Current Neurology and Neuroscience Reports

, Volume 11, Issue 2, pp 227–234

Hypocretin and Its Emerging Role as a Target for Treatment of Sleep Disorders

Authors

    • Stanford University Sleep Medicine
  • Christian Guilleminault
    • Stanford University Sleep Medicine
Article

DOI: 10.1007/s11910-010-0172-9

Cite this article as:
Cao, M. & Guilleminault, C. Curr Neurol Neurosci Rep (2011) 11: 227. doi:10.1007/s11910-010-0172-9

Abstract

The neuropeptides hypocretin-1 and -2 (orexin A and B) are critical in the regulation of arousal and maintenance of wakefulness. Understanding the role of the hypocretin system in sleep/wake regulation has come from narcolepsy-cataplexy research. Deficiency of hypocretin results in loss of sleep/wake control with consequent unstable transitions from wakefulness into non–rapid eye movement (REM) and REM sleep, and clinical manifestations including daytime hypersomnolence, sleep attacks, and cataplexy. The hypocretin system regulates sleep/wake control through complex interactions between monoaminergic/cholinergic wake–promoting and GABAergic sleep–promoting neuronal systems. Research for the hypocretin agonist and the hypocretin antagonist for the treatment of sleep disorders has vigorously increased over the past 10 years. This review will focus on the origin, functions, and mechanisms in which the hypocretin system regulates sleep and wakefulness, and discuss its emerging role as a target for the treatment of sleep disorders.

Keywords

HypocretinOrexinNarcolepsyCataplexySleepWakefulnessHypothalamusInsomniaArousalAlmorexant

Introduction

The neuropeptide hypocretin (also known as orexin) has received much attention in the past 10 years and has emerged as a key topic in investigative research for novel pharmacologic therapies in sleep disorders treatment. Advances on narcolepsy-cataplexy research have showed that the hypocretin system undoubtedly plays a central role in mechanisms that promote arousal as well as maintenance of wakefulness. Consequences of hypocretin deficiency include excessive daytime sleepiness, inappropriate transitions between wakefulness and sleep, and cataplexy. Hypocretin neurons have widespread connections throughout the central nervous system (CNS) and innervate noradrenergic, serotonergic, dopaminergic, histaminergic, and cholinergic neuronal pathways. Research has shown that this peptide modulates whole-body energy expenditure, reward mechanisms, addiction, and ventilatory control. However, it is the critical role of hypocretin as a regulator of sleep/wake control that has made it a target for potential novel therapeutic modalities for sleep disorders.

The Discovery of Hypocretin

The discovery of hypocretin and its involvement in sleep/wake regulation represents a significant advancement in sleep research. In 1998, de Lecea et al. [1] discovered two mRNAs encoding for the same neuropeptides, named hypocretin-1 and -2. In the same year, Sakurai et al. [2] independently discovered the same neuropeptides while screening for ligands for orphan G-protein-coupled receptors, named orexin A and B. The hypocretins are produced exclusively by neurons located in the lateral posterior hypothalamus, a region intimately involved in the regulation of behavioral and homeostatic processes. The hypocretin signaling system consists of two peptides and their receptors, HCRTR-1 and HCRTR-2 (OX1R and OX2R). Hypocretin-1 and -2 are produced by cleavage of a common precursor polypeptide, named preprohypocretin (prepro-orexin), which is a single 131 amino-acid prepropeptide that is cleaved to produce the 33 and 38 amino-acid peptides, respectively. HCRTR-1 has substantially higher infinity for hypocretin-1, whereas HCRTR-2 binds to hypocretin-1 and -2 with equal affinity [3].

Hypocretin and Neuronal Sleep/Wake Circuitry

Although produced exclusively in the lateral hypothalamus, hypocretin axonal projections are found throughout the CNS; cerebral cortex, thalamus, hypothalamus, and brainstem (with the exception of the cerebellum). The distribution of HCRTR-1 or HCRTR-2 is exclusive to specific areas [3]. Dense concentrations of HCRTR-2 are found specifically in hypothalamic areas (arcuate nucleus, tuberomammillary nucleus [TMN], paraventricular nucleus), with little to no HCRTR-1 activity in these regions [4]. HCRTR-2 is also expressed in the cerebral cortex, nucleus accumbens, subthalamic nucleus, paraventricular thalamus, anterior pretectal nucleus, and the raphe nuclei. Outside the hypothalamus, HCRTR-1 is found abundantly in the dorsal raphe (DR) nucleus and locus coeruleus (LC). The LC exclusively expresses HCRTR-1, whereas the TMN exclusively expresses HCRTR-2. Both receptors are found in the raphe nuclei and ventral tegmental area [5••]. The discovery of selective distribution of hypocretin receptors is especially important for pharmacologic modulation of this peptide when targeting specific sleep disorders.

