Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study
This article has been corrected.
VIEW CORRECTIONPublication: American Journal of Psychiatry
Abstract
Objective:
About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray.
Methods:
This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures.
Results:
Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=−4.0, SE=1.69, 95% CI=−7.31, −0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.
Conclusions:
Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.
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Received: 15 February 2019
Revision received: 13 March 2019
Accepted: 28 March 2019
Published online: 21 May 2019
Published in print: June 01, 2019
Corrected: 11 July 2019
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Supported by Janssen Research and Development, Titusville, N.J.Dr. Popova, Dr. Daly, Ms. Cooper, Ms. Lane, Dr. Lim, Ms. Mazzucco, Dr. Hough, Dr. Manji, Dr. Drevets, and Dr. Singh are employees of Janssen Research and Development and hold company equity. Dr. Trivedi has consulted for or served on advisory boards of AcademyHealth, Acadia Pharmaceuticals, Akili Interactive, Alkermes, Allergan Pharmaceuticals, Avanir Pharmaceuticals, Axsome Therapeutics, Boehringer Ingelheim, Brintellix Global, Bristol-Myers Squibb, Caudex, Cerecor, Forest Pharmaceuticals, Global Medical Education, Health Research Associates, Insys, Janssen Pharmaceutical, Jazz Pharmaceutical, Johnson & Johnson Pharmaceutical Research and Development, Lilly Research Laboratories, Lundbeck Research USA, Medscape, Merck, Mitsubishi Pharma, MSI Methylation Sciences, Navitor, One Carbon Therapeutics, Otsuka America Pharmaceutical, Oxford Pharmagenesis, Pamlab, Pfizer, Sage Therapeutics, and Takeda Global Research; he has received royalties from Janssen Research and Development; he has received research support from the Agency for Healthcare Research and Quality, the Cancer Prevention and Research Institute of Texas, Janssen Research and Development, Johnson & Johnson, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, NIDA, NIMH, and the Patient-Centered Outcomes Research Institute; he has author agreements from Janssen Asia Pacific and Oxford University Press; and he has received editorial compensation from Engage Health Media, Healthcare Global Village, and Oxford University Press. Dr. Thase has served as a consultant or independent contractor to Acadia, Akili, Alkermes, Allergan (Forest, Naurex), AstraZeneca, Axsome, Cerecor, Eli Lilly, Fabre-Kramer, Gerson Lehrman Group, Guidepoint Global, Lundbeck, Johnson & Johnson, MedAvante, Merck, Moksha8, Nestlé (Pamlab), Neuralstem, Novartis, Otsuka, Pfizer, Shire, Sage, Sunovion, and Takeda; he has received grant or research support from Acadia, the Agency for Healthcare Research and Quality, Alkermes, Allergan (Forest), AssureRx Health, Avanir, Axsome, Intracellular, Janssen Pharmaceuticals, Johnson & Johnson (including for the present study), NIMH, Otsuka, the Patient-Centered Outcomes Research Institute, and Takeda; he has received royalties from the American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton & Company; his spouse is employed by Peloton Advantage, which does business with a number of pharmaceutical companies. Dr. Shelton has served as a consultant to Acadia Pharmaceuticals, Allergan, Cerecor, Janssen Pharmaceutica, MSI Methylation Sciences, Naurex, and Takeda Pharmaceuticals; he has received grant support from Acadia Pharmaceuticals, the Agency for Healthcare Research and Quality, Alkermes, Allergan, Avanir Pharmaceuticals, Cerecor, Genomind, Intracellular Therapies, Janssen Pharmaceutica, Myriad Genetics, Navitor Pharmaceuticals, NeuroRx, NIMH, Novartis, Otsuka Pharmaceuticals, the Patient-Centered Outcomes Research Institute, Sage Therapeutics, and Takeda Pharmaceuticals. Dr. Molero is supported by Clínica Universidad de Navarra and has received research grants from the Ministry of Education (Spain), the Government of Navarra (Spain), the Spanish Foundation of Psychiatry and Mental Health, and AstraZeneca; he is a clinical consultant for MedAvante-ProPhase and has received lecture honoraria from or has been a consultant for AB-Biotics, Janssen, Novumed, Roland Berger, and Scienta. Dr. Vieta has received grants from and/or served as consultant, adviser, or CME speaker for AB-Biotics, Allergan, Angelini, AstraZeneca, the Brain and Behavior Foundation, Bristol-Myers Squibb, Dainippon Sumitomo, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, the Generalitat de Catalunya (2014 SGR 398), GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sage, Sanofi-Aventis, Servier, the Seventh European Framework Programme (ENBREC), Shire, the Spanish Ministry of Science and Innovation, the Stanley Medical Research Institute, Sunovion, and Takeda. Dr. Bajbouj has received research grants from the Deutsche Forschungsgemeinschaft, the German Federal Ministry for Education and Research, and the Germany Ministry of Health; he has served as a consultant on or advisory boards for Parexel, Janssen, and Johnson & Johnson; and he has received lecture support from Servier. Dr. Manji is named on a patent, which is assigned to Icahn School of Medicine at Mount Sinai, Yale University, and NIH; no financial benefit was received from this patent.
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