Bjarke Ebert and Keith A Wafford

Natural Insomnia Program

Insomnia Homeopathic Cure

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CONTENTS

20.1 Introduction 329

20.2 Sleep Basics 330

20.3 Pharmacological Modulation of the Sleep System 332

20.3.1 Induction and Maintenance of Sleep 332

20.3.1.1 Benzodiazepines and Benzodiazepine Receptor Agonists 332

20.3.2 Modulating Slow Wave Sleep and Slow Wave Activity 336

20.3.2.1 GABAa Receptor Agonists 336

20.3.2.2 5-HT2A Antagonists 337

20.3.3 Orexinergics 338

20.3.4 Melatonin and Melatonergic Agonists 338

20.4 Concluding Remarks 339

Further Readings 339

20.1 INTRODUCTION

Problems with sleep (falling asleep, maintaining sleep, waking up early, or not feeling refreshed after sleep) can occur in some patients as a disease in its own right and in other patients as a comorbidity associated with diseases like depression, stress, and pain. In addition to the impairment of daytime alertness and reduced performance, chronic insomnia has dire consequences for the quality of life. Clinical epidemiological studies have linked poor sleep with depression, increased blood pressure, and type 2 diabetes. The treatment of poor sleep may therefore have more wide ranging effects than purely increase the sleep time during the night. However, when novel hypnotics have been developed over the last decades, focus has not been on the improvement of quality of life or day time function in general, but rather the metrics of sleep. The reason for this is probably, that the regulatory guidelines indicate that hypnotics should be characterized in primary insomniacs, which are insomnia patients devoid of clinical consequences of the impaired sleep. With the absence of daytime consequences pharmaceutical companies, academia, and regulatory authorities in unison have neglected or forgotten that sleep is not about metrics during the night but the quality of life during the day.

Hypnotic drugs used to treat insomnia sufferers are characterized by their effects on induction and maintenance of sleep. These hypnotics—primarily benzodiazepines and benzodiazepine receptor agonists (BzRAs)—are highly effective drugs, which are able to induce and maintain sleep. When it comes to improvement of daytime performance and thereby the quality of life; however, existing hypnotic drugs may not improve or may even worsen these types of parameters.

This chapter will cover the basics of sleep physiology, followed by a description of different treatment modalities from the current benzodiazepines and BzRAs to novel strategies like 5-HT2A, GABAa receptor agonists, melatonergics, and orexinergics, which may advance the treatment of sleep problems.

20.2 SLEEP BASICS

Sleep is a state of the brain, which is shared by most organisms from invertebrates to mammals. The mechanisms underlying the transition from awake to sleep are now understood in some detail, whereas the function of sleep still remains enigmatic. As illustrated in Figure 20.1, the transition from wake to sleep is associated with a change in the activity of different neuronal pathways. Earlier sleep was considered a resting state of the brain—an impression conveyed by the clinical signs of sleep: reduced blood pressure, reduced heart rate, immobility, and reduced sensitivity toward external stimuli. However, measurements of brain activity and imaging studies performed during sleep have clearly shown that sleep is an active state of the brain. Sleep itself is not homogenous, and can be divided into various states representing different patterns of electrical activity. The underlying biology and complex interaction of various neurotransmitter systems in initiating, maintaining, and shaping sleep are now beginning to be better understood, paving the way for more precise and effective pharmacological treatment of sleep disorders.

Like waking, sleep is an active state of the brain. During this heterogeneous and rapidly changing state several restorative functions take place, although the neural substrates of somatic and cognitive restoration remain elusive.

Sleep is generally considered to consist of two substates, rapid eye movement (REM) and nonrapid eye movement (NREM) sleep, which alternate to form a cycle lasting approximately 90 min (Figure 20.2). REM and NREM sleep can clearly be differentiated on the basis of a number of physiological variables including muscle tone, electroencephalographic (EEG), and electromyelographic (EMG) features, and the presence or absence of REMs. Distinct physiological roles for REM and NREM stages have been proposed, but compelling empirical data are scarce.

