Real-world evolution of intranasal esketamine use in Gipuzkoa (Spain) across 2023–2025 cohorts

Background

Intranasal esketamine is an established treatment option for treatment-resistant depression. Although its efficacy has been demonstrated in randomised clinical trials,¹ real-world data are essential to understand how it is used in everyday clinical settings and how patient profiles and treatment strategies evolve over time.^2,3 A previous analysis of the 2023 and 2024 Gipuzkoa cohorts suggested changes in patient selection and pharmacological strategy during the first years of implementation.

Aims

To extend the comparison to the 2025 cohort and characterise the clinical profile of patients receiving intranasal esketamine across three consecutive years, and to explore whether wider availability has translated into earlier referral.

Methods

Retrospective analysis of 106 patients initiating intranasal esketamine between January 2023 and December 2025 at Donostia University Hospital, Gipuzkoa, Spain: 44 in 2023, 37 in 2024 and 25 in 2025, with cohorts defined by calendar year. Variables extracted from medical records included duration of illness, previous depressive episodes, duration of the index episode, baseline MADRS score, comorbidity with personality disorder, antidepressants used, potentiation (lithium, antipsychotic, mood stabiliser) and electroconvulsive therapy. Continuous variables were compared using Kruskal-Wallis tests and categorical variables using chi-square or Fisher’s exact tests, after Shapiro-Wilk normality testing. Pairwise post-hoc comparisons used Mann-Whitney or Fisher’s exact tests with Bonferroni correction.

Results

Four variables differed significantly across cohorts. Comorbidity with personality disorder increased progressively from 32% in 2023 to 57% in 2024 and 68% in 2025 (p=0.008), with the 2023 vs 2025 comparison confirmed post-hoc (pBonf=0.016). Mood stabiliser potentiation also increased markedly, from 7% to 30% and 56% (p<0.001), with significant post-hoc differences for 2023 vs 2024 (pBonf=0.025) and 2023 vs 2025 (pBonf<0.001). Baseline MADRS score decreased significantly, from 40.9 ± 5.8 to 39.5 ± 4.4 and 37.6 ± 3.0 (p=0.030), although scores remained within the severe depression range. Antipsychotic potentiation showed a borderline increase, from 73% to 84% and 96% (p=0.050). Electroconvulsive therapy during the index episode decreased from 24% in 2023 to 6% in 2024 and 16% in 2025, with a non-significant rebound in 2025 (p=0.094). Notably, indicators of chronicity at esketamine initiation showed no significant differences: duration of illness (16.2 vs 22.9 vs 19.6 years; p=0.099), previous episodes (3.6 vs 3.6 vs 3.4; p=0.463), duration of the current episode (30.1 vs 30.0 vs 32.8 months; p=0.052) and antidepressants used (5.1 vs 4.3 vs 4.3; p=0.062). No differences were observed in age, sex or diagnostic distribution.

Conclusions

Across three consecutive years, the profile of patients receiving intranasal esketamine in Gipuzkoa appears to have shifted towards greater clinical complexity, particularly higher comorbidity with personality disorder and more frequent pharmacological potentiation. Baseline depressive severity decreased significantly while remaining within the severe range, and electroconvulsive therapy use decreased compared with the first cohort. Despite broader availability of esketamine, no evidence of earlier referral was observed: patients continued to initiate

References

1. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on its place in therapy. CNS Drugs. 2021;35(8):775–788.
2. Zhdanava M, Pilon D, Shah A, et al. Real-world treatment patterns and characteristics among patients with treatment-resistant depression initiated on esketamine. J Affect Disord. 2023;324:329–338.
3. Samalin L, Mekaoui L, Röthärmel M, et al. Use of esketamine nasal spray in patients with treatment-resistant depression in routine practice: a real-world French study. Depress Anxiety. 2024;2024:7262794.