2026 ECNP Congress

PS01-1098

Interim analysis of HIPOCRAT-ESK study: depression severity and functional changes after 5-month esketamine nasal spray treatment in Spanish real-world population

Narcis Cardoner Álvarez — A. Ibanez Cuadrado, E. Baca García, S. Benavente López, J.M. Crespo Iglesias, L. Gutiérrez Rojas, D.J. Palao Vidal, M. García Dorado, P. Hinojar Merín · Hospital Santa Creu i Sant Pau, Psychiatry, Barcelona, Spain

2026 ECNP Congress

Background

Treatment-resistant depression (TRD), commonly defined as failure to achieve a clinically meaningful response after at least two adequate antidepressant trials, affects approximately one third of patients with major depressive disorder and represents a major unmet medical need [1].

Compared with non-resistant depression, TRD is associated with greater symptom severity, chronicity, functional impairment, and a substantially higher individual and societal burden [2].

Patients with TRD also experience increased healthcare utilization and a higher risk of adverse outcomes, including excess mortality, underscoring the need for improved characterization and evidence-based treatment strategies [3].

Esketamine nasal spray represents an innovative therapeutic option, with a mechanism of action based on modulation of the glutamatergic pathway aimed at enhancing neuroplasticity [4].

The HIPOCRAT-ESK study aims to assess functional remission after 6 months of treatment with esketamine nasal spray in TRD patients in Spain; this interim analysis evaluates outcomes at 5 months of follow-up.

Methods

This interim analysis evaluates clinical improvement using patient-reported (PHQ-9) and clinician-reported (MADRS) scales, clinicians’ subjective perception of improvement (Yes/No), return-to-work rates, and patient-reported outcomes (EQ-5D-5L). Adverse events and treatment discontinuations were also analyzed.

Patients were eligible if considered candidates for esketamine nasal spray based on investigators’ clinical judgment, and treatment was prescribed in routine clinical practice according to the local SmPC. The analysis follows the Statistical Analysis Plan (version 02-00, 17-Mar-2026) and includes data up to approximately the fifth month of follow-up (Visit 8/Day 155), with database cutoff on 23-Feb-2026. Given the descriptive nature of the study, quantitative variables are summarized using mean, standard deviation, 95% confidence intervals, median, percentiles (P25–P75), minimum, and maximum; qualitative variables are described using absolute and relative frequencies.

Results

A total of 122 patients were included; 65.6% were female, with a mean age of 49.6 years. All patients had TRD, with a mean duration of the current episode of 18.3 months and a mean of 3.9 previous episodes. At baseline, 50% of patients were on medical leave, with a mean duration of 470.6 days. Suicidal ideation was highly prevalent: 59.8% of patients reported suicidal ideation within the 6 months prior to study inclusion, and 37.7% reported suicidal ideation at baseline. Mean baseline MADRS and PHQ-9 scores were 37.2 and 20.8, respectively.

At 5 months, MADRS decreased by 18.9 points (50.8% reduction) and PHQ-9 by 6.5 points (31.25% reduction), both clinically meaningful. Functional outcomes improved in parallel, with reductions of 2.0 lost days and 1.7 unproductive days as measured by SDS. Investigators reported clinical improvement in 91.8% of patients, and 11.5% of medical leaves were resolved during follow-up.

A total of 14 patients discontinued treatment, mainly due to withdrawal of consent. Adverse events were consistent with the established safety profile of esketamine and resolved after administration; the most frequently reported adverse event was dizziness (46.8%).

Conclusion

This interim analysis of the HIPOCRAT-ESK study suggests significant and clinically meaningful improvements in depressive symptoms and daily functioning after 5 months of esketamine nasal spray in a real-world Spanish TRD population characterized by high baseline severity, long disease duration, and marked functional impairment.

References

  1. McIntyre RS et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023.
  2. Fiorillo A et al. Treatment-resistant depression: epidemiology, clinical features, burden and treatment. Front Psychiatry. 2025.
  3. Lundberg J et al. Association of treatment-resistant depression with patient outcomes and healthcare resource utilization. JAMA Psychiatry. 2023.
  4. Ramos-Quiroga JA, Mora F, Arostegui S, Cardoner N, Etxeandia-Pradera JI, Gómez-Juanes R, Gómez-Revuelta M, Montes JM, Vieta E. Treatment-Resistant Depression and intranasal esketamine: Spanish clinical consensus on practical aspects. Eur. J. Psychiat. 2025 39 (3); 100313