Hypocretin and Hypocretin Receptors

Normal transition between wakefulness into non-REM or REM sleep requires preferential selectivity of each receptor. By using hypocretin receptor knockout mice models, Willie et al. [6] identified distinct processes that are responsible for sustaining wakefulness by controlling transitions from wakefulness into non-REM sleep versus transitions into REM sleep. Maintaining wakefulness and normal transition from wake into non-REM sleep requires intact HCRTR-2 signaling through activation of HRCTR-2–expressing histaminergic TMN neurons. Conversely, the same authors indicated that appropriate transition into REM sleep requires both HCRTR-2–dependent and HCRTR-1–dependent mechanisms [6]. Dual receptor (HCRTR-1 and HCRTR-2) and preprohypocretin knockout mice exhibited phenotypic narcolepsy symptoms, severe cataplexy, and direct transition from wakefulness into REM sleep. However, HCRTR-2–deficient mice exhibited only a mild form of cataplexy and REM sleep intrusion into wakefulness. This suggests that HCRTR-1– and HCRTR-2–dependent mechanisms are both required for maintaining wakefulness and normal transition into REM sleep [6]. Clinical implications of these findings are important in ongoing development of pharmacologic hypocretin agonists and antagonists.

Hypocretin and Regulation of Sleep/Wakefulness

Wake-promoting nuclei and their neuronal projections—noradrenergic LC, serotonergic DR, histaminergic TMN, and cholinergic pedunculopontine (PPT)–laterodorsal tegmental nuclei (LDT)—project diffusely to the forebrain and thalamus to promote arousal [7]. LC, DR, TMN, and PPT-LDT neurons fire rapidly during wakefulness, decrease firing during non-REM sleep, and cease firing during REM sleep [8]. The wake-promoting nuclei are innervated by neurons of the ventrolateral preoptic nucleus (VLPO) [9]. These sleep-promoting neurons of the VLPO containing the neuroinhibitory transmitter γ-aminobutyric acid (GABA) are exclusively active during sleep [10].

To understand the inputs of the hypocretin neuronal system, collaborative researchers mapped this system using anterograde and retrograde tracers [11, 12, 13••]. They found that during wakefulness, excitatory cholinergic cells of the basal forebrain (BF) innervate hypocretin neurons and vice versa, creating a positive feedback loop that reinforces their activities. Studies have shown that the BF may be a key site through which hypocretin neurons activate the cortex and promote arousal by direct activation of cortically projecting wake-promoting cholinergic neurons from the BF [14, 15]. Dynorphin is an inhibitory neuropeptide coproduced by all hypocretin neurons. Arrigoni et al. [13••] showed that hypocretin and dynorphin exert distinct functions on two classes of cortical-projecting BF neurons: cholinergic and noncholinergic type. Cholinergic cortical-projecting neurons are directly excited by hypocretin but not dynorphin. The noncholinergic neurons further comprise of two groups; one representing wake-promoting neurons that are directly excited by hypocretin, the other comprising of sleep-active GABAergic neurons that are directly inhibited by dynorphin [13••]. Dynorphin and hypocretin may synergistically act together to promote cortical arousal. In addition, hypocretin neurons innervate wake-promoting monoaminergic cells in the brainstem (LC, DR, TMN) to maintain excitatory activity [16]. Hypocretin neurons fire rapidly during wakefulness, decrease firing during non-REM sleep, and cease firing during REM sleep [17]. During sleep, VLPO sleep-active neurons send inhibitory projections to cholinergic cells and hypocretin neurons, resulting in decreased activity of wake-active neurons in the brainstem [11, 12].

