At least one third of patients with major depressive disorder do not experience adequate response to several rounds of antidepressant therapy, and a core 20% fail to respond to available antidepressants and evidence-based psychotherapies. Advanced neuromodulation approaches have been developed including repetitive transcranial magnetic stimulation and vagal nerve stimulation, but all have significant limitations. Ketamine, a dissociative anesthetic that has been available in the US since 1970, has been developed as a novel antidepressant for difficult to treat depression (DTD) and major depressive disorder with suicidal ideation (MDDSI) over the last 15 years. Following early studies by Drs. Robert Berman and colleagues at Yale University and Carlos Zarate and collaborators at the intramural program of the NIMH, evidence of the effectiveness of IV ketamine and, later, an intranasal form of the S(+)-enantiomer of ketamine called esketamine has steadily accumulated. This culminated in the approval of esketamine (SpravatoTM) for DTD in 2019 and MDDSI in 2020. Ketamine and esketamine have been among the most “rationally developed” medications in Psychiatry, in that they target one of the putative underlying pathophysiological mechanisms underlying depression, neuroplasticity. This presentation will review the clinical data in support of the effectiveness of ketamine and esketamine for DTD and MDDSI; the limitations, adverse effects, and controversies surrounding their use; their hypothesized mechanisms of action and how that relates to theoretical causal processes for depression. Participants should understand if and how they might use esketamine in their practice. They should also be able to describe the theoretical mechanisms, benefits and limitations of esketamine to their patients. This should help them make rational decisions about choosing among the available advanced treatment options for depression.

**This content was captured at the 2021 APA Annual Meeting and may reference information from various sources and terminology from previous editions of the DSM.

Learning Objectives

• Have a deeper understanding of the basic pathophysiology of depression and how this is addressed by ketamine. 
• Articulate a clear understanding of the clinical trial evidence for both ketamine and intranasal esketamine
• Understand the risks and side effects of ketamine and esketamine treatment and will be able to describe them accurately and thoroughly to their patients
• Understand the place of esketamine therapy among other neuromodulation approaches such as ECT and rTMS
• Articulate the limitations of ketamine treatment and controversies surrounding it

Target Audience

Psychiatrists, Residents/Fellows

Estimated Time to Complete

Estimated Duration: 75 minutes
Begin Date: May 1st, 2022
End Date: May 1st, 2025

How to Earn Credit

Participants who wish to earn AMA PRA Category 1 Credit ™ or a certificate of participation may do so by completing all sections of the course including the evaluation. After evaluating the program, course participants will be provided with an opportunity to claim hours of participation and print an official CME certificate (physicians) or certificate of participation (non-physicians) showing the completion date and hours earned. 

Continuing Education 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 enduring CME activity for a maximum of 1.25 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

Program Presenters

• Richard Shelton, M.D., University of Alabama Birmingham, Reports no financial relationships with commercial interests.

Program Planners

• Jacqueline Maus Feldman, M.D., Chairperson, Scientific Program Committee, Reports no financial relationships with commercial interests.
• Robert O. Cotes, M.D., Vice-Chairperson, Scientific Program Committee, Reports no financial relationships with commercial interests. 
• Uchenna Okeye, M.D., Vice-Chairperson, Scientific Program Committee, Reports no financial relationships with commercial interests. 
• Katie Putnam, Membership Development Manager, American Psychiatric Association. Reports no financial relationships with commercial interests.
• Ally Brown, Former Associate Director, Online Learning, American Psychiatric Association. Reports no financial relationships with commercial interests.

Accessibility for Participants with Disabilities

The American Psychiatric Association is committed to ensuring accessibility of its website to people with disabilities. If you have trouble accessing any of APA’s online resources, please contact us at 202-559-3900 for assistance.

Technical Requirements

This internet-based CME activity is best experienced using any of the following:

• The latest and 2nd latest public versions of Google Chrome, Mozilla Firefox, or Safari
• Internet Explorer 11+

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 Acrobat Reader, Microsoft PowerPoint, and Windows Media Player.

Optimal System Configuration:

• Browser: Google Chrome (latest and 2nd latest version), Safari (latest and 2nd latest version), Internet Explorer 11.0+, Firefox (latest and 2nd latest version), or Microsoft Edge (latest and 2nd latest version)
• Operating System: Windows versions 8.1+, Mac OS X 10.5 (Leopard) +, Android (latest and 2nd latest version), or iOS/iPad OS (latest and 2nd latest version)
• Internet Connection: 1 Mbps or higher

Minimum Requirements:

• Windows PC: Windows 8.1 or higher; 1 GB (for 32-bit)/2 GB (for 64-bit) or higher RAM; Microsoft DirectX 9 graphics device with WDDM driver; audio playback with speakers for programs with video content
• Macintosh: Mac OS X 10.5 or higher with latest updates installed; Intel, PowerPC G5, or PowerPC G4 (867MHz or faster) processor; 512 MB or higher RAM; audio playback with speakers for programs with video content

For assistance: Contact educme@psych.org for questions about this activity | Contact learningcenter@psych.org for technical assistance