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AJP CME: June 2019 - 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

Activity Type:

  • Journal CME

Release Date: 6/1/2019

Expiration Date: 5/31/2021

  • AMA PRA Category 1: 1
  • Participation: 1



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.


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Educational Objective

The participant will recognize the dosing regimen of esketamine nasal spray for induction of effect and pattern of the most common postdosing adverse events.

Target Audience

This program is designed for all psychiatrists in clinical practice, residents in Graduate Medical Education programs, medical students interested in psychiatry, and other physicians who wish to advance their current knowledge of clinical medicine.

Estimated Time to Complete

Duration: 1 hour
Begin Date: June 1, 2019
End Date: May 31, 2021

How to Earn Credit

In order to earn CME credit, subscribers should read through the material presented in the article. After reading the article, complete the quiz and submit your evaluation and study hours (up to 1 AMA PRA Category 1 Credit™).  A score of 60% or higher is required to receive credit.


The American Psychiatric Association (APA) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The APA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Faculty and Planner Disclosures

Title: 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

Authors: Vanina Popova, M.D., Ella J. Daly, M.D., Madhukar Trivedi, M.D., Kimberly Cooper, M.S., Rosanne Lane, M.A.S., Pilar Lim, Ph.D., Christine Mazzucco, M.Sc., David Hough, M.D., Michael E. Thase, M.D., Richard C. Shelton, M.D., Patricio Molero, M.D., Ph.D., Eduard Vieta, M.D., Ph.D., Malek Bajbouj, M.D., Husseini Manji, M.D., Wayne C. Drevets, M.D., Jaskaran B. Singh, M.D.

Affiliations: Janssen Research and Development, Beerse, Belgium (V.P.), Titusville, N.J. (E.J.D., R.L., P.L., D.H., H.M., W.C.D.), Spring House, Pa. (K.C.), and San Diego (J.B.S.); University of Texas Southwestern Medical Center, Dallas (M.T.); Janssen Inc. Canada, Toronto (C.M.); Perelman School of Medicine, University of Pennsylvania, Philadelphia (M.E.T.); University of Alabama School of Medicine, Birmingham (R.C.S.); Clinica Universidad de Navarra, Pamplona, Spain (P.M.); Institute of Neuroscience, University of Barcelona, Barcelona, Spain (E.V.); Charité Universitätsmedizin Berlin, Berlin (M.B.).

Disclosures: 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.

Discussion of unapproved or investigational use of products*: No.

*APA policy requires disclosure by CME authors of unapproved or investigational use of products discussed in CME programs. Off-label use of medications by individual physicians is permitted and common. Decisions about off-label use can be guided by scientific literature and clinical experience.

Program Planners

Ned H. Kalin, M.D. (Editor-in-Chief, AJP); Carolyn Rodriguez, M.D., Ph.D. (Deputy Editor, AJP); Michael D. Roy (Editorial Director, AJP); Michael A. Pogachar (Online Content Manager, Journals). Dr. Kalin has served as a consultant to the Board of Scientific Advisors, the Pritzker Neuropsychiatric Disorders Research Consortium, and the Skyland Trail Advisory Board and as Councilor, Society of Biological Psychiatry. Dr. Rodriguez has served as a consultant to Allergan, Blackthorn, Epiodyne, and Rugen. Mr. Roy and Mr. Pogachar report no financial relationships with commercial interests.

Hardware/Software Requirements

This internet-based CME activity is best experienced using Internet Explorer 8+, Mozilla Firefox 3+, Safari 4+. This Web site requires that JavaScript and session cookies be enabled. Certain activities may require additional software to view multimedia, presentation, or printable versions of the content. These activities will be marked as such and will provide links to the required software. That software may be: Adobe Flash, Adobe Acrobat, Microsoft PowerPoint, and Windows Media Player.
Optimal System Configuration:
  • Flash Player: Adobe Flash Player 10.1+ 
  • Browser: Firefox 3+, Internet Explorer 8.0+, Safari 4.0+, or Google Chrome 7.0+ 
  • Operating System: Windows XP+ or Mac OS X 10.4+ 
  • Internet Connection: 1 Mbps or higher
  • Screen Resolution: 1024 x 768 pixels.

Minimum Requirements:

  • Windows PC:500-MHz Pentium II; Windows XP or higher; 128 MB RAM; Video Card at least 64MB of video memory; Sound Card at least 16-bit; Macromedia Flash Player 10 or higher, audio playback with speakers for programs with video content; Firefox 1.1+, Internet Explorer 7.0+, Safari 1.0+, Google Chrome, or Opera
  • Macintosh: Mac OS X 10.3 or higher with latest updates installed; 1.83MHz Intel Core Duo or faster; RAM: 128MB or more; Video Card: at least 64MB of video memory; Sound Card: at least 16-bit

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