Esketamine and Acceptance and Commitment Therapy (ACT) for Treatment-Resistant Depression: An Intervention-Development Framework and Treatment Manual

Abstract

In 2019, the U.S. Food and Drug Administration (FDA) approved a patented formulation and delivery method of esketamine, the S-enantiomer of ketamine, for patients with treatment-resistant depression (TRD). While ketamine-based treatments share similarities with serotonin 2 A receptor-mediated “classic psychedelics” like psilocybin regarding subjective drug effects and stimulation of neuroplasticity, the therapeutic potential of these effects has not been fully considered for esketamine. There is also a notable lack of research on standardized therapeutic approaches that could be offered with esketamine to optimize such effects and potentially enhance treatment outcomes. This paper describes the rationale, development, and structure of an Acceptance and Commitment Therapy (ACT)-based manual designed to accompany esketamine treatment for TRD. ACT has been previously identified as an evidence-based candidate for use in psychedelic-assisted therapy for its distinct theoretical alignment with proposed mechanisms of change relevant to psychedelics and mood disorders. The model proposed here leverages the repeated dosing of esketamine, the FDA-mandated two-hour monitoring period following drug administration, and drug-related effects to enhance experiential engagement with core ACT principles, including present-moment awareness, acceptance and willingness, values and committed action, and cognitive defusion and psychological flexibility. This intervention has not been empirically tested, and there is insufficient evidence at this time to determine whether esketamine-assisted ACT improves aspects of treatment effectiveness (e.g., the magnitude, speed, and durability of response), tolerability, or safety compared to esketamine alone.

In the evidence

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

• State of the evidence: Esketamine for depression ?Unclear

  Proposes an ACT-based therapy manual to accompany esketamine, arguing its psychedelic-like effects and monitoring period create therapeutic opportunities, but states the intervention is untested.

  Synthesized October 22, 2026

Comparable studies

Other theoretical and historical papers on esketamine for depression, most cited first.