Safety and efficacy with esketamine in treatment-resistant depression: long-term extension study
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Importance
The rates of relapse and suicide risk are higher in treatment-resistant depression (TRD) vs non-treatment-resistant major depressive disorder. Even among patients with TRD who initially respond, the majority (70%) relapse within 6 months.
Objective
To evaluate the long-term safety and efficacy of esketamine nasal spray, combined with an oral antidepressant, in patients with TRD.
Design
Phase 3, open-label, single-arm long-term extension study (SUSTAIN-3) conducted from June 2016 to December 2022.
Setting
Outpatient.
Participants
Adults with TRD who participated in ≥1 of 6 phase 3 “parent” studies continued esketamine by either entering a 4-week induction phase followed by an optimization/maintenance phase of variable duration (n = 458) or directly entering the optimization/maintenance phase of SUSTAIN-3 (n = 690), based on their individual response to study drug at the endpoint of the parent study.
Interventions
Intranasal esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance (weekly, every-other-week, or every-4-weeks), under direct supervision by site staff.
Main Outcomes and Measures
To assess the long-term safety of esketamine. Efficacy endpoints included the change in depressive symptoms, assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).
Results
A total of 1148 patients were enrolled. Total exposure to esketamine was 3777 cumulative patient-years. Mean (median, range) exposure to esketamine in SUSTAIN-3 was 42.9 (45.8, range 0-79) months. The most common adverse events were headache (36.9%), dizziness (33.9%), nausea (33.6%), dissociation (25.5%), nasopharyngitis (23.8%), somnolence (23.1%), dysgeusia (20.2%), and back pain (20.0%). During the study, 5.3% and 6.4% of participants discontinued due to lack of efficacy or adverse event, respectively. Nine participants died: COVID-19-related (n = 3), pneumonia (n = 2), and completed suicide, myocardial infarction, multiple injuries, unknown cause (n = 1 each). The mean MADRS total score decreased during induction, and this reduction persisted during optimization/maintenance (mean [SD] change from baseline-to-phase endpoint of each phase: induction: −12.8 [9.73]; optimization/maintenance: + 0.2 [9.93]). A total of 35.6% of participants were in remission at the induction endpoint, and 48.5% and 49.6% at week 112 and optimization/maintenance endpoint, respectively.
Conclusions and Relevance
In the SUSTAIN-3 final dataset, no new safety signals were identified during long-term treatment with intermittently-dosed esketamine, combined with oral antidepressant, and improvement in depression generally persisted among participants who remained on maintenance treatment. These results add to the accumulated evidence on TRD treatment with esketamine.
Trial Registration
clinicaltrials.gov identifier: NCT02782104.
The rates of relapse and suicide risk are higher in treatment-resistant depression (TRD) vs non-treatment-resistant major depressive disorder. Even among patients with TRD who initially respond, the majority (70%) relapse within 6 months.
Objective
To evaluate the long-term safety and efficacy of esketamine nasal spray, combined with an oral antidepressant, in patients with TRD.
Design
Phase 3, open-label, single-arm long-term extension study (SUSTAIN-3) conducted from June 2016 to December 2022.
Setting
Outpatient.
Participants
Adults with TRD who participated in ≥1 of 6 phase 3 “parent” studies continued esketamine by either entering a 4-week induction phase followed by an optimization/maintenance phase of variable duration (n = 458) or directly entering the optimization/maintenance phase of SUSTAIN-3 (n = 690), based on their individual response to study drug at the endpoint of the parent study.
Interventions
Intranasal esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance (weekly, every-other-week, or every-4-weeks), under direct supervision by site staff.
Main Outcomes and Measures
To assess the long-term safety of esketamine. Efficacy endpoints included the change in depressive symptoms, assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).
Results
A total of 1148 patients were enrolled. Total exposure to esketamine was 3777 cumulative patient-years. Mean (median, range) exposure to esketamine in SUSTAIN-3 was 42.9 (45.8, range 0-79) months. The most common adverse events were headache (36.9%), dizziness (33.9%), nausea (33.6%), dissociation (25.5%), nasopharyngitis (23.8%), somnolence (23.1%), dysgeusia (20.2%), and back pain (20.0%). During the study, 5.3% and 6.4% of participants discontinued due to lack of efficacy or adverse event, respectively. Nine participants died: COVID-19-related (n = 3), pneumonia (n = 2), and completed suicide, myocardial infarction, multiple injuries, unknown cause (n = 1 each). The mean MADRS total score decreased during induction, and this reduction persisted during optimization/maintenance (mean [SD] change from baseline-to-phase endpoint of each phase: induction: −12.8 [9.73]; optimization/maintenance: + 0.2 [9.93]). A total of 35.6% of participants were in remission at the induction endpoint, and 48.5% and 49.6% at week 112 and optimization/maintenance endpoint, respectively.
Conclusions and Relevance
In the SUSTAIN-3 final dataset, no new safety signals were identified during long-term treatment with intermittently-dosed esketamine, combined with oral antidepressant, and improvement in depression generally persisted among participants who remained on maintenance treatment. These results add to the accumulated evidence on TRD treatment with esketamine.
Trial Registration
clinicaltrials.gov identifier: NCT02782104.
Date Issued
2025-06-01
Date Acceptance
2025-04-23
Citation
International Journal of Neuropsychopharmacology, 2025, 28 (6)
ISSN
1461-1457
Publisher
Oxford University Press (OUP)
Journal / Book Title
International Journal of Neuropsychopharmacology
Volume
28
Issue
6
Copyright Statement
© The Author(s) 2025. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Subjects
Humans
Ketamine
Antidepressive Agents
Treatment Outcome
Drug Therapy, Combination
Administration, Intranasal
Adult
Aged
Middle Aged
Female
Male
Nasal Sprays
Depressive Disorder, Treatment-Resistant
Outcome Assessment, Health Care
COVID-19
Publication Status
Published
Article Number
pyaf027
Date Publish Online
2025-05-04