Dissociation and antidepressant response to subcutaneous esketamine: a clinical study

Introduction: Ketamine and esketamine have reemerged as promising interventions for treatment-resistant depression (TRD), yet debate persists regarding the clinical relevance of acute dissociative experiences. This secondary exploratory analysis aimed to examine whether dissociative experiences induced by subcutaneous esketamine differed according to antidepressant response and were associated with depressive symptoms in patients with TRD. Methods: Patients received up to eight weekly subcutaneous doses of esketamine. Dissociation was assessed using the Clinician-Administered Dissociative States Scale (CADSS), and depressive symptoms were evaluated using the Montgomery–Åsberg Depression Rating Scale (MADRS) and Beck Depression Inventory-II (BDI-II). Responders were defined as patients who achieved a ≥50% reduction in MADRS scores from baseline to the end of treatment, whereas participants who did not meet this criterion were classified as non-responders. Results: Of 30 patients eligible for inclusion, 23 were included in the final analysis (mean age, 34.3 years; 65.2% female). Dissociation levels remained stable across treatment sessions. Responders exhibited significantly higher CADSS total scores (p = 0.024) and derealization scores (p = 0.011) compared with non-responders across the treatment period. There were no significant differences in depersonalization or amnesia scores between responders and non-responders (p = 0.056 and p = 0.089, respectively). Conclusion: These exploratory findings suggest that dissociative experiences, particularly derealization, may represent clinically relevant to antidepressant outcomes following subcutaneous esketamine treatment in TRD, although further prospective studies with larger samples and dose-controlled designs are needed before their clinical utility can be established.