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

Treatment-resistant depression remains a major clinical burden because many patients do not respond adequately to sequential antidepressant treatments. Intranasal esketamine offers a rapidly acting, glutamate-based mechanism that differs from conventional monoaminergic drugs, but most studies have focused on average treatment effects rather than whether response varies by sex or age. The paper frames this gap in terms of plausible biological differences in endocrine state, brain plasticity, neuroinflammation, and ageing-related changes that could alter how esketamine produces antidepressant effects. Persico and colleagues set out to use real-world data from the REAL-ESK study to assess the overall antidepressant effect of intranasal esketamine over three months, test whether longitudinal depression scores and categorical outcomes differed by sex, and explore whether age modified these patterns using a <65 versus ≥65 years cut-off. The study is presented as a secondary analysis designed to examine heterogeneity in routine clinical practice rather than efficacy under trial conditions.

This was a secondary analysis of REAL-ESK, a multicentre, observational, retrospective Italian cohort study of adults with treatment-resistant depression treated with intranasal esketamine in routine care. Data were drawn from medical records across university, hospital, and community psychiatric settings, with assessments at baseline (T0), about one month (T1), and about three months (T2). The sample in this analysis included 210 adults with unipolar treatment-resistant depression, and the report states that concomitant SSRI or SNRI treatment was used in line with regulatory guidance. The primary outcome for this analysis was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score across the three time points. Response was defined as at least a 50% reduction in MADRS from baseline, and remission as a MADRS score of 10 or less at T2. Safety outcomes included treatment-emergent adverse events and discontinuation. The dosing schedule followed the summary of product characteristics: younger adults generally started at 56 mg, with dose and maintenance adjustments up to 84 mg; in those older than 65 years, treatment began at 28 mg with adjustments in 28 mg increments. The main longitudinal analysis used repeated-measures ANOVA with time as the within-subject factor, with Greenhouse-Geisser correction when sphericity was violated. Sex differences at individual time points were tested with post-hoc contrasts corrected using the Holm procedure. Response and remission were compared with chi-squared tests, and risk ratios with 95% confidence intervals were calculated when relevant. The authors also performed an age-stratified analysis (<65 versus ≥65 years), running separate repeated-measures models within each age group and comparing male-female change scores with Welch’s t-tests. A sensitivity analysis additionally adjusted the main longitudinal sex effect for age, baseline MADRS severity, and psychiatric comorbidity. The analyses were carried out in SPSS and JASP, with two-sided significance set at 0.05.

The analysed cohort comprised 210 adults with a mean age of 52.84 ± 12.63 years; 107 were male and 103 were female. Baseline MADRS scores were similar by sex, with females at 34.17 ± 10.14 and males at 35.35 ± 9.45. Across the full sample, depressive symptoms fell substantially over time. Repeated-measures ANOVA showed a strong time effect on MADRS scores (F = 340.707, p < 0.001, partial eta squared = 0.297), indicating marked improvement from baseline to follow-up. There was also a significant time-by-sex interaction (F = 3.283, p = 0.043) and a significant main sex effect (F = 4.643, p = 0.032), suggesting that the pattern of improvement differed modestly between men and women. In the covariate-adjusted sensitivity analysis, the direction of the sex-related pattern remained the same. At T2, categorical outcomes matched the continuous score findings. Response occurred in 59.2% of males (63/107) versus 41.1% of females (42/103), and remission in 32.0% of males versus 16.5% of females (17/103); both differences were statistically significant. The paper reports that men had lower MADRS scores at T2 than women, with a mean difference of -3.95 and Holm-adjusted p = 0.023. In the age-stratified analysis, both sexes improved strongly in the <65 years group and the ≥65 years group. Among participants younger than 65 years, male-female differences in MADRS reduction were small and not significant at either T1 or T2 after correction. Among participants aged 65 years or older, the differences numerically favoured men and were larger, especially at T2, but they did not remain significant after Holm correction and were presented as exploratory. The extracted text does not clearly report any age-stratified response or remission percentages. Safety findings were broadly similar between sexes. There were no significant differences in hypertension, dissociative phenomena, sedation, hypomania, psychomotor agitation, anxiety, headache/dizziness, or paresthesia/diplopia. Discontinuation occurred in 9.3% of males and 3.9% of females, but this difference was not statistically significant.

The authors interpret the findings as showing that intranasal esketamine produced a substantial and sustained antidepressant effect in a naturalistic treatment-resistant depression cohort over three months. They argue that both women and men benefited, but that men showed somewhat greater improvement by the end of follow-up, with higher response and remission rates. They emphasise that the age-stratified signal was small in younger adults and numerically larger in those aged 65 years or older, but that this pattern did not survive correction for multiple comparisons and should therefore be considered exploratory rather than definitive evidence of a sex-by-age interaction. Persico and colleagues place the results within current models of rapid-acting antidepressants, noting that esketamine is thought to act through glutamatergic disinhibition, increased AMPA throughput, and downstream BDNF and mTOR-related synaptogenesis. They suggest that these plasticity mechanisms may be shaped by endocrine and ageing-related factors, while also cautioning that their data do not include direct measurements of hormonal status, menopause, or pharmacokinetics. They discuss several possible contributors to the observed sex and age patterns, including vascular ageing, immune-inflammatory tone, white-matter integrity, concomitant medications such as benzodiazepines, illness course, and cognitive reserve. They also mention, as a hypothesis for future study, that menstrual cycle phase or hormonal milieu could modulate response, but state that this was not measured here. The authors note that tolerability and discontinuation were broadly comparable between sexes, so safety does not appear to explain the outcome differences. They stress the limitations of the observational design, including lack of randomisation, incomplete control over concomitant treatments, and residual confounding. They also highlight that the older subgroup was small, limiting fully adjusted analyses and making the age-stratified findings unstable. Overall, they argue that the results justify prospective studies specifically powered to test sex-by-age effects and to examine hormonal, vascular, metabolic, and medication-related moderators of response.