2026 ECNP Congress

PS01-1029

Real-world outcomes of esketamine in major depressive disorder with comorbid anxiety or trauma and stress-related disorders (ELLIPSE Study)

Pierre-Michel Llorca — P. de Maricourt, L. Mekaoui, M. Rothärmel, I. Rodriguez, H. Lacour, B. Grenier, M. Mabred, J. Dupin, C. Wicart · CHU Clermont-Ferrand/Université Clermont Auvergne/CNRS/INP Clermont Auvergne, Service de Psychiatrie/Institut Pascal UMR 6602, Clermont-Ferrand, France

2026 ECNP Congress

Introduction

Psychiatric comorbidities, including anxiety disorders and trauma and stress-related disorders (TSRD), are frequent in major depressive disorder (MDD) and may worsen symptom burden, suicidality, functioning and treatment outcomes [1–3]. Esketamine nasal spray was approved in Europe in December 2019 for treatment-resistant depression (two previous antidepressant failures), but real-world data in MDD patients with these comorbidities remain limited [4].

Objectives

To describe 12-month clinical and safety outcomes after esketamine initiation in adults with unipolar MDD and baseline anxiety or TSRD treated in routine French practice.

Methods

ELLIPSE is a French, prospective, multicenter, observational study of adults with unipolar MDD initiating esketamine in routine care [5]. Visits were scheduled at baseline, D8, M1, M2, M3, M6, M9, M12. Anxiety disorder and TSRD subgroups were investigator-defined using DSM-5 criteria. Outcomes: depression severity (MADRS), quality of life (QLDS), suicidality (CGI-SS-R, range 0-6), and treatment-emergent adverse events (TEAEs).

Results

In the overall cohort (N=200), 79 patients (39.5%) had baseline anxiety disorder, 48 (24.0%) had TSRD, and 17 (8.5%) had both. Baseline/Follow-up scores are shown in Table, and 65.7% experienced ≥1 TEAE and 11.1% discontinued due to a TEAE.

In the anxiety subgroup, mean age was 46.7 (16.8) years, 60.8% were female and were followed for a median (Q1-Q3) duration of 11.9 (6.7-12.2) months. Among patients still under esketamine, mean MADRS changes from baseline were -13.8 at M1, -18.0 at M2, -15.5 at M6 and -19.5 at M12. 62.2% reported ≥1 TEAE, 8.5% a serious TEAE, 42.7% a treatement-related TEAE, and 12.2% a TEAE leading to discontinuation. Most frequent treatment-related TEAEs were dissociative states (30.5%), and increased blood pressure (12.2%).

In the TSRD subgroup, mean age was 42.1 (15.6) years, 75.0% were female, were followed for a median (Q1-Q3) duration of 12.0 (5.5-12.2) months. Among patients still under esketamine, mean MADRS changes from baseline were -13.6 at M1, -16.6 at M2, -17.4 at M6 and -11.5 at M12. 85.7% reported ≥1 TEAE, 14.3% a serious TEAE, 63.3% a treatment-related TEAE, and 10.2% a TEAE leading to discontinuation. Most frequent treatment-related TEAEs were dissociative states (51.0%), blood pressure increased (20.4%), and dizziness (10.2%).

Conclusions

In routine French clinical practice, esketamine was associated with sustained improvement in depressive symptoms in adults with unipolar MDD and comorbid anxiety disorders or TSRD, despite high baseline burden. The safety profile was consistent with that observed in the overall ELLIPSE cohort, supporting the clinical relevance of esketamine across comorbid populations.

Table. MADRS, QLDS, CGI-SS-R evolution under esketamine

Mean(SD) Baseline anxiety N=79 Baseline TSRD N=48 Total Population N=200
MADRS
Baseline 32.2(7.0) 33.4(6.2) 31.9(7.0)
D8 25.3(10.5) 25.6(9.6) 25.3(9.3)
M1 18.1(9.1) 19.6(10.3) 18.9(9.1)
M2 12.8(7.5) 16.5(9.6) 15.6(9.1)
M3 14.5(8.8) 16.6(8.0) 15.6(9.1)
M6 13.9(8.6) 16.1(5.8) 14.9(8.6)
M9 14.6(8.7) 18.2(8.4) 17.2(9.3)
M12 8.2(6.9) 19.5(10.3) 12.4(9.4)
QLDS
Baseline 20.4(3.7) 21.2(3.2) 20.8(3.8)
D8 18.3(4.8) 19.9(4.0) 19.4(4.4)
M1 16.8(4.9) 18.4(4.5) 17.7(5.0)
M2 14.3(4.8) 15.8(4.3) 16.3(5.2)
M3 14.7(5.6) 16.6(4.8) 15.9(5.4)
M6 13.8(4.6) 13.3(3.3) 14.6(5.1)
M9 14.8(4.5) 14.1(5.7) 15.4(5.2)
M12 11.3(3.3) 15.5(5.9) 13.5(4.7)
CGI-SS-R
Baseline 1.9(1.4) 2.4(1.6) 1.9(1.4)
D8 1.5(1.4) 1.2(1.4) 1.3(1.3)
M1 0.8(1.1) 0.8(1.2) 0.8(1.1)
M2 0.3(0.6) 0.7(1.0) 0.6(0.9)
M3 0.6(0.9) 0.6(0.9) 0.7(1.0)
M6 0.5(0.9) 0.4(0.6) 0.5(0.9)
M9 0.3(0.7) 0.6(1.0) 0.6(1.0)
M12 0.2(0.4) 0.7(0.8) 0.4(0.7)

References

  1. Kalin NH. The Critical Relationship Between Anxiety and Depression. AJP 2020; 177: 365–367.
  2. Angelakis S, Nixon RDV. The Comorbidity of PTSD and MDD: Implications for Clinical Practice and Future Research. Behav change 2015; 32: 1–25.
  3. Wang S-M, Pae C-U. Major depressive disorder: how to evaluate and manage patients with psychiatric and medical comorbidities. In: Carvalho AF, McIntyre RS (eds) Mental Disorders in Primary Care. Oxford University PressOxford, pp. 277–293.
  4. European Medicines Agency. Spravato : EPAR - Product Information, https://www.ema.europa.eu/en/documents/product-information/spravato-epar-product-information_en.pdf (December 2019).
  5. Llorca P-M, Mékaoui L, Rotharmel M, et al. Real world clinical practice, efficacy and safety of esketamine nasal spray in MDD patients: the French ELLIPSE study. Eur Psychiatr 2025; 68: S317–S317.