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

This post hoc analysis of three RCTs using esketamine in patients with treatment-resistant depression (TRD) (n=721) found no sex differences when using esketamine for TRD. Across the three trials, it was found that the efficacy and overall safety of esketamine in patients with TRD were similar for both men and women. The most common adverse events in esketamine-treated patients were nausea, dissociation, dizziness, and vertigo, each reported at a rate higher in women than men.

Abstract

“The objective of this analysis was to determine if there are sex differences with esketamine for treatment-resistant depression (TRD). Post hoc analyses of three randomized, controlled studies of esketamine in patients with TRD (TRANSFORM-1, TRANSFORM-2 [18–64 years], TRANSFORM-3 [≥ 65 years]) were performed. In each 4-week study, adults with TRD were randomized to esketamine or placebo nasal spray, each with a newly initiated oral antidepressant. Change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was assessed by sex in pooled data from TRANSFORM-1/TRANSFORM-2 and separately in data from TRANSFORM-3 using a mixed-effects model for repeated measures. Use of hormonal therapy was assessed in all women, and menopausal status was assessed in women in TRANSFORM-1/TRANSFORM-2. Altogether, 702 adults (464 women) received ≥ 1 dose of intranasal study drug and antidepressant. Mean MADRS total score (SD) decreased from baseline to day 28, more so among patients treated with esketamine/antidepressant vs. antidepressant/placebo in both women and men: TRANSFORM-1/TRANSFORM-2 women—esketamine/antidepressant -20.3 (13.19) vs. antidepressant/placebo -15.8 (14.67), men—esketamine/antidepressant -18.3 (14.08) vs. antidepressant/placebo -16.0 (14.30); TRANSFORM-3 women—esketamine/antidepressant -9.9 (13.34) vs. antidepressant/placebo -6.9 (9.65), men—esketamine/antidepressant -10.3 (11.96) vs. antidepressant/placebo -5.5 (7.64). There was no significant sex effect or treatment-by-sex interaction (p > 0.35). The most common adverse events in esketamine-treated patients were nausea, dissociation, dizziness, and vertigo, each reported at a rate higher in women than men. The analyses support antidepressant efficacy and overall safety of esketamine nasal spray are similar between women and men with TRD. The TRANSFORM studies are registered at clinicaltrials.gov (identifiers: NCT02417064 (first posted 15 April 2015; last updated 4 May 2020), NCT02418585 (first posted 16 April 2015; last updated 2 June 2020), and NCT02422186 (first posted 21 April 2015; last updated 29 September 2021)).”

Authors: Robyn R. Jones, Marlene P. Freeman, Susan G. Kornstein, Kimberely Cooper, Ella J. Daly, Carla M. Canuso & Susan Nicholson

Summary

Post hoc analyses of three studies of esketamine in patients with treatment-resistant depression (TRD) showed no significant sex differences in MADRS total score reduction or treatment-by-sex interaction. The most common adverse events were nausea, dissociation, dizziness, and vertigo, and the overall safety was similar between women and men.

Introduction

Women have a twofold higher risk of major depressive disorder (MDD) than men, and are more likely to experience concurrent symptoms of generalized anxiety disorder, somatoform disorder, bulimia, and atypical depression.

Different factors may explain why women respond differently to antidepressants than men, including differences in neuronal circuitry, hormone levels, and drug metabolism.

Esketamine nasal spray is a first-in-class glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist that has been approved by the US Food and Drug Administration, the European Medicines Agency, and multiple other health authorities for treating treatment-resistant depression.

A post hoc analysis of three short-term phase 3 studies was conducted to determine if there were differences in efficacy and safety between women and men in patients with TRD.

Study design

The TRANSFORM trials examined the effects of esketamine nasal spray on treatment-resistant depression.

Patients

The studies enrolled outpatients with recurrent, moderate-to-severe MDD and had TRD, defined as non-response to two or more oral antidepressants during the current episode.

Key exclusion criteria included suicidal ideation or behavior, psychotic or bipolar disorders, moderate or severe substance use disorder, and positive test result(s) for specified drugs of abuse.

Study drug dosing

Patients continued taking their current antidepressant during the 4-week screening/prospective observational phase. Non-responders were randomized to double-blind treatment with esketamine nasal spray or placebo nasal spray combined with a newly initiated oral antidepressant taken daily.

Assessments

Improvement in symptoms of depression was assessed using the MADRS, and patient-reported outcomes included an assessment of function using the Sheehan Disability Scale and severity of anxiety using the Generalized Anxiety Disorder 7-item Scale.

