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

Abstract

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.

Hypocretins (orexins): The ultimate translational neuropeptides

“…Seltorexant is being investigated in patients with MDD and co‐morbid insomnia [102, 103], in which it improved sleep and depressive symptoms over 28 days of dosing and enhanced NREM delta power, a feature not replicated by other hypnotics [103]. A Phase IIb study (NCT03227224) reported clinically relevant reductions in depressive symptoms in MDD patients with suboptimal responses to antidepressants with adjunct seltorexant, and more so, in patients with sleep disturbances [104]. Further clinical studies are ongoing as posted in clinicaltrials.gov (NCT04532749, NCT04533529).…”

“…A Phase IIb study (NCT03227224) reported clinically relevant reductions in depressive symptoms in MDD patients with suboptimal responses to antidepressants with adjunct seltorexant, and more so, in patients with sleep disturbances [104].…”

Investigational Drugs for the Treatment of Depression (Part 1): Monoaminergic, Orexinergic, GABA-Ergic, and Anti-Inflammatory Agents

“…In a phase IIb, randomized, placebo-controlled, adaptive dose-finding study, 287 patients with MDD who had an insufficient response to 1-3 SSRI/SNRI during the current episode were randomized to placebo or seltorexant (20 or 40 mg) as add-ons to the currently administered antidepressant ( Savitz et al, 2021 ). A significant reduction in depressive symptoms (MADRS scores) was observed for seltorexant (20 mg), and in the subset of patients with sleep disturbance, the difference between seltorexant 20 mg and placebo was larger ( Savitz et al, 2021 ).…”

“…TEAE, treatment-emergent adverse events; AE, adverse events; SAE, severe adverse events; EPS, extrapyramidal symptoms. Based on the data from Mi et al, 2021 ; Ball et al, 2015 ; Carhart-Harris et al, 2016 ; COMPASS, 2021 ; Citrome, 2019 ; Fava et al, 2018 ; Durgam et al, 2016 ; Fava et al, 2019 ; Loebel et al, 2022 ; Savitz et al, 2021 ; Kanes S. et al, 2017 ; Gunduz-Bruce et al, 2019 ; Deligiannidis et al, 2021 ; Dichtel et al, 2020 ; Tyring et al, 2006 ; Langley et al, 2010 ; Raison et al, 2013 ; Abbasi et al, 2012 .…”

What evidence is there for implicating the brain orexin system in neuropsychiatric symptoms in dementia?

“…For example, in trials with DORAs/SO2RAs for insomnia and depression (55,56) the drugs were administered at bedtime, and in a trial with SO1RA for binge eating disorder the drug was given during morning and evening meals (NCT04753164) (57). In the context of the possible use of OXR antagonists for the treatment of NPS in PwD, bedtime administration has the advantages of maximizing the drug's efficacy on nighttime problems and reducing the risk of daytime somnolence; however, little effect may be expected on disturbances that mostly manifest during the day [except those instances where amelioration of daytime symptoms is achieved through improved nighttime problems, as in the case of depression (56)]. Conversely, daytime dosing may have a greater impact on symptoms, which are expressed during the day, but (depending on the dose) it may be associated with a higher risk of somnolence.…”