Orexinergic

Daridorexant (Quviviq) is a dual orexin receptor antagonist from Idorsia, approved for adult insomnia in the United States and the European Union in 2022. With a half-life of about 8 hours it is the shortest-acting of the three licensed orexin antagonists. In two 3-month phase 3 trials in 1,854 adults, 50 mg cut time awake during the night by 18–23 minutes and time to fall asleep by about 11 minutes compared with placebo, and improved self-rated daytime sleepiness; 25 mg did less and 10 mg had no effect on measured sleep. Benefits held over a further 9 months with no withdrawal or rebound insomnia.

Lemborexant (Dayvigo) is a dual orexin receptor antagonist from Eisai, approved for adult insomnia in the United States in 2019 and in Japan, Canada, Australia and several Asian countries. In older adults it shortened the time to fall asleep and cut night-time waking more than both placebo and extended-release zolpidem, and in a 12-month trial its benefits over placebo at 6 months were still present at a year. It had the largest effect on falling asleep of the three licensed orexin antagonists in a 2025 network meta-analysis; the price is a long half-life of 17–19 hours and dose-related somnolence, most of all at 10 mg.

Seltorexant (JNJ-42847922, MIN-202) is an investigational selective orexin-2 receptor antagonist from Janssen, developed with Minerva Neurosciences as an add-on treatment for major depression with insomnia symptoms. Unlike the licensed dual orexin antagonists it binds the OX2 receptor about 100 times more tightly than OX1, and its half-life is only 2–3 hours. Added to an antidepressant, 20 mg at bedtime lowered depression scores by about 3 points more than placebo in a phase 2 trial, mostly in people with marked insomnia, and a 586-patient phase 3 trial reported a 2.6-point advantage; a head-to-head phase 3 trial against quetiapine missed its primary endpoint, and as of mid-2026 it was not approved anywhere.

Suvorexant (Belsomra) was the first orexin receptor antagonist licensed for insomnia, approved in the United States in 2014. Instead of damping the whole brain through GABA-A receptors, as benzodiazepines and Z-drugs do, it blocks both receptors for orexin, the hypothalamic peptide that keeps people awake. At the licensed 15–20 mg doses, people in two 3-month trials reported 11–22 more minutes of sleep a night than on placebo, and polysomnography measured 17–31 fewer minutes awake after falling asleep, with smaller and less consistent effects on how quickly they fell asleep. Next-day sleepiness is its main drawback, and it is a Schedule IV controlled substance in the United States.