Efficacy and Safety of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression Who Completed a Second Induction Period: Analysis of the Ongoing SUSTAIN-3 Study
This subgroup analysis of SUSTAIN-3 (n=96) studies patients with treatment-resistant depression (TRD) who received a second induction and maintenance treatment with esketamine nasal spray (ESK) plus oral antidepressant (AD) after a relapse in SUSTAIN-1.
Authors
- Daniel Fu
- Scott Wilkinson
- Ibrahim Turkoz
Published
Abstract
Background
Treatment-resistant depression (TRD) is a chronic illness requiring long-term treatment. Esketamine nasal spray (ESK) has been studied in several long-term trials of patients with TRD, including SUSTAIN-1 (NCT02493868) and SUSTAIN-3 (NCT02782104). This subgroup analysis of SUSTAIN-3 evaluated patients with TRD who received a second induction (IND) and maintenance treatment with ESK plus oral antidepressant (AD) after a relapse in SUSTAIN-1.
Methods
Patients aged 18-64 years who achieved stable remission or response with ESK and subsequently relapsed after randomization to continue ESK or switch to placebo nasal spray (PBO) in SUSTAIN-1 and entered the IND phase of SUSTAIN-3 were included in this interim analysis. Response (≥50% improvement in total score from baseline for Montgomery-Åsberg Depression Rating Scale [MADRS] and Patient Health Questionnaire 9-item [PHQ-9]), remission (MADRS score ≤12; PHQ-9 total score <5), changes in depression rating scores (measured as mean change from baseline), and safety were evaluated (incidence of treatment-emergent and serious adverse events [AE]).
Results
Of the 96 eligible patients who entered IND in SUSTAIN-3, 32 (33.3%) were taking ESK+AD at the time of relapse in SUSTAIN-1 and 64 (66.7%) were taking AD+PBO. Substantial improvements in depressive symptoms were observed over the second IND phase in both groups and were maintained over the optimization/maintenance (OP/M) phase. MADRS response rates following a second IND were 71.9% and 73.4% for previously relapsed (PR) ESK+AD and PR-AD+PBO, respectively; remission rates were 62.5% and 60.9%, respectively. During the IND and OP/M phases, 58.3% and 83.3% of patients experienced a treatment-emergent AE, respectively. No patients discontinued due to an AE during the second IND.
Conclusions
Patients with TRD benefitted from receiving a second IND and maintenance treatment with ESK and no new safety signals were identified.
Research Summary of 'Efficacy and Safety of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression Who Completed a Second Induction Period: Analysis of the Ongoing SUSTAIN-3 Study'
Introduction
Women have about a twofold greater lifetime risk of major depressive disorder than men and often differ from men in clinical presentation, comorbidities, age at onset, episode duration, and treatment response. Previous studies have reported inconsistent sex differences in antidepressant efficacy and tolerability, and factors such as reproductive lifecycle stage, use of hormone therapy, neuronal circuitry, and drug metabolism have been proposed as contributors. Esketamine, the S-enantiomer of ketamine and an NMDA receptor antagonist, is approved in several jurisdictions for treatment-resistant depression (TRD) in conjunction with an oral antidepressant; its pivotal Phase 2 and Phase 3 trials provide a dataset suitable for secondary analyses of sex effects. Jones and colleagues undertook a post hoc analysis of three short-term Phase 3 trials (TRANSFORM-1, TRANSFORM-2, TRANSFORM-3) to assess whether efficacy and safety of esketamine nasal spray differ between women and men with TRD. The primary aims were to compare improvement in depressive symptoms, comorbid anxiety, and response and remission rates by sex; secondary aims focused on whether menopausal status or use of hormonal therapy among women influenced these outcomes and whether clinical factors distinguished responders from non-responders.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Castro, M., Wilkinson, S. T., Al Jurdi, R. K., Petrillo, M. P., Zaki, N., Borentain, S., Fu, D. J., Turkoz, I., Sun, L., Brown, B., & Cabrera, P. (2023). Efficacy and Safety of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression Who Completed a Second Induction Period: Analysis of the Ongoing SUSTAIN-3 Study. CNS Drugs, 37(8), 715-723. https://doi.org/10.1007/s40263-023-01026-3
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References (1)
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Chen, X., Hou, X., Bai, D. et al. · American Journal of Psychiatry (2019)
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Ammendolia, I., Mannucci, C., Esposito, E. et al. · Pharmaceuticals (2025)
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