Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials

Women have about a twofold greater lifetime risk of major depressive disorder than men and frequently differ from men in clinical presentation, comorbidities and treatment course. Previous large observational studies have reported earlier age at onset, greater episode severity and longer episode duration in women, and sex differences have been reported for response and adverse effects with conventional antidepressants. Findings have been mixed for newer treatments: some studies report no sex difference in rapid-acting ketamine response, while others show variable effects related to menopausal status or hormone therapy with biogenic-amine antidepressants. Jones and colleagues conducted a post hoc analysis of three short-term, phase 3 randomized controlled TRANSFORM trials of esketamine nasal spray plus a newly initiated oral antidepressant in patients with treatment-resistant depression (TRD). The analysis aimed primarily to determine whether efficacy (change in depressive symptoms, response and remission rates, and comorbid anxiety) and overall safety differ between women and men. Secondarily, among women the investigators examined whether outcomes varied by menopausal status or by use of systemic hormonal therapy, and whether clinical factors differentiated responders from non-responders to inform clinical decision-making for women with TRD.

The analysis used data from three phase 3, double-blind, active-controlled, multicentre TRANSFORM trials. Each trial had three phases: a 4-week screening/prospective observational phase to identify non-responders to current antidepressant therapy, a 4-week double-blind treatment phase during which patients received twice-weekly intranasal esketamine or matching placebo together with a newly initiated daily oral antidepressant (SSRI or SNRI), and a post-treatment safety follow-up. TRANSFORM-1 and TRANSFORM-2 enrolled adults aged 18–64 and were pooled for analyses; TRANSFORM-3 enrolled adults aged ≥65 and was analysed separately. Key eligibility required non-response to at least two prior oral antidepressants during the current episode; major exclusions included recent suicidality, psychotic or bipolar disorder, recent moderate-to-severe substance use disorder, and positive drug screens. Dosing varied by study: TRANSFORM-1 used fixed 56 mg and 84 mg doses; TRANSFORM-2 used flexible dosing beginning at 56 mg with possible escalation to 84 mg; TRANSFORM-3 used flexible dosing with options 28 mg, 56 mg and 84 mg. Independent, blinded raters assessed depressive symptoms with the Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline and during treatment. Secondary and patient-reported measures included the Sheehan Disability Scale (SDS), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder-7 (GAD-7; assessed in TRANSFORM-1/2). Female reproductive lifecycle and hormone use were systematically documented with the Massachusetts General Hospital questionnaire. Efficacy analyses included all randomized patients who received at least one dose of intranasal study drug and one dose of oral antidepressant; safety analyses included all patients who received at least one dose of either medication. TRANSFORM-1 and TRANSFORM-2 data were pooled. The primary endpoint was change from baseline to day 28 in MADRS total score and was analysed by mixed-effects model for repeated measures (MMRM) with baseline MADRS as covariate and fixed effects for treatment, study (pooled TRANSFORM-1/2), region, oral antidepressant class (SSRI or SNRI), day, sex and relevant interactions; patient was a random effect. SDS and PHQ-9 used the same MMRM framework with their respective baselines as covariates. Change in GAD-7 was analysed by analysis of covariance. Response (≥50% MADRS reduction) and remission (MADRS ≤ 12) at day 28 were compared by treatment and sex using the generalized Cochran–Mantel–Haenszel test. Adverse events were summarised by treatment group and sex. The trials had ethics approval and all participants provided written informed consent.