Real sleep in a living brain is a continuous state without clear transitions. Therefore, a temporal description of the waves and alterations in the amount of both frequencies and amplitudes should most likely be based on an analysis of these waveforms. However, for historical reasons sleep stages are described as either REM or NREM stages 1-4 using visual scoring criteria based, in part, on the quantity and gross type of EEG waveforms per unit time. These are combined together graphically into a hypnogram as shown in Figures 20.2 and 20.3. NREM stages 1 and 2 have been described as

Laterodorsal Thalamic Nucleus

FIGURE 20.1 Neuronal pathways active during wake and sleep. Left: During wake, several arousal systems are active. These include monoaminergic (noradrenalin and serotonin originating in LC, Raphe, and TMN) and orexinergic (originating in LH) systems. Right: During sleep, the inhibitory GABA (VLPO) and melaton-ergic systems (originating in the pineal gland and projecting to thalamus) take over and initiate and maintain sleep and the transition between different sleep stages. PPT, pedunculopontine nuclei; LDT, laterodorsal tegmental nuclei; LC, locus coeruleus; TMN, tuberomammillary nucleus; vPAG, A10 cell group; LH, lateral hypothalamus; BF, basal forebrain; VLPO, ventrolateral preoptic nucleus; PeF, perifornical neurons.

FIGURE 20.1 Neuronal pathways active during wake and sleep. Left: During wake, several arousal systems are active. These include monoaminergic (noradrenalin and serotonin originating in LC, Raphe, and TMN) and orexinergic (originating in LH) systems. Right: During sleep, the inhibitory GABA (VLPO) and melaton-ergic systems (originating in the pineal gland and projecting to thalamus) take over and initiate and maintain sleep and the transition between different sleep stages. PPT, pedunculopontine nuclei; LDT, laterodorsal tegmental nuclei; LC, locus coeruleus; TMN, tuberomammillary nucleus; vPAG, A10 cell group; LH, lateral hypothalamus; BF, basal forebrain; VLPO, ventrolateral preoptic nucleus; PeF, perifornical neurons.

Awake

Sleep spindle

Wave peak

Stage I

ivuavc ucarv

1 cycle 1s = 13 cycles trough

Stage II

Stage III

Stage IV

Stage IV

FIGURE 20.2 EEG patterns in humans during wake and different sleep stages. (Data from Pace-Schott, E.F. and Hobson, J.A., Nat. Rev. Neurosci, 3, 591, 2002.)

21,000

c 10,500e

W REM

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0123456789 Elapsed time (h)

FIGURE 20.3 SWS and SWA. The bottom panel illustrates a hypnogram showing the amount of time spent in the different sleep stages over the course of the night, using traditional visual scoring criteria. Each progression through the five stages (stages 1-4 and REM) constitutes a sleep cycle. The top panel represents a fast Fourier transformation of EEG data. The frequency band selected for power analysis was 0.75-4.5 Hz. This representation illustrates that SWA is present throughout the night, even when the sleeper does not reach stage 3 or 4 according to traditional visual scoring criteria. (From Ebert, B. et al., Pharmacol. Ther, 112, 612, 2006. With permission.)

light sleep, while stages 3 and 4 are often described as deep or slow wave sleep (SWS). The hallmark waveform of SWS consists of rhythmic, low frequency waves (~0.5-4.5 Hz) with large amplitude. The amount of slow waves can be quantified by a Fourier transformation, whereby any pattern can be described by a combination of a series of sinusoidal waves with different frequencies and amplitudes. The numeric amplitude squared is a reflection of the amount of a certain frequency and is termed power. The power spectrum for slow waves (slow wave activity or SWA) during NREM sleep (Figure 20.3 top) is particular strong during stages 3 and 4, but are present throughout the sleep period, although to a much smaller extent.

SWS/SWA in particular may play an important role in somatic and cognitive restoration, including the consolidation of certain forms of procedural and declarative memory. A substantial diminution in the amount of SWS/SWA occurs across the human lifespan. This decline is beginning already in adolescence and middle-aged adults have only 25% of the SWS observed in young adults, whereas the elderly have almost none. While the clinical importance of these phenomena is unknown, it is reasonable to speculate that they may be related to the increase of sleep complaints associated with aging.