A clinician-rated questionnaire was used to assess reproductive lifecycle status, history of worsening mood during the luteal phase of the menstrual cycle, length and regularity of menstrual cycles, and use of exogenous hormones.

Statistical analyses

Data from the TRANSFORM-1 and TRANSFORM-2 studies were pooled to analyze efficacy and adverse events.

Baseline characteristics and psychiatric history were summarized by sex using descriptive statistics. Comorbid anxiety was determined using the MINI or GAD-7 total score.

The primary efficacy endpoint in the TRANSFORM studies was analyzed by sex using a mixed-effects model for repeated measures (MMRM). Changes in SDS, PHQ-9, and GAD-7 were analyzed using analysis of covariance.

Response rate and remission rate were evaluated by treatment group and sex, and frequency distributions were provided for adverse events as a measure of safety.

Results

Across the TRANSFORM trials, 702 patients received intranasal study drug and 705 patients received either study drug. Most randomized patients completed double-blind treatment.

In the TRANSFORM studies, women and men were similar with respect to demographic and baseline clinical characteristics. Women received an MDD diagnosis at an earlier age and had a shorter current episode of MDD.

The majority of patients in the TRANSFORM-1/2 studies had comorbid anxiety symptoms at baseline, with no difference in prevalence between sexes. Hormonal therapy was common in pre-menopausal women, perimenopausal women, and post-menopausal women, with the exception of higher levothyroxine usage by women.

The MADRS total score decreased from baseline to day 28 among both women and men treated with esketamine/antidepressant compared to antidepressant/placebo. There was no significant sex effect or treatment-by-sex interaction.

In the TRANSFORM trials, esketamine/antidepressant achieved similar response rates in pre-menopausal and post-menopausal women, and a between treatment group trend was observed for response rate among pre-menopausal and post-menopausal women. Hormone therapy had no impact on response rate in the esketamine/antidepressant arm.

Esketamine showed treatment benefit for both women and men in the pooled TRANSFORM-1/TRANSFORM-2 trials. There was no treatment-by-sex-interaction for SDS and PHQ-9, but a trend towards significance for GAD-7.

The most common adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, and vertigo. The incidences of nausea and dissociation were higher among women than among men, regardless of age, and the incidences of vertigo and dizziness were numerically higher and lower, respectively, among younger women vs. younger men.

Esketamine caused serious adverse events in two women and four men, including headache, hip fracture, increased blood pressure, and multiple injuries/road traffic accident.

A minority of patients discontinued intranasal study drug due to adverse events in the TRANSFORM studies (esketamine: 20/415, 4.8%; placebo: 5/287, 1.7%). 12 women and 8 men discontinued study drug prematurely due to multiple events in some cases.

Discussion

Esketamine nasal spray in conjunction with an oral antidepressant improved depressive symptoms in both women and men with TRD, but the treatment-by-sex interaction was not statistically significant. Furthermore, the between-group difference observed vs. antidepressant/placebo was in the range considered clinically meaningful.

Both women and men treated with esketamine/antidepressant had higher proportions of responders and patients in remission at day 28 as compared to antidepressant/placebo, and the treatment benefit of esketamine was observed based on the patient-reported outcomes of functioning, severity of anxiety, and depressive symptoms.

Sex differences in efficacy outcomes have been reported for other antidepressants, although findings have been inconsistent. Differences in study design, patient selection criteria, study drug, and response criteria may explain the inconsistency in these findings across studies.

Although mixed findings have been reported regarding the effect of menopausal status on response to anti-depressants, a pooled analysis of 8 randomized, controlled trials found that older women exhibited lower remission rates on SSRI than younger women, a trend that was reversed for those taking hormone replacement therapy.

Esketamine appears to be equally effective in treating post-menopausal women with TRD as it is in treating pre-menopausal women, suggesting that anti-depressants with a glutamatergic mechanism of action, unlike biogenic amines, may not be impacted by the reproductive life cycle of women.

Esketamine-treated patients experienced dissociation, headache, nausea, dizziness, and vertigo, at a higher rate in women than in men, and increased blood pressure was reported most often among older women.

Limitations

The current post hoc analysis includes a relatively large number of participants, an active-controlled design, validated diagnostic assessments for comorbid psychiatric disorders, and systematic ascertainment of menopausal status and other sex-specific data. However, the results should be interpreted with caution given small sample sizes.