For US Healthcare Professionals
IT TAKES
a comprehensive understanding
of orexin science
TO SUPPORT YOUR PATIENTS
WITH NT1
Orexin is a key regulator of the sleep-wake cycle5-8
Dr Foldvary-Schaefer of the Cleveland Clinic talks about orexin and the role of orexin loss in narcolepsy type 1 (NT1).
A loss of orexin is the underlying cause of NT15
Orexin (hypocretin) is a key neuropeptide produced by neurons in the lateral hypothalamus that is involved in orchestrating a cascade of downstream biological functions.6-8
Orexin helps to stabilize wakefulness and govern the transitions between sleep and wake states. During the day, orexin signaling activates areas of the brain, via monoaminergic and cholinergic circuitry, that support arousal, and the sleep system is suppressed. In the evening, the sleep system becomes activated, and monoaminergic and cholinergic circuitry and orexin neurons are inhibited to maintain sleep. Orexin helps to stabilize both sleep and wakefulness by regulating communication and activity between the sleep and wake systems.8
In NT1, a loss of orexin causes the sleep-wake cycle to be dysregulated. The sleep and wake systems set up a mutually inhibitory circuit, causing abrupt transitions between the sleep and wake states throughout the day and night.8
Orexin signaling activates neurotransmitters located throughout the brain, including dopamine, serotonin, and histamine. A loss of orexin and disrupted orexin signaling can have a devastating impact on functions beyond the sleep-wake cycle, including muscle tone, alertness, mood, cognitive functioning, and appetite.4,6-8
Click each area to learn how orexin loss can impact key functions in the body.5-8
Attention
Patients with NT1 may struggle with the ability to sustain attention over prolonged periods of time and may have difficulty with tasks requiring vigilance.7
Sleep/Wakefulness
The disruption in the brain’s ability to maintain sleep and wake states can make it harder to sustain wakefulness during the day and experience undisturbed sleep at night.8
Cognition
Patients with NT1 may experience difficulties with cognitive processes such as memory, learning, and concentration.7
Mood
Patients with NT1 may experience challenges with mood regulation and emotional responses.6,7
Muscle tone
Disruption in REM sleep regulation may allow motor inhibition pathways to activate during strong emotions, which can result in partial or complete episodes of cataplexy.4
GABA and glutamate contribute to sleep-wake regulation and are present across multiple brain regions within the arousal network, including the hypothalamus, basal forebrain, brainstem, and midbrain (including the ventral tegmental area).24
Adapted from Toor B, et al. Front Neurol Neurosci. 2021,7 De Luca R, et al. Nat Commun. 2022,5 Sakurai T. Nat Rev Neurosci. 2007,8 and Mahoney CE, et al. Nat Rev Neurosci. 2019.6 Depiction is for illustrative purposes.
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Orexin signaling is impaired in people with NT14
Loss of orexin is thought to cause a disruption in orexin signaling, which destabilizes the sleep-wake cycle. This disruption is thought to result in a range of symptoms that may vary in scope and severity from person to person with NT1 and include5-7,18:
- Excessive daytime sleepiness (EDS)
- Cataplexy
- Sleep paralysis
- Hypnagogic and hypnopompic hallucinations
- Disrupted nighttime sleep
Cumulatively, these symptoms can have far-reaching effects, such as difficulty with sustained attention, depression, and limited ability to engage in work, school, social activities, and relationships.6,7,13
Areas affected by impaired orexin signaling
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NREM, non-rapid eye movement; REM, rapid eye movement.