20.3 PHARMACOLOGICAL MODULATION OF THE SLEEP SYSTEM

The treatment of sleep disorders currently focuses at inducing and maintaining sleep. This is ensured via the positive modulation of the GABAa receptor system. Other drugs with sedative side effects (e.g., antihistamines and antidepressants) are also used, but these are often prescribed off-label, and have not been evaluated within this indication with the same rigor as the hypnotics. In addition to this, new pharmacological agents, such as, antagonists at orexin receptors, which are involved in wake promotion, and 5HT2A antagonists, which promote SWS are in clinical development. Since most reported studies with these compounds have included patients with primary insomnia, and thus no comorbidity (meaning either other disease or functional consequences of the sleep disturbances), it still remains an open question whether these approaches might constitute an advantage over the BzRAs in this regard. Finally, modification of the circadian rhythm, which in depressed patients and in elderly patients is severely impaired, is being targeted using melatonin and melaton-ergic agonists.

20.3.1 Induction and Maintenance of Sleep

20.3.1.1 Benzodiazepines and Benzodiazepine Receptor Agonists

Using the benzodiazepine structure as a template, thousands of molecules with similar pharmacological activities in vivo have been developed. Structure-activity studies have identified essential and forbidden areas of the structure and this analysis has led to the development of the so-called non-benzodiazepine hypnotics (hypnotics without the 1,4 benzodiazepine ring structure) (Figure 20.4).

Diazepam

Flunitrazepam

Lorazepam

Diazepam

Flunitrazepam

Lorazepam

Zaleplon

Zaleplon

Zolpidem Flumazenil

FIGURE 20.4 Structure of BzRAs and the competitive benzodiazepine receptor antagonist flumazenil.

Since all these compounds are increasing activity at the GABAa receptor via a positive allosteric interaction with one common binding motif, the term agonist has been applied. It should be noted, however, that the activity of benzodiazepines is dependent on the activation of the receptor by GABA, the ligand that directly gates the ion channel (see Chapter 15). These compounds are best referred to as positive allosteric modulators or BzRAs.

The GABAa receptor is a pentameric structure composed of five subunits surrounding a central ion channel pore. The receptor subunits comprise of families of related proteins termed a1-6, P1-3, g1-3, 8, e, p, 9, and p. The majority of receptors are composed of 2a, 2b, and 1g subunits. Other subunits can substitute for g, such as, 8 to form a benzodiazepine insensitive subtype of receptor. The binding site for BzRAs is located at the interface between a and g subunits in the pentameric assembly of subunits (Figure 20.5). Since the g subunit of the GABAA receptor contains a binding motif for a synaptic intercellular protein, g containing receptors are predominantly synaptically located.

Detailed pharmacological studies have revealed that BzRAs enhance the opening frequency of the activated receptor, thereby allowing more current (more specifically chloride ions) to pass through the receptor-controlled channel within a fixed period of time. On the macroscopic level,

Presynaptic GABA-releasing neuron

Synapse

Synapse

Synaptic inhibition

C GABA-containing vesicle Q y GABAa receptor g S GABAA rec'epSi

Postsynaptic cell x

Synaptic inhibition

Tonic inhibition

Synaptic Extra synaptic

Synaptic Extra synaptic

FIGURE 20.5 Top: Localization of GABAA receptors. g containing GABAA receptors are predominantly located in the synapse and determine phasic inhibition. In contrast, 8 containing GABAA receptors are located outside the synapse (extra-synaptically) and contribute to tonic inhibition. Bottom: Synaptic and extra-synaptic receptors are different in subunit composition and pharmacology. Whereas synaptic receptors contain the g subunit and are sensitive to BzRAs, extra-synaptic receptors contain 8 (or only a and b) and are insensitive to modulation by BzRAs. The binding site for BzRAs is located at the interface of a and g, whereas the GABA binding site is located at the interface between a and b.

FIGURE 20.5 Top: Localization of GABAA receptors. g containing GABAA receptors are predominantly located in the synapse and determine phasic inhibition. In contrast, 8 containing GABAA receptors are located outside the synapse (extra-synaptically) and contribute to tonic inhibition. Bottom: Synaptic and extra-synaptic receptors are different in subunit composition and pharmacology. Whereas synaptic receptors contain the g subunit and are sensitive to BzRAs, extra-synaptic receptors contain 8 (or only a and b) and are insensitive to modulation by BzRAs. The binding site for BzRAs is located at the interface of a and g, whereas the GABA binding site is located at the interface between a and b.

this is detected as an enhanced response to a fixed concentration of GABA or a leftward parallel shift of the GABA concentration response curve.