Of 711 randomized patients across the TRANSFORM trials, efficacy was evaluated in 702 patients (464 women, 238 men) and safety in 705 patients. Completion rates of the double-blind phase were high for both sexes (women 90.7% [427/471]; men 86.3% [207/240]). Baseline demographics and psychiatric history were generally similar between women and men within each study; by design TRANSFORM-3 enrolled older patients (≥65). In pooled TRANSFORM-1/2 about 48.0% (182/379) of women were pre-menopausal. Common medical comorbidities included hypertension, cardiovascular disease, diabetes and thyroid disease, with thyroid disease and levothyroxine use more common in women; cardiovascular disease and diabetes were more common in older men. Mean MADRS scores decreased from baseline to day 28 in all groups, with greater improvement in patients treated with esketamine plus an oral antidepressant versus antidepressant plus placebo for both women and men. Reported mean (SD) MADRS change at day 28 was, in pooled TRANSFORM-1/2: women esketamine/antidepressant −20.3 (13.19) versus antidepressant/placebo −15.8 (14.67); men esketamine/antidepressant −18.3 (14.08) versus antidepressant/placebo −16.0 (14.30). In TRANSFORM-3 the corresponding values were: women −9.9 (13.34) versus −6.9 (9.65); men −10.3 (11.96) versus −5.5 (7.64). Least-squares mean differences versus antidepressant/placebo reported in the discussion were in the clinically meaningful range (about 2–3 points): in pooled TRANSFORM-1/2 the treatment difference was numerically larger in women (LS mean difference −4.5, SE 1.41; 95% CI −7.26, −1.70) than men (LS mean difference −1.6, SE 2.04; 95% CI −5.60, 2.41); in TRANSFORM-3 the point estimates favored men numerically but confidence intervals overlapped. The MMRM analyses found no statistically significant main effect of sex or treatment-by-sex interaction (p > 0.35). Responder and remission proportions at day 28 were numerically higher with esketamine/antidepressant than with antidepressant/placebo for both sexes. In TRANSFORM-3 the remission (but not response) rate was numerically higher among older women versus older men, but numbers were small. By menopausal status (TRANSFORM-1/2), pre-menopausal and post-menopausal women receiving esketamine achieved similar response rates; a small peri-menopausal cohort (n ≈ 24–25) had numerically lower response. Hormonal therapy use showed a differential pattern: in the antidepressant/placebo arm hormone users had higher response at day 28 (73.7% [14/19]) than non-users (40.3% [48/119]), whereas in the esketamine/antidepressant arm response was 54.2% (28/48) in hormone users versus 62.3% (104/167) in non-users. Improvements in functioning (SDS) and self-reported depressive symptoms (PHQ-9) mirrored MADRS findings, with no significant sex effect or treatment-by-sex interaction (p > 0.20). For GAD-7 there was no treatment-by-sex interaction (p > 0.52); a trend for a sex effect (p = 0.07) suggested greater anxiety score change in women irrespective of treatment. The most common treatment-emergent adverse events (incidence > 20% in esketamine groups) were nausea, dissociation, dizziness and vertigo. Nausea and dissociation occurred at higher rates in women than men across age groups. Patterns for dizziness and vertigo varied by age subgroup. Increased blood pressure was reported overall in 9.3% of esketamine-treated patients but was numerically higher in younger men (12.8%) and older women (17.8%). Most adverse events were mild to moderate, occurred on dosing days, resolved the same day, and were generally not treatment-limiting. Median duration of dissociation events ranged from about 0.7 to 1 hour; 3.1% were classified as severe, none were considered serious. Serious adverse events during esketamine treatment were reported for two women (0.7%) and four men (2.9%); one male participant died on day 55 following a road traffic accident that was considered doubtfully related to study medication. Discontinuations due to adverse events occurred in 4.8% (20/415) of esketamine-treated patients versus 1.7% (5/287) in the placebo arm; among esketamine discontinuations 12 were women and 8 were men, with a range of events cited (e.g., increased systolic blood pressure, dizziness, nausea, depression, headache).

Jones and colleagues interpret the results as showing similar and clinically meaningful antidepressant benefit of esketamine nasal spray plus an oral antidepressant in both women and men with TRD over 4 weeks. Although point estimates of treatment difference versus antidepressant/placebo varied by sex and by study (pooled TRANSFORM-1/2 versus TRANSFORM-3), the treatment-by-sex interaction was not statistically significant and confidence intervals overlapped, supporting no robust sex-based efficacy difference. The magnitude of the between-group effect for both sexes was stated to be within the range considered clinically meaningful (about 2–3 points on MADRS) and comparable with effects seen in trials of recently approved biogenic-amine antidepressants versus placebo. The authors note that the absence of sex differences may relate in part to similar pharmacokinetics of esketamine between males and females, and they situate their findings amid inconsistent prior literature on sex differences for other antidepressant classes. Regarding menopausal status and hormone use, the analysis suggested that post-menopausal women achieved benefit comparable to pre-menopausal women; peri-menopausal women constituted a small group with numerically lower response. Use of hormonal therapy was associated with higher response in the antidepressant/placebo arm but did not increase response in the esketamine arm. The investigators highlight that adverse events such as nausea and dissociation were reported more commonly in women and that increased blood pressure was relatively more frequent in older women. Key limitations acknowledged by the authors include the post hoc nature of the sex-stratified analyses, lack of stratification by sex at randomization, small sample sizes for subgroup analyses (particularly menopausal subgroups and TRANSFORM-3), differences in dosing in TRANSFORM-3 (including a lower 28 mg option), exclusion of patients with some common comorbidities, and limited racial diversity, all of which constrain generalisability. The authors recommend cautious interpretation of subgroup findings and note that the overall findings support data-informed decision-making for women with TRD treated with esketamine.

These post hoc analyses support that esketamine nasal spray, combined with an oral antidepressant, provides antidepressant efficacy and an overall safety profile in women with TRD that is not notably different from that observed in men. The findings are presented as additional evidence to inform clinical decision-making for women with treatment-resistant depression.