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

Summary & key facts

Researchers tested an intranasal spray of esketamine, a form of ketamine, in adults whose major depression had not improved after at least two antidepressants. In a carefully controlled study, 67 people stayed on their regular antidepressant and were randomly given placebo or one of three esketamine doses twice a week. After one week, those who got esketamine showed faster and bigger drops on a standard depression rating scale than placebo, higher doses worked better, and some benefit lasted for more than two months with less frequent dosing. A few people stopped because of side effects. The trial was small, so bigger studies are needed to confirm the results and safety.

Key facts:

• About one-third of people with major depression do not get better with available antidepressants, which is why this study focused on treatment-resistant cases.
• Sixty-seven adults with treatment-resistant major depression entered the randomized part of the study and 60 completed the first two weeks of blinded treatment.
• Participants kept taking their usual antidepressant while receiving either placebo or esketamine nasal spray twice weekly at doses of about 28 mg, 56 mg, or 84 mg.
• After one week, people who got esketamine improved more on a standard depression rating scale than those who got placebo, with roughly 4 points more improvement at the lowest dose, about 6 points at the middle dose, and about 9 points at the highest dose.
• The study found a clear dose-response: higher esketamine doses were linked to bigger improvements in depressive symptoms.
• Improvement appeared to last for over two months even when dosing was reduced to weekly and then every two weeks during the open-label phase.
• Side effects caused study withdrawal in 3 of about 56 people given esketamine during the double-blind phase (about 5%), while none of the placebo group stopped for side effects in that phase.
• Reported serious issues that led people to stop included fainting, headache, a dissociative reaction (a disturbing feeling of being disconnected or changed), and one ectopic pregnancy; one person stopped during the later open-label phase.
• The authors describe this as an early, phase 2 trial. Because it involved a small number of people, the results support doing larger trials rather than proving long-term benefit or safety for everyone.

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