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Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant DepressionA Randomized Clinical Trial

Educational Objective
To 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 treatment-resistant depression in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.
1 Credit CME
Key Points

Question  What are the long-term effects of esketamine nasal spray in patients with treatment-resistant depression?

Findings  Of the 297 adults with treatment-resistant depression who were randomized in the maintenance phase of this clinical trial, those who continued treatment with intermittently administered esketamine nasal spray plus an oral antidepressant had a significantly delayed time to relapse vs those treated with oral antidepressant plus placebo nasal spray after 16 weeks of initial treatment with esketamine and an antidepressant.

Meaning  Continued treatment with esketamine nasal spray plus an antidepressant can sustain antidepressant effects among patients with treatment-resistant depression to a greater extent than an oral antidepressant alone.

Abstract

Importance  Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.

Objective  To 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 Participants  In 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.

Interventions  Patients 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 Measures  Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.

Results  Among 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 Relevance  For 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 Registration  ClinicalTrials.gov identifier: NCT02493868

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Article Information

Accepted for Publication: March 25, 2019.

Published Online: June 5, 2019. doi:10.1001/jamapsychiatry.2019.1189

Open Access: This article is published under the JN-OA license and is free to read on the day of publication.

Corresponding Author: Ella J. Daly, MD, Department of Neuroscience, Janssen Research and Development LLC, 1125 Trenton-Harbourton Rd, Titusville, NJ 08560 (edaly2@its.jnj.com).

Author Contributions: Drs Drevets and Singh contributed equally to the work as senior authors. Dr Daly had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Daly, Trivedi, Janik, Lane, Lim, Duca, Hough, Thase, Shelton, Manji, Drevets, Singh.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Daly, X. Li, Lane, Lim, Duca, Hough, Thase, Zajecka, Manji, Singh.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Zhang, X. Li, Lane, Lim.

Obtained funding: Hough, Divacka, Drevets.

Administrative, technical, or material support: H. Li, Zajecka, Bitter, Shelton, Molero.

Supervision: Daly, Janik, Hough, Thase, Blier, Manji, Drevets, Singh.

