Efficacy and Safety of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression Who Completed a Second Induction Period: Analysis of the Ongoing SUSTAIN-3 Study

Women have about a twofold greater lifetime risk of major depressive disorder than men and often differ from men in clinical presentation, comorbidities, age at onset, episode duration, and treatment response. Previous studies have reported inconsistent sex differences in antidepressant efficacy and tolerability, and factors such as reproductive lifecycle stage, use of hormone therapy, neuronal circuitry, and drug metabolism have been proposed as contributors. Esketamine, the S-enantiomer of ketamine and an NMDA receptor antagonist, is approved in several jurisdictions for treatment-resistant depression (TRD) in conjunction with an oral antidepressant; its pivotal Phase 2 and Phase 3 trials provide a dataset suitable for secondary analyses of sex effects. Jones and colleagues undertook a post hoc analysis of three short-term Phase 3 trials (TRANSFORM-1, TRANSFORM-2, TRANSFORM-3) to assess whether efficacy and safety of esketamine nasal spray differ between women and men with TRD. The primary aims were to compare improvement in depressive symptoms, comorbid anxiety, and response and remission rates by sex; secondary aims focused on whether menopausal status or use of hormonal therapy among women influenced these outcomes and whether clinical factors distinguished responders from non-responders.

The analysis uses data from three Phase 3, double-blind, active-controlled, multicentre trials (TRANSFORM-1, TRANSFORM-2, TRANSFORM-3) conducted between August 2015 and February 2018. Each study comprised a 4-week screening/prospective observational phase to assess response to the patient’s current antidepressant(s), a 4-week double-blind treatment phase in which non-responders were randomised to twice-weekly esketamine nasal spray or matching placebo nasal spray plus a newly initiated daily oral antidepressant (SSRI or SNRI), and a post-treatment safety follow-up (up to 24 weeks for TRANSFORM-1/2 and 2 weeks for TRANSFORM-3). At randomisation participants met criteria for TRD, defined as non-response to at least two prior oral antidepressants in the current episode. Key exclusions included recent suicidal intent or behaviour, psychotic or bipolar disorders, recent moderate/severe substance use disorder, and positive drug screens. Dosing differed by study: TRANSFORM-1 used fixed esketamine doses of 56 mg and 84 mg; TRANSFORM-2 used flexible dosing of 56 mg and 84 mg; TRANSFORM-3 (older adults ≥65 years) included 28 mg, 56 mg, and 84 mg options. Independent, blinded raters assessed depressive symptoms with the Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline and during treatment. 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). Reproductive lifecycle status and exogenous hormone use (oral contraceptives, hormone replacement therapy) were prospectively documented using the Massachusetts General Hospital Female Reproductive Lifecycle and Hormones Questionnaire. Efficacy analyses included all randomised 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 were pooled for primary analyses. The primary endpoint was change from baseline to day 28 in MADRS total score, analysed by sex using a mixed-effects model for repeated measures (MMRM) with baseline score as covariate and fixed effects for treatment, study (for pooled analyses), region, oral antidepressant class, day, sex, and their interactions, plus a random patient effect. SDS and PHQ-9 used similar MMRM models; GAD-7 change used analysis of covariance. Response (≥ 50% reduction in MADRS) and remission (MADRS ≤ 12) at day 28 were analysed by treatment and sex using the Cochran–Mantel–Haenszel test. Adverse events were summarised by frequency by treatment group and sex.

