Expert opinion on pharmacotherapy of narcolepsy.
BACKGROUND
Narcolepsy is a neurodegenerative disorder resulting in the instability of the sleep-wake cycle and marked by low levels of hypocretin in cerebrospinal fluid. Sleep instability is marked by brisk, sleep-onset REM periods and sleep fragmentation, while the waking state is interrupted by the intrusion of REM sleep and sometimes accompanied by cataplectic attacks.


METHODS
Current pharmacologic interventions that aim to address three primary features of this disorder; excessive daytime sleepiness (EDS), cataplexy and automatic behaviors, and sleep fragmentation. We review and compare the use of traditional and new stimulants in the treatment of EDS. For the treatment of cataplexy and automatic behaviors, serotonergic and noradrenergic agents are considered. The role of gamma-hydroxybutyrate (GHB) is also explored in its ability to reduce daytime sleepiness and catapletic attacks and to consolidate sleep. Findings are based on a PubMed literature search of clinical and basic science research papers spanning 1977-2009.


RESULTS
A comprehensive understanding of the various existing and promising future treatments for narcolepsy. For each of these treatments, we evaluate risks versus benefits of treatment, and proposed pharmacologic mechanisms of action. We conclude with a review of new treatment approaches, including thyrotropin-releasing hormone (TRH), histamine agonists, immunotherapy and hypocretin replacement therapies.


CONCLUSIONS
Narcolepsy is an autoimmune, neurodegenerative disorder that results in significant sleep-wake instability with or without cataplectic attacks. Current treatments aim symptomatically to reconsolidate the sleep and waking states and to reduce daytime attacks of cataplexy. Future treatments aim primarily towards correcting the causal deficiency of hypocretin or preventing the autoimmune response that results in the loss of hypocretin cells.
Zaharna
Mia
M
Stanford Medical Outpatient Center, Sleep Medicine Division MC5704, Stanford University, Redwood City, Stanford, CA 94063, USA.
Dimitriu
Alex
A
Guilleminault
Christian
C
D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use; D001559:Benzhydryl Compounds / Q000627:therapeutic use; D002110:Caffeine / Q000627:therapeutic use; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use; D007167:Immunotherapy; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000627:therapeutic use; D000077408:Modafinil; D009290:Narcolepsy / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics / Q000627:therapeutic use; D000068797:Orexins; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D012978:Sodium Oxybate / Q000627:therapeutic use
D000929:Antidepressive Agents, Tricyclic; D001559:Benzhydryl Compounds; D002110:Caffeine; D000697:Central Nervous System Stimulants; D006993:Hypnotics and Sedatives; D047908:Intracellular Signaling Peptides and Proteins; D000077408:Modafinil; D009479:Neuropeptides; D000068797:Orexins; D017367:Selective Serotonin Reuptake Inhibitors; D012978:Sodium Oxybate