Managing Insomnia with Seltorexant, an Orexin-2 Receptor Antagonist
|
Reviewed by Dat Tien Nguyen, B.A, ScM.
Translated by Nhi Phuong Quynh Le, B.A |
Posted on December 15th, 2025
|
Insomnia is increasingly common, yet treatment options remain limited. Currently, only two major classes of medications are approved: benzodiazepines and non-benzodiazepine hypnotics such as zolpidem. These drugs are effective for some patients but often come with drawbacks, including daytime drowsiness, dependence, tolerance, and a higher risk of cognitive impairment in older adults. To explore better alternatives, Johnson & Johnson funded a study evaluating the use of seltorexant for insomnia.
The trial enrolled 364 adults with an average age of 57.8 years, all diagnosed with insomnia according to DSM-5 criteria. Individuals with other sleep disorders-such as obstructive sleep apnea, restless leg syndrome, or parasomnias-were excluded. At baseline, participants showed substantial sleep disturbance, with an average Insomnia Severity Index score of 20.2 out of 28. Their average time to persistent sleep (LPS) was 87.4 minutes, and their wake time after sleep onset during the first six hours (WASO-6) averaged 79.4 minutes.
Participants were randomly assigned to receive either placebo, zolpidem, or seltorexant at bedtime. Zolpidem, given at 5 mg or 10 mg depending on local practice, acts by enhancing GABA-A receptor activity to reduce neuronal firing. Seltorexant works through a different pathway: it blocks the orexin-2 receptor, which plays a key role in maintaining wakefulness. The new drug was tested at doses of 5 mg, 10 mg, and 20 mg.
After a single dose, the 20 mg seltorexant group showed the strongest response, outperforming both placebo and zolpidem. In this group, the time to persistent sleep dropped from a baseline of about 70 minutes to just 20 minutes. Follow-up on day 13 confirmed that the benefits were maintained without evidence of developing tolerance. Side-effect profiles were similar across seltorexant doses and comparable to zolpidem and placebo. The medication also appeared equally effective across different age groups. While these results are encouraging, longer-term studies are needed to evaluate sustained effectiveness, potential tolerance, and long-term safety.
The trial enrolled 364 adults with an average age of 57.8 years, all diagnosed with insomnia according to DSM-5 criteria. Individuals with other sleep disorders-such as obstructive sleep apnea, restless leg syndrome, or parasomnias-were excluded. At baseline, participants showed substantial sleep disturbance, with an average Insomnia Severity Index score of 20.2 out of 28. Their average time to persistent sleep (LPS) was 87.4 minutes, and their wake time after sleep onset during the first six hours (WASO-6) averaged 79.4 minutes.
Participants were randomly assigned to receive either placebo, zolpidem, or seltorexant at bedtime. Zolpidem, given at 5 mg or 10 mg depending on local practice, acts by enhancing GABA-A receptor activity to reduce neuronal firing. Seltorexant works through a different pathway: it blocks the orexin-2 receptor, which plays a key role in maintaining wakefulness. The new drug was tested at doses of 5 mg, 10 mg, and 20 mg.
After a single dose, the 20 mg seltorexant group showed the strongest response, outperforming both placebo and zolpidem. In this group, the time to persistent sleep dropped from a baseline of about 70 minutes to just 20 minutes. Follow-up on day 13 confirmed that the benefits were maintained without evidence of developing tolerance. Side-effect profiles were similar across seltorexant doses and comparable to zolpidem and placebo. The medication also appeared equally effective across different age groups. While these results are encouraging, longer-term studies are needed to evaluate sustained effectiveness, potential tolerance, and long-term safety.