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Sex- and Age-Stratified Differences in Antidepressant Response to Intranasal Esketamine in Treatment-Resistant Depression: A Secondary Analysis of the REAL-ESK Study

  • Giacomo d'Andrea 1,2,†,   
  • Luca Persico 1,†,   
  • Clara Cavallotto 1,*,   
  • Serena Panichella 1,   
  • Alessia Santeusanio  1,   
  • Alessandra Di Tullio 1,   
  • Michela D'Angola 1,   
  • Arianna Rosati 1,   
  • Antonio Inserra 1,   
  • Gianfranco Tamagnini 2,   
  • Cristina Di Puorto 3,   
  • Virginio Salvi 4,   
  • Beniamino Tripodi 4,   
  • Domenico De Berardis  5,   
  • Vassilis Martiadis 6,   
  • Milena Piccirillo 3,   
  • Fabiola Raffone 6,   
  • Tommaso Vannucchi 7,   
  • Andrea Barra 8,   
  • Matteo Lupi 9,   
  • Livia Miotti 10,   
  • Andrea Di Cesare 11,   
  • Mauro Pettorruso 1,2

Received: 21 Feb 2026 | Revised: 31 May 2026 | Accepted: 16 Jun 2026 | Published: 25 Jun 2026

Abstract

Background: Intranasal esketamine (ESK-NS) is an effective treatment for treatment-resistant depression (TRD), but whether antidepressant outcomes differ by sex and age remains insufficiently explored. Methods: This secondary analysis of the REAL-ESK study included 210 patients with TRD treated with ESK-NS in routine clinical practice and assessed at baseline (T0), one month (T1), and three months (T2). The primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) scores. Repeated-measures ANOVA tested Time and Time × Sex effects, with post-hoc contrasts corrected using the Holm procedure. Response and remission at T2 were compared by sex. Exploratory analyses stratified patients by age (<65 vs. ≥65 years). Results: MADRS scores decreased markedly over time (Time: F = 340.707, p < 0.005), with a significant Time × Sex interaction (F = 3.283, p = 0.043). At T2, men had lower MADRS scores than women (Δ = −3.95, Holm p = 0.023) and showed higher response and remission rates. In age-stratified analyses, sex differences were small and non-significant among participants <65 years. In those ≥65 years, the T2 contrast numerically favored men, but did not reach significance in post-hoc Holm’s correction and should be considered exploratory. Safety outcomes and discontinuation rates were broadly comparable between sexes. Conclusions: ESK-NS was associated with substantial antidepressant improvement in a real-world TRD cohort. Findings suggest a modest overall male advantage, while age-stratified patterns remain exploratory. Endocrine, vascular, inflammatory, pharmacokinetic, and treatment-context factors should be investigated in prospective studies.

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DOI
10.53941/cna.2026.100009
Issue
Volume 2, Issue 2
How to Cite
d’Andrea, G.; Persico, L.; Cavallotto, C.; Panichella, S.; Santeusanio , A.; Di Tullio, A.; D’Angola, M.; Rosati, A.; Inserra, A.; Tamagnini, G.; Di Puorto, C.; Salvi, V.; Tripodi, B.; De Berardis , D.; Martiadis, V.; Piccirillo, M.; Raffone, F.; Vannucchi, T.; Barra, A.; Lupi, M.; Miotti, L.; Di Cesare, A.; Pettorruso, M. Sex- and Age-Stratified Differences in Antidepressant Response to Intranasal Esketamine in Treatment-Resistant Depression: A Secondary Analysis of the REAL-ESK Study. Clinical Neuropsychopharmacology and Addiction 2026, 2 (2), 9. https://doi.org/10.53941/cna.2026.100009.
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