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 DOI: 10.53941/cna.2026.100009 via OpenAlex
Summary
AI-generated from the abstractIntranasal esketamine substantially reduced depression severity in 210 patients with treatment-resistant depression treated in routine clinical practice. Depression scores improved markedly over three months, and men showed a modest advantage over women by the end of treatment, with lower depression ratings and higher rates of response and remission. Among patients under 65 years, sex differences were small and not statistically significant; among those 65 and older, men appeared to benefit more numerically, but this difference did not hold up after statistical correction and remains uncertain. Discontinuation rates and safety outcomes were similar between sexes. The authors call for future studies to examine hormonal, vascular, inflammatory, and other factors that might explain the observed sex differences.
Study at a glance
| Characteristics | Secondary analysis of a prospective cohort study Peer reviewed |
|---|---|
| Sample size | 210 |
| Population | Adults with treatment-resistant depression treated with intranasal esketamine in routine clinical practice |
| Topics | Depression |
| Keywords | Discontinuation Antidepressant Depression economics Rating scale Analysis of variance |
| Key finding | Intranasal esketamine was associated with substantial antidepressant improvement, and men showed a modest overall advantage in depression outcomes compared to women, though age-stratified sex differences were not statistically significant after correction. |
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.