Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation

Am J Psychiatry. 2021 May 1;178(5):383-399. doi: 10.1176/appi.ajp.2020.20081251. Epub 2021 Mar 17.


Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.

Keywords: Bipolar Disorder; Esketamine; Ketamine; Major Depressive Disorder; Suicide; Treatment-Resistant Depression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antidepressive Agents / therapeutic use*
  • Delivery of Health Care
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Depressive Disorder, Treatment-Resistant / psychology
  • Dissociative Disorders / chemically induced
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Humans
  • Hypertension / chemically induced
  • Implementation Science
  • Ketamine / therapeutic use*
  • Lower Urinary Tract Symptoms / chemically induced
  • Monitoring, Physiologic
  • Patient Selection
  • Personnel Staffing and Scheduling
  • Psychoses, Substance-Induced / etiology
  • Substance-Related Disorders
  • Suicidal Ideation


  • Antidepressive Agents
  • Excitatory Amino Acid Antagonists
  • Esketamine
  • Ketamine