BzRAs can, depending on their ability to shift the GABA dose response curve, be characterized as full or partial agonists. The efficacy (or rather maximum effect) of the BzRA is determined at a concentration, which saturates the allosteric binding site, whereby the GABA concentration is the determining factor.

Variation in a subunit and g subunit confer a degree of heterogeneity at the benzodiazepine binding site, and it has been possible to develop several binding-affinity based selective BzRAs. It should be noted however that the g2 subunit is by far the most predominant subtype and limits the selectivity based on a-subtype. To date, compounds with modest a1 selectivity and a5 selectivity have been discovered. Those with a1 selectivity appear to be more sedative in nature than nonselective BzRAs. Since the binding site for BzRAs is allosteric in nature, it has also been possible to generate compounds with functional selectivity, behaving as agonists at one subtype but antagonists at another. Compounds with some selectivity for a1 have been developed as hypnotic agents, such as, zolpidem (Ambien) and zaleplon (Sonata).

By the application of molecular biology techniques, it has been possible to identify the amino acid residues essential for the affinity of the BzRAs. The mutation of one single amino acid (Histidine 101 to Arginine) can completely abolish benzodiazepine affinity and this difference in pharmacology can be observed when BzRAs are compared at a1 and a1 H101R containing GABAa receptors. By introducing the a1 H101R mutation in mice, it has been possible to show that the strong sedative effects of the unselective benzodiazepine diazepam and the a1 selective BzRA zolpidem were strongly reduced. Furthermore, sleep studies with zolpidem in these transgenic mice strongly indicated that the hypnotic effects of zolpidem indeed are mediated primarily via a1 containing GABAA receptors. These types of studies are obviously very valuable for the characterization of the contribution of different receptor populations to the overall pharmacological consequences of a compound in vivo. However, the pharmacological consequences of a compound are a composite of interactions with potentially several different types of receptors. In order to address the potential for functional heterogeneity in vivo, it is necessary to obtain knowledge on exposure (CNS concentrations and eventually a time dependent profile) and activity (potency and efficacy) at the relevant individual receptor populations. Very seldom are all these data available. However, in a recent study, a series of compounds were systematically characterized at different human GABAA receptors, expressed in Xenopus oocytes, by means of electrophysiology. Since most of these compounds have been characterized clinically and BzRAs freely penetrate the blood-brain barrier (BBB), a very good estimate of both CNS exposure and receptor activation can be obtained.

As illustrated in Figure 20.6, CNS concentrations for these compounds are well above the EC50 values at the individual receptor combinations. A compound like indiplon in fact is used clinically at such a high concentration that the functional selectivity is not determined by the subunit dependent potency, but rather by the maximum response at the different receptor types. This means that the in vitro selectivity of these compounds, which is seen at very low concentrations, is misleading when the clinical relevant concentrations are factored in. Consequently, interpretation of in vivo data from man or animal studies, solely based on the in vitro profile may be highly ambiguous.

BzRAs have several serious clinical limitations. Firstly, a fading in response after long-term treatment or tolerance. Secondly, risks for development of dependence especially over long-term treatment, and thirdly, abuse liability. All these aspects can be addressed in preclinical studies, and very consistently, BzRAs (irrespective of in vitro subtype selectivity) have been shown to possess all these risk factors. However, although compounds may show development of tolerance in animal studies, this may not be directly translatable into the clinical situation. Examples of this are the fast acting hypnotics zolpidem and indiplon, which after long-term dosing in animals induces a down regulation in GABAA receptors, predictable for tolerance development and withdrawal symptoms. However, very few reports on these types of side effects are available in the clinical literature to date, and as a consequence, the American FDA has now removed the restriction of only short term

Zolpidem (|M) Zopiclone (|M)
Zaleplon (|M) Indiplon (|M)

-a,p3y2 -a2p3y2 - a3p3y2 -a5p3y2

FIGURE 20.6 Modulation of 3 |lM GABA by a series of BzRAs at therapeutic relevant concentrations. The therapeutic relevant concentration is marked with a blue box. Dose response curves are from in vitro functional experiments in Xenopus oocytes. (Adapted from Petroski, R.E. et al., J. Pharmacol. Exp. Ther., 317, 369, 2006.)

use of these BzRAs. The reason for the discrepancy between animal and human data most likely relates to differences in levels and duration of exposure. Most preclinical studies are conducted with the aim of demonstrating a certain pharmacological effect. Therefore most tolerance development studies and receptor down regulation studies are carried out with constant and high exposure, which under normal circumstances may be highly irrelevant from a clinical perspective, but certainly addresses aspects of the mechanisms underlying tolerance development. In contrast, therapeutic exposure with hypnotics usually last for only a few hours per 24 h and the peak concentration is selected as a compromise between optimal effectiveness and side effects. The duration of exposure relative to nonexposure is therefore very small and this may allow resensitization of desensitized receptors and prevent significant down regulation.

