Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study

Summary & key facts

This study tested whether adding a short course of esketamine nasal spray to a newly started oral antidepressant helps adults whose depression did not get better with at least two previous antidepressants. Over four weeks, people who received esketamine plus an antidepressant had a bigger and faster drop in depression symptoms than people who switched to a new antidepressant plus a placebo nasal spray. Side effects such as feeling disconnected, nausea, dizziness, and a bad taste were more common with esketamine but usually began soon after dosing and went away within about 1.5 hours. The results apply to the first 28 days of treatment and do not answer longer-term benefits or risks.

Key facts:

• The study enrolled adults with moderate to severe depression who had not gotten better after at least two antidepressants in the current episode.
• Researchers screened about 435 people, randomly assigned 227 to treatment, and 197 completed the 28-day double-blind phase.
• Participants switched to either esketamine nasal spray (given twice a week at 56 or 84 mg) plus a newly started oral antidepressant, or to a newly started oral antidepressant plus a placebo nasal spray.
• After 28 days, the group who received esketamine plus an antidepressant had a greater reduction in depression symptoms than the group who received antidepressant plus placebo. The difference on the study's depression scale was about 4 points in favor of esketamine.
• Clinically meaningful improvement with esketamine was also seen at earlier time points, meaning some people felt better sooner.
• The most common side effects with esketamine were dissociation (a feeling of being disconnected), nausea, vertigo, bad taste, and dizziness. These side effects were more common than with placebo and usually started soon after dosing and went away within about 1.5 hours.
• About 7% of patients receiving esketamine stopped the study drug because of side effects, compared with about 1% of patients receiving placebo nasal spray.
• The study supports that esketamine can act rapidly in people with treatment-resistant depression, but the trial only lasted 28 days, so it does not show longer-term safety or effectiveness.

Abstract

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.

Topics

Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes Psychedelics and Drug Studies Treatment of Major Depression

Categories

Health Sciences Medicine Pharmacology

Tags

Adverse effect Alternative medicine Anesthesia Antidepressant Depression (economics) Economics Hippocampus Internal medicine Macroeconomics Medicine Nasal administration Nasal spray Pathology Pharmacology Placebo Tolerability Treatment-resistant depression

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Poor sleep Sadness or low mood