Narcolepsy: Pathophysiology and Pharmacology

Narcolepsy, which affects 1 in 2000 people in the general population, is characterized by excessive daytime sleepiness (EDS), cataplexy, and other dissociated manifestations of rapid eye movement sleep (hypnagogic hallucinations and sleep paralysis). The disease is currently treated with amphetamine-like central nervous system stimulants (for EDS) and antidepressants (for cataplexy). Some compounds from other classes, such as modafinil (a non-amphetamine wake-promoting compound for EDS) and sodium oxybate (a short-acting sedative for EDS and cataplexy, administered at night), are also employed. The major pathophysiology of human narcolepsy has recently been revealed by the extension of discoveries of narcolepsy genes in animal models: hypocretin/orexin ligand deficiency has been shown in about 90% of human narcolepsy-cataplexy. This finding led directly to the development of new diagnostic tests (i.e., cerebrospinal fluid hypocretin measures). Hypocretin replacement is also likely to be a new therapeutic option for hypocretin-deficient narcolepsy, but is still not available in humans. In this review, the pharmacologic and pathophysiologic aspects of narcolepsy are discussed..