Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression. A Randomized Clinical Trial

Ella J. Daly, MD; Madhukar H. Trivedi, MD; Adam Janik, MD; Honglan Li, MD, PhD; Yun Zhang, PhD; Xiang Li, PhD; Rosanne Lane, MAS; Pilar Lim, PhD; Anna R. Duca, BSN; David Hough, MD; Michael E. Thase, MD; John Zajecka, MD; Andrew Winokur,MD, PhD; Ilona Divacka, MBA, MD; Andrea Fagiolini, MD; Wiesław J. Cubała, MD, PhD; István Bitter,MD, PhD; Pierre Blier,MD, PhD; Richard C. Shelton, MD; Patricio Molero,MD, PhD; Husseini Manji, MD;Wayne C. Drevets, MD; Jaskaran B. Singh, MD

JAMA Psychiatry, 2019

doi : 10.1001/jamapsychiatry.2019.1189
Published online June 5, 2019.

 

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 84mg) 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 relapsewas 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 121who 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 thosewhoachieved stable response compared with antidepressant and placebo treatment. The mostcommonadverse events reported for esketamine-treated patients after randomizationwere transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (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.

TRIAL REGISTRATION : ClinicalTrials.gov identifier: NCT02493868

Depression is the leading cause of disability worldwide and is associated with a 10-year reduction in life expectancy.1,2Achievingandmaintainingremission,the goals of treatment for this recurrent disease, improves functioning, reduces suicide risk, and leads to greater clinical stability.3 Patients who have not responded to at least 2 different antidepressants in the current depressive episode are considered to have treatment-resistantdepression (TRD).4 Patients with treatment resistant major depressive disorder (MDD) experience relapse at a high errate than do those with treatment-responsive MDD. Even when patients with TRD respond to treatment, the overall relapse rate while continuing treatment with the same antidepressant is high after 2 (65%;within 3.1months) and 3 failed trials (71.1%; within 3.3 months).3 There is a substantial unmet need for effective treatments that can sustain antidepressant benefits for the populationwith TRD. Several short-term studies5-12 with racemic ketamine and a stereoisomer, esketamine, have demonstrated efficacy for TRD. In contrast to available data about short-term antidepressant effects of esketamine and ketamine,13,14 little isknown about maintaining antidepressant effects in the long term.We report the findings of, to our knowledge, the first controlled maintenance study of esketamine that evaluated whether continued use of intermittently administered esketamine nasal spray plus an oral antidepressant can sustain antidepressant effects among patients with TRD to a greater extent than an oral antidepressant alone.

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