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, Madhukar H Trivedi, Adam Janik, Honglan Li, Yun Zhang, Xiang Li, Rosanne Lane, Pilar Lim, Anna R. Duca, David Hough, Michael E. Thase, John Zajecka, Andrew Winokur, Ilona Divacka, Andrea Fagiolini, Wiesław J. Cubała, István Bitter, Pierre Blier, Richard C. Shelton, Patricio Molero & 3 others Husseini Manji, Wayne C. Drevets, Jaskaran B. Singh

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 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. 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.

Original languageEnglish (US)
JournalJAMA Psychiatry
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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Treatment-Resistant Depressive Disorder
Nasal Sprays
Secondary Prevention
Antidepressive Agents
Randomized Controlled Trials
Placebos
Recurrence
Therapeutics
Numbers Needed To Treat
Dysgeusia
Dissociative Disorders
Remission Induction
Vertigo
Dizziness
Random Allocation

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients with Treatment-Resistant Depression : A Randomized Clinical Trial. / Daly, Ella J.; Trivedi, Madhukar H; Janik, Adam; Li, Honglan; Zhang, Yun; Li, Xiang; Lane, Rosanne; Lim, Pilar; Duca, Anna R.; Hough, David; Thase, Michael E.; Zajecka, John; Winokur, Andrew; Divacka, Ilona; Fagiolini, Andrea; Cubała, Wiesław J.; Bitter, István; Blier, Pierre; Shelton, Richard C.; Molero, Patricio; Manji, Husseini; Drevets, Wayne C.; Singh, Jaskaran B.

In: JAMA Psychiatry, 01.01.2019.

Research output: Contribution to journalArticle

Daly, EJ, Trivedi, MH, Janik, A, Li, H, Zhang, Y, Li, X, Lane, R, Lim, P, Duca, AR, Hough, D, Thase, ME, Zajecka, J, Winokur, A, Divacka, I, Fagiolini, A, Cubała, WJ, Bitter, I, Blier, P, Shelton, RC, Molero, P, Manji, H, Drevets, WC & Singh, JB 2019, 'Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients with Treatment-Resistant Depression: A Randomized Clinical Trial', JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2019.1189
Daly, Ella J. ; Trivedi, Madhukar H ; Janik, Adam ; Li, Honglan ; Zhang, Yun ; Li, Xiang ; Lane, Rosanne ; Lim, Pilar ; Duca, Anna R. ; Hough, David ; Thase, Michael E. ; Zajecka, John ; Winokur, Andrew ; Divacka, Ilona ; Fagiolini, Andrea ; Cubała, Wiesław J. ; Bitter, István ; Blier, Pierre ; Shelton, Richard C. ; Molero, Patricio ; Manji, Husseini ; Drevets, Wayne C. ; Singh, Jaskaran B. / Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients with Treatment-Resistant Depression : A Randomized Clinical Trial. In: JAMA Psychiatry. 2019.
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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 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. 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.",
author = "Daly, {Ella J.} and Trivedi, {Madhukar H} and Adam Janik and Honglan Li and Yun Zhang and Xiang Li and Rosanne Lane and Pilar Lim and Duca, {Anna R.} and David Hough and Thase, {Michael E.} and John Zajecka and Andrew Winokur and Ilona Divacka and Andrea Fagiolini and Cubała, {Wiesław J.} and Istv{\'a}n Bitter and Pierre Blier and Shelton, {Richard C.} and Patricio Molero and Husseini Manji and Drevets, {Wayne C.} and Singh, {Jaskaran B.}",
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TY - JOUR

T1 - Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients with Treatment-Resistant Depression

T2 - A Randomized Clinical Trial

AU - Daly, Ella J.

AU - Trivedi, Madhukar H

AU - Janik, Adam

AU - Li, Honglan

AU - Zhang, Yun

AU - Li, Xiang

AU - Lane, Rosanne

AU - Lim, Pilar

AU - Duca, Anna R.

AU - Hough, David

AU - Thase, Michael E.

AU - Zajecka, John

AU - Winokur, Andrew

AU - Divacka, Ilona

AU - Fagiolini, Andrea

AU - Cubała, Wiesław J.

AU - Bitter, István

AU - Blier, Pierre

AU - Shelton, Richard C.

AU - Molero, Patricio

AU - Manji, Husseini

AU - Drevets, Wayne C.

AU - Singh, Jaskaran B.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 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. 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.

AB - 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 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. 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.

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