The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia

Abstract

Background: Insomnia is common in patients with major depressive disorder. Although antidepressants improve mood, insomnia often persists as a result of physiological hyperarousal. The orexin-2 receptor is increasingly being recognized as a new target for the treatment of persistent insomnia in major depressive disorder . Aim: This exploratory study investigated the effects of seltorexant on objective sleep parameters and subjective depressive symptoms in antidepressant treated major depressive disorder patients with persistent insomnia. Methods: Twenty male and female patients received a single dose of 10, 20, 40 mg seltorexant and placebo with a washout period of seven days in a double-blind four-way crossover study. Effects on latency to persistent sleep, total sleep time and sleep efficiency were assessed with polysomnography. Subjective changes in mood were explored by the Quick Inventory of Depressive Symptomatology Self-Report. Safety was recorded and suicidal ideation and behavior were assessed with the Columbia Suicide Severity Rating Scale. Results: Latency to persistent sleep was significantly shorter for all doses of seltorexant compared to placebo. Placebo least square mean was 61.05 min with least square mean ratios treatment/placebo (80% confidence interval) of 0.32 (0.24–0.44), 0.15 (0.11–0.2) and 0.17 (0.12–0.23) 19.69, 9.2, 10.15 for 10, 20 and 40 mg seltorexant respectively, (all p<0.001). Total sleep time was significantly longer for all doses of seltorexant compared to placebo. Sleep efficiency was significantly improved. The Quick Inventory of Depressive Symptomatology Self-Report demonstrated a trend to mood-improvement for the 40 mg group. Conclusions: Seltorexant showed a statistically significant, dose-dependent decrease in latency to persistent sleep, and increase in total sleep time and sleep efficiency combined with a tendency toward subjectively improved mood.

The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder

“…A contributing factor to these risks for suvorexant is its long half-life (about 12 h). In contrast, such risks appear to be mitigated with the relatively short half-life (2–3 h) of seltorexant and the absence of cataplexy as observed in the current study and in literature 40 . Overall, treatment with seltorexant showed antidepressant effects on core depressive symptoms as well as a trend towards improving patients’ self-reported sleep experience.…”

“…In healthy subjects, doses ranging from 10 to 80 mg were considered safe 39 . The 20 mg dose for seltorexant was selected based on the predicted OXR2 occupancy, as well as the tolerability, and benefit/risk on sleep parameters established in previous studies 40–42 . From the phase I study program, it was clear that seltorexant at the dose used consistently induced sedation at a level that was expected to be approximated by diphenhydramine at a dose of 25 mg based on the summary of product characteristics.…”

“…Seltorexant is CNS penetrant and demonstrates high in vitro affinity (pKi = 8.0) for the human OX2R with a 2 logs selectivity ratio versus the human OX1R 39 , making it a suitable candidate drug to specifically antagonize OX2R. Seltorexant was shown to improve sleep in patients with major depressive disorder (MDD) suffering from comorbid insomnia 40 . The selective histamine-1 receptor (H1R) diphenhydramine, was applied as a negative control because of its sedative properties and demonstrated lack of known mood-enhancing effects.…”

Emotionale und depressive Störungen bei Kindern und Jugendlichen

“…Einerseits verschlimmern Schlafprobleme depressive Störungen, andererseits kann ihre Behandlung auch die Depression bessern. Hier laufen im Erwachsenenalter Studien zu medikamentösen Interventionen, die gegebenenfalls in der Zukunft auch Ergebnisse für Jugendliche erwarten lassen [35]. Auch der Einsatz spezifischer Ernährungszusätze wird immer wieder diskutiert, dazu gehören z.…”

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

“…Intense research led to compounds currently investigated in late stage clinical trials for the treatment of insomnia, e. g. lemborexant ( 2 ) from Eisai or daridorexant ( 3 ) from Idorsia, both DORA's inhibiting orexin 1 and orexin 2 receptors (OX 1 R and OX 2 R, respectively). Seltorexant ( 4 ), a selective OX 2 R antagonist co‐developed by Janssen and Minerva Neurosciences is as well in clinical development for the treatment of insomnia . The therapeutic potential of selective OX 1 R antagonists is also investigated such as SB‐334867 ( 5 ) from GlaxoSmithKline, JNJ‐61393215 from Janssen, and ACT‐539313 from Idorsia.…”