This should also be borne in mind with the development of sustained release formulations, in that tolerance development may be more likely to occur with this type of therapy, where receptors are exposed to the drug for longer. Since these are relatively new to the market, no clinical data has yet been published on these new formulations.

Preclinical studies have, as indicated above, consistently demonstrated that BzRAs are abus-able. Since all hypnotic BzRAs possess a very strong affinity for al containing receptors, it has been assumed that this subunit drives both abuse liability and hypnotic effects. If this indeed is the case, BzRA-based compounds will always be associated with this problem. However, as illustrated above, at clinically meaningful concentrations, BzRAs all show significant activities at a2 and a3

containing receptors. Abuse liability studies conducted by Professor Ator at Johns Hopkins School of medicine, have indicated that the level of a2 modulation may be a primary determinant of self-administration, suggesting that truly functionally selective a1 modulators, may be devoid of abuse potential.

Currently no compounds with this particular pharmacological profile have been reported, but since several large pharmaceutical companies have conducted BzRA projects over the last 2-3 decades, these compounds may already have been synthesized.

An alternative to the full BzRAs are partial BzRAs, which in insomnia-related indications are sufficiently efficacious to induce the desired induction and maintenance of sleep. As an example, EVT-201 is active throughout the night and at the same time devoid of residual effects as measured the next morning. The clinical advantage of partial positive allosteric modulators over full BzRAs should in principle be a reduced risk of tolerance development, and this may be demonstrated in preclinical studies. However, it will be important to establish these benefits in the clinical setting.

20.3.2 Modulating Slow Wave Sleep and Slow Wave Activity 20.3.2.1 GABAA Receptor Agonists

Since the GABA receptor system is the major inhibitory neurotransmitter system in the CNS, it is hardly surprising that GABAa receptor agonists and positive allosteric modulators are sedative. However, sleep is not just a period of unconsciousness. Sleep is a very dynamic process with a large degree of ongoing neuronal general and unspecific dampening of neuronal activity. Therefore, sleep-enhancing agents will act somewhat differently to anesthetics, which produce unconsciousness combined with insensitivity to external stimuli and often combined with analgesia. Hence anesthetics like propofol and etomidate do not induce sleep, but rather nonrousable unconsciousness. While these are very different processes, it is now clear that anesthetics act at least in part through sleep-inducing pathways, and do not just produce a general dampening effect throughout the CNS. Further work will further differentiate these processes.

Quite surprisingly, GABAa receptor agonists appear to affect sleep in a very particular manner. Studies by Lancel and coworkers and later by Winsky-Sommerer and Tobler have demonstrated that muscimol and gaboxadol (Figure 20.7) specifically modulate sleep stages in a manner, which is highly dependent on particular receptor populations. Gaboxadol and muscimol which both penetrates the BBB are functionally selective for the extra-synaptically located 8-subunit containing GABAA receptors (non-g containing receptors, which are insensitive to modulation by BzRAs; see Figure 20.5). This functional selectivity for extra-synaptic receptors is in fact shared by all GABAA receptor agonists. However, since gaboxadol and muscimol readily penetrates the BBB, only these compounds have been characterized using in vivo studies.

Binding affinity using a radiolabeled agonist for the GABA binding site demonstrates little in the way of subtype selectivity for a variety of agonists and subtypes. This is understandable since the agonist binding site, which is located at the interface between a and b subunits remains conserved across all receptor subunits characterized so far. The functional consequences of receptor activation, however, are highly dependent on the receptor subunit composition. As illustrated in Figure 20.8, the potency and relative maximum response of gaboxadol cover the ranges from low o h2n

GABA Gaboxadol

FIGURE 20.7 Structures of GABA, gaboxadol, and muscimol.

