Controlled studies have shown short-term efficacy of esketamine for treatment-resistant
depression (TRD), but long-term effects remain to be established.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.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.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.Time to relapse was examined in patients who achieved stable remission,
as assessed using a weighted combination log-rank test.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 were transient dysgeusia, vertigo, dissociation, somnolence,
and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated
with an antidepressant and placebo.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.ClinicalTrials.gov identifier:
NCT02493868.
