Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression

Summary & key facts

Researchers tested an intranasal esketamine spray in adults with major depression who had not improved after trying at least two antidepressants. Sixty-seven people were randomly assigned to get either a placebo spray or one of three esketamine doses while they kept taking their usual antidepressant. Esketamine reduced depressive symptoms faster than placebo, and higher doses worked better. The improvement appeared to last for more than two months even when dosing was reduced. A few people stopped because of side effects. The study was small, so these results need to be confirmed in larger trials.

Key facts:

• The study included 67 adults with major depressive disorder who had not responded to at least two previous antidepressants.
• People were randomly put into one of four groups: a placebo spray or esketamine spray at about 28 mg, 56 mg, or 84 mg. The sprays were given twice a week during the main comparison period while participants stayed on their usual antidepressant.
• After one week, all three esketamine doses reduced depression scores more than placebo. The size of the benefit grew with higher doses.
• When the study moved to an open phase and the sprays were given less often, the improvement in symptoms seemed to hold for roughly two months.
• A small number of people stopped treatment because of side effects: three people on esketamine stopped during the controlled phase, while no one on placebo did. One person stopped during the open phase.
• Reported side effects that led to stopping included fainting, headache, a dissociative reaction (feeling detached or unreal), and one pregnancy complication. The study does not prove these were caused by the drug.
• This was an early-stage, small study. The results suggest esketamine may work quickly for treatment-resistant depression, but larger studies are needed to be sure about how well it works and how safe it is.

Abstract

Importance: Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. Objective: To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). Design, Setting, and Participants: This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. Interventions: In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. Main Outcomes and Measures: The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Results: Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy). Conclusions and Relevance: In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials. Trial Registration: clinicaltrials.gov identifier: NCT01998958.

Topics

Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes Neurotransmitter Receptor Influence on Behavior Treatment of Major Depression

Categories

Health Sciences Medicine Pharmacology

Tags

Adverse effect Alternative medicine Amygdala Anesthesia Antidepressant Clinical endpoint Depression (economics) Economics Hippocampus Internal medicine Macroeconomics Major depressive disorder Medicine Pathology Placebo Randomized controlled trial Treatment-resistant depression

Substances

Ketamine

Conditions & symptoms

Depression Feeling disconnected from others Lack of energy or motivation Sadness or low mood