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

Recourt, Kasper; Boer, P. de; Zuiker, Rob; Luthringer, R.; Kent, Justine; Ark, Peter van der; Hove, Ilse Van; Gerven, Joop van; Jacobs, Gabriël; Nueten, Luc Van; Drevets, Wayne C.

doi:10.1038/s41398-019-0553-z

Cited by 48 publications

(42 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, some clinical studies have reported contradictory results of OxR2. Seltorexant (JNJ-42847922/MIN-202), an OxR2 antagonist, was reported to induce antidepressant effects in clinical patients ( Brooks et al, 2019 ; Recourt et al, 2019 ). It is noteworthy that patients enrolled in these clinical trials with MDD were likely to be very different from animal models of CSDS in terms of brain states and mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Mice treated with chronic mild stress (CMS) showed an increased percentage of Fos-positive orexinergic neurons in the PeF/LHA ( Nollet et al, 2011 ). Multiple reports have also emphasized the regulatory role of OxR2 in depressive-like behaviors in animals ( Arendt et al, 2014 ; Scott et al, 2011 ; Staton et al, 2018 ) and MDD in human trials ( Brooks et al, 2019 ; De Boer et al, 2018 ; Recourt et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lateral hypothalamus orexinergic inputs to lateral habenula modulate maladaptation after social defeat stress

Wang

Dong

et al. 2021

Neurobiology of Stress

View full text Add to dashboard Cite

Social stress, a common stressor, causes multiple forms of physical and mental dysfunction. Prolonged exposure to social stress is associated with a higher risk of psychological disorders, including anxiety disorders and major depressive disorder (MDD). The orexinergic system is involved in the regulation of multiple motivated behaviors. The current study examined the regulatory effect of orexinergic projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) in depression- and anxiety-like behaviors after chronic social defeat stress. When mice were defeated during social interaction, both orexinergic neurons in the LHA and glutamatergic neurons in the LHb were strongly activated, as indicated by the FosTRAP strategy. Infusion of orexin in the LHb significantly alleviated social avoidance and depression-like behaviors induced by chronic social defeat stress. Administration of an orexin receptor 2 antagonist in the LHb further aggravated the depressive phenotype. Photoactivation of orexinergic cell bodies in the LHA or terminals in the LHb relieved anxiety-like behaviors induced by chronic social defeat stress. Collectively, we identified the antidepressant and anxiolytic effects of the circuit from LHA orexinergic neurons to the LHb in response to chronic social stress, providing new evidence of the antidepressant properties of LHA orexin circuits.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lateral hypothalamus orexinergic inputs to lateral habenula modulate maladaptation after social defeat stress

Wang

Dong

et al. 2021

Neurobiology of Stress

View full text Add to dashboard Cite

show abstract

“… 147 , 148 Seltorexant (JNJ-42847922) is an OX2R antagonist currently in phase 3 clinical development for the treatment of insomnia and major depressive disorder. 149 A phase 2b active- and placebo-controlled study in adult and elderly subjects with insomnia disorder found that seltorexant at 5, 10 and 20 mg significantly improved LPS versus placebo. 150 Greater improvement in LPS was also seen with seltorexant 20 mg compared with zolpidem.…”

Section: Introductionmentioning

confidence: 99%

Advances in the Treatment of Chronic Insomnia: A Narrative Review of New Nonpharmacologic and Pharmacologic Therapies

Rosenberg¹,

Citrome²,

Drake³

2021

NDT

View full text Add to dashboard Cite

Chronic insomnia disorder, which affects 6–10% of the population, is diagnostically characterized by ongoing difficulties with initiating or maintaining sleep occurring at least three times per week, persisting for at least 3 months, and associated with daytime impairment. While chronic insomnia is often considered a condition primarily related to impaired sleep, the disorder can also adversely affect domains of physical and mental health, quality of life, and daytime function, which highlights the importance of treating the multidimensional sleep disorder. Owing to misperceptions about the safety and effectiveness of treatment options, many individuals with insomnia may not seek professional treatment, and alternatively use ineffective home remedies or over-the-counter medications to improve sleep. Some physicians may even believe that insomnia is remediated by simply having the patient “get more sleep”. Unfortunately, treatment of insomnia is not always that simple. The disorder’s complex underlying pathophysiology warrants consideration of different nonpharmacologic and pharmacologic treatment options. Indeed, recent insights gained from research into the pathophysiology of insomnia have facilitated development of newer treatment approaches with more efficacious outcomes. This narrative review provides a summary of the diagnostic criteria and pathophysiology of insomnia and its subtypes. Further, this review emphasizes new and emerging nonpharmacologic and pharmacologic treatments for chronic insomnia, including recent enhancements in approaches to cognitive behavioral therapy for insomnia (CBT-I) and the new dual orexin receptor antagonist (DORA) pharmacologics. These advances in treatment have expanded the treatment options and are likely to result in improved outcomes in patients with chronic insomnia.

show abstract

“…Seltorexant, a potent and highly selective antagonist of orexin-2 receptor, is being developed as a treatment for MDD due to its potential role in normalizing sleep ( Bonaventure et al, 2015 ). In exploratory clinical studies, seltorexant displayed antidepressant effects by improving core symptoms of depression in patients with MDD regardless of sleep impairment and improved sleep efficiency in patients with insomnia ( Brooks et al, 2019 ; Recourt et al, 2019 ). The present study investigated the antidepressant effects, safety, and tolerability of various doses of seltorexant as adjunctive therapy in patients with MDD who had experienced inadequate response to the current antidepressant therapy.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study

Savitz

Wajs

Zhang

et al. 2021

International Journal of Neuropsychopharmacology

View full text Add to dashboard Cite

Background Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD). Methods To replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1-3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant which the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160 th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40 mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index scores (ISI ≥15 vs ISI <15). Primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6. Results Mixed-Model for Repeated Measures (MMRM) analysis showed a greater improvement in MADRS total score in the seltorexant 20 mg group vs placebo at weeks 3 and 6; least-square means (LSM) difference (90% CI): -4.5 (-6.96;-2.07), p=0.003 and -3.1 (-6.13; -0.16), p=0.083, respectively. The improvement in MADRS score at week 6 for seltorexant 20 mg was greater in patients with baseline ISI ≥15 vs those with ISI <15; LSM difference (90% CI) vs placebo: -4.9 (-8.98;-0.80) and -0.7 (-5.16;3.76), respectively. The most common (≥5%) adverse events with seltorexant were somnolence, headache, and nausea. Conclusions A clinically meaningful reduction of depressive symptoms was observed for seltorexant 20 mg. In the subset of patients with sleep disturbance (ISI ≥15), a larger treatment difference between seltorexant 20 mg and placebo was observed, warranting further investigation. No new safety signal was identified.

show abstract

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

Cited by 48 publications

References 49 publications

Lateral hypothalamus orexinergic inputs to lateral habenula modulate maladaptation after social defeat stress

Lateral hypothalamus orexinergic inputs to lateral habenula modulate maladaptation after social defeat stress

Advances in the Treatment of Chronic Insomnia: A Narrative Review of New Nonpharmacologic and Pharmacologic Therapies

Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study

Contact Info

Product

Resources

About