2026 ECNP Congress

PS01-1251

Intranasal esketamine in treatment-resistant depression with and without comorbid borderline personality disorder: a multicenter real-world longitudinal study

Edoardo Grechi — F. Mazzoni, F. Raffone, A. De Ciechi, N. Girone, M. Macellaro, G. Martinotti, B.M. Dell'Osso, V. Martiadis, M. Olivola · Università degli Studi di Milano, Department of Mental Health and Addiction Services- Azienda Socio Sanitaria Territoriale ASST Fatebenefratelli-Sacco, Milano, Italy

2026 ECNP Congress

Background

Treatment-resistant depression (TRD) is a severe clinical condition associated with persistent symptoms, functional impairment, and increased suicide risk [1]. It represents a high-burden condition even after adequate trials of conventional antidepressants, often requiring complex and multimodal treatment strategies. Intranasal esketamine has demonstrated rapid antidepressant effects, but its effectiveness in complex real-world populations—particularly in patients with comorbid borderline personality disorder (BPD)—remains insufficiently understood [2]. Personality disorders, and BPD in particular, are often associated with greater clinical severity, impulsivity, and poorer treatment outcomes, raising questions about their impact on esketamine response and potential differences in longitudinal treatment trajectories [3].

Aims

The primary aim of this study was to evaluate the longitudinal trajectory of depressive symptoms in patients with TRD treated with intranasal esketamine, comparing those with and without comorbid BPD in a multicenter naturalistic clinical context. Secondary aims included assessing response and remission rates, as well as changes in anxiety, impulsivity, and cognitive functioning over a six-month follow-up.

Methods

This multicenter, prospective, real-world observational study included 90 adult outpatients with TRD recruited from four Italian psychiatric centers between September 2024 and September 2025. Participants were divided into two groups: 45 with comorbid BPD and 45 without personality disorders. Depressive symptoms were measured using the Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline, 2 weeks, 1 month, 3 months, and 6 months. Response was defined as a ≥50% reduction in MADRS score, and remission as MADRS ≤10 at 6 months. Secondary outcomes included anxiety (HAM-A), impulsivity (BIS-11), and cognitive function (MoCA). Statistical analyses included repeated-measures models and sensitivity analyses adjusting for clinical confounders including concomitant pharmacological and psychotherapeutic treatments.

Results

Depressive symptoms significantly decreased over time across the entire sample, with a large effect size. A significant time × BPD interaction indicated faster early improvement in the BPD group. Despite higher baseline severity, symptom trajectories converged between groups over time. At 6 months, remission was achieved in 53.3% of patients, with no significant difference between groups (48.9% in BPD vs. 57.8% in non-PD). However, response rates were significantly higher in the BPD group from one month onward, reaching 97.8% at 6 months compared to 77.8% in the non-PD group. Anxiety and impulsivity significantly decreased during follow-up, with greater reductions in the BPD group. Cognitive performance remained stable, indicating no evidence of deterioration. No serious adverse events occurred, and no patients discontinued treatment.

Conclusions

Intranasal esketamine was associated with rapid and sustained improvement in TRD in a real-world clinical setting. Comorbid BPD did not negatively impact remission rates and was associated with faster response kinetics. These findings suggest that BPD should not be considered a limiting factor for esketamine treatment and support its use in complex clinical populations within integrated care models and personalized, measurement-based treatment approaches.

References

  1. McIntyre, R. S., Alsuwaidan, M., Baune, B. T., Berk, M., Demyttenaere, K., Goldberg, J. F., et al., 2023. Treatment-resistant depression: Definition, prevalence, detection, management, and investigational interventions. World Psychiatry, 22(3), 394–412. https://doi.org/10.1002/wps.21099
  2. Daly, E. J., Singh, J. B., Fedgchin, M., Cooper, K., Lim, P., Shelton, R. C., Thase, M. E., Winokur, A., Van Nueten, L., Manji, H., Drevets, W. C., 2018. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry, 75(2), 139–148. https://doi.org/10.1001/jamapsychiatry.2017.3739
  3. Gunderson, J. G., Morey, L. C., Stout, R. L., Skodol, A. E., Shea, M. T., McGlashan, T. H., Zanarini, M. C., Grilo, C. M., Sanislow, C. A., Yen, S., Daversa, M. T., Bender, D. S., 2004. Major depressive disorder and borderline personality disorder revisited: Longitudinal interactions. Journal of Clinical Psychiatry, 65(8), 1049–1056. https://doi.org/10.4088/JCP.v65n0804