References
1. Krahn LE, Zee PC, Thorpy MJ. Current understanding of narcolepsy 1 and its comorbidities: what clinicians need to know. Adv Ther. 2022;39(1):221-243. doi:10.1007/s12325-021-01992-4 2. Maski K, Steinhart E, Williams D, et al. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden, and treatment efficacy. J Clin Sleep Med. 2017;13(3):419-425. doi:10.5664/jcsm.6494 3. Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881-1893. doi:10.5664/jcsm.9328 4. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662. doi:10.1056/NEJMra1500587 5. De Luca R, Nardone S, Grace KP, et al. Orexin neurons inhibit sleep to promote arousal. Nat Commun. 2022;13(1):4163. doi:10.1038/s41467-022-31591-y 6. Mahoney CE, Cogswell A, Koralnik IJ, Scammell TE. The neurobiological basis of narcolepsy. Nat Rev Neurosci. 2019;20(2):83-93. doi:10.1038/s41583-018-0097-x 7. Toor B, Ray LB, Pozzobon A, Fogel SM. Sleep, orexin and cognition. Front Neurol Neurosci. 2021;45:38-51. doi:10.1159/000514960 8. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci. 2007;8(3):171-181. doi:10.1038/nrn2092 9. Lipford MC, Ip W, Awasthi S, et al. Demographic characteristics and comorbidities of patients with narcolepsy: a propensity-matched cohort study. Sleep Adv. 2024;5(1):zpae067. doi:10.1093/sleepadvances/zpae067 10. Szabo ST, Thorpy MJ, Mayer G, Peever JH, Kilduff TS. Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy. Sleep Med Rev. 2019;43:23-36. doi:10.1016/j.smrv.2018.09.006 11. Ortiz LE, Morse AM, Krahn L, et al. A survey of people living with narcolepsy in the USA: path to diagnosis, quality of life, and treatment landscape from the patient’s perspective. CNS Drugs. 2025;39(suppl 1):S23-S36. doi:10.1007/s40263-024-01142-8 12. Bassi C, Biscarini F, Zenesini C, et al. Work productivity and activity impairment in patients with narcolepsy type 1. J Sleep Res. 2024;33(3):e14087. doi:10.1111/jsr.14087 13. Davidson RD, Biddle K, Nassan M, Scammell TE, Zhou ES. The impact of narcolepsy on social relationships in young adults. J Clin Sleep Med. 2022;18(12):2751-2761. doi:10.5664/jcsm.10212 14. Quaedackers L, Pillen S, Overeem S. Recognizing the symptom spectrum of narcolepsy to improve timely diagnosis: a narrative review. Nat Sci Sleep. 2021;13:1083-1096. doi:10.2147/NSS.S278046 15. Bassetti CLA, Adamantidis A, Burdakov D, et al. Narcolepsy-clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat Rev Neurol. 2019;15(9):519-539. doi:10.1038/s41582-019-0226-9 16. Luca G, Haba-Rubio J, Dauvilliers Y, et al. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J Sleep Res. 2013;22(5):482-495. doi:10.1111/jsr.12044 17. Black J, Reaven NL, Funk SE, et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med. 2017;33:13-18. doi:10.1016/j.sleep.2016.04.004 18. Morse AM, Kim SY, Harris S, Gow M. Narcolepsy: beyond the classic pentad. CNS Drugs. 2025;39(suppl 1):S9-S22. doi:10.1007/s40263-024-01141-9 19. Yan Z, Li J, Yu Y, Qiu S, Wang B, Tang J. Comparative efficacy of new wake-promoting agents for narcolepsy–a network meta-analysis. BMC Neurol. 2025;25(1):466. doi:10.1186/s12883-025-04328-9 20. Dauvilliers Y, Mignot E, Del Río Villegas R, et al. Oral orexin receptor 2 agonist in narcolepsy type 1. N Engl J Med. 2023;389(4):309-321. doi:10.1056/NEJMoa2301940 21. Johns M. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14(6):540-545. 22. Yu J, Zhou Y, Han X, Li Z, Chen F, Zhang L. Impaired vigilance in patients with narcolepsy type 1: a psychomotor vigilance task study. Nat Sci Sleep. 2024;16:2021-2028. doi:10.2147/NSS.S491893 23. Dauvilliers Y, Barateau L, Lopez R, et al. Narcolepsy Severity Scale: a reliable tool assessing symptom severity and consequences. Sleep. 2020;43(6):zsaa009. doi:10.1093/sleep/zsaa009 24. Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev. 2012;92(3):1087-1187. doi:10.1152/physrev.00032.2011
Hello, my name is Nancy Foldvary- Schaefer and I’m a neurologist and neurophysiologist at Cleveland Clinic in Cleveland, Ohio. I’ve been in practice since 1995 and I’ve been very active in the field of sleep medicine. My interest is in the area of central nervous system hypersomnia disorders in particular, and novel therapies to treat patients with these disorders.
Today, on behalf of Takeda, I’ll be discussing the role of orexin in narcolepsy type 1, or NT1, as well as differentiating between NT1 and narcolepsy type 2.
In terms of symptoms, narcolepsy type 1 is a central disorder of hypersomnolence that requires, at a high level, excessive daytime sleepiness and cataplexy for a diagnosis.
