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CNS &
Neurological Disorders -Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 6, Number 1, February 2007
Contents
Therapeutic Opportunities in the Treatment of Sleep
Disorders
Guest Editor: Margaret Bradbury
Editorial
Pp. 1-2
The Prevalence, Morbidities, and Treatments of Insomnia
Pp. 3-16
Gary K. Zammit
[Abstract] [Full
Text Article]
Effects of Psychiatric Medications on Sleep and Sleep
Disorders Pp. 17-29
Nicholas A. DeMartinis and Andrew Winokur
[Abstract] [Full
Text Article]
Histaminergic Control of Sleep-Wake Cycles: Recent
Therapeutic Advances for Sleep and Wake Disorders
Pp. 31-43
A.J. Barbier and M.J. Bradbury
[Abstract] [Full
Text Article]
Neuropeptides as Possible Targets in Sleep Disorders:
Special Emphasis on Hypocretin-Deficient Narcolepsy
Pp. 45-62
Nobuhiro Fujiki and Seiji Nishino
[Abstract] [Full
Text Article]
T-Type Calcium Channels and Thalamocortical Rhythms
in Sleep: A Perspective from Studies of T-Type Calcium Channel
Knockout Mice Pp. 63-69
Jungryun Lee and Hee-Sup Shin
[Abstract] [Full
Text Article]
Genomic and Proteomic Approaches Towards an Understanding
of Sleep Pp. 71-81
Bruce F. O’Hara, Jane Ding, Rebecca L. Bernat and
Paul Franken
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Editorial
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). Jungryun Lee and Hee-Sup Shin
delve into the role of T-type calcium channels in producing
the unique patterns of neuronal firing during slow wave sleep.
They also review the effects of deleting the α1G
subunit of the T-type calcium channel in mice on EEG patterns
and on sleep-wake behaviors, suggesting that modulation of
ion channels may be an important future area for sleep research
and drug development.
Expanding beyond our current understanding of the neurobiological
elements regulating sleep, researchers are applying genomic
and proteomic methodologies to sleep physiology- an approach
that may lead to a new set of therapies. In the final chapter,
Bruce O’Hara and colleagues review the application of
genomics and proteomics to the study of sleep biology in preclinical
models. They also discuss recent insights gained from these
approaches.
These six chapters provide some insight into the current state
of affairs for sleep biology. Equally important, these chapters
demonstrate the considerable gaps in our understanding of
the basic neurobiology regulating sleep, and highlight the
room for new medications for sleep therapy. In particular,
new discoveries may one day refine our definitions and diagnoses
of sleep disorders, help control the variability in patient
responses to medications, and provide new pathways for discovering
better drug targets. I hope the present volume will be a helpful
compendium of where our field is and needs to go in the coming
years.
REFERENCES
[1] National Sleep Foundation, Washington DC, USA,
2002, 1.
[2] Sleep, 2005, 28, 1049.
[3] Fullerton, D. S. Am. J. Manag. Care, 2006,
12, S246.
[4] Smith, M. T., Perlis, M. L., Park, A., Smith, M. S., Pennington,
J., Giles, D. E., Buysse, D. J. Am. J. Psychiatry,
2002, 159, 5.
[5] Walsh, J. K. J. Clin. Psychiatry, 2004,
65(Suppl 8), 13.
[6] Walsh, J. K., Engelhardt, C. L. Sleep, 1999,
22(Suppl 2), S386.
[7] Winkelman, J., Pies, R. Ann. Clin. Psychiatry,
2005, 17, 31.
Margaret Bradbury
Neurocrine Biosciences
12790 El Camino Real
San Diego
CA 92130
USA
E-mail: mbradbury@neurocrine.com
[Back to top]
The Prevalence, Morbidities, and Treatments of Insomnia
Gary K. Zammit
[Full
Text Article]
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.
[Back to top]
Effects of Psychiatric Medications on Sleep and Sleep
Disorders
Nicholas A. DeMartinis and Andrew Winokur
[Full
Text Article]
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.
[Back to top]
Histaminergic Control of Sleep-Wake Cycles: Recent
Therapeutic Advances for Sleep and Wake Disorders
A.J. Barbier and M.J. Bradbury
[Full
Text Article]
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.
[Back to top]
Neuropeptides as Possible Targets in Sleep Disorders:
Special Emphasis on Hypocretin-Deficient Narcolepsy
Nobuhiro Fujiki and Seiji Nishino
[Full
Text Article]
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.
[Back to top]
T-Type Calcium Channels and Thalamocortical Rhythms
in Sleep: A Perspective from Studies of T-Type Calcium Channel
Knockout Mice
Jungryun Lee and Hee-Sup Shin
[Full
Text Article]
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.
[Back to top]
Genomic and Proteomic Approaches Towards an Understanding
of Sleep
Bruce F. O’Hara, Jane Ding, Rebecca L. Bernat and
Paul Franken
[Full
Text Article]
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.
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