Trauma re-experiencing episodes during esketamine treatment in patients with treatment-resistant depression and comorbid PTSD: a retrospective case series

Eur J Psychotraumatol. 2026 Dec;17(1):2609425. doi: 10.1080/20008066.2025.2609425. Epub 2026 Apr 1.

ABSTRACT

Background: Posttraumatic stress disorder (PTSD) is a severe and frequent affection that is highly comorbid to major depressive disorder. Comorbid PTSD and depression increase the risk of treatment-resistant depression (TRD), with a high risk of functional impairment and suicide. Esketamine nasal spray is a recent validated treatment for TRD, but its efficacy on comorbid TRD-PTSD remains insufficiently documented. In particular, it is unknown whether traumatic re-experiencing may occur during esketamine treatment and if so, how it influences clinical outcomes.Objectives: Our objective was to describe trauma re-experiencing episodes during esketamine sessions and their impact on clinical trajectories within an ecological sample of patients with comorbid TRD-PTSD.Methods: We retrospectively collected clinical data of patients receiving esketamine nasal spray for TRD for whom at least one trauma re-experiencing episodes had been identified by clinicians during esketamine sessions across 11 psychiatric departments.Results: Between February 2020 and March 2023, 22 adult patients with TRD met inclusion criteria. In sixteen patients (72.7%) trauma re-experiencing episodesdisappeared as the sessions progressed. In six patients (27.3%), esketamine treatment was stopped because of trauma re-experiencing episodes. When esketamine was continued, favourable clinical outcomes were observed both for depression and PTSD (depression response rate: 45.5% and remission rate: 22.7%; PTSD improvement rate: 45.5% and remission: 18.2%).Limitations: The retrospective design of the study and the absence of a comparator group are the main limitations of our study.Conclusions: Our results suggest that esketamine can be safely administered to patients with comorbid PTSD and TRD, and that the occurrence of trauma re-experiencing episodes does not hinder clinical response.

PMID:41919730 | DOI:10.1080/20008066.2025.2609425