Orexin and the Destabilization of Wakefulness in Narcolepsy


In this custom video series, Stephen Stahl, MD, PhD, discusses the underlining cause of narcolepsy and the role of the neurotransmitter orexin (hypocretin) in the stabilization of wakefulness.

Debra Stultz, MD: Welcome. Thank you for joining us. I’m Dr Debra Stultz. I’m a sleep doctor and psychiatrist in Barboursville, West Virginia, at Stultz Sleep & Behavioral Medicine. I’m honored to have Dr Stephen Stahl with us. He is the chairman of the Neuroscience Education Institute and an adjunct professor with the University of California, San Diego [School of Medicine]. He needs no introduction because anybody exposed to this program has grown up in psychiatry, and sleep, and medicine on his books about neurotransmitters and diagrams. You’ve done so much to advance our field. It’s my honor to be here with you, so thank you for joining us.

Stephen Stahl, MD, PhD: Thank you for the kind introduction. I’m glad to be here.

Debra Stultz, MD: We’re going to be talking about narcolepsy treatment. Narcolepsy can be a complicated illness, and there are many causes of narcolepsy. Give me your idea about what’s involved in the disorder of narcolepsy from your standpoint?

Stephen Stahl, MD, PhD: A lot of people have traditionally thought about narcolepsy as falling asleep and sleep attacks, and certainly it is that. But why? Why would you fall asleep suddenly? What we’ve learned is the story of this new neurotransmitter that maybe the listeners haven’t heard about in their training or medical school. It’s called orexin. Some people call it hypocretin. It’s interesting, neurologists and psychiatrists call the same thing different terms. But that little sucker lives in the small part of the lateral hypothalamus, and if you have disruption of that part of the brain, it stops making orexin. Why do you care? Because orexin doesn’t make you awake, but it stabilizes wakefulness. Narcolepsy is the destabilization of wakefulness. What ends up happening is you’re not awake; you’re asleep.

You may not know this, but I may have fallen asleep for a microsleep episode ever since I even started this talk. Because if you actually do EEGs [electroencephalograms] on all of us—I’ve seen the EEGs from pilots going in an airplane across the Atlantic. They have microsleep episodes that are fast, and they wake up again because they have good orexin controls. What happens if you lose your orexins? When that little impulse comes to fall asleep, you do. We lose orexins for a number of reasons. I mean, nobody really knows why, but there seems to be a cause of narcolepsy where your immune system goes wild and eats your lateral hypothalamus. You lose your orexins, and then you don’t stabilize wakefulness anymore. It’s a very fascinating illness. You have arousal neurotransmitters and sleep neurotransmitters, but you also have stabilization of arousal neurotransmitters.

Debra Stultz, MD: Right. I often describe it to my patients as like a light that flickers on and off. Sometimes it’s on, sometimes it’s off, sometimes it’s just flickering. You have a flickering of sleep into wake during the day, and you have a flickering of wake into sleep at night. It’s an unsteady situation.

Transcript edited for clarity.


Dr Stephen Stahl is clinical professor of psychiatry and neuroscience at the University of California Riverside, adjunct professor of psychiatry at the University of California San Diego, and honorary fellow in psychiatry at the University of Cambridge. Over the past 12 months (January 2020 - December 2020), Dr Stahl has served as a consultant to Acadia, Alkermes, Allergan, AbbVie, Arbor Pharmaceuticals, Axovant, Axsome, Celgene, Concert, Clearview, EMD Serono, Eisai Pharmaceuticals, Ferring , Impel NeuroPharma, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen, Karuna, Lilly, Lundbeck, Merck, Otsuka, Pfizer, Relmada, Sage Therapeutics, Servier, Shire, Sunovion, Takeda, Taliaz, Teva, Tonix, Tris Pharma, and Viforpharma; he is a board member of Genomind; he has served on speakers bureaus for Acadia, Lundbeck, Otsuka, Perrigo, Servier, Sunovion, Takeda, Teva, and Vertex; and he has received research and/or grant support from Acadia, Avanir, Braeburn Pharmaceuticals, Eli Lilly, Intra-Cellular Therapies, Ironshore, ISSWSH, Neurocrine, Otsuka, Shire, Sunovion, and TMS NeuroHealth Centers.

Dr Debra Stultz is the Director and Owner of Stultz Sleep and Behavioral Health in Barboursville, West Virginia. Dr Stultz earned her medical degree from Marshall University School of Medicine in Huntington, West Virginia. She completed a residency in psychiatry and a fellowship in child and adolescent psychiatry through West Virginia University at their Charleston Division through Charleston Area Medical Center in Charleston, West Virginia. She is board certified in psychiatry, sleep medicine, and behavioral sleep medicine. With a special interest in Narcolepsy, she treats a variety of sleep disorders and psychiatric issues. She is also the editor for the Clinical TMS Society newsletter, on their Board of Directors, and the chairman of the TMS and Sleep Disorders Affinity Group. Dr Stultz is on the advisory committee for Harmony Biosciences and is a speaker for Harmony Biosciences and Jazz Pharmaceuticals.

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