Depersonalization and derealization, embodiment abnormalities and salience alterations: impact on medium-term esketamine treatment outcomes

The recent approval of intranasal esketamine in many European countries has indeed sparked interest in exploring its efficacy and mechanisms in greater detail. While much research has focused on its neurochemical actions, particularly its effects on glutamate receptors, fewer studies have delved into the potential impact of its "ancillary” effects on long-term disease outcomes. Indeed, it is well know that ketamine administration can produce dissociative symptoms [1], and that they influence prognosis [2]; however, there is few studies focusing on the role of esketamine-induced depersonalization and derealization in parallel with other constructs, such as salience alterations and embodiment abnormalities. Efficacy of esketamine on treatment-resistant forms of depression urges an inquiry not only in the neurochemical pathways it is affecting, but also on the psychological domains which often determine the severity of clinical pictures. Starting from the hypothesis that these experiences might play a role in the healing process from depressive episodes, we launched a study in several mental health clinics across Tuscany. Our aim was to examine 32 patients treated with intranasal esketamine using a comprehensive battery of assessments. These included widely-used measures such as the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Scale (HAM-A), as well as assessments of aberrant salience (through the Aberrant Salience Inventory, ASI), disability (through the World Health Organization Disability Assessment Scale, WHODAS), embodied sense of self (through the Embodied Sense of Self Scale, ESSS) [3], and dissociative experiences (through Dissociative Experiences Scale II, DES II, and an ad-hoc semi-structured interview for depersonalization and derealization symptoms); the latter, developed for this study, also contributes to collect some qualitative data, such as the "dissociative effects” duration and a non-clinical description of them by the patient. Sociodemographic and anamnestic variables were collected, too. Patients were to be assessed at baseline, at one month (after induction phase), at three months and at six months. The study, which is still ongoing, has recruited 20 patients; unfortunately, we encountered challenges, with a notable dropout rate: esketamine administration was discontinued within one month for three patients, while only eight patients continued treatment for at least three months. Preliminary analysis revealed a lack of correlation between larger variations in the scores in scales measuring salience and embodiment alterations and improvements in MADRS symptoms; similarly, an higher degree of dissociative symptoms like depersonalization or derealization at baseline did not predict improvement. However, the high dropout rate presents a significant limitation, hindering our ability to draw definitive conclusions from these initial data. Moreover, the degree of dissociative experiences reported by the patients was much lower than expected. Moving forward, it will be essential to address issues of treatment adherence and dropout rates the proscetuion of the study. Additionally, exploring the potential therapeutic benefits of "ancillay experiences” induced by esketamine treatment, like depersonalization and derealization experiences, as well as embodiment and salience variations, warrants further investigation, potentially shedding light on novel pathways for improving outcomes in depression therapy.