Safety and efficacy with esketamine in treatment-resistant depression: long-term extension study.
Naim Zaki, Li Nancy Chen, Rosanne Lane, Teodora Doherty, Wayne C. Drevets, Randall L. Morrison, Gerard Sanacora, Samuel T. Wilkinson, Allan H. Young, Acioly L T Lacerda, Jong-Woo Paik, Vanina Popova, Dong-Jing Fu
The International Journal of Neuropsychopharmacology June 6, 2025 DOI: 10.1093/ijnp/pyaf027 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Open-label, single-arm long-term extension study Peer reviewed |
|---|---|
| Sample size | 1,148 |
| Population | Adults with treatment-resistant depression who participated in ≥1 of 6 phase 3 parent studies |
| Interventions | Esketamine nasal spray oral antidepressant |
| Dose | flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance (weekly, every-other-week, or every-4-weeks) |
| Duration | Mean 42.9 months (median 45.8, range 0-79 months) of esketamine exposure |
| Topics | Depression Esketamine |
| Keywords | Efficacy Long-term Safety Depression treatment Mental health therapy Esketamine medication Clinical research Treatment resistance |
| Citations | 32 |
| Registration | NCT02782104 |
| Key points | Long-term treatment with intermittently-dosed esketamine plus an oral antidepressant showed no new safety signals and depression improvement generally persisted among participants who remained on maintenance treatment. |
Abstract
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. To evaluate the long-term safety and efficacy of esketamine nasal spray, combined with an oral antidepressant, in patients with TRD. Phase 3, open-label, single-arm long-term extension study (SUSTAIN-3) conducted from June 2016 to December 2022. Outpatient. 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. 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. 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). 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. 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. clinicaltrials.gov identifier: NCT02782104.
Comparable studies
Other non-randomized and open-label trials on esketamine for depression, most cited first.
Citations in the library
Cited by 25
- The Effect of Ketamine on the Immune System in Patients with Treatment-Resistant Depression International Journal of Molecular Sciences August 1, 2025
- Rapid antidepressant potential of nitrous oxide: current state and major questions. Molecular Psychiatry June 1, 2026
- Esketamine/Ketamine: Dual‐Action Mechanisms and Clinical Prospects beyond Anesthesia in Psychiatry, Immunology, and Oncology Advanced Science December 14, 2025
- Long-term treatment with esketamine nasal spray in patients with treatment resistant depression: Results from the ESCAPE-LTE study. European Neuropsychopharmacology June 1, 2026
- Long-term effectiveness and side-effects of intranasal esketamine in treatment-resistant depression: real-world, single-arm study of over 100 sessions. BJPsych Open January 23, 2026
and 20 more in the library
Cites 10
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
- Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression The Journal of Clinical Psychiatry April 20, 2020
and 5 more in the library