anti-cholinergic) side-effects limits the use of these drugs, especially in the elderly. Among newer antidepressants, nefazodone and mirtazapine have hypnotic properties and thus clearly differ from serotonin reuptake inhibitors. Nefazodone, besides inhibiting serotonin reuptake, has an inhibiting effect on postsynaptic 5-HT2 receptors mediating its sleep-promoting action. This could be demonstrated in depressed patients and healthy probands; an ongoing study in patients with psychophysiological insomnia shows promising tendencies. Mirtazapine has a pharmacological profile combining enhancement of both noradrenergic and serotonergic neurotransmission with specific 5-HT2 and 5-HT3 receptor blockade; its action on sleep has been demonstrated in depressed patients and in healthy controls.

Thus, sleep-promoting antidepressants appear to be a useful alternative to "classical" hypnotics in the pharmacological treatment of insomnia, especially chronic insomnia.

M. Lancel report sleep-EEG effects of the GABA_A agonist THIP. Age-related sleep alterations predispose older people to chronic insomnia. While the ability to fall sleep hardly changes, the number and duration of nocturnal awakenings increase and the amount of deep sleep progressively decreases with advancing age. As particularly elderly tend to use sleeping pills to improve their sleep, there is an urgent need for hypnotics that selectively increase sleep consolidation and sleep intensity and have a low tolerability and dependency potential.

Recent studies in the rat demonstrated that the selective GABA_A receptor agonist 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP) dose-dependently increases the duration of the non-REM sleep episodes and enhances the slow frequency components in the EEG within non-REM sleep. These effects can be induced during the circadian rest phase as well as during the activity phase, when spontaneous sleep is highly fragmented and shallow. Further research revealed that the somnogenic effects of THIP remain present during chronic (5-day) treatment and that abrupt drug withdrawal is not associated with negative sleep effects. To investigate whether THIP affects sleep in humans in a similar fashion, we assessed nocturnal sleep in young, good-sleeping subjects after the oral administration of placebo and one dose of THIP. THIP significantly increased the sleep efficiency index and the amount of visually scored SWS, on average by 25 min, and augmented slow wave activity, while attenuating spindle activity in the EEG within non-REM sleep (see Fig. 3).

The results of these studies indicate that THIP is able to increase sleep maintenance and sleep intensity, without interferring with REM sleep, and that tolerance to its somnogenic action does not develop rapidly. Possibly THIP, or related compounds, may have prospects in the treatment of insomnias characterized by frequent or long-lasting nocturnal awakenings and/or by non-refreshing, too light sleep. As such sleep disturbances are very prevalent in aged people, we are currently investigating the influence of THIP on night sleep in a group of elderly subjects.

Figure legend: Effect of 20 mg THIP, given orally at bedtime to 10 young healthy subjects, on the visually scored sleep parameters (left graph) and on average slow wave activity within non-REM sleep (right graph). Data are means + SEM. For plotting purposes, the sleep stages are expressed as deviation from placebo (min. after THIP - min. after placebo) and the slow wave activity values (0.8-4.3 Hz), which are plotted in the middle of the 2-h intervals, as percentage of the average slow wave activity within non-REM sleep during the entire placebo night. TIB = Time In Bed; TST = Total Sleep Time; S1 = Stage 1; S2 = Stage 2; SWS = Slow Wave Sleep. Significant differences between the treatments are indicated by ** (p<0.01, Wilcoxon matched pairs signed rank test for vigilance stages and 2-sided, piared t-test for slow wave activity).