Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy

Steven T Szabo,Michael J Thorpy,Geert Mayer,John H Peever,Thomas S Kilduff

doi:10.1016/j.smrv.2018.09.006

Abstract

Excessive daytime sleepiness (EDS) and cataplexy are common symptoms of narcolepsy, a sleep disorder associated with the loss of hypocretin/orexin (Hcrt) neurons. Although only a few drugs have received regulatory approval for narcolepsy to date, treatment involves diverse medications that affect multiple biochemical targets and neural circuits. Clinical trials have demonstrated efficacy for the following classes of drugs as narcolepsy treatments: alerting medications (amphetamine, methylphenidate, modafinil/armodafinil, solriamfetol [JZP-110]), antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors), sodium oxybate, and the H3-receptor inverse agonist/antagonist pitolisant. Enhanced catecholamine availability and regulation of locus coeruleus (LC) norepinephrine (NE) neuron activity is likely central to the therapeutic activity of most of these compounds. LC NE neurons are integral to sleep/wake regulation and muscle tone; reduced excitatory input to the LC due to compromise of Hcrt/orexin neurons (likely due to autoimmune factors) results in LC NE dysregulation and contributes to narcolepsy/cataplexy symptoms. Agents that increase catecholamines and/or LC activity may mitigate EDS and cataplexy by elevating NE regulation of GABAergic inputs from the amygdala. Consequently, novel medications and treatment strategies aimed at preserving and/or modulating Hcrt/orexin-LC circuit integrity are warranted in narcolepsy/cataplexy.

Highlights

1 in 2000 people are diagnosed with narcolepsy and more than 50% of patients report that their first symptoms occurred before 16 years of age [1]
Narcolepsy is a neurological disorder of hypersomnia and its associated Excessive daytime sleepiness (EDS) and cataplexy are disabling to many patients
No elevations in the rate of narcolepsy were reported in the US where only nonadjuvanted vaccines were used [37], or elsewhere in Europe, where the closely-related MF59 adjuvant was used in the H1N1 vaccine Focetria® (Novartis Vaccines & Diagnostics, 2007) [38]. These results suggest that the adjuvant AS03 could be problematic, no elevation in narcolepsy rates were observed in Canada where AS03 was used as a component of the H1N1 vaccine Arepanrix® (GlaxoSmithKline, 2009) [39]

Summary

Excessive daytime sleepiness (EDS) and cataplexy are common symptoms of narcolepsy, a sleep disorder associated with the loss of hypocretin/orexin (Hcrt) neurons. Enhanced catecholamine availability and regulation of locus coeruleus (LC) norepinephrine (NE) neuron activity is likely central to the therapeutic activity of most of these compounds. Due to compromise of Hcrt/orexin neurons (likely due to autoimmune factors) results in LC NE dysregulation and contributes to narcolepsy/cataplexy symptoms. Agents that increase catecholamines and/or LC activity may mitigate EDS and cataplexy by elevating NE regulation of GABAergic inputs from the amygdala. Novel medications and treatment strategies aimed at preserving and/or modulating Hcrt/orexin–LC circuit integrity are warranted in narcolepsy/cataplexy. Keywords narcolepsy; cataplexy; excessive daytime sleepiness; mechanism of action; autoimmune; hypocretin; orexin; amygdala; locus coeruleus; norepinephrine

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