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 June 25, 2026 Luca Persico, Giacomo D’andrea, Clara Cavallotto et al.
Intranasal 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.