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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Drs Daly, Janik, H. Li, Zhang, X. Li, Lim, Hough, Manji, Drevets, and Singh and Mss Lane and Duca are employees of Janssen Research & Development LLC and hold company equity. Dr Manji reports holding a patent, which is assigned to Icahn School of Medicine at Mount Sinai, Yale University, and the National Institutes of Health; no financial benefit was received from this patent. Dr Trivedi reports consulting for or serving on the advisory board of Alkeremes Inc, Akili Interactive, Allergan Pharmaceuticals, Arcadia Pharmaceuticals, Avanir Pharmaceuticals, Brintellix Global, Bristol Myers Squibb, Caudex, Cerecor, Forest Pharmaceuticals, Global Medical Education Inc, Health Research Associates, Insys, Johnson & Johnson Pharmaceutical Research & Development, Lilly Research Laboratories, Lundbeck Research USA, Medscape, Merck & Co Inc, Mitsubishi Pharma, MSI Methylation Sciences–Pamlab Inc, Navitor, Otsuka America Pharmaceutical Inc, One Carbon Therapeutics, Otsuka America Pharmaceutical Inc, Pfizer Inc, and Takeda Global Research; receiving royalties from Janssen Research and Development LLC; having author agreements with Janssen Asia Pacific and the Oxford University Press; and receiving grants from the Agency for Healthcare Research and Quality, the Cancer Prevention and Research Institute of Texas, the National Institute of Mental Health, National Institute of Drug Abuse, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Advancing Translational Sciences, Johnson & Johnson, and the Patient-Centered Outcomes Research Institute (PCORI). Dr Thase reports serving as an advisor or consultant for Acadia, Akilii, Alkermes, Allergan (Forest, Naurex), AstraZeneca, Axome, Cerecor, Eli Lilly and Company, Fabre-Kramer, Gerson Lehrman Group, Guidepoint Global, Johnson & Johnson, Janssen, Lundbeck, MedAvante, Merck & Co, moksha8, Nestlé (PamLab), Novartis, Otsuka, Pfizer, Shire, Sunovion, and Takeda; receiving grant support from Acadia, the Agency for Healthcare Research and Quality, Alkermes, Allergan (Forest), Avanir, Axome, Intracellular, Janssen, the National Institute of Mental Health, Otsuka, PCORI, and Takeda; and receiving royalties from American Psychiatric Press, Guilford Publications, Herald House, and W.W. Norton & Company Inc. Dr Zajecka reports consulting for or serving on the advisory board of Avanir (Depression Data Safety Monitoring Board), Alkermes, ElMindA, Forest, Naurex, Lundbeck, PamLab/Nestle, Shire, and Takeda and receiving grant or research support from Actavis, Alkermes, Allergan, AstraZeneca, Axesome, Cyberonics, ElMindA, Forest, the Cheryl T. Herman Foundation, Hoffman-LaRoche, Janssen, Johnson & Johnson, Lundbeck, Naurex, Neuralstem, Otsuka, the National Institutes of Health, Shire, Taisho, and Takeda. Dr Divacka reports receiving research grants from Axovant, Lundbeck, Servier, and Janssen. Dr Fagiolini reports serving as a consultant and/or a speaker and/or has received research grants from Allergan, Angelini, Generici DOC, Lundbeck, Italfarmaco, Janssen, Mylan, Otsuka, Pfizer, Recordati, Roche, and Sanofi Aventis. Dr Cubała reports serving as a consultant and/or receiving research grants from Alkermes, Allergan, Auspex Pharmaceuticals, Biogen, BMS, Cephalon, Ferrier, Forest Laboratories, GedeonRichter, GW Pharmaceuticals, Janssen, KCR, Eli Lilly and Company, Lundbeck, Minerva, the National Institutes of Health, NeuroCog, Orion, Otsuka, Sanofi, and Servier and serving as a consultant for GW Pharmaceuticals, Janssen, KCR, Quintiles, Roche, and Sanofi. Dr Bitter reports serving as a consultant to and/or speaker for Angelini, Gedeon Richter, Janssen/Janssen-Cilag, Eli Lilly and Company, Lundbeck, Pierre Fabre, and Servier. Dr Blier reports serving a consultant and/or receiving research grants from Allergan, Bristol Myers Squibb, Janssen, Lundbeck, Meda-Valeant, Otsuka, Pfizer, Pierre Fabre Médicaments, Sunovion, and Takeda. Dr Shelton reports serving as a consultant to Acadia Pharmaceuticals, Allergan Inc, Cerecor Inc, Clintara LLC, Janssen Pharmaceutica, Lundbeck A/S, Medtronic Inc, MSI Methylation Sciences Inc, Naurex Inc, Nestle’ Health, Pfizer Inc, and Takeda Pharmaceuticals and receiving grant support from Acadia Pharmaceuticals, Alkermes Inc, Allergan Inc, Assurex Health, Avanir Pharmaceuticals, Cerecor Inc, Genomind, Intracellular Therapies, Janssen Pharmaceutica, Otsuka Pharmaceuticals, Nestle’ Health, Novartis Inc, and Takeda Pharmaceuticals. Dr Molero reports receiving research grants from the Ministry of Education (Spain), the Government of Navarra (Spain), the Spanish Foundation of Psychiatry and Mental Health, and AstraZeneca; serving as a clinical consultant for MedAvante-ProPhase; and has receiving lecture honoraria from and/or consulting for Scienta, AB-Biotics, Novumed, and Janssen. Dr Winokur reported serving as a consultant to Alkermes and to Janssen. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

This study used data for those patients who had been undergoing treatment with esketamine nasal spray plus an oral antidepressant for 16 weeks and who, after meeting criteria for either stable remission (primary analysis) or stable response (secondary analysis), were randomized (separately) to continue treatment with esketamine nasal spray plus an oral antidepressant or to discontinue treatment with esketamine and switch to placebo nasal spray and continue use of the oral antidepressant. Stable remission was defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 12 or lower for 3 or more of the last 4 weeks of the optimization phase, with up to 1 excursion (MADRS total score >12) or 1 missing MADRS assessment permitted at week 13 or 14 only. Stable response was defined as 50% or greater reduction in MADRS total score from baseline in the last 2 weeks of the optimization phase, but without achieving stable remission criteria. Patients who were lost to follow-up or discontinued treatment after randomization were included in the analysis. aOne patient with stable response was incorrectly randomized in the group with stable remission. bOne patient who did not meet stable remission or stable response criteria at the end of the optimization phase was incorrectly randomized in the group with stable response.

Figure 2.. Kaplan-Meier Estimates of Time to Relapse

One patient who achieved stable response was incorrectly randomized as a patient who achieved stable remission at the end of the optimization phase. One patient did not meet stable remission or stable response criteria and was incorrectly randomized as a patient with stable response. The most common cause of censoring participants was based on being relapse free at study end (see Table 2 legend). Vertical lines indicate censored observations.