SEATTLE, WA—Almorexant, a hypocretin receptor antagonist, produced fewer acute cognitive effects than the GABAA receptor modulator zolpidem, according to results of a randomized controlled trial presented at SLEEP 2015.

These data “provide support for the hypothesis that hypocretin receptor antagonists produce less functional impairment than benzodiazepine receptor agonists,” because the latter class of agents cause a general inhibition of neural activity, whereas hypocretin receptor antagonists “specifically disfacilitate wake-promoting systems,” Thomas C. Neylan, MD, of the University of California, San Francisco, San Francisco, CA, reported.

Previously, almorexant was found to have less acute cognitive impairment than placebo in animal studies. Therefore, “this study aimed to confirm if the same effect would be found in human subjects,” he noted.

In the study, healthy male and female subjects underwent testing with a neurocognitive battery, the psychomotor vigilance task, and the maintenance of wake test before, during, and after almorexant 100mg (n= 48), almorexant 200mg (n=53), zolpidem 10mg (n=49), or placebo (n=52), each of which was administered at 3:00pm daily.

“For most cognitive measures, performance under zolpidem was significantly worse than almorexant or placebo,” Dr. Neylan stated. “For example, change in ‘for errors of commission’ on the continuous performance test under zolpidem was significantly worse than in each of the other three arms (all P-values =0.17).”

For almorexant, performance decrements were less than zolpidem but in some cases greater than placebo, with some measures demonstrating a dose effect. “For example, total scores on the Rey Auditory Verbal Learning Test decreased from 54 to 48 under zolpidem, while remaining nearly unchanged under almorexant 200mg (54 to 53) and almorexant 100mg (55 to 55), and increased nonsignificantly under placebo (52 to 54),” he noted. For these scores, interaction F(3, 195) equaled 7.60 (P<0.001).

This change was significantly worse with zolpidem when compared with any of the other three arms (all P<0.01). Almorexant 200mg was marginally worse than placebo (P=0.06), while almorexant 100mg did not differ significantly from either placebo or almorexant 200mg.

On the psychomotor vigilance task, changes in mean reaction time under zolpidem and almorexant 200mg did not differ significantly (P=0.14); however, both zolpidem and almorexant 200mg differed significantly from almorexant 100mg and placebo.