Sleep disorders

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Research into sleep disorders (see 6.06 Sleep) has intensified over the last decade given new generations of hypnotics and the success of the novel wake-promoting agent modafinil. The sleep spectrum involves insomnia, narcolepsy, and excessive daytime sleepiness (EDS). Dyssomnias are primary sleep disorders characterized by an abnormal amount, quality, or timing of sleep, and include primary insomnia, narcolepsy, and breathing-related sleep disorder. Primary insomnia is defined as a difficulty in initiating or maintaining sleep, or an inability to obtain restorative sleep. Insomnia is a highly prevalent sleep disorder estimated to affect 35% of the population during the course of a year, with 60% of those afflicted reporting chronic insomnia lasting longer than 1 month. Chronic insomnia is often accompanied by impairments in social and occupational function. Insomnia is roughly twice as common in females as in males, is more frequently observed in patients 60 years and older, and is comorbid with a number of other disorders including depression, Parkinson's disease, and AD. Narcolepsy is a chronic disorder characterized by repeated irresistible sleep attacks, cataplexy, and vivid hallucinations caused by an intrusion of rapid eye movement (REM) sleep into the transitional period between sleep and wake. These attacks typically last from a few seconds to several minutes, and occur at any time without warning. In addition, narcoleptics experience frequent wakening during the night resulting in an overall decrease in night-time sleep duration and quality. Narcolepsy afflicts approximately 200 000 people in the USA and is the third most diagnosed primary sleep disorder in sleep clinics. However, the disorder is believed to be underdiagnosed and actual prevalence may be higher. Of the breathing-related sleep disorders, obstructive sleep apnea (OSA) is the most common, being characterized by repeated obstruction of the upper airway during sleep. These apneic episodes typically last from 20 to 30 s and occur as many as 300 times in a single night. Episodes are typically noted as silent periods that interrupt loud snoring. This disruption in normal breathing leads to frequent awakenings, disruption in sleep architecture, and consequent nonrestorative sleep. In addition, OSA is associated with an increased risk of stroke, heart attack, and high blood pressure. OSA is very common, estimated to affect over 12 million individuals in the USA. The disorder is more common in males than females and is associated with risk factors including obesity and large neck size.

Diagnosis of sleep disorders is usually made by the primary care physician based on patient interview and clinical examination. It is unusual for a patient to be referred to a specialist or sleep clinic for follow-up polysomnography due to the subtle distinctions necessary for accurate diagnosis. For example, the three primary dyssomnias discussed have distinct etiologies and diverse treatments, yet for the most part all three present clinically as EDS. It is therefore not surprising that narcolepsy is not definitively diagnosed in most patients until 10-15 years after the first symptoms become apparent, or that only an estimated 30% of all insomniacs are diagnosed.

From a disease causality perspective, more than 90% of narcoleptic individuals carry the human leukocyte antigen (HLA) gene haplotype, HLA-DR2/DQ1, a reliable genetic marker for narcolepsy with a 100% association of the disease, but this is neither a necessary nor a sufficient causative factor for the disorder. A COMT polymorphism has been associated with the severity of narcolepsy although it may be noted that COMT polymorphisms have also been associated with gender differences in sensitivity to pain, breast cancer, and schizophrenia. Mutations in the orexin/hypoctein systems in both canines and humans have been associated with narcolepsy-cataplexy and numerous genes have been identified in Drosophila melanogaster that affect sleep/wake behaviors including circadian clock genes.

As mentioned above, the choice of treatment for dyssomnia depends upon the diagnosis. Insomnia is typically treated with BZ hypnotics (e.g., triazolam) or more commonly non-BZ hypnotics (e.g., Zolpidem). Significant adverse effects are observed with these compounds including a next day 'hangover' effect that can significantly impair function, tolerance, rebound of REM sleep on withdrawal, and addiction. While the non-BZ hypnotics are better tolerated, the same liabilities exist. Patients are occasionally treated with sedating TCAs (e.g., amitriptyline) with mixed results.

Narcoleptic patients are typically treated with stimulant amphetamines or more recently with the novel wake-promoting drug, modafinil. The amphetamines (e.g., methylphenidate) are effective at reducing daytime sleepiness, but carry significant liabilities including irritability, night-time sleep disruption, tolerance, abuse potential, and rebound hypersomnolence. A characteristic of central nervous system (CNS) stimulants like amphetamine is that their positive effects on wake promotion are accompanied by a rebound hypersomnolence following withdrawal, a more profound sleepiness than that which initially led to the use of medication.

Modafinil can alleviate excessive daytime sleepiness without these adverse effects and does not induce tolerance, indicating a lower abuse potential. Both TCAs and SSRIs are effective in treating this aspect of narcolepsy. OSA is typically treated by lifestyle changes such as weight loss and decreased alcohol consumption. Patients may also be placed on a nasal continuous positive airway pressure (CPAP) device. CPAP acts to keep the airway open during the night thus avoiding the apneic episodes. Modafinil is also approved for use in OSA patients with EDS.

Prognosis for these sleep disorders is good for patients with narcolepsy or OSA, and relatively good for patients suffering from insomnia. As discussed above, the currently available treatments for insomnia produce significant adverse effects, so their use is somewhat limited, particularly in the elderly population. Future development of compounds that act outside of the GABA system and restore normal sleep architecture will represent a major breakthrough in the treatment of insomnia and include histamine H receptor agonists, ligands interacting with the orexin/hypocretin system, 5HT2, and melatonin receptor modulators. For wake promotion, there is considerable focus on histamine H3 inverse agonists, modulators of monoamine availability and of the orexin/hypocretin system. It is anticipated that the considerable work ongoing in Drosophilia will aid in identifying new targets for the pharmacotherapy of sleep disorders. An overriding issue however, is the relatively poor diagnosis rate. This is a significant unmet need since these disorders are not only debilitating but in many case life-threatening.

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Healthy Sleep

Healthy Sleep

A Guide to Natural Sleep Remedies. Many of us experience the occasional night of sleeplessness without any consequences. It is when the occasional night here and there becomes a pattern of several nights in arow that you are faced with a sleeping problem. Repeated loss of sleep affects all areas of your life The physical, the mental, and theemotional. Sleep deprivation can affect your overall daily performance and may even havean effecton your personality.

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