Summary: Esketamine combined with antidepressants acts rapidly to help alleviate symptoms in those with treatment-resistant depression.
Source: American Psychiatric Association
New research supports the effectiveness and safety of esketamine nasal spray in treating depression in people who have not responded to previous treatment. The research will be published online today in the American Journal of Psychiatry. This study is one of the key studies that led to the recent Food and Drug Administration (FDA) approval of esketamine nasal spray, in conjunction with an oral antidepressant, for use in people with treatment-resistant depression.
Depression is common, and as many as one-third of people with depression are considered treatment resistant–not finding relief from symptoms even after trying several antidepressants. Esketamine offers a new fast-acting treatment for people that have not responded to other depression treatments.
Michael Thase, M.D., one of the study authors, described the study during a briefing held during the Annual Meeting of the American Psychiatric Association. The phase 3, double-blind, active-controlled study was conducted at 39 outpatient centers from August 2015 to June 2017 and involved nearly 200 adults with moderate to severe depression and a history of not responding to at least two antidepressants. Participants were randomly assigned to one of two groups. One group was switched from their current treatment to esketamine nasal spray (56 or 84 mg twice weekly) plus a newly initiated antidepressant (duloxetine, escitalopram, sertraline, or extended-release venlafaxine). The other group was switched from their current treatment to a placebo nasal spray in combination with a new antidepressant.
The improvement in depression among those in the esketamine group was significantly greater than the placebo group at day 28. Similar improvements were seen at earlier points in time.
Adverse events in the esketamine group generally appeared shortly after taking the medication and resolved by 1.5 hours later while patients were in the clinic. The most common side effects included dissociation, nausea, vertigo, dysgeusia (distortion of the sense of taste) and dizziness. Seven percent of patients in the esketamine group discontinued the study due to side effects.
“This trial of esketamine was one of the pivotal trials in the FDA’s review of this treatment for patients with treatment resistant depression. Not only was adjunctive esketamine therapy effective, the improvement was evident within the first 24 hours,” Thase said. “The novel mechanism of action of esketamine, coupled with the rapidity of benefit, underpins just how important this development is for patients with difficult to treat depression.”
In an accompanying commentary in the American Journal of Psychiatry, Alan Schatzberg, M.D., at Stanford University School of Medicine, highlights several areas where information about the best use of esketamine is lacking, such as how long and how often to prescribe it, and raises concerns about the potential for abuse. While he notes that esketamine could be useful for many patients with depression, he cautions that “there are more questions than answers with intranasal esketamine, and care should be exercised in its application in clinical practice.”
The commentary describes esketamine’s relationship to ketamine, an anesthetic in use for decades that has also been used recreationally as a party drug. While ketamine administered intravenously at sub-anesthetic doses is an effective treatment being used for refractory depression, at present, intravenous ketamine for the treatment of depression has not been approved by the FDA, although it can be prescribed off-label. Ketamine is composed of molecules that are mirror images of each other (S-ketamine and R-ketamine). It is the intranasal formulation of the S-ketamine molecule (i.e., esketamine) that received FDA approval.
Funding: Funding for the study was provided by Janssen Research and Development, Titusville, New Jersey. Joint first authors Vanina Popova, M.D., and Ella J. Daly, M.D., and several co-authors are employees of Janssen Research and Development.
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
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.