This double-blind, randomized, placebo-controlled study (N=126) was conducted at multiple sites between January 2014 and September 2015. The sample included patients with DSM-IV-TR diagnosis of MDD with inadequate response to 2 or more antidepressants. The study consisted of 4 phases. (1) screening, (2) double-blind treatment (days 1-15), (3) optional open-label treatment (days 15-74), and (4) posttreatment follow up (8 weeks). 67 patients were randomized and 60 completed the study. The participants were randomized (3:1:1:1) to placebo (n=33), esketamine 28 mg (N=11), 56 mg (N=11), or 84 mg (N=12) twice weekly in period 1. In the 2nd period, 28 placebo-treated participants with moderate to severe symptoms were rerandomized (1:1:1:1) to one of the 4 treatment arms; those with mild symptoms continued receiving placebo. The participants continued their antidepressant medication during the study. The primary efficacy endpoint was change from baseline in the Montgomery-Asberg Depression rating scale (MADRS) total score.