Esketamine Nasal Spray Combined With an Oral Antidepressant for Relapse Prevention in Treatment-Resistant Depression: Results of a Double-Blind, Randomized Withdrawal, Multicenter Study (SUSTAIN-1)

Background: Numerous studies have demonstrated short-term efficacy of esketamine in treatment-resistant depression (TRD), whereas long-term antidepressant effects remain to be established.

Methods: This was a double-blind, randomized withdrawal, multicenter study (NCT02493868) of adults with TRD. After 16 weeks of treatment with esketamine nasal spray (56 or 84 mg) plus oral antidepressant, patients who achieved stable remission, and separately those who achieved stable response (without remission), were randomized 1:1 to esketamine plus the same antidepressant or to continue the same antidepressant but switch to placebo nasal spray. The primary efficacy endpoint – time-to-relapse in stable remitters – was assessed using a weighted-combination log-rank test.

Results: Among stable remitters, median time-to-relapse (95% CI) was not estimable (NE) for the esketamine+antidepressant group (50% relapse rate not reached based on Kaplan-Meier estimates) and 273.0 (97.0; NE) days for the antidepressant+placebo group. Twenty-four (26.7%) patients in the esketamine+antidepressant group and 39 (45.3%) patients in the antidepressant+placebo group relapsed (2-sided p=0.003, weighted-combination test). Treatment with esketamine+antidepressant decreased the risk of relapse by 51% compared to antidepressant+placebo among stable remitters: weighted estimate of hazard ratio (95% CI): 0.49 (0.29; 0.84). The most common adverse events reported for esketamine+antidepressant-treated patients during the maintenance phase were dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence 20.4–27.0%), each reported for <7% of antidepressant+placebo-treated patients.

Conclusions: This study demonstrated that continued treatment with esketamine nasal spray plus antidepressant leads to significant, clinically meaningful superiority compared to antidepressant alone for relapse prevention among patients with TRD and provides further safety data regarding longer-term treatment.