On August 15, 2019, pitolisant (Wakix) received FDA approval for narcolepsy, making it the first release of a histamine-3 (H₃) antagonist.

Unlike other narcolepsy medications, pitolisant is not a controlled substance and lacks abuse potential. Those other options for narcolepsy are the stimulants (methylphenidate and amphetamine), the modafinils, sodium oxybate (Xyrem), and the newly released solriamfetol (Sunosi), a dopamine and norepinephrine reuptake inhibitor that we reviewed in the June/July issue of TCPR. Pitolisant has been compared to modafinil in 2 head-to-head trials, where pitolisant had similar efficacy but better tolerability (total n = 260) (Romigi A et al, Drug Des Devel Ther 2018;12:2665–2675).

Pitolisant’s main side effects are insomnia, headache, nausea, and anxiety. As a weak CYP3A4 inducer, it may decrease oral contraceptives.

The H₃ histamine receptor is mainly found in the brain, where it regulates wakefulness, appetite, and memory. Pitolisant blocks the H₃ receptor, and this blockade causes downstream effects of increased dopamine and acetylcholine in the prefrontal cortex. That profile has led to investigations of pitolisant in ADHD, dementia, obesity, and cognitive symptoms of schizophrenia. So far the results have not proved as promising as the narcolepsy findings, but most of those trials are incomplete or unpublished. It’s an intriguing mechanism, and we expect to learn more about its psychiatric effects in the future (Syed YY, Drugs 2016;76(13):1313–1318).