This double-blind, randomized Phase III trial (n=227) finds no significant difference between esketamine plus a new antidepressant versus only the antidepressant (and a placebo) at day 28 on depression scores (MADRS). The study reports one death in the esketamine group. It also states esketamine to be “effective and safe” though only the first claim could be credibly made if one only looks at the immediate (24-hour) effects.
“Objective: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray.
Methods: This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures.
Results: Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.
Conclusions: Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.”
Authors: Vanina Popova, Ella J. Daly, Madhukar Trivedi, Kimberly Cooper, Rosanne Lane, Pilar Lim, Christine Mazzucco, David Hough, Michael E. Thase, Richard C. Shelton, Patricio Molero, Eduard Vieta, Malek Bajbouj, Husseini Manji, Wayne C. Drevets, Jaskaran B. Singh
Summary of Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Plus a Newly Initiated Oral Antidepressant in Adult Patients with Treatment-Resistant Depression
Major depressive disorder is a common psychiatric disorder worldwide, and in China, the 12-month prevalence of MDD is 2.1%, with an estimated lifetime MDD prevalence of 3.4%. A subset of MDD patients experience treatment-resistant depression, and there is no approved therapy for TRD.
Esketamine nasal spray is approved for treating adults with TRD and MDD with acute suicidal ideation or behaviour.
In a pivotal, Phase III, global, multicenter study, esketamine nasal spray plus a newly initiated oral AD improved depressive symptoms in adult patients with TRD versus oral AD plus placebo, and clinically meaningful benefit 24 hours after the first dose.
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Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Plus a Newly Initiated Oral Antidepressant in Adult Patients with Treatment-Resistant Depression: A Randomized, Double-Blind, Multicenter, Active-Controlled Study Conducted in China and USA
Cite this paper (APA)
Chen, X., Hou, X., Bai, D., Lane, R., Zhang, C., Canuso, C., ... & Fu, D. J. (2023). Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Plus a Newly Initiated Oral Antidepressant in Adult Patients with Treatment-Resistant Depression: A Randomized, Double-Blind, Multicenter, Active-Controlled Study Conducted in China and USA. Neuropsychiatric Disease and Treatment, 693-707.
Institutes associated with this publicationJohnson & Johnson
One of the largest pharmaceutical companies in the world, Johnson & Johnson are responsible for bringing esketamine to market in the form of Spravato.
The psychedelics given at which dose and how many timesKetamine 26 - 56
mg | 8x
Linked Research Papers
Notable research papers that build on or are influenced by this paperEsketamine Nasal Spray for the Rapid Reduction of Depressive Symptoms in Major Depressive Disorder With Acute Suicidal Ideation or Behavior
This pooled analysis (n=456) of the two ASPIRE studies (comparing ketamine to placebo, both with standard care) finds significant improvements in depression scores immediately (4 & 24 hours) up to 25 days later (all similar reductions). The study also showed improvements on suicidal ideation (which all patients had), most for those with a history of suicide attempt.
Linked Clinical TrialA Study to Evaluate the Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression
This Phase III trial (n=252) investigated the effect of esketamine (58-84mg, 8x) on treatment-resistant depression (TRD). Ultimately the trial didn't find significant results at 28 days.