Long-Term Safety and Maintenance of Response With Esketamine Nasal Spray in Participants With Treatment-Resistant Depression: Interim Results of the SUSTAIN-3 Study.
Naim Zaki, Li Nancy Chen, Rosanne Lane, Teodora Doherty, Wayne C. Drevets, Randall L. Morrison, Gerard Sanacora, Samuel T. Wilkinson, Vanina Popova, Dong-Jing Fu
Focus (American Psychiatric Publishing) April 1, 2026 DOI: 10.1176/appi.focus.26024111 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Open-label, long-term extension study Peer reviewed |
|---|---|
| Sample size | 1,148 |
| Population | Adults with treatment-resistant depression who completed a phase 3 parent study |
| Interventions | Intranasal esketamine oral antidepressant |
| Duration | Up to 4.5 years |
| Topics | Depression Esketamine |
| Key points | Long-term esketamine treatment maintained improvements in depression ratings with no new safety signal over up to 4.5 years. |
Abstract
Patients with treatment-resistant depression (TRD) have higher rates of relapse and pronounced decreases in daily functioning and health-related quality of life compared to patients with major depressive disorder who are not treatment-resistant, underscoring the need for treatment choices with sustained efficacy and long-term tolerability. Adults with TRD who participated in ≥1 of 6 phase 3 "parent" studies could continue esketamine treatment, combined with an oral antidepressant, by enrolling in phase 3, open-label, long-term extension study, SUSTAIN-3. Based on their status at parent-study end, eligible participants entered a 4-week induction phase followed by an optimization/maintenance phase, or directly entered the optimization/maintenance phase of SUSTAIN-3. Intranasal esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance. At the interim data cutoff (01 December 2020), 1148 participants were enrolled, 458 at induction and 690 at optimization/maintenance. Mean (median) cumulative duration of maintenance esketamine treatment was 31.5 (37.7) months (totaling 2769 cumulative patient-years). Common treatment-emergent adverse events (≥20%) were headache, dizziness, nausea, dissociation, somnolence, and nasopharyngitis. Mean Montgomery-Åsberg Depression Rating Scale (MADRS) total score decreased during induction, and this reduction persisted during optimization/maintenance (mean [SD] change from the baseline to the endpoint of each phase: induction -12.8 [9.73]; optimization/maintenance +1.1 [9.93]), with 35.6% and 46.1% of participants in remission (MADRS total score ≤12) at induction and optimization/maintenance endpoints, respectively. Improvement in depression ratings generally persisted among participants who remained in maintenance treatment, and no new safety signal was identified during long-term treatment (up to 4.5 years) using intermittent-dosed esketamine in conjunction with daily antidepressant. Appeared originally in Neuropsychopharmacology 2023; 48: 1225-1233.
Comparable studies
Other non-randomized and open-label trials on esketamine for depression, most cited first.