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

Abstract

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.

In the evidence

This study is part of the evidence base for 4 syntheses in the library. Here is how each one recorded it.

• State of the evidence: Esketamine for depression ↑Supports

  Expert synthesis concludes ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, while flagging safety, tolerability, and implementation uncertainties.

  Synthesized October 22, 2026

• State of the evidence: Ketamine for depression ↑Supports

  Expert synthesis concludes ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, with unresolved safety, tolerability, and implementation questions.

  Synthesized October 22, 2026

• State of the evidence: Esketamine ↑Supports

  An international expert group concludes that ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, while noting remaining safety, tolerability, and implementation concerns.

  Synthesized September 27, 2026

• State of the evidence: Ketamine ↑Supports

  Concludes ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, while flagging unresolved questions on safety, tolerability, and clinical implementation.

  Synthesized October 25, 2026

Comparable studies

Other narrative reviews on esketamine for depression, most cited first.