The Wakefulness Neurotransmitter

The thought of histamines might conjure up images of itchy hives or the tickling sensation just before a sneeze, but scientists have come to realize there is much more to histamines than their connection to allergies. Recent research reveals that histamines play a vital role in wakefulness.

Produced by brain cells in the hypothalamus, histamines are neurotransmitters that promote wakefulness, and they have been of increasing interest to medical researchers who want to uncover new ways of treating narcolepsy.

“This is an exciting time for patients with central nervous system disorders of hypersomnolence (narcolepsy and idiopathic hypersomnia), due to the number of new drugs under development and increasing awareness of the burden of disease,” says neurologist Nancy Foldvary-Schaefer, DO, MS, a physician at Cleveland Clinic’s Sleep Disorders Center and staff member in the Cleveland Clinic Epilepsy Center in Ohio.

The Impact of Narcolepsy

Narcolepsy impacts the lives of approximately 126,000 people in the United States alone, according to recent data from the Stanford Sleep Epidemiology Research Center.¹ The sleep disorder has profound implications on quality of life. As a more nuanced understanding of narcolepsy emerges, more and more treatment options offer potential pathways to relief.

The latest milestone came in June 2024 when the U.S. Food and Drug Administration (FDA) approved the histamine-targeting medication pitolisant (Wakix, Harmony Biosciences) for the treatment of excessive daytime sleepiness in pediatric patients ages 6 and above. This approval marked a major step forward in providing wake-promoting therapy for some of the youngest narcolepsy patients.

“There are fewer options for children for treatment of narcolepsy, so I think any new treatment is good news,” says sleep specialist Oliver Sum-Ping, MD, a clinical assistant professor at Stanford University School of Medicine in California. “It has been helpful to have this additional medication available. There are some good treatments, but many patients are still experiencing symptoms, so any new treatment that comes online is helpful.”

A Unique Approach

Pitolisant is currently the only non-scheduled wake-promoting medication approved to treat narcolepsy symptoms. The drug first received FDA approval in 2019 for the treatment of excessive daytime sleepiness in adults with narcolepsy, and by the following year, its indication had expanded to treat cataplexy in adults with narcolepsy.

While the medication’s mechanism of action is not fully understood, it is thought that pitolisant may increase the synthesis and release of histamines in the brain.

“Traditional stimulants get absorbed, and one can often feel the stimulating effect kick in; same once the drug is wearing off,” explains Dr. Foldvary-Schaefer. “Pitolisant doesn’t have that abrupt effect, so patients tend to report feeling more alert without the fluctuations that occur with stimulants.”

The medication has also shown minimal risk for abuse in studies, and for some patients, it might also be better tolerated than other wake-promoting medications used to treat narcolepsy.^2,3  

The Evolution of Histamine Research

The first clues of histamines’ role in the sleep-wake cycle began to surface more than a century ago during the encephalitis lethargica epidemic that spread across Europe and later worldwide toward the end of World War I. The condition was first described in 1917 by Austrian psychiatrist and neurologist Constantin von Economo as causing “sleepy sickness” and associated with lesions and inflammation in the posterior hypothalamus of the brain.⁴ Although this atypical form of encephalitis is believed to have disappeared a decade after it started, studying the illness led von Economo to identify distinct centers for sleep and wakefulness in the brain.⁴

He proposed the posterior hypothalamus housed neurons that promote wakefulness. Over the past 15 years, researchers have identified populations of neurons in this region that are key for promoting wakefulness, including histamines, and have gained a greater understanding of how they regulate sleep/wake behavior.⁵

“This discovery led to the development of treatments for narcolepsy and a more comprehensive understanding of the systems in the brain that collectively promote wakefulness that could be targets for future drug development,” says Dr. Foldvary-Schaefer.

While there is still more to uncover, it is now understood that histamine-secreting neurons in the brain innervate the cerebral cortex, thalamus, and other wake-promoting regions in the brain, similar to other neurotransmitters that promote wakefulness, such as norepinephrine, dopamine, and orexin.⁵ Continued research will help to further define the distinct mechanisms of histamines and how they operate, and that knowledge will almost certainly open the door to even more therapeutic possibilities for sleep-wake disorders.

“One of the particularly appealing things about pitolisant is it works quite differently than a lot of the other medications that are used for narcolepsy,” says Dr. Sum-Ping. “When we are thinking about treatment options, it is important to keep histamines in mind.”

By Lisa Spear

Source: SleepWorld Magazine

References

1. Ohayon MM, Duhoux S, Grieco J, Côté ML. Prevalence and incidence of narcolepsy symptoms in the US general population. Sleep Med X. 2023;6:100095. doi: 10.1016/j.sleepx.2023.100095.
2. de Biase S, Pellitteri G, Gigli G L, Valente M. Evaluating pitolisant as a narcolepsy treatment option. Expert OpinPharmacother. 2021;22(2):155–62. doi:10.1080/14656566.2020.1817387.
3. Lamb YN. Pitolisant: a review in narcolepsy with or without cataplexy. CNS Drugs. 2020;34(2):207–18. doi:10.1007/s40263-020-00703-x.
4. da Mota Gomes M. Encephalitis lethargica epidemic milestones in early sleep neurobiology researches. Sleep Med. 2020;74:349–56. doi: 10.1016/j.sleep.2020.08.019.5. Scammell TE, Jackson AC, Franks NP, Wisden W, Dauvilliers Y. Histamine: neural circuits and new medications. Sleep. 2019;42(1):zsy183. doi: 10.1093/sleep/zsy183.