Of 711 randomised patients across the TRANSFORM trials, 702 were included in efficacy analyses (464 women, 66.1%; 238 men, 33.9%) and 705 in safety analyses. Most participants completed double-blind treatment (women 90.7%; men 86.3%). Baseline demographic and clinical characteristics were generally similar between sexes within each study; TRANSFORM-3 enrolled older patients by design. In pooled TRANSFORM-1/2, 71.5% of patients had comorbid anxiety symptoms at baseline, with no sex difference in prevalence. Common medical comorbidities included hypertension, cardiovascular disease, diabetes and thyroid disease, with cardiovascular disease and diabetes more frequent in older men and thyroid disease more common in women. Mean reductions in MADRS total score from baseline to day 28 were greater with esketamine plus oral antidepressant than with oral antidepressant plus placebo for both sexes. In pooled TRANSFORM-1/2 the mean (SD) MADRS change at day 28 was −20.3 (13.19) for women receiving esketamine/antidepressant versus −15.8 (14.67) for women receiving antidepressant/placebo; corresponding values for men were −18.3 (14.08) versus −16.0 (14.30). In TRANSFORM-3 the mean (SD) changes were −9.9 (13.34) versus −6.9 (9.65) for women, and −10.3 (11.96) versus −5.5 (7.64) for men. The analysis did not demonstrate a significant sex effect or treatment-by-sex interaction (p > 0.35). The between-group differences versus antidepressant/placebo for both sex subgroups fell within a range the authors describe as clinically meaningful (approximately 2–3 points). Responder and remission proportions at day 28 were numerically higher with esketamine/antidepressant than with antidepressant/placebo in both women and men. In TRANSFORM-3, remission (but not response) was numerically higher among older women than older men, but small sample sizes limit firm conclusions. By menopausal status in TRANSFORM-1/2, pre-menopausal and post-menopausal women treated with esketamine had similar response rates; peri-menopausal women (n = 25) showed a numerically lower response to esketamine/antidepressant. Hormonal therapy use in TRANSFORM-1/2 was associated with a higher response rate at day 28 in the antidepressant/placebo arm (hormone users 73.7% [14/19] vs non-users 40.3% [48/119]) but not in the esketamine/antidepressant arm (hormone users 54.2% [28/48] vs non-users 62.3% [104/167]). Patient-reported outcomes showed treatment benefit for functioning (SDS) and self-reported depressive symptoms (PHQ-9) for both sexes in pooled TRANSFORM-1/2; analyses for SDS and PHQ-9 did not show significant sex effects or treatment-by-sex interactions (p > 0.20). For GAD-7 there was no treatment-by-sex interaction (p > 0.52), although a sex effect trended toward significance (p = 0.07), indicating greater change from baseline among women regardless of treatment. The most frequent adverse events (incidence > 20% in esketamine recipients) were nausea, dissociation, dizziness and vertigo. Incidences of nausea and dissociation were higher among women than men across ages. Patterns for dizziness and vertigo varied by age subgroup and sex. Increased blood pressure was reported in 9.3% overall and was numerically higher among younger men (12.8%) and older women (17.8%). Most adverse events occurred on dosing days, were mild or moderate, resolved the same day, and were generally not treatment-limiting. Dissociation events had a median duration of about 0.7–1 hour within the post-dose observation period; 3.1% of dissociation events were classified as severe and none were judged serious. Serious adverse events during esketamine treatment were reported for two women (0.7%) and four men (2.9%); one death occurred on day 55 after a road traffic accident that was considered doubtfully related to study drug. Discontinuations due to adverse events occurred in 4.8% (20/415) of esketamine-treated patients versus 1.7% (5/287) of placebo nasal spray recipients; 12 women and 8 men discontinued esketamine prematurely for adverse events.

Jones and colleagues interpret the findings as indicating similar and generally robust antidepressant effects of esketamine nasal spray plus an oral antidepressant in both women and men with TRD over the 4-week double-blind treatment period. Although the magnitude of the between-group difference versus oral antidepressant plus placebo varied numerically by sex across studies (for example, numerically larger in women in pooled TRANSFORM-1/2 and larger in men in TRANSFORM-3), the treatment-by-sex interaction was not statistically significant and confidence intervals overlapped, so the authors do not conclude sex-based differential efficacy. They note the observed between-group differences fall within a range considered clinically meaningful and are consistent with effects seen in trials of recently approved biogenic amine antidepressants compared with placebo. The discussion raises possible explanations for the absence of sex differences, including the lack of sex differences in esketamine pharmacokinetics reported elsewhere, and contrasts the results with inconsistent sex effects reported for other antidepressant classes. The authors highlight findings related to reproductive factors: peri-menopausal women comprised a small subgroup with numerically lower response to esketamine, while post-menopausal women appeared to derive similar benefit to pre-menopausal women; concomitant hormonal therapy increased response in the antidepressant/placebo arm but not in the esketamine arm. Safety findings showed some sex-specific patterns, with higher rates of nausea and dissociation in women and variable patterns for dizziness, vertigo and increased blood pressure by age and sex. The authors relate this to broader evidence that women have higher rates of adverse drug reactions for some medications. Limitations acknowledged by the study team include the post hoc nature of the analyses, lack of stratification by sex at randomisation, higher female participation which nonetheless reflects the epidemiology of depression, small sample sizes for menopausal subgroup and TRANSFORM-3 analyses (the latter also differed in dosing, including a 28 mg option), exclusion of patients with some common comorbidities, and low representation of non-white participants. These factors limit the generalisability of some subgroup findings and warrant cautious interpretation.

These post hoc analyses support the antidepressant efficacy and overall safety of esketamine nasal spray for women with treatment-resistant depression, without notable differential effects based on sex. The authors suggest the findings contribute to data-informed decision-making for women with TRD.