Described by Saper et al. [7], the excitatory wake-promoting circuitry consisting of monoaminergic and cholinergic neurons, and the inhibitory sleep-promoting VLPO circuitry together make up a “flip-flop” circuitry. This reciprocal inhibitory relationship between sleep and wake represents a “bistability” state in which sleep and wake, each by strongly inhibiting each other, create a feedback loop that allows the circuitry to be “bistable” [7], and in doing so maintain the stability of sleep and wakefulness. Hypocretin neuronal projections represent a crucial link in this complex loop between wake-promoting monoaminergic neurons and sleep-promoting VLPO neurons, which may be the key factor in proper regulation of wakefulness. Loss of this hypocretin link would potentially create an unstable state in which wake-promoting regions and sleep-active regions would abruptly switch back and forth. Narcolepsy-cataplexy is an example of a dysfunction in this mutually inhibitory stable circuit.

Evidence from studies has supported the crucial role of the hypocretin system in arousal as well as stabilization of wakefulness. Prior studies have shown that histaminergic TMN, noradrenergic LC, serotonergic DR, cholinergic BF, and dopaminergic ventral tegmental neurotransmitter systems are extensively innervated by hypocretin neurons. The evidence for hypocretin-1 and -2 in the control of wakefulness has been demonstrated in animal studies. Intracerebroventricular (ICV) infusion of hypocretin-1 or -2 in animals during the light period (sleep) results in increased wake time, physical activity, and decreased non-REM and REM sleep [18, 19]. Application of hypocretin directly into the LC, TMN, LDT, and lateral preoptic area resulted in effects similar to ICV hypocretin injection on wakefulness and sleep [15, 2023]. In vivo slice electrophysiology studies have shown that hypocretin increases firing rates of monoaminergic neurons in the LC, serotonergic neurons in the DR, histaminergic neurons in the TMN, and cholinergic neurons in the BF and LDT [5••], but have no effect on the GABAergic neurons in the VLPO. First reported by Brevig et al. [24], injection of hypocretin-1 in a rat pontine reticular nucleus, a region involved in wakefulness and REM sleep, increases wakefulness that is mediated by GABAergic transmission of GABAA receptors. These findings indicate that activities of wake-promoting regions are without a doubt regulated by hypocretin.

Hypocretin Neuronal Spasticity

In addition to its role in sleep regulation, the lateral hypothalamus is involved in autonomic nervous system regulation, feeding behavior, and sensorimotor functioning. Internal and external stimuli are both responsible for promoting arousal and maintaining wakefulness. There is growing evidence that hypocretin neurons adapt or change in response to internal and external stimuli, consequently changing the arousal state of animals [25, 26]. An example is food deprivation–inducing synaptic plasticity of hypocretin neurons in mouse models [25]. Food deprivation increases wakefulness and decreases sleep in animal models; however, food deprivation does not promote arousal in mice lacking hypocretin neurons [27], suggesting that hypocretin-mediated mechanisms play some part in energy balance and behavioral processes that are critical for survival. Behavioral and environmental factors are likely to play a part in hypocretin neuronal spasticity that ultimately may change arousal threshold and sleep/wake control mechanisms [28••]. Further research is needed to confirm this hypothesis.

Hypocretin and Narcolepsy-Cataplexy

Our understanding of the physiologic roles of the hypocretin system in arousal and maintenance of wakefulness comes from the discovery of the hypocretin gene/ligand and its association with narcolepsy-cataplexy. In 1999, using a familial Doberman pinscher narcolepsy model, Stanford researchers identified an autosomal-recessive mutation in the hypocretin receptor 2 gene (HCRTR-2) responsible for narcolepsy in canines [29]. Simultaneously, Chemelli et al. [30] reported the development of phenotypic narcolepsy symptoms in preprohypocretin knockout mice similarly to human narcolepsy. These preprohypocretin knockout mice exhibited short waking periods, frequent sleep-onset REM periods, and cataplexy [30].

In the following year, Nishino et al. [31] reported that hypocretin-1 (orexin A) was undetectable in the cerebrospinal fluid of up to 95% of patients with narcolepsy-cataplexy. Postmortem brain tissues of narcoleptic patients have undetectable levels of prehypocretin RNA and loss of hypocretin peptides [32, 33]. However, melatonin-concentrating hormone neurons located in the same region as the hypocretin neurons were found to be intact in postmortem brain tissue, suggesting that the loss of hypocretin was not a result of generalized neuronal degeneration in this region [33]. Investigators discovered three substances that normally colocalize with hypocretin-containing neurons: dynorphin, neuronal activity-regulated pentraxin, and insulin-like growth factor–binding protein 3, all of which were found to be deficient in postmortem human brain tissues [34, 35]. Taken altogether, these findings suggest that selective postnatal hypocretin neuronal cell death is the major pathophysiologic process in human narcolepsy-cataplexy.