While narcolepsy type 2 also has excessive daytime sleepiness as part of its diagnostic criteria, there is an absence of cataplexy. In addition, there is no known biomarker for narcolepsy type 2.
Orexin is a neuropeptide that is produced from a specific group of neurons in the lateral hypothalamic area and posterior hypothalamus. Orexin is critically important in terms of the brain’s maintenance of sleep and wake, as well as muscle tone. We understand that many neurotransmitters are either turned on or turned off with sleep and wakefulness respectively, orexin is a key regulator of many of those neurotransmitters. Orexin is involved in a variety of biological functions beyond sleep and wakefulness, like appetite.
Sleep and wakefulness are intimately connected. When we wake, the neurotransmitters and systems within the brain that support wakefulness turn on, and technically those that manage sleep turn off or are suppressed.
In the evening, the opposite happens. Wake-promoting systems get dampened and sleep-promoting systems get activated. Orexin helps to stabilize that switch between sleep and wakefulness, and it does so by regulating communication and activity between those 2 systems. So during the day, orexin activates wake-promoting neurotransmitters that help us stay alert and awake, and in the evening, orexin activity naturally decreases and it helps coordinate that smooth transition to sleep. Sleep-promoting neurotransmitters become more active at night and cause the wake system to dampen or quiet down.
Orexin-producing neurons send widespread excitatory projections throughout the central nervous system to other known neurotransmitters that have very active roles in maintaining sleep and wakefulness.
These include:
- dopamine
- norepinephrine
- histamine
- serotonin
- and acetylcholine
Orexin has significant connections with so many other neurotransmitters in the brain, and signals to all of these downstream neurotransmitters help to stabilize the sleep-wake cycle but also can influence many other brain functions, including:
- alertness
- mood
- cognitive function
- and appetite
First and foremost, a loss of orexin causes the sleep-wake cycle to be dysregulated, and the boundaries between sleep states and wake states are destabilized. Instead of feeling awake or asleep, sleep and wakefulness become intermixed, with abrupt disruptions in wake from sleep, and vice versa, leading to many of the symptoms that we see in patients with narcolepsy type 1.
Without sufficient orexin in the brain, downstream neurotransmitters don’t receive consistent orexin signaling, and so this can lead to a disruption and dysregulation of a number of functions that are regulated within the central nervous system, including:
- alertness
- cognitive functioning, specifically memory and attention
- mood and emotion regulation
- as well as energy level and the maintenance of energy throughout the day
Narcolepsy type 1 is caused by a loss of orexin neurons. It’s a serious neurological condition that can cause ongoing challenges and significant impairments in the quality of life of those who are affected.
Narcolepsy type 1 requires both excessive daytime sleepiness and cataplexy for diagnosis.
Cataplexy differentiates narcolepsy type 1 from narcolepsy type 2. Cataplexy is a sudden, temporary loss of muscle tone that’s triggered by strong emotions, and this varies from individual to individual. It may be subtle or it may be more extreme. It can be partial with slurred speech or a droopy face, or it may be complete where the person may fall to the ground.
Another key symptom of NT1 is disrupted nighttime sleep: fragmented, poor-quality sleep with frequent, brief awakenings.
Next is sleep paralysis. People with narcolepsy may experience an inability to move when falling asleep or as they wake up. It’s usually a frightening experience because the person feels awake, but the muscles don’t move.
Finally, hypnopompic and hypnagogic hallucinations are thought of as dreamlike visions. Hypnopompic hallucinations occur upon awakening, whereas hypnagogic hallucinations occur at sleep onset. These are actually elements of REM sleep.
While the scope and severity of symptoms of NT1 can differ between individuals, most patients with NT1 struggle with a variety of challenges that really affect their ability to function optimally during the day. In my practice, I’ve seen patients struggle with:
- engaging in work, at school
- difficulty participating in social activities and then challenges in relationships
- depression, anxiety, and other mood complaints
- and cognitive complaints such as memory and attention
I have patients who have declined important events like weddings for fear of having a cataplexy event in public; I have patients who can no longer drive; who have lost their jobs because of performance issues. It can be really hard for my patients to live with and articulate these challenges.
So many of my patients with narcolepsy type 1 are unhappy, frustrated, or even depressed about their condition, their difficulties, and where they are in life. When I explain that orexin deficiency is the underlying cause, that there’s an underlying neurobiology of this disorder, that really helps them. It enables them to understand more about their symptoms and helps alleviate some of the guilt and shame they may feel.