Safety and Efficacy with Esketamine in Treatment-Resistant Depression: Long-Term Extension Study
In the phase 3 SUSTAIN-3 long-term extension (1,148 patients, 3,777 patient‑years), intermittent intranasal esketamine plus an oral antidepressant showed no new safety signals and an adverse event profile consistent with earlier studies. Depression severity improved during induction and was generally maintained during optimisation/maintenance, with remission in 35.6% at induction and about 48–50% at week 112/maintenance endpoint.
Authors
- Gerard Sanacora
- Allan Young
- Daniel Fu
Published
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.
Research Summary of 'Safety and Efficacy with Esketamine in Treatment-Resistant Depression: Long-Term Extension Study'
Introduction
Treatment-resistant depression (TRD) is associated with markedly elevated rates of relapse, disability, and suicide risk relative to non-treatment-resistant major depressive disorder. Even among patients with TRD who achieve an initial response to standard antidepressants, approximately 70% relapse within six months, and longer periods of inadequate treatment are associated with progressively worsening prognosis. The unmet need for treatments providing sustained efficacy in TRD has long been recognised. Esketamine nasal spray — the S-enantiomer of ketamine — demonstrated rapid antidepressant effects in short-term trials and received regulatory approval for TRD, but long-term safety and maintenance efficacy data were required to inform sustained clinical use. The SUSTAIN-3 study aimed to evaluate the long-term safety and efficacy of esketamine nasal spray combined with an oral antidepressant in adults with TRD over an extended treatment period, encompassing both an induction phase and a prolonged optimisation and maintenance phase.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Zaki, N., Chen, L. (., Lane, R., Doherty, T., Drevets, W. C., Morrison, R. L., Sanacora, G., Wilkinson, S. T., Young, A. H., Lacerda, A. L. T., Paik, J., Popova, V., & Fu, D. (2025). Safety and Efficacy with Esketamine in Treatment-Resistant Depression: Long-Term Extension Study. International Journal of Neuropsychopharmacology, 28(6). https://doi.org/10.1093/ijnp/pyaf027
References (1)
Papers cited by this study that are also in Blossom
Martinotti, G., Vita, A., Fagiolini, A. et al. · Journal of Affective Disorders (2022)
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Mallevays, M., Fuet, L., Danon, M. et al. · MedRvix (2026)
Samalin, L., Rothärmel, M., Mekaoui, L. et al. · Journal of Psychiatric Research (2026)
Reif, A., Anıl, Y. A., Bitter, I. et al. · European Neuropsychopharmacology (2026)
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