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Narcolepsy/hypocretin deficiency (now called type 1 narcolepsy) is a lifelong neurologic disorder with well-established diagnostic criteria and etiology. Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness (EDS) and symptoms of dissociated rapid eye movement sleep such as cataplexy (sudden loss of muscle tone), hypnagogic hallucinations (sensory events that occur at the transition from wakefulness to sleep), sleep paralysis (inability to perform movements upon wakening or sleep onset), and nocturnal sleep disruption. As these symptoms are often disabling, most patients need life-long treatment. The treatment of narcolepsy is well defined, and, traditionally, amphetamine-like stimulants (i.e., dopaminergic release enhancers) have been used for clinical management to improve EDS and sleep attacks, whereas tricyclic antidepressants have been used as anticataplectics. However, treatments have evolved to better-tolerated compounds such as modafinil or armodafinil (for EDS) and adrenergic/serotonergic selective reuptake inhibitors (as anticataplectics). In addition, night-time administration of a short-acting sedative, c-hydroxybutyrate (sodium oxybate), has been used for the treatment for EDS and cataplexy. These therapies are almost always needed in combination with non-pharmacologic treatments (i.e., behavioral modification). A series of new drugs is currently being tested in animal models and in humans. These include a wide variety of hypocretin agonists, melanin- concentrating hormone receptor antagonists, antigenspecific immunopharmacology, and histamine H3 receptor antagonists/inverse agonists (e.g., pitolisant), which have been proposed for specific therapeutic applications, including the treatment of Alzheimer's disease, attention-deficit hyperactivity disorder, epilepsy, and more recently, narcolepsy. Even though current treatment is strictly symptomatic, based on the present state of knowledge of the pathophysiology of narcolepsy, we expect that more pathophysiology-based treatments will be available in the near future.
Narcolepsy/hypocretin deficiency (now called type 1 narcolepsy) is a lifelong neurologic disorder with well-established diagnostic criteria and etiology. Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness (EDS) and symptoms of dissociated rapid eye movement sleep such as cataplexy (sudden loss of muscle tone), hypnagogic hallucinations (sensory events that occur at the transition from wakefulness to sleep), sleep paralysis (inability to perform movements upon wakening or sleep onset), and nocturnal sleep disruption. As these symptoms are often disabling, most patients need life-long treatment. The treatment of narcolepsy is well defined, and, traditionally, amphetamine-like stimulants (i.e., dopaminergic release enhancers) have been used for clinical management to improve EDS and sleep attacks, whereas tricyclic antidepressants have been used as anticataplectics. However, treatments have evolved to better-tolerated compounds such as modafinil or armodafinil (for EDS) and adrenergic/serotonergic selective reuptake inhibitors (as anticataplectics). In addition, night-time administration of a short-acting sedative, c-hydroxybutyrate (sodium oxybate), has been used for the treatment for EDS and cataplexy. These therapies are almost always needed in combination with non-pharmacologic treatments (i.e., behavioral modification). A series of new drugs is currently being tested in animal models and in humans. These include a wide variety of hypocretin agonists, melanin- concentrating hormone receptor antagonists, antigenspecific immunopharmacology, and histamine H3 receptor antagonists/inverse agonists (e.g., pitolisant), which have been proposed for specific therapeutic applications, including the treatment of Alzheimer's disease, attention-deficit hyperactivity disorder, epilepsy, and more recently, narcolepsy. Even though current treatment is strictly symptomatic, based on the present state of knowledge of the pathophysiology of narcolepsy, we expect that more pathophysiology-based treatments will be available in the near future.
Although not discernible at first glance, sleep is a highly active and regulated brain state. Although we spend practically one third of our lifetimes in this stage, its importance is often taken for granted. Sleep loss can lead to disease, error and economic loss. Our understanding of how sleep is achieved has greatly advanced in recent years, and with that, the management of sleep disorders has improved. There is still room for improvement and recently many new compounds have reached clinical trials with a few being approved for commercial use. Areas covered: In this review, the authors make the case of sleep disorders as a matter of public health. The mechanisms of sleep transition are discussed emphasizing the wake and sleep promoting interaction of different brain regions. Finally, advances in pharmacotherapy are examined in the context of chronic insomnia and narcolepsy. Expert opinion: The orexinergic system is an example of a breakthrough in sleep medicine that has catalyzed drug development. Nevertheless, sleep is a topic still with many unanswered questions. That being said, the melanin-concentrating hormone system is becoming increasingly relevant and we speculate it will be the next target of sleep medication.
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