2026 ECNP Congress

PS02-2111

Trajectories of social cognition during esketamine treatment in treatment-resistant depression with and without borderline personality disorder

Valentina Casati — V. Martiadis, F. Mazzoni, F. Raffone, A. De Ciechi, N. Girone, M. Macellaro, G. Martinotti, B.M. Dell’Osso, M. Olivola · University of Milan, Department of Mental Health and Addiction - ASST Fatebenefratelli Sacco, Milan, Italy

2026 ECNP Congress

Background

Intranasal esketamine produces rapid antidepressant effects in treatment-resistant depression (TRD) [1]; however, its longitudinal impact on social cognition remains unclear. Social cognition encompasses processes such as emotion recognition, mental state attribution, and interpersonal understanding, which are frequently impaired in depressive disorders. Social-cognitive dysfunction, including impairments in mentalization and theory of mind, is associated with poorer functional outcomes [2] and is particularly relevant in individuals with comorbid borderline personality disorder (BPD), where disturbances in mentalization represent a core feature [3]. The aim of this study was to examine trajectories of social-cognitive functioning during esketamine treatment and to compare patterns between patients with and without borderline personality disorder.

Methods

: This multicentre, prospective, observational study included 90 outpatients initiating intranasal esketamine in routine care and followed them for six months. Patients were recruited from specialised outpatient services delivering esketamine as part of standard clinical care. Participants met DSM-5 criteria for a current major depressive episode with treatment resistance, defined as inadequate response to at least two antidepressant trials. Self-reported reflective functioning was assessed using the Reflective Functioning Questionnaire (RFQ-8), and theory of mind decoding using the Reading the Mind in the Eyes Test (RMET), at baseline, 2 weeks, 1 month, 3 months, and 6 months. Participants were stratified by borderline personality disorder diagnosis (n = 45) versus no personality disorder (n = 45). Esketamine was administered intranasally under clinical supervision in combination with ongoing oral antidepressant therapy, following routine care protocols. Linear mixed-effects models tested the effects of time, group, and time × group interaction, adjusting for age, sex, and baseline depression severity.

Results

Both reflective functioning and theory of mind improved significantly over time (both p < 0.001). At baseline, the borderline personality disorder group showed greater impairment (RFQ-8: 3.90 vs 3.21; RMET: 15.53 vs 22.07). RMET performance rapidly converged between groups by 2 weeks and remained comparable thereafter. RFQ-8 trajectories differed significantly between groups (time × group p < 0.001), with a steeper early improvement in the borderline personality disorder group and a transient advantage at one month, followed by progressive attenuation of between-group differences. Correlations between RFQ-8 and RMET were weak across time points (|ρ| ≤ 0.19), suggesting partially distinct processes.

Conclusions

During routine esketamine treatment, both self-reported mentalization and performance-based theory of mind improved and largely converged between patients with and without borderline personality disorder. These findings suggest that social-cognitive domains may be modifiable during treatment and could represent clinically relevant targets beyond symptom reduction. The observed patterns support the feasibility of monitoring social cognition in real-world esketamine treatment settings and highlight its potential relevance for understanding functional recovery. However, causal interpretation is limited by the observational design, and future controlled studies are needed to clarify whether these changes reflect specific treatment effects, practice effects, or broader clinical improvement.

References

  1. Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, Thase ME, Winokur A, Van Nueten L, Manji H, Drevets WC. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Feb 1;75(2):139-148. doi: 10.1001/jamapsychiatry.2017.3739. PMID: 29282469; PMCID: PMC5838571.
  2. Bora E, Berk M. Theory of mind in major depressive disorder: A meta-analysis. J Affect Disord. 2016 Feb;191:49-55. doi: 10.1016/j.jad.2015.11.023. Epub 2015 Nov 23. PMID: 26655114.
  3. Fonagy P, Luyten P. A developmental, mentalization-based approach to the understanding and treatment of borderline personality disorder. Dev Psychopathol. 2009 Fall;21(4):1355-81. doi: 10.1017/S0954579409990198. PMID: 19825272.