Sex- and Age-Stratified Differences in Antidepressant Response to Intranasal Esketamine in Treatment-Resistant Depression: A Secondary Analysis of the REAL-ESK Study
Luca Persico, Giacomo D’andrea, Clara Cavallotto, Serena Panichella, Alessia Santeusanio, Alessandra di Tullio, Michela D'angola, Arianna Rosati, Antonio Inserra, Gianfranco Tamagnini, Cristina di Puorto, Virginio Salvi, Beniamino Tripodi, Domenico de Berardis, Vassilis Martiadis, Milena Piccirillo, F. Raffone, Tommaso Vannucchi, Andrea Barra, Matteo Lupi, Livia Miotti, Andrea di Cesare, Mauro Pettorruso
Clinical Neuropsychopharmacology and Addiction June 25, 2026 Peer reviewed DOI: 10.53941/cna.2026.100009 via OpenAlex
Summary
Intranasal esketamine (ESK-NS) significantly improved depression scores over three months in patients with treatment-resistant depression, with a notable decrease in Montgomery–Åsberg Depression Rating Scale (MADRS) scores. Men had lower MADRS scores than women at the three-month mark and showed higher response and remission rates. Age-stratified analyses revealed minor non-significant sex differences in those under 65, while a numerical advantage for men was observed in those 65 and older, which should be considered exploratory.
Study at a glance
| Design | secondary analysis |
|---|---|
| Sample size | 210 |
| Population | patients with treatment-resistant depression treated with intranasal esketamine |
| Key finding | Men had lower MADRS scores than women at three months and showed higher response and remission rates. |
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.