Toward Integrating Intranasal Esketamine with Traumatic-Memory Psychotherapy in Treatment-Resistant Depression: A Narrative Review and Feasibility-Oriented Protocol Proposal

Trauma-related autobiographical memories can manifest as involuntary, vivid, emotionally charged intrusions that perpetuate avoidance, negative emotions, and functional impairment. While these memories are central to post-traumatic stress disorder (PTSD), they also occur across diagnoses and are often reported in depressive disorders, including treatment-resistant depression (TRD). Although trauma-focused psychotherapies are effective, their routine implementation can be limited by dropout, residual symptoms, and difficulty engaging patients with severe depression, dissociation, or complex comorbidities. Intranasal esketamine is an approved rapid-acting treatment for TRD and has been hypothesized to create transient conditions that may facilitate psychotherapeutic work on traumatic memories. This narrative review synthesizes clinical and translational evidence on ketamine and esketamine for PTSD and trauma-related symptoms, with particular attention to the distinction between intravenous ketamine studies, intranasal esketamine data, and studies combining these compounds with psychotherapy. Currently, the most robust evidence in this area comes from three randomised trials of intravenous ketamine for PTSD. In contrast, data on intranasal esketamine and psychotherapy-combination approaches are mainly from pilot studies, retrospective analyses, or case reports. We additionally propose a pragmatic, feasibility-oriented protocol integrating intranasal esketamine with a structured traumatic-memory intervention for TRD patients with clinically relevant trauma-memory symptoms. The novelty of the proposal does not lie in claiming efficacy, but in specifying a standardised imagery rescripting module and predefining two timing hypotheses. The proposal targets patients with TRD with relevant trauma-memory symptoms, and it embeds the intervention within existing esketamine-care infrastructure. Overall, the available literature supports mechanistic plausibility and preliminary feasibility more than clinical efficacy. The evidence base remains small, heterogeneous, and largely uncontrolled, and controlled studies are needed before efficacy claims can be made.