Clinical Summary: Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2)
Patients with treatment-resistant depression often need sustained symptom control, but long-term ketamine-class treatment raises practical concerns about blood pressure, dissociation, cognition, urinary toxicity, sedation, and misuse. This study gives clinicians up to 1 year of safety and maintenance data for esketamine nasal spray plus an oral antidepressant in a large treatment-resistant depression cohort.
Key Findings
- TEAEs were reported in 723/802 patients (90.1%); the most common were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%).
- Seventy-six patients (9.5%) discontinued esketamine due to TEAEs, and serious TEAEs were reported in 55/802 patients (6.9%).
- MADRS total score decreased during induction by mean [SD] −16.4 [8.76] (n = 756), and among responders who continued treatment the mean [SD] change from OP/MAINT baseline to endpoint was 0.3 [8.12].
- At the IND phase endpoint, 78.4% were responders and 47.2% were remitters (MADRS ≤ 12); at the OP/MAINT phase endpoint, 76.5% were responders and 58.2% were remitters.
- Mean blood pressure increases peaked at 40 minutes postdose, with the greatest mean (SD) change of 9.6 (11.99) mm Hg systolic and 5.6 (8.32) mm Hg diastolic in IND and 9.2 (11.30) mm Hg systolic and 5.9 (7.28) mm Hg diastolic in OP/MAINT; treatment-emergent acute hypertension occurred in 33/802 patients (4.1%), and 4 patients met discontinuation criteria due to elevated BP.
In treatment-resistant depression, long-term esketamine nasal spray plus an oral antidepressant had a manageable safety profile over up to 1 year, with depressive symptom gains maintained in patients who responded. The main monitoring priorities are transient postdose adverse effects and blood pressure elevations rather than progressive cognitive or bladder toxicity signals in this dataset.
Practice Implications
- Monitor patients closely on dosing days for dizziness, dissociation, nausea, headache, and sedation, as most esketamine-related TEAEs occurred shortly after administration and resolved the same day.
- Check blood pressure before and after dosing; acute hypertension occurred in 33/802 patients (4.1%), and 4 patients were withdrawn for elevated BP.
- Discuss urinary symptoms during maintenance treatment, but note that there was no case of interstitial/ulcerative cystitis and 5 adverse events of cystitis resolved while continuing esketamine treatment.
- For patients who respond, consider that less frequent maintenance dosing may be feasible: during OP/MAINT, 24.0% received weekly dosing, 38.1% were maintained on every-other-week dosing, and 37.8% switched more than once between schedules based on the algorithm.