Conflict of Interest Disclosures: Drs Daly, Janik, H. Li, Zhang, X. Li, Lim, Hough, Manji, Drevets, and Singh and Mss Lane and Duca are employees of Janssen Research & Development LLC and hold company equity. Dr Manji reports holding a patent, which is assigned to Icahn School of Medicine at Mount Sinai, Yale University, and the National Institutes of Health; no financial benefit was received from this patent. Dr Trivedi reports consulting for or serving on the advisory board of Alkeremes Inc, Akili Interactive, Allergan Pharmaceuticals, Arcadia Pharmaceuticals, Avanir Pharmaceuticals, Brintellix Global, Bristol Myers Squibb, Caudex, Cerecor, Forest Pharmaceuticals, Global Medical Education Inc, Health Research Associates, Insys, Johnson & Johnson Pharmaceutical Research & Development, Lilly Research Laboratories, Lundbeck Research USA, Medscape, Merck & Co Inc, Mitsubishi Pharma, MSI Methylation Sciences–Pamlab Inc, Navitor, Otsuka America Pharmaceutical Inc, One Carbon Therapeutics, Otsuka America Pharmaceutical Inc, Pfizer Inc, and Takeda Global Research; receiving royalties from Janssen Research and Development LLC; having author agreements with Janssen Asia Pacific and the Oxford University Press; and receiving grants from the Agency for Healthcare Research and Quality, the Cancer Prevention and Research Institute of Texas, the National Institute of Mental Health, National Institute of Drug Abuse, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Advancing Translational Sciences, Johnson & Johnson, and the Patient-Centered Outcomes Research Institute (PCORI). Dr Thase reports serving as an advisor or consultant for Acadia, Akilii, Alkermes, Allergan (Forest, Naurex), AstraZeneca, Axome, Cerecor, Eli Lilly and Company, Fabre-Kramer, Gerson Lehrman Group, Guidepoint Global, Johnson & Johnson, Janssen, Lundbeck, MedAvante, Merck & Co, moksha8, Nestlé (PamLab), Novartis, Otsuka, Pfizer, Shire, Sunovion, and Takeda; receiving grant support from Acadia, the Agency for Healthcare Research and Quality, Alkermes, Allergan (Forest), Avanir, Axome, Intracellular, Janssen, the National Institute of Mental Health, Otsuka, PCORI, and Takeda; and receiving royalties from American Psychiatric Press, Guilford Publications, Herald House, and W.W. Norton & Company Inc. Dr Zajecka reports consulting for or serving on the advisory board of Avanir (Depression Data Safety Monitoring Board), Alkermes, ElMindA, Forest, Naurex, Lundbeck, PamLab/Nestle, Shire, and Takeda and receiving grant or research support from Actavis, Alkermes, Allergan, AstraZeneca, Axesome, Cyberonics, ElMindA, Forest, the Cheryl T. Herman Foundation, Hoffman-LaRoche, Janssen, Johnson & Johnson, Lundbeck, Naurex, Neuralstem, Otsuka, the National Institutes of Health, Shire, Taisho, and Takeda. Dr Divacka reports receiving research grants from Axovant, Lundbeck, Servier, and Janssen. Dr Fagiolini reports serving as a consultant and/or a speaker and/or has received research grants from Allergan, Angelini, Generici DOC, Lundbeck, Italfarmaco, Janssen, Mylan, Otsuka, Pfizer, Recordati, Roche, and Sanofi Aventis. Dr Cubała reports serving as a consultant and/or receiving research grants from Alkermes, Allergan, Auspex Pharmaceuticals, Biogen, BMS, Cephalon, Ferrier, Forest Laboratories, GedeonRichter, GW Pharmaceuticals, Janssen, KCR, Eli Lilly and Company, Lundbeck, Minerva, the National Institutes of Health, NeuroCog, Orion, Otsuka, Sanofi, and Servier and serving as a consultant for GW Pharmaceuticals, Janssen, KCR, Quintiles, Roche, and Sanofi. Dr Bitter reports serving as a consultant to and/or speaker for Angelini, Gedeon Richter, Janssen/Janssen-Cilag, Eli Lilly and Company, Lundbeck, Pierre Fabre, and Servier. Dr Blier reports serving a consultant and/or receiving research grants from Allergan, Bristol Myers Squibb, Janssen, Lundbeck, Meda-Valeant, Otsuka, Pfizer, Pierre Fabre Médicaments, Sunovion, and Takeda. Dr Shelton reports serving as a consultant to Acadia Pharmaceuticals, Allergan Inc, Cerecor Inc, Clintara LLC, Janssen Pharmaceutica, Lundbeck A/S, Medtronic Inc, MSI Methylation Sciences Inc, Naurex Inc, Nestle’ Health, Pfizer Inc, and Takeda Pharmaceuticals and receiving grant support from Acadia Pharmaceuticals, Alkermes Inc, Allergan Inc, Assurex Health, Avanir Pharmaceuticals, Cerecor Inc, Genomind, Intracellular Therapies, Janssen Pharmaceutica, Otsuka Pharmaceuticals, Nestle’ Health, Novartis Inc, and Takeda Pharmaceuticals. Dr Molero reports receiving research grants from the Ministry of Education (Spain), the Government of Navarra (Spain), the Spanish Foundation of Psychiatry and Mental Health, and AstraZeneca; serving as a clinical consultant for MedAvante-ProPhase; and has receiving lecture honoraria from and/or consulting for Scienta, AB-Biotics, Novumed, and Janssen. Dr Winokur reported serving as a consultant to Alkermes and to Janssen. No other disclosures were reported.

Funding/Support: This study was funded by Janssen Research & Development LLC.

Role of the Funder/Sponsor: Employees of Janssen Research & Development LLC were involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentations: This study was presented at the American Society of Clinical Psychopharmacology 2018 Annual Meeting; May 30, 2018; Miami, Florida; 31st European College of Neuropsychopharmacology Congress; October 7, 2018; Barcelona, Spain; US Psych Congress; October 26, 2018; Orlando, Florida; and the German Association for Psychiatry, Psychotherapy and Psychosomatics e.V. 2018 Congress; November 30, 2018; Berlin, Germany.

Data Sharing Statement: See Supplement 3.

