Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial

Abstract

Importance: Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants.

Objective: To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD).

Design, setting, and participants: This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings.

Interventions: In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks.

Main outcomes and measures: The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.

Results: Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy).

Conclusions and relevance: In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials.

Trial registration: clinicaltrials.gov identifier: NCT01998958.

Figure 1.. Disposition of Participants

Seven participants started the follow-up phase earlier than day 74, having received 2 weeks of study drug during the open-label phase of the study. AE indicates adverse event; ECG, electrocardiogram; MDD, major depressive disorder; OL, open-label; QIDS-SR₁₆, 16-item Quick Inventory of Depressive Symptoms–Self-Report; SAFER, State vs Trait, Assessibility, Face Validity, Ecological Validity, Rule of Three Ps; TRD, treatment-resistant depression; WBP, withdrawal by participant. ^aParticipants could have multiple reasons for being a screen failure. ^bParticipants entered the follow-up phase if they did not choose to withdraw from the study.

Figure 2.. Mean Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score Over Time in Double-Blind Phase

Changes shown in periods 1 (A) and 2 (B). Period 2 consisted only of participants who had received placebo in period 1 and had moderate to severe symptoms (n = 28). Period 1 (days 1-8) and period 2 (days 8-15) are discussed in the Design section of the Methods and shown in the vertical axis of Figure 1. BL indicates baseline; 2H, 2 hours post dose. Error bars indicate SE.

Figure 3.. MADRS Total Score: Mean Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score From Baseline to Follow-up End Point for Participants Who Entered the Open-Label Phase

Period 1 (days 1-8), period 2 (days 8-15), open-label period (days 15-74), and the follow-up period (days 74-130) are discussed in the Design section of the Methods and shown in the vertical axis of Figure 1. BL indicates baseline; error bars, SE.