Daly EJ, Trivedi MH, Janik A, et al. - Given a short-term efficacy of esketamine for treatment-resistant depression (TRD), researchers here focussed on the long-term effects of esketamine nasal spray in these patients. In this phase 3, multicenter, double-blind, randomized withdrawal study, 705 adults TRD were enrolled. Of these, 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. Following 16 weeks of esketamine treatment, stable remission or stable response was achieved in 297, which then entered the randomized withdrawal phase. These 297 patients were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. Observations revealed significantly delayed time to relapse among patients who continued treatment with intermittently administered esketamine nasal spray plus an oral antidepressant vs those treated with oral antidepressant plus placebo nasal spray after 16 weeks of initial treatment with esketamine and an antidepressant. These findings support the efficacy of continued treatment with esketamine nasal spray plus an antidepressant in sustaining antidepressant effects among patients with TRD to a greater extent compared with an oral antidepressant alone.