• Ella J Daly, Madhukar H Trivedi, Adam Janik, Honglan Li, Yun Zhang, Xiang Li, Rosanne Lane, Pilar Lim, Anna R Duca, David Hough, Michael E Thase, John Zajecka, Andrew Winokur, Ilona Divacka, Andrea Fagiolini, Wieslaw J Cubala, István Bitter, Pierre Blier, Richard C Shelton, Patricio Molero, Husseini Manji, Wayne C Drevets, and Jaskaran B Singh.
• Department of Neuroscience, Janssen Research and Development LLC, Titusville, New Jersey.
• JAMA Psychiatry. 2019 Sep 1; 76 (9): 893-903.

ImportanceControlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.ObjectiveTo assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.Design, Setting, And ParticipantsIn this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.InterventionsPatients who achieved stable remission and those who achieved stable response (without remission) 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.Main Outcomes And MeasuresTime to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.ResultsAmong the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.Conclusions And RelevanceFor patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.Trial RegistrationClinicalTrials.gov identifier: NCT02493868.

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