Episode 2: Update on Rapid-Onset Therapies for Major Depressive Disorder


The new fast-acting antidepressants esketamine, an NMDA receptor antagonist, and positive allosteric modulators of GABAergic neurotransmission brexanolone and zuranolone have created an important and exciting paradigm shift in the treatment of depression. 

Learning Objectives

After completing this educational activity, you should be able to: 

  • Implement faster-acting antidepressant treatment for patients with major depressive disorder for whom treatment has been delayed or suboptimal 

Target Audience

Psychiatrists; primary care physicians; and nurse practitioners & physician assistants in psychiatry and primary care settings 

Program Description

In this video Anita Clayton, MD, and Michael Thase, MD, discuss established and novel treatment options for patients with depression. The current treatment paradigm for depression includes monoamine oxidase inhibitors (MAOIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs) with a treatment algorithm that begins with first-line antidepressants, followed by switching to another first-line antidepressant, and thirdly incorporating combination or adjunctive therapies. These approaches have led to little improvement, with 2 to 3 out of 10 people continuing with little significant improvement even after persisting through multiple trials. Observations have led researchers to think outside the box and create new mechanisms of action that have demonstrated rapid onset of action for patients with depression. N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the more potent esketamine, as well as neuroactive steroid (NAS) gamma-aminobutyric acid (GABA) receptor–positive allosteric modulators zuranolone and brexanolone have shown dramatic rapidity of action and longer duration of response. Both esketamine and brexanolone have been FDA-approved, with zuranolone in phase 3 clinical trials. These new approaches to treatment offer new hope to patients with depression and have inspired a wave of excitement for clinicians and researchers. 

From the Series: Expediting Results, Improving Treatment Outcomes in Patients with Major Depressive Disorder

Activity summary
Available credit: 
  • 0.50 AMA PRA Category 1 Credit™
  • 0.50 Participation
Activity opens: 
Activity expires: 

Support Statement

Supported by an educational grant from Sage Therapeutics and Biogen. 

Learning Objective

After completing this educational activity, you should be able to:

  • Implement faster-acting antidepressant treatment for patients with major depressive disorder for whom treatment has been delayed or suboptimal 

Release and Expiration Dates

This CME activity was published in January 2023 and is eligible for AMA PRA Category 1 Credit™ through February 29, 2024. 

Statement of Need and Purpose

Standard therapeutics for acute major depressive disorder (MDD) often take weeks to months to achieve response and remission, resulting in considerable morbidity and disruption in patients’ personal, professional, family, and social lives, as well as the risk for suicidal behavior. Clinicians often switch antidepressants in an effort to improve response, although little evidence supports this strategy compared with continuing the initial medication. Advancements in the understanding of the pathology of MDD have led to the development of rapid-acting antidepressants. Clinicians need education on new and emerging therapy options that could offer expedited results to reduce morbidity and also, via a shorter duration of treatment, reduce the burden of ongoing adverse effects. Additionally, understanding the patient perspective would aid clinicians in communicating about treatment options with them. 

Unlabeled and Investigational Usage

The faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience any reference to an unlabeled or investigational use.

No endorsement of unapproved products or uses is made or implied by coverage of these products or uses.

Please refer to the official prescribing information for each product for discussion of approved indicators, contraindications and warnings.

Review Process

The faculty members agreed to provide a balanced and evidence-based presentation and discussed the topics and CME objectives during the planning sessions. The faculty’s submitted content was validated by CME Institute staff, and the activity was evaluated for accuracy, use of evidence, and fair balance by the Chair and a peer reviewer who is without conflict of interest.

The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter

© Copyright 2023 Physicians Postgraduate Press, Inc.

Faculty Affiliation

Photo of Michael Thase, MD Michael Thase, MD 
Professor of Psychiatry 
Perlman School of Medicine 
University of Pennsylvania 
Philadelphia, PA 

Photo of Anita Clayton, MD Anita Clayton, MD 
Professor & Chair 
Department of Psychiatry and Neurobehavioral Sciences 
Professor, Clinical Obstetrics & Gynecology 
University of Virginia School of Medicine 
Charlottesville, VA 

Financial Disclosure 

The CME Institute adheres to the Standards for Integrity and Independence in Accredited Continuing Education of the Accreditation Council for Continuing Medical Education (ACCME). Any individuals in a position to control the content of a continuing education activity, including faculty, content developers, reviewers, staff, and others, are required to disclose to learners the presence or absence of any relevant financial relationships with an ACCME-defined ineligible company within the preceding 24 months of the activity. The ACCME defines an “ineligible company” as one whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

The CME Institute has mitigated all relevant conflicts of interest prior to the commencement of the activity. None of the individuals involved in the content have relevant financial relationships with ineligible companies except the following:

Dr Thase has received consluting fees from Acadia, Inc., Akili, Inc., Alkermes PLC, Allergan, Inc., Axsome Therapeutics, Inc., BioHaven, Inc., Bocemtium Consulting, S.L., Boehringer Ingelheim International, CatalYm GmbH, Clexio Biosciences, Gerson Lehrman Group, Inc., H. Lundbeck, A/S, Jazz Pharmaceuticals, Janssen, Johnson & Johnson, Luye Pharma Group, Ltd., Merck & Company, Inc., Otsuka Pharmaceutical Company, Ltd., Pfizer, Inc., Sage Pharmaceuticals, Seelos Pharmaceuticals, Sunovion Pharmaceuticals, Inc., and Takeda Pharmaceutical Company, Ltd.; has received grant/research support from Acadia, Inc., Allergan, Inc., AssureRx Health, Axsome Therapeutics Inc., BioHaven, Inc., Intracellular, Inc., Johnson & Johnson, Otsuka Pharmaceutical Company, Ltd., Patient-Centered Outcomes Research Institute (PCORI), and Takeda Pharmaceutical Company, Ltd.; and has served on the advisory board for Janssen and Lundbeck, A/S.  

Dr Clayton has equity interest/stocks in Mediflix, LLC; stock options with Eurythmics and S1 Biopharma; has received consulting fees from Brii Biosciences, Fabre-Kramer, Field Trip Health, Janssen Research & Development, LLC, Mind Cure Health, Praxis Precision Medicines, PureTech Health, S1 Biopharma, Sage Therapeutics, Takeda/Lundbeck, Vella Bioscience, Inc, and WCG Med Avante-ProPhase; has served on the advisory board for AbbVie, Inc, Ovoca Bio plc, Praxis Precision Medicines, S1 Biopharma, and Sage Therapeutics; and has received royalties/copyright from Ballantine Books/Random House, Changes in Sexual Functioning Questionnaire, and Guilford Publications. 

Michael R. Page, PharmD, RPh
Independent Medical Director/Medical Writer
Plainsboro, New Jersey
Dr. Page is a consultant for BioCentric, Inc. and American Medical Communications, Inc.

None of the other planners, reviewers, and CME Institute staff for this educational activity have relevant financial relationships with ineligible companies to disclose. All relevant financial relationships have been mitigated.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note: The American Nurses Credentialing Center (ANCC) and the American Academy of Physician Assistants (AAPA) accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by the ACCME.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Available Credit

  • 0.50 AMA PRA Category 1 Credit™
  • 0.50 Participation


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