-O' Muscimol

Gaboxadol (|M)

FIGURE 20.8 Dose response curves for gaboxadol at different GABAa receptor populations expressed in Xenopus oocytes. The therapeutic relevant concentration is 1-2 micromolar. (Data from Storustovu, S. and Ebert, B., J. Pharmacol. Exp. Ther, 316, 1351, 2006.)

Gaboxadol (|M)

FIGURE 20.8 Dose response curves for gaboxadol at different GABAa receptor populations expressed in Xenopus oocytes. The therapeutic relevant concentration is 1-2 micromolar. (Data from Storustovu, S. and Ebert, B., J. Pharmacol. Exp. Ther, 316, 1351, 2006.)

efficacy and low potency to high potency and high efficacy. For example at non-g-subunit containing GABAA receptors, gaboxadol elicits a larger maximal response than GABA. a48 containing GABA receptors are located extra-synaptically and are present at neurons projecting to areas contributing to the modulation of sleep. One of these important areas is the ventrobasal region of the thalamus, which seems to play a key role for the hypnotic activity of gaboxadol. In normal animals, gaboxadol enhances the amount of SWS and, in particular, the SWA as recorded using EEG technology. Furthermore, in mice lacking the 8 subunit, Gaboxadol dose not enhance SWA, illustrating the contribution of this receptor population to the physiological effects of gaboxadol. Since the relative in vitro profile of gaboxadol is shared by other GABAA receptor agonists, including partial agonists, a novel CNS penetrant GABAA receptor agonist most likely will share the hypnotic effects of gaboxadol.

Gaboxadol was in clinical development for insomnia but was discontinued due to variable effects on sleep induction in the final studies. However, since the clinical development program only included primary insomniacs, little is known about the clinical consequences of enhanced SWS and SWA. The hypnotic profile of gaboxadol indicates that GABAA receptor agonists may play a role in diseases where reduced SWS or enhanced and early onset of REM sleep is a core part of the disease. These conditions include psychiatric diseases (e.g., depression, anxiety, and bipolar disorder), neurological diseases (Alzheimer's disease and Parkinson's disease), stress and chronic pain syndromes.

20.3.2.2 5-HT2A Antagonists

As speculated above, compounds with positive effects on SWS may have a particular value in a number of diseases. Therefore other strategies for enhancing SWS have been attempted. A very promising approach relates to the inhibition of a subpopulation of serotonergic receptors: 5-HT2A receptors. Compounds with antagonist properties at these receptors were initially developed in the psychosis area, but at lower doses these drugs demonstrated a selective and short-term enhancement of the SWS/SWA during the night. Examples of these compounds are ritanserin, ketanserin, and eplivanserin (Figure 20.9). Interestingly, none of these compounds have yet demonstrated effects on

Ketanserin o

Eplivanserin

Ritanserin

Eplivanserin

FIGURE 20.9 Structure of the 5-HT2A antagonists ketanserin, ritanserin, and eplivanserin.

the classical objective endpoints: induction and maintenance in clinical studies carried out to date. Therefore in order to have the compounds approved, a clinically meaningful consequence of the enhanced SWS has to be demonstrated. This means that effects on daytime performance must be available at the time of registration. If these compounds are approved for the treatment of insomnia, this may change the possibility for treating insomnia associated with depression or anxiety.

20.3.3 Orexinergics

Under normal circumstances, a reciprocal inhibition between the wake promoting orexinergic system and the GABAergic sleep-enhancing system exists. Preclinical experiments have demonstrated that the endogenous peptide orexin is wake promoting. Recent interest from a number of pharmaceutical companies have resulted in the development of selective orexin receptor antagonists acting at OR-1 or OR-2 receptors for the promotion of sleep. The role played by OR-1 and OR-2 receptors in sleep is still not completely established. Preclinical data have demonstrated the hypnotic effects of orexinergic antagonists GSK649868 and ACT-078573 (Figure 20.10). Indeed one nonselective antagonist (ACT-078573) has been shown to promote REM and non-REM sleep in healthy human volunteers. However, one important question is whether hyperfunction of the orexinergic system is involved in the pathophysiology of insomnia and whether orexin-based therapies have any unwanted side effects.

