Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study.
Adult
Aged
Antidepressive Agents
/ administration & dosage
Depressive Disorder, Major
/ drug therapy
Double-Blind Method
Drug Therapy, Combination
Female
Humans
Male
Middle Aged
Pyrimidines
/ administration & dosage
Pyrroles
/ administration & dosage
Treatment Outcome
Triazoles
/ administration & dosage
Adjunctive therapy
major depressive disorder
orexin-2
seltorexant
Journal
The international journal of neuropsychopharmacology
ISSN: 1469-5111
Titre abrégé: Int J Neuropsychopharmacol
Pays: England
ID NLM: 9815893
Informations de publication
Date de publication:
08 12 2021
08 12 2021
Historique:
received:
24
12
2020
revised:
04
06
2021
accepted:
27
07
2021
pubmed:
30
7
2021
medline:
16
3
2022
entrez:
29
7
2021
Statut:
ppublish
Résumé
Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD). 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 the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160th 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 (ISI) scores (ISI ≥ 15 vs < 15). The primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6. Mixed-Model for Repeated Measures 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 difference (90% CI): -4.5 (-6.96; -2.07), P = .003; and -3.1 (-6.13; -0.16), P = .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; least-square means 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. 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. ClinicalTrials.gov Identifier: NCT03227224. Poster presented at 58th Annual Meeting of American College of Neuropsychopharmacology (ACNP), December 8-11, 2019, Orlando, FL.
Sections du résumé
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 the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160th 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 (ISI) scores (ISI ≥ 15 vs < 15). The primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6.
RESULTS
Mixed-Model for Repeated Measures 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 difference (90% CI): -4.5 (-6.96; -2.07), P = .003; and -3.1 (-6.13; -0.16), P = .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; least-square means 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.
REGISTRATION
ClinicalTrials.gov Identifier: NCT03227224.
PREVIOUS PRESENTATION
Poster presented at 58th Annual Meeting of American College of Neuropsychopharmacology (ACNP), December 8-11, 2019, Orlando, FL.
Identifiants
pubmed: 34324636
pii: 6330263
doi: 10.1093/ijnp/pyab050
pmc: PMC8653874
doi:
Substances chimiques
Antidepressive Agents
0
Pyrimidines
0
Pyrroles
0
Triazoles
0
seltorexant
AIS8N3O50B
Banques de données
ClinicalTrials.gov
['NCT03227224']
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
965-976Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.
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