CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 6, Issue 1, 2007

Sleep disorders, including chronic insomnia, continue to be considerably under-treated medical conditions. A recent poll conducted by the National Sleep Foundation [1] estimated that a quarter of the respondents considered their sleep poor to fair. When quizzed by symptoms, even more individuals qualified for an insomnia diagnosis. As recently as 2005, a National Institutes of Health State of the Science Conference was convened to discuss the manifestation and management of chronic insomnia [2]. The panel concluded that insomnia ranks highly among the critical public health issues facing the U.S. In addition, the panel recognized a bi-directional relationship between mood disorders and sleep disorders, highlighting that insomnia is a prevalent risk factor for depression. Several studies also identify insomnia as a significant risk factor for absenteeism, impaired job performance and accidents [3, 4]. The burden of insomnia on society is significant; recent estimates suggested direct costs of approximately US$13.9 billion in 1995, with indirect costs less well-defined, but also substantial [5, 6]. Despite the prevalence of sleep disorders, a majority of those with sleep disorders do not receive outside support whether through behavioral modifications or medication [4]. The mainstay in insomnia treatment has been benzodiazepines and newer modulators of the GABA-A receptor. While there continue to be efforts in this area, new drug discovery efforts for sleep disorders is spreading into new pharmacological arenas with growing understanding of basic mechanisms of sleep regulation. This special issue of CNS and Neurological Disorders- Drug Targets will provide an overview of current and future approaches to treating insomnia and other sleep disorders. Although not an exhaustive list of all potential new targets, these chapters bring important insights into some of the most exciting areas for new therapies for sleep disorders. In the first chapter, Gary Zammit, a leader in clinical trials for new sleep medications, reviews the prevalence and current treatments for insomnia ranging from behavior therapy to over-the-counter medications, to current on and off-label prescription options. He also provides additional discussions of potential upcoming treatments in the areas of GABA modulation and melatonin receptor activation, and provides insight into future directions for research and clinical trial development. Nicholas DeMartinis and Andrew Winokur, experts in the interactions between mood disorders and sleep, review the impact of psychiatric medicines on disordered sleep, assessing their role in both primary insomnia and in other sleep disorder syndromes. They also discuss current efforts by the pharmaceutical industry to reposition psychiatric medications for labeled use in sleep disorders. While antihistamine-containing products are widely available and used frequently for acute insomnia treatment [7], the evidence supporting their beneficial effect is not consistent. In the third chapter, Ann Barbier and Margaret Bradbury examine the neurobiological rationale for the use of antihistamines in over-the-counter treatment of insomnia. The current antihistamines most likely produce their sedative effects via antagonism of the H1 receptor. However, recent preclinical and clinical data suggest that histamine H3 receptors may also be promising targets for the treatment of wake and sleep disorders. Many neuropeptides have been recently identified, and some have been found to significantly modulate sleep. In recent years, Seiji Nishino and colleagues have been instrumental in revealing the link between disruptions in the orexin / hypocretin system and narcolepsy with cataplexy. The authors provide an extensive review of the orexin system, and also review the effects of various neuropeptides in normal and pathophysiological sleep states. The last two chapters move away from GABA-A receptor modulators and G-protein coupled receptors to more novel areas. Modulation of ion channels remains a relatively poorly explored area in sleep research, despite the fact that electrical activity is at the very core of sleep and its measurement through the electroencephalogram (EEG).....

Insomnia is a common condition that often is co-morbid with other illnesses. It is associated with significant morbidities, including nighttime distress, impaired cognitive functioning, impaired daytime functioning, and increased risk of accidents. People with insomnia utilize healthcare services more often than those without insomnia, and they are at greater risk for the development of certain health problems; most notably psychiatric illness such as depression. It is now known that the significant impact of insomnia warrants diagnosis and treatment. Behavioral and psychopharmacological treatments have been available for some time. However, formerly common classes of therapeutics such as the barbiturates and benzodiazepines have been replaced by new allosteric modulators of the GABAA receptor and other therapeutics with novel mechanisms of action. This article presents existing approaches to insomnia treatment, and reviews new treatments, therapeutic targets, and treatment approaches to insomnia under development that may offer promise to practitioners and patients.

Insomnia is a significant public health concern that has prompted substantial efforts to develop treatment and management strategies. A significant proportion of complaints of insomnia are related to psychiatric conditions such as anxiety disorders and depression, and treatments for these disorders are known to exert both direct and indirect benefits on sleep as well as some negative effects on sleep and sleep physiology. Insomnia is also a prominent symptom of a number of other psychiatric disorders, including schizophrenia and bipolar disorder. The observed impact of a variety of psychiatric medications on insomnia has prompted an empirically derived practice of treating non-psychiatric disorder-related insomnia with psychiatric medications by clinicians searching for alternatives to established medication treatments for primary insomnia. This article aims to review the evidence of the impact of psychiatric medications on sleep physiology, sleep disorders in psychiatric conditions, and on primary sleep disorders. The potential for exploiting the relevant pharmacological mechanisms of action in drug development for primary insomnia will be addressed as well.