Additional Contributions: The following investigators participated in the study: Belgium: Geert De Bruecker, Sven Estercam, Stefaan Geerts, and Hans van den Ameele; Brazil: Rodolfo Campos, Norton Sateg Castro, Gerardo de Araujo Filho, Clarissa Gama, Hamilton Grabowski, Jacson Hubner, Acioly Lacerda, Ricardo Moreno, Gustavo Ottoni, Cintia Perico, Fabio Lopes Rocha, Sandra Ruschel, and Fabio Souza; Canada: Pierre Blier and Arun Ravindran; Czech Republic: Martin Anders, Ilona Divacka, Erik Herman, Marta Holanova, Lubos Janu, Bronislav Kobeda, Oto Markovic, Alexander Nawka, Simona Papezova, Dita Protopopova, and Zdenek Solle; Estonia: Anu Arold; France: Mocrane Abbar, Helene Denizot, Philippe Desbonnet, Raphael Gaillard, and Nemat Jaafari, Germany: Malek Bajbouj, Ralf Bodenschatz, Nadine Dreimüller, and Jana Thomsen; Hungary: István Bitter, László Csekey, Sándor Fekete, Gábor Feller, Ede Frecska, Janos Kalman, Agnes Kertesz, Zsuzsanna Kiss, Tamas Kurimay, Zoltan Makkos, Erzsebet Payer, and Gyorgy Szekeres; Italy: Eugenio Aguglia, Andrea Fagiolini, Giuseppe Maina, and Gabriele Sani; Mexico: Gabriel Alejo, Mario Caceres, Vicente Escaname, Erasmo Saucedo, Juan Luis Vazquez, and Sergio Villasenor; Poland: Hanna Badzio-Jagiello, Agnieszka Bijakowska, Wiesław J. Cubała, Marek Domanski, Mieczyslaw Janiszewski, Ireneusz Kaczorowski, Bartosz Loza, Dariusz Malicki, Tomasz Markowski, Mariusz Perucki, Agata Szulc, Napoleon Waszkiewicz, Adam Wichniak, and Marcin Wojnar; Slovakia: Zuzana Janikova, Abdul Shinwari, and Livia Vavrusova; Spain: Patricio Molero, Francisco Montańes, Angel Luis Montejo, Diego Jose Palao, Jose Maria Pelayo, Josep Antoni Ramos, Salvador Ros, Joan Salva, Pedro Manual Sanchez, and Eduard Vieta; Sweden: Peter Bosson, Anders Luts, Maria Markevind, and Miranda Michaneck; Turkey: Cengiz Akkaya, Umut Mert Aksoy, Sibel Cakir, Serdar Suleyman Can, Sel Demet, Nesrin Dilbaz, Mehmet Cagdas Eker, Atila Erol, Huseyin Gulec, Oguz Karamustafalioglu, Elvan Ozalp, Meram Can Saka, Lut Tamam, Halil Ibrahim Tas, Brahim Taymur, and Tuba Yilman; United States: Alabama: Richard Shelton; Arkansas: Paul Wylie; California: Jason Bermak, Jesse Carr, Daniel Chueh, Corinna Gamez, Vishaal Mehra, Michael Plopper, and David Walling; Connecticut: Andrew Winokur; Florida: Morteza Nadjafi, Sonia Rente, Elias Sarkis, Kelley Yokum, and Jose Zaglul; Georgia: Robert Riesenberg; Illinois: Angelos Halaris, Andrew Kim, Mark Lerman, Cosme Lozano, Brett Plyler, Jeffrey Ross, John Sonnenberg, and John Zajecka; Kansas: Matthew Macaluso and Mikel Thomas; Louisiana: Kashinath Yadalam; Maryland: Alan Jonas, Adam Kaplin, and Robert Litman; Massachusetts: Gregory Labun, Irina Mezhebovsky, Mohammed Munir, Anthony Rothschild, Daniel Rutrick, and James Whalen; Michigan: Joel Young; Missouri: Howard Ilivicky; New York: Michael Liebowitz and Matthew Milak; North Carolina: James Barker; Oklahoma: Courtney Nixon; Pennsylvania: Sanjay Chandragiri, Shivkumar Hatti, and Michael Thase; Rhode Isalnd: Linda Carpenter; Texas: Rayan Al Jurdi, Michael Downing, Andrew Klymiuk, Divyansu Patel, Asim Shah, and Madhukar Trivedi; Virginia: Anita Clayton; Wisconsin: Cary Kohlenberg. Sandra Norris, PharmD, Norris Communications Group LLC, supported by Janssen Research and Development LLC, provided medical writing assistance. Ellen Baum, PhD, Janssen Global Services LLC, provided additional editorial support and was not compensated. Dr Norris was compensated for her work. Dr Baum is an employee of Janssen. We thank the study patients for their participation in this study.

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