Pitolisant and the Role of Histamine in Narcolepsy


In this custom video series, experts discuss the uniqueness of pitolisant as a treatment option within the setting of narcolepsy and the role histamine plays in wakefulness.

Debra Stultz, MD: Let’s move on and talk about pitolisant, or Wakix.

Stephen Stahl, MD, PhD:This is an interesting drug that has a unique mechanism of action, different from anything that has ever been used before. It is pro histamine. Usually I say it’s histaminergic, but every audience I’ve had since I started talking about this hears antihistamine when I say histamine. No, it’s the opposite of an antihistamine. The so-called antihistamines are H1 postsynaptic antagonists, and you must know that histamine is a neurotransmitter in the brain. It doesn’t just make you itch. It’s an arousal neurotransmitter. It comes from an important part of the sleep-wake switch in your hypothalamus. These neurons go into the brain and arouse you and normally make you attentive and are even involved in cognition. You want to boost histamine in your brain, and you can do that by a couple of different mechanisms. Did you know that the presynaptic nerve has an auto receptor on it? It’s called an H3 receptor, and it’s there to be a brake and shut off histamine release. If you cut the brake cable, guess what? Histamine comes out, and the histamine comes out and wakes you up.

Debra Stultz, MD: Yes.

Stephen Stahl, MD, PhD: It’s going to be dancing on those postsynaptic H1 receptors—histamine itself, but the drug releases histamine.

Debra Stultz, MD: This is an exciting medication. It’s been FDA approved for excessive daytime sleepiness and cataplexy. There have been some studies on it helping with sleep paralysis and hypnagogic hallucinations. The other main advantage of it is it’s not a controlled substance, so that’s a major advantage given a lot of the other medicines we have to deal with in narcolepsy.

Stephen Stahl, MD, PhD: We’re late to the party. The United States got this, but overseas in Europe it’s been available for longer. My colleagues in Europe had much more experience with it than we did. They like it because it’s not overstimulating, it’s not a controlled substance, it’s not abusable, and it’s effective. It wakes you up and it has a refreshing effect, not like when you use too many stimulants; you’re way too much awake and people don’t like that. It’s almost better to not take the drug sometimes. This is not an adverse effect of pitolisant.

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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