The role of histaminergic neurotransmission in the promotion of waking has been extensively studied in preclinical species. Appreciation for the role of histamine continues to expand with increasing understanding of the interaction of histamine within the broad network of neuromodulators that regulate sleep and wake. The effects of histamine on waking are transduced through the H1 and the H3 receptors in the central nervous system. Brain penetrant over-the-counter antihistamines comprised of antagonist actions at H1 receptors as well as varying degrees of antimuscarinic properties are marketed as sleep aids, based on their well-known daytime drowsiness side effects. The data supporting their use as sedatives, however, are not consistent. H3 receptors are presynaptic receptors that limit histamine release as well as that of monoamine neurotransmitters thought to participate in the maintenance of waking. In this review, we discuss the existing studies on various antihistamines and antagonists of the H1 receptor in the regulation of sleep in preclinical studies, normal subjects and in subjects with sleep disorders. In addition, we review the current data available on the use of ligands at H3 receptors for the modulation of sleep and wake.

Sleep disorders are disturbances of usual sleep patterns or behaviors caused by deregulation of neuronal synchronicity and of the balance of the neurotransmitter system involved in sleep regulation. Insomnia and hypersomnia are frequent sleep disorders, and these are most often treated pharmacologically with hypnotics and wake-promoting compounds. These compounds act on classical neurotransmitter systems, such as benzodiazepines on gamma amino butyric acid (GABA)A receptors, and amphetamine-like stimulants on monoaminergic terminals to modulate neurotransmission. In addition, acetylcholine, amino acids, lipids and proteins (cytokines) and peptides, are known to significantly modulate sleep, and thus, are possibly involved in the pathophysiology of some sleep disorders. Due to recent developments in molecular biological techniques, many neuropeptides have been newly identified, and some are found to significantly modulate sleep. Recent discoveries also include the finding that the impairment of hypocretin/orexin neurotransmission (a recently isolated hypothalamic neuropeptide and receptor system), is the major pathophysiology of narcolepsy with cataplexy. A hypocretin replacement therapy is anticipated to reverse the disease symptoms in humans. In this article, we will review the history of neuropeptide research, sleep modulatory effects of various neuropeptides, and the general strategies for the pharmacological therapeutics targeting the peptidergic systems by referring to hypocretin-deficient narcolepsy as an immediate example.

Sleep is characterized by synchronized electrical activities of the thalamocortical network, which can be identified as the EEG oscillations during sleep. T-type calcium channels have been implicated in the occurrence of sleep waves, and burst firings in the thalamic neurons driven by these channels are known to be essential for modulation of sleep rhythms. Studies showed that α1G T-type calcium channel knockout mice had defects in sleep waves such as lack of delta oscillations (1-4 Hz) and alteration of sleep spindles (7-15 Hz), which are known to be modulated by T-currents in the thalamus. The mutation also affected the sleep-wake transition, thus resulting in decreased NREM sleep and increased sleep disturbance. These findings support the idea that α1G T-type calcium channels contribute to sleep waves as well as to behavioral state of sleep.

The basic functions of sleep are still unclear, however, recent advances in genomics and proteomics have begun to contribute to our understanding of both normal and pathological sleep. In this review, we focus primarily on normal sleep and wake that have been studied in model organisms such as mice. Mice have been especially valuable since many different inbred strains exist that differ in sleep-related traits, and genes can be altered by either mutagenesis or targeted approaches. Advances in QTL (Quantitative Trait Loci) analysis have also helped to identify important sleep related genes, and several other QTLs have been mapped as a first step toward finding the genes that underlie basic sleep traits. In addition to more traditional genetic approaches, the abundance of different mRNAs across sleep and wake can now be studied and compared in different brain regions much more thoroughly using microarray methods. Progress at the protein level has been more difficult, but a few studies have begun to investigate changes in proteins during sleep and wake, and we present some of our own preliminary data in this area. A knowledge of which genes and proteins control or respond to changes in sleep will not only help answer fundamental questions, but may also suggest novel drug targets for improving multiple aspects of sleep and wake.

Due to an over look on part of the authors, the title of the article “Density is Density - On the Relation Between Quantity of T-Type Ca2+ Channels and Neuronal Electrical Behavior”, published in the journal CNS and Neurological Disorders-Drug Targets, Volume 5, Issue 6, December 2006, pg. 655-62 was printed incorrectly in the article. The correct title is “Density is Destiny - On the Relation Between Quantity of T-Type Ca2+ Channels and Neuronal Electrical Behavior”.