Hara et al. [36] produced the ataxin-3 (a gene product involved in cell apoptosis) transgenic mouse model in which mice were born with a normal number of hypocretin cells that degenerate with aging, leading to a deficiency in hypocretin, similar to findings in human narcolepsy. Conversely, Mieda et al. [37] demonstrated that chronic overproduction of hypocretin from an ectopically expressed transgene successfully prevented the development of narcolepsy-cataplexy in hypocretin neuron-ablated mice. However, transgenic mice with constitutive activation of hypocretinergic tone in which hypocretin is expressed in a diffuse, ectopic pattern in the brain in an unregulated fashion exhibited abnormal sleep and wakefulness patterns, including fragmented non-REM sleep in the light period and incomplete REM atonia with abnormal myoclonic activity during REM sleep [38••]. These findings suggest that hypocretin neurons need to be switched off to maintain consolidated non-REM sleep as well as the muscle atonia that accompanies REM sleep.

Although research has shown that hypocretin neurons and their functions are selectively damaged in human narcolepsy, the cause is yet to be found. Because of its strong association with HLA alleles, the loss of hypocretin neurons is thought to be autoimmune mediated; recent discoveries further support this hypothesis [39•]. Narcolepsy-cataplexy affects 1 in 2000 individuals, with a prevalence that is close to 0.04%. The two most important symptoms of narcolepsy are excessive daytime sleepiness and cataplexy. Patients suffer from uncontrolled sleepiness and falling asleep at inappropriate times. Cataplexy is characterized by a sudden loss of postural muscle tone triggered by emotional stimuli such as laughter or anger. Loss of muscle tone ranges from jaw dropping and slurring of speech to knees buckling, to complete bilateral collapse of postural muscles. Consciousness is preserved during a cataplectic attack. Narcolepsy is considered to be a disorder of non-REM and REM sleep instability. Non-REM sleep dysregulation is characterized by abrupt transitions from wake into this state (ie, excessive daytime sleepiness and sleep attacks). REM sleep dysregulation is characterized by abrupt transitions from wake into complete or partial REM sleep (ie, sleep-onset REM periods, cataplexy, hypnagogic hallucinations, sleep paralysis).

Clinical Implications

Evidence from research has demonstrated that hypocretin is critical in arousal and stabilization of wakefulness. This has led to numerous efforts focusing on pharmacologic modulation of this pathway in an effort to find new treatment modalities for various sleep disorders. The development of hypocretin receptor agonists would provide a novel treatment modality for narcolepsy or disorders that cause unwanted sleepiness. Conversely, the development of hypocretin receptor antagonists would provide novel therapies for insomnia or sleep promotion. Furthermore, based on our knowledge of hypocretin receptor selectivity in sleep/wake control, the development of selective hypocretin agonists or antagonists may provide selective benefits in the treatment of narcolepsy, insomnia, and other disorders of sleep and wakefulness.

Hypocretin and Sleep Disorders Treatment

Hypocretin Agonists

In contrast to hypocretin antagonists, the development of hypocretin agonists has shown to be more difficult; therefore, progress has been much slower. Limiting factors in delivering hypocretin agonists to the CNS include the blood–brain barrier and characteristics of the compound such as size, solubility, necessary transport systems, and half-life. Given these constraints, hypocretin analogues (prodrug) and hypocretin mimetics (nonpeptide agonists) are potential options. Animal studies have shown success, although short lived with intravenous (IV) and ICV injections of hypocretin-1 in alleviating narcoleptic symptoms [18, 37]. Experiments on narcoleptic mouse models have shown that ICV injection of hypocretin-1 can reverse narcolepsy including cataplexy [37]. Nishino [40] intravenously administered high doses of hypocretin-1 in ligand-deficient narcoleptic dogs and found that only a small portion of hypocretin-1 penetrated the CNS, producing only short-lasting anticataplectic effects. In addition, ICV and IV administration are not the most feasible forms of delivery in the clinical setting.

Intranasal administration of hypocretin-1 holds promise because this route delivers the compound directly into the brain and does not rely on bypassing the blood–brain barrier, and it is much easier to deliver compared with ICV and IV routes [41•, 42]. Dhuria et al. [41•] demonstrated that compared with the IV route, intranasal delivery of hypocretin-1 resulted in significantly higher brain tissue-to-blood concentrations at 2 h after administration in rats. To date, the development of nonpeptide hypocretin agonists has not been reported.

