• Maggie Fedgchin, Madhukar Trivedi, Ella J Daly, Rama Melkote, Rosanne Lane, Pilar Lim, Dawn Vitagliano, Pierre Blier, Maurizio Fava, Michael Liebowitz, Arun Ravindran, Raphael Gaillard, Hans Van Den Ameele, Sheldon Preskorn, Husseini Manji, David Hough, Wayne C Drevets, and Jaskaran B Singh.
• Janssen Research and Development, Department of Neuroscience, Titusville, New Jersey.
• Int. J. Neuropsychopharmacol. 2019 Oct 1; 22 (10): 616-630.

BackgroundAbout one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression.MethodsThis Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested.ResultsStatistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache.ConclusionsStatistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression.Trial RegistrationClinicalTrials.gov identifier: NCT02417064.© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.

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