Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial.

In adults with treatment-resistant depression who had not responded to at least two prior oral antidepressants, esketamine nasal spray taken alone (without an oral antidepressant) reduced depressive symptoms more than a placebo. Over four weeks, both a 56 mg and an 84 mg dose of esketamine produced significantly greater improvements on the Montgomery-Åsberg Depression Rating Scale than placebo, with effects apparent as early as 24 hours after the first dose. Common side effects included nausea, dissociation, dizziness, and headache. The findings suggest that esketamine monotherapy could offer a new treatment option for patients who cannot tolerate or do not respond to oral antidepressants.

Study at a glance

Abstract

Esketamine nasal spray, administered in conjunction with an oral antidepressant, is approved for treatment-resistant depression (TRD). However, the efficacy of esketamine nasal spray administered as monotherapy for patients with TRD has not yet been evaluated. To assess the efficacy and safety of esketamine monotherapy compared to placebo in reducing depressive symptoms in patients with TRD. This phase 4, double-blind, placebo-controlled randomized clinical trial was conducted from November 2020 to January 2024 at 51 outpatient centers in the US. Adults with major depressive disorder (DSM-5 criteria) without psychotic features who experienced inadequate response (≤25% improvement) to 2 or more oral antidepressants during the current depressive episode were eligible for inclusion. Data analyses were conducted from March 1, 2024, to July 8, 2024. After a 2-week or longer antidepressant-free period, participants were randomized at a 1:1:2 ratio to fixed-dose intranasal esketamine (56 mg or 84 mg) or matching intranasal placebo, administered twice weekly for 4 weeks. Change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 28 (primary efficacy end point) and to 24 hours post-first dose (day 2; key secondary efficacy end point) were analyzed by a mixed-effects model using repeated measures. In this multicenter randomized clinical trial, 378 participants who met prerandomization MADRS severity criteria received 1 or more study drug doses (esketamine, 56 mg [n = 86]; esketamine, 84 mg [n = 95]; or placebo [n = 197]). Mean (SD) participant age was 45.4 (14.1) years, 231 participants (61.1%) were female, and baseline mean (range) MADRS total score was 37.3 (28-50). At day 28, the least-square (LS) mean difference (SE) between esketamine and placebo was -5.1 (1.42) (95% CI, -7.91 to -2.33) for the 56-mg dose and -6.8 (1.38) (95% CI, -9.48 to -4.07) for the 84-mg dose (for each, 2-sided P < .001). Observed effect sizes were 0.48 and 0.63 for the 56-mg and 84-mg dose groups, respectively. At day 2 (approximately 24 hours post-first dose), the between-group difference was significant for both esketamine doses: -3.8 (1.29) (95% CI, -6.29 to -1.22; 2-sided P = .004) for 56 mg and -3.4 (1.24) (95% CI, -5.89 to -1.00; 2-sided P = .006) for 84 mg. The most common treatment-emergent adverse events reported for esketamine (combined doses) were nausea (56 participants [24.8%]), dissociation (55 [24.3%]), dizziness (49 [21.7%]), and headache (43 [19.0%]). According to results of this multicenter, double-blind randomized clinical trial, esketamine monotherapy may expand treatment options for adult patients with TRD by addressing an unmet need of patients experiencing treatment-limiting tolerability concerns and nonresponse with oral antidepressants. ClinicalTrials.gov Identifier: NCT04599855.