Hypocretin Antagonists

Unlike hypocretin agonist, the development of hypocretin antagonist has shown much progress in its pursuit for novel therapeutic options for insomnia. Insomnia is characterized by difficulty falling asleep (sleep-onset insomnia), difficulty staying asleep (sleep-maintenance insomnia), or nonrestorative sleep resulting in daytime impairment. Chronic insomnia is the most common sleep disorder, with a prevalence of 10% to 15% in the US adult population [43].

Available options for insomnia include pharmacologic therapy and/or cognitive behavioral therapy for insomnia (CBT-I). Medications approved for the treatment of transient or chronic insomnia include benzodiazepine receptor agonists, non-benzodiazepine receptor agonists, and melatonin receptor agonist. The efficacy of these medications is not consistent in that some individuals experience no improvement of insomnia, whereas others experience negative or intolerable side effects. Many of the available hypnotics are associated with a significant side-effect profile including cognitive and psychosocial impairment, anterograde amnesia, and rebound insomnia when discontinued. In addition, they are associated with development of tolerance, addiction, and death by overdose. The efficacy of CBT-I is well documented and it is recognized as the treatment of choice over pharmacologic treatment for chronic insomnia. However, CBT-I is limited in that it is not widely available, potentially time consuming for the patient, and requires a skilled psychologist appropriately trained in CBT-I. Although not approved for the treatment of insomnia, other categories of medications commonly used for insomnia include sedating antidepressants, antipsychotics, antihistamines, and herbal supplements. The efficacy of these medications is not well documented and adverse effects may occur. With the current available options, it is not surprising that new pharmacologic compounds are vigorously being investigated.

Pharmacologic blockade of hypocretin receptors to promote sleep by decreasing wakefulness theoretically would be the ideal treatment for those who suffer from insomnia. In 2007, Brisbare-Roch et al. [44••] introduced the first orally administered dual hypocretin receptor antagonist (ACT-078573) that selectively blocks both hypocretin receptors and is effective in promoting sleep. Almorexant, developed by Actelion (Allschwil/Basel, Switzerland) in collaboration with GlaxoSmithKline (Research Triangle Park, NC), is the first compound to have been developed based on the hypothesis that antagonism of the hypocretin receptors promotes sleep. The compound is an orally active dual hypocretin-1 and -2 receptor antagonist that readily crosses the blood–brain barrier. Preclinical studies in rats and dogs found that the compound increases non-REM and REM sleep, and decreases wakefulness without evidence of cataplectic symptoms. After repeated dosing, tolerance and motor impairment were not seen.

Clinical trials of almorexant have shown similar results to preclinical studies. Almorexant has been shown to promote sleep in a dose-dependent manner without next day performance side effects in both healthy male volunteers and in patients with primary insomnia. A phase 1 clinical trial in 70 healthy male volunteers assessing tolerability, safety, pharmacokinetics, and pharmacodynamics revealed that doses up to 1,000 mg were well tolerated and there were no safety concerns [45••]. A multicenter study in patients with primary insomnia indicated that almorexant significantly improved sleep efficiency as measured by polysomnography, at 100, 200, and 400 mg in a dose-dependent manner [46]. Although the study was not powered, results indicated that almorexant decreased sleep-onset latency and wake after sleep onset. Almorexant also increased percentage of time spent in REM and non-REM sleep, a contrast to available hypnotics such as GABA agonists, which decrease REM sleep. Almorexant was not associated with any relevant negative effects on next-day performance (assessed by fine motor testing and mean reaction time). Repeated dosing of almorexant did not show tolerance or motor impairment, which is supported by findings from preclinical studies, differentiating almorexant from current available hypnotics. Most importantly, cataplexy and abnormal REM behavior were not seen, suggesting that reversible, transient blockade of hypocretin receptor is somehow different from irreversible loss of hypocretin function as seen in narcoleptics [44••]. Development of cataplexy is most concerning with dual hypocretin receptor blockade, and although results are promising, long-term trials designed to assess this potential disabling side effect when the medication is taken for extended period of time are necessary.