20.3.4 Melatonin and Melatonergic Agonists

Melatonin (Figure 20.11) is an endogenous hormone, which in response to darkness is secreted from the pineal gland and subsequently activates the G-protein coupled melatonin receptors (MT1-3). Activation of MT1 and 2 leads to a release of GABA in the hypothalamus and this contributes to the entrainment of the circadian cycle. Melatonin is therefore a compound, which may

Melatonin

Melatonin r

Ramelteon

FIGURE 20.11 Structures of melatonin and the melatonergic agonist ramelteon.

bring a person with a disrupted sleep pattern in synchrony with their normal circadian rhythm. Several studies have provided contradictory results for melatonin; a situation that has led to a discussion about the value of melatonin as a drug. Data with a modified release formulation of melatonin has consistently demonstrated that in patients with a dysfunctional melatonin system (e.g., elderly), subjective sleep parameters and subjective daytime quality of life were significantly enhanced after 4 weeks of treatment. This formulation of melatonin was approved for primary insomnia in elderly and may reflect a change in the attitude of the European authorities, such that subjective parameters are sufficient for obtaining regulatory approval. In addition to melatonin, one melatonergic agonist is currently approved for insomnia in the U.S. Ramelteon (Figure 20.11) has been demonstrated to robustly induce sleep (using polysomnography-EEG measurements) in primary insomniacs. However, the effects in terms of minutes faster asleep are smaller than those observed for BzRAs. This does not necessarily predict a weaker effect on daytime performance. A correlation between reduction in time to sleep and subjective (or objective) daytime performance has never been established. The really exciting aspect of these compounds is therefore not whether they may induce or maintain sleep, but whether they will have positive consequences for the quality of life during the day.

20.4 CONCLUDING REMARKS

The development of hypnotics has for years been limited by our lack of insight into the mechanisms underlying sleep and how these translate into daytime function. With the ongoing integration of electrophysiology, molecular biology, imaging techniques, and cognitive research, focus in insomnia is moving from sleep induction and maintenance to effects of sleep on cognition and other types of daytime performance. The acceptance of insomnia as a chronic disease of its own and not as a symptom of other diseases stresses the need for novel types of hypnotic drugs. The coming years may therefore open up for hypnotic compounds focusing entirely on cognitive or psychiatric consequences of insomnia. The desired receptor profile of such compounds still remains to be established and this together with the medicinal chemistry challenges will be a challenge in the coming decade.

FURTHER READINGS

Akerstedt, T., Billiard, M., Bonnet, M., Ficca, G., Garma, L., Mariotti, M., Salzarulo, P., and Schultz, H. 2002.

Awakening from sleep. Sleep Med. Rev. 6: 267-286. Curry, D.T., Eisenstein, R.D., and Walsh, J.K. 2006. Pharmacologic management of insomnia: Past, present, and future. Psychiatr. Clin. North Am. 29: 871-893. Ebert, B., Wafford, K.A., and Deacon, S. 2006. Treating insomnia: Current and investigational pharmacological approaches. Pharmacol. Ther. 112: 612-629 Kryger, M., Roth T., and Dement W.C., eds. Principles and Practice of Sleep Medicine. Philadelphia: W.B. Saunders, 2005.

NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults. 2005. NIH Consens. State Sci. Statements 22: 1-30. Nofzinger, E.A. 2004. What can neuroimaging findings tell us about sleep disorders? Sleep Med. 5 (Suppl 1): S16-S22.

Pace-Schott, E.F. and Hobson, J.A., 2002. The neurobiology of sleep: Genetics, cellular physiology and subcortical networks. Nat. Rev. Neurosci. 3: 591-605.

Petroski, R.E., Pomeroy, J.E., Das, R., Bowman, H., Yang, W., Chen, A.P., and Foster, A.C. 2006. Indiplon is a high-affinity positive allosteric modulator with selectivity for alphal subunit-containing GABAA receptors. J. Pharmacol. Exp. Ther. 317: 369-377.

Storustovu, S. and Ebert, B. 2006. Pharmacological characterization of agonists at delta containing GABAA receptors: Functional selectivity for extra synaptic receptors is dependent on absence of gamma. J. Pharmacol. Exp. Ther. 316: 1351-1359.

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Sleeping Sanctuary

Sleeping Sanctuary

Salvation For The Sleep Deprived The Ultimate Guide To Sleeping, Napping, Resting And  Restoring Your Energy. Of the many things that we do just instinctively and do not give much  of a thought to, sleep is probably the most prominent one. Most of us sleep only because we have to. We sleep because we cannot stay awake all 24 hours in the day.

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