2026 ECNP Congress

PS04-4098

Real-world evidence on add-on esketamine or atypical antipsychotics for treatment-resistant depression: effects on suicide attempts, hospitalization, and mortality rates outcomes

Firaol Ayele — V. Gálvez, M. Fradera, A. Siscart, M. Perez, V. Soria, D. Palao · Institut d’Investigació i Innovació Parc Taulí I3PT-CERCA- Parc Taulí Hospital Universitari, Mental Health and Neuroscience Area, Sabadell, Spain

2026 ECNP Congress

Introduction

Treatment-resistant depression is a complex and heterogeneous condition that continues to represent a major therapeutic challenge in clinical practice. It is estimated that up to 30–55% of patients do not respond, or respond only partially, after trials with at least two different antidepressant medications. [1–4]. This lack of response is associated with substantial functional impairment, increased healthcare utilization, and an elevated risk of suicide. Although strategies such as antidepressant add-on treatment with intranasal esketamine and atypical antipsychotics are recommended in clinical guidelines, there remains a need to better understand their comparative effectiveness and safety in routine clinical settings [5]. Thus, evidence derived from real-world data may give insight into an understanding the real-world comparative effectiveness and safety of these interventions, which is critical for optimizing the care of this population. The present study aims to evaluate the comparative effectiveness and safety of add-on intranasal esketamine versus add-on atypical antipsychotics in patients with TRD treated with an antidepressant using real-world clinical data (RWD).

Methods

A retrospective cohort study was conducted using data from the TriNetX global health research network, with a seven-year time window (from March 5, 2019, to March 5, 2026). TriNetX data were drawn from real-world clinical settings, and Electronic Medical Record (EMR) data were analyzed from a total of 63 Health Care Organizations (HCOs). The study population consisted of adults aged 18 or older with a diagnosis of major depressive disorder (MDD), either single episode or recurrent, identified using the International Classification of Diseases, Tenth Revision (ICD-10) diagnostic codes, including F32 and F33. Eligible patients (exposure) were receiving treatment with an antidepressant medication, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or other antidepressant classes, in combination with either intranasal esketamine or an atypical antipsychotic. The primary outcomes of interest were the incidence of suicide attempts, all-cause hospitalization, and all-cause mortality. To reduce potential confounding, propensity score matching was applied based on age and sex, generating balanced cohorts for comparison.

Results

A total of 18,300 patients were allocated into two matched cohorts (corresponding to each treatment group) after applying propensity score matching. Each cohort was composed of 9,150 individuals: the cohort treated with antidepressants plus intranasal esketamine (5,310 females [58.0%]; mean [SD] age: 50.3 +/- 20.3 years) or the antidepressants plus atypical antipsychotics cohort (5,230 females [57.2%]; mean [SD] age: 50.6 +/- 19.9 years). The rate of suicidal attempts was significantly lower among patients treated with antidepressant add-on intranasal esketamine (6.1% versus 13.3%, p < 0.001). In contrast, no statistically significant differences were observed between the two groups in terms of all-cause hospitalization or all-cause mortality.

Conclusions

In real-world clinical practice, the combination of intranasal esketamine with antidepressants was associated with a significantly lower risk of suicide attempts compared to augmentation with atypical antipsychotics in patients with treatment-resistant depression. However, both cohorts demonstrated comparable rates of all-cause hospitalization and all-cause mortality. These findings suggest that intranasal esketamine may offer a specific advantage in reducing suicide-related outcomes, while broader safety outcomes appear similar between treatments.

References

  1. Fiorillo, A., Demyttenaere, K., Martiadis, V. & Martinotti, G. Editorial: Treatment resistant depression (TRD): epidemiology, clinic, burden and treatment. Front. Psychiatry 16, 1588902 (2025).
  2. McIntyre, R. S. et al. Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry 22, 394–412 (2023).
  3. Thomas, L. et al. Prevalence of treatment-resistant depression in primary care: cross-sectional data. Br. J. Gen. Pract. 63, e852–e858 (2013).
  4. Sinyor, M., Schaffer, A. & Levitt, A. The sequenced treatment alternatives to relieve depression (STAR* D) trial: a review. Can. J. Psychiatry 55, 126–135 (2010).
  5. Kasper, S. et al. Practical recommendations for the management of treatment-resistant depression with esketamine nasal spray therapy: basic science, evidence-based knowledge and expert guidance. World J. Biol. Psychiatry 22, 468–482 (2021).