Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression

Abstract

IMPORTANCE Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. OBJECTIVE To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. DESIGN, SETTING, AND PARTICIPANTS In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. INTERVENTIONS Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. MAIN OUTCOMES AND MEASURES Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. RESULTS Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization weretransientdysgeusia,vertigo,dissociation,somnolence,anddizziness(incidence,20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo. CONCLUSIONS AND RELEVANCE For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.

Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results from the Clinical Development Program

“…Safety data were analyzed in an All Randomized, Blinded Trials TRD Population [4][5][6][7]9] and in an All Clinical Trials TRD Population [4][5][6][7][8][9], both including patients who received at least one dose of intranasal study drug.…”

“…and one open-label phase III study of esketamine nasal spray in adults with TRD (Table 1 [4][5][6][7][8][9]).…”

“…Eligible patients received esketamine nasal spray (28 mg (only for patients 65 years and older) to 84 mg twice weekly, once weekly, or every other week; Table 1) in combination with an oral antidepressant for 4-52 weeks. In the phase III studies [5][6][7][8][9], patients received a new oral antidepressant [one of the following options: a selective serotonin reuptake inhibitor (SSRI: escitalopram or sertraline) or a serotonin and norepinephrine reuptake inhibitor (SNRI: duloxetine or venlafaxine extended release)], which was initiated at the start of the induction phase, whereas in the adjunctive phase II study [4], no new antidepressant was initiated and patients were permitted to continue their ongoing oral antidepressant treatment. In the placebo-controlled studies, patients randomized to placebo received intranasal study drug [i.e., water for injection with bittering agent (to imitate the bitter taste of esketamine) and a preservative] that was provided in a disposable nasal spray device with identical appearance and packaging to that of esketamine nasal spray.…”

“…Ketamine, an antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor (an ionotropic glutamate receptor), was shown to exhibit rapid onset and robust, short-term antidepressant effect in patients with treatmentresistant depression (TRD) [1][2][3]. Esketamine, the S-enantiomer of ketamine racemate, was recently approved by the United States (US) Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) as an intranasal formulation for adults with TRD based on efficacy and safety findings from short-term phase II/III studies [4][5][6][7][8][9] and longer-term phase III studies [7,8].…”

Ketamine in Major Depressive Disorder: Mechanisms and Future Perspectives

“…Relapse was significantly delayed in the ketamine group. 85 In a recent study, IN ketamine flexible doses (28, 56, or 84 mg) twice weekly for 4 weeks with oral antidepressants significantly reduced the depressive symptoms in TRD patients. 86 In contrast, an abstract of an unpublished study using the same design showed that IN ketamine plus oral antidepressant did not significantly reduce the depressive symptoms in TRD patients >65 years of age in all the study regions except in the United States.…”