SAN FRANCISCO – In treatment-resistant depression, a switch to a new antidepressant combined with inhaled esketamine (Spravato) led to better symptom improvement than did a switch to a new antidepressant plus placebo, results from a new trial show. The treatment effect of esketamine was modest but had a number needed to treat for remission of just five.

About 30% of patients with major depressive disorder are treatment resistant. They are at risk of suicidal behavior and self-harm during the interval between starting a new medication and onset of efficacy. Esketamine, with its rapid onset of efficacy associated with its stimulation of synaptogenesis through inhibition of the N-methyl-D-aspartate receptor, gained Food and Drug Administration approval in March for the treatment of treatment-resistant depression in adults.

The findings were part of a phase 3 study presented at a press conference at the annual meeting of the American Psychiatric Association and simultaneously published in the American Journal of Psychiatry (2019. doi: 10.1176/appi.ajp.2019.19020172).

