Background/Objectives: Esketamine-related dissociation is a transient, pharmacologically induced altered state that differs from the trait-like pathological dissociation typically observed in trauma-related conditions. While most studies have quantified these effects using the Clinician-Administered Dissociative States Scale (CADSS), patients’ subjective phenomenology and meaning-making remain underexplored. This qualitative exploratory study investigated how patients narrate, interpret, and integrate dissociative experiences occurring during intranasal esketamine treatment for treatment-resistant depression (TRD). Methods: We conducted semi-structured interviews with 36 adults with TRD who were receiving intranasal esketamine in outpatient settings in Northern Italy (2022–2024). Interviews focused on the most salient dissociative experiences during treatment. Transcripts were anonymized and analyzed using inductive thematic analysis. Two researchers coded the data independently; discrepancies were resolved by consensus, and recruitment continued until thematic saturation was reached. Results: Four experiential domains emerged: sensory alteration and perceptual flow (10/36, 27.8%), time suspension and chronological drift (21/36, 58.3%), body and space alteration (20/36, 55.6%), and psychic distance from suffering (30/36, 83.3%). While a minority described transient distress or loss of control, most narratives framed dissociation as neutral or subjectively meaningful, often associated with a temporary reduction in ruminative self-focus and depressive distress. Conclusions: A narrative, phenomenological lens complements quantitative research by clarifying what esketamine-induced dissociation feels like to patients and how it is appraised in context. The findings do not imply a causal or mediating role in antidepressant efficacy. Rather, they suggest that dissociation functions as a transitional subjective state, the clinical relevance of which depends on anticipation, framing, monitoring, and integration. These results support the use of structured psychoeducation, in-session support, and post-session integration within real-world esketamine programs.

Background: Suicidal ideation (SI) represents a clinical challenge in patients with treat-ment-resistant depression (TRD), and the management of this condition would be as rap-id and effective as possible. Intranasal Esketamine has shown promise in patients with TRD due to its rapid onset of action on both SI and depressive symptoms. Since this med-ication has been recently approved, real-world data on its efficacy remains scarce, and lit-tle is known about which patients are most likely to benefit from this approach. Aims: This study aimed 1) to evaluate the efficacy of intranasal Esketamine on SI and depressive symptoms and 2) to find potential predictors of clinical response. Methods: Patients with TRD who received intranasal Esketamine were included in the study. Clinical evaluations and psychometric assessments were made at baseline (T0) and at five subsequent time points (one week [T1], one month [T2], two months [T3], three months [T4], and six months [T5]). SI was assessed using the Columbia Suicide Severity Rating Scale (C-SSRS), and depressive symptoms were evaluated using the Montgomery–Åsberg Depression Rating Scale (MADRS). Furthermore, socio-demographic, clinical, and pharmacological data were collected. Results: Eighty patients diagnosed with TRD were enrolled. Suicidal ideation (C-SSRS items 1–5) decreased from 1.56 ± 1.65 at baseline to 0.78 ± 1.28 at T1 and 0.12 ± 0.52 at T5 (all p < .001). MADRS fell from 31.81 ± 7.94 to 23.62 ± 9.08 and 10.19 ± 7.33 at the same time points (all p < .001). By T1, 68.4% achieved SI response on the C-SSRS. MADRS response rate increased from 16.7% at T1 to an overall response of 62.5% at T5. Male sex predicted lower odds of early response on the C-SSRS (OR = 0.21, p = .031); no other baseline variable was significant as a predictor. Conclusions: Intranasal Esketa-mine has been shown to be effective in the rapid reduction and lysis of SI in patients with TRD. Male gender was found as a negative predictor of response, suggesting the im-portance of considering gender differences during treatment planning.