Given the positive results with preclinical and clinical trials, Actelion has entered a phase 3 multicenter trial, known as the RESTORA (Restore Physiological Sleep with the Orexin Antagonist Almorexant) trial, which is designed to test efficacy and safety in 670 patients with primary insomnia. In this study, patients are randomized to two doses of almorexant (100 mg and 200 mg), compared with placebo and zolpidem (10 mg) on sleep-onset latency and wake after sleep onset as measured by polysomnography. Secondary objectives included self-reported time to fall asleep and wake time during sleep; safety and tolerability were also tested. Results of this trial are pending.

In 2008, Merck (Whitehouse Station, NJ) disclosed a dual hypocretin receptor antagonist MK-4305, which entered phase 3 clinical trial for the treatment of insomnia in 2009 [47]. In preclinical studies, MK-4305 significantly decreased active wake with a concurrent increase in REM and delta sleep, and no daytime impairment. MK-4305 and almorexant are the only two hypocretin dual receptor antagonists currently in clinical development. The advantages of almorexant including improving sleep initiation, sleep maintenance, increasing REM sleep, lack of tolerance and motor impairment with repeated dosing, and most importantly lack of cataplexy symptoms, make this compound superior to current available hypnotics.

Hypocretin-1 and -2 receptors are preferentially distributed in the CNS and have distinctive activities in sleep/wake control. The preferential and selective characteristic of each receptor is a focus for ongoing research in the development of a selective hypocretin antagonist. Hoffmann-La Roche Ltd (Basel, Switzerland) has published animal model data on a novel hyprocretin-2 receptor antagonist (EMPA) [48]. It will be interesting to see if selective hypocretin antagonism has an advantage over dual antagonism.

Hypocretin Antagonist and Sleep-Disordered Breathing

Results from a study by Han et al. [49•] showed that hypercapnic and hypoxic responsiveness in patients with narcolepsy-cataplexy are influenced by hypocretin. Patients with narcolepsy-cataplexy (defined by low hypocretin-1 or positive HLA DQB1*0602 status) had a higher apnea-hypopnea index, a lower minimal oxygen saturation, and depressed hypoxic responsiveness during sleep compared with controls. Controls with positive HLA status also had a lower hypoxic responsiveness compared to controls with negative HLA status (P < 0.0001), but both control groups had no significant differences in the hypercapnic responsiveness, indicating that a lower hypoxic responsiveness is a result of positive DQB1*0602 status.

Li and Nattie [50] reported that systemic administration of almorexant affects central chemoreception in a vigilance state– and diurnal cycle–dependent manner in rats. This is evidenced by a decrease in the respiratory response to increased carbon dioxide rebreathing during wakefulness and only during the dark period of the diurnal cycle. Interestingly, almorexant also significantly decreased the number of sighs and post-sigh apneas in both parts of the circadian cycle. More importantly, there was a trend toward increased spontaneous apneas in the light period and REM sleep in the dark period. Hypocretin seems to have an influence on ventilatory chemosensitivity. The effect of a dual hypocretin receptor antagonist in decreasing the respiratory drive may contribute negatively to sleep-disordered breathing such as obstructive or central sleep apnea. Further research is needed to elucidate the significance of these findings.

Conclusions

Pharmacologic modulation of the peptide hypocretin is leading the way in an ongoing search for the ideal compound for sleep disorders treatment. Hypocretin antagonist has tremendous potential as the ideal treatment for insomnia. Almorexant, the first hypocretin dual receptor antagonist in clinical trials, has been shown to have a rapid onset of action to combat sleep-onset insomnia, persistent effect through the night to combat sleep maintenance insomnia, and rapid elimination so motor impairment and related effects are not experienced during the day. Available data suggest that dual hypocretin receptor antagonist may be the most successful pharmacologic treatment in development for insomnia; however, safety profile is still under investigation and long-term results remain to be seen. Similarly, hypocretin agonist has potential for the treatment of narcolepsy and other sleep disorders that cause unwanted sleepiness. The development of hypocretin agonist has not met much progress compared with its counterpart. Although its prevalence is much lower than insomnia, narcolepsy is a lifelong disease and novel treatment modalities would benefit those who suffer from this condition. Sleep disorders that cause unwanted sleepiness such as obstructive sleep apnea, hypersomnias, and circadian rhythm–related disorders would potentially benefit from hypocretin agonist. Similar to hypocretin antagonists, the need for hypocretin agonists is clearly present.

Disclosure

No potential conflicts of interest relevant to this article were reported.

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