Randomized, Double-Blind Study of Fixed-Dose Esketamine Nasal Spray Plus Oral Antidepressant vs. Active Control in Treatment-Resistant Depression

Aim:  Compare efficacy and safety of fixed doses of esketamine nasal spray plus oral antidepressant (AD) to oral AD plus placebo nasal spray for treatment-resistant depression (TRD).

Methods:  Adults with moderate-to-severe depression and non-response to ≥2 ADs in the current depressive episode were randomized (1:1:1) to esketamine (56 mg or 84 mg) or placebo nasal spray plus a new AD. The primary efficacy endpoint was change from baseline to Day 28 in MADRS total score, assessed by a mixed-effects model for repeated measures.

Results: 315 (of 346) randomized patients completed the treatment phase. Primary endpoint results numerically favored both esketamine plus AD groups over AD plus placebo. Statistical superiority (between-group difference LS mean, [95% CI]) was not demonstrated with esketamine 84 mg plus AD compared to AD plus placebo (-3.2 [-6.88, 0.45]; 2-sided p-value=0.088), therefore esketamine 56 mg plus AD could not be formally evaluated (-4.1 [-7.67, -0.49]). The most common adverse events reported for esketamine-treated patients were nausea, dissociation, dizziness, vertigo, and headache.  Most adverse events occurred on nasal spray dosing days, were mild or moderate in severity, and resolved the same day. 

Conclusion: Esketamine 84 mg plus oral AD demonstrated clinically meaningful treatment benefit in adults with TRD compared to a new oral AD plus placebo nasal spray, but did not reach statistical significance. The difference in LS means between both esketamine plus AD groups compared to oral AD plus placebo was larger than the mean difference of 2 points seen with approved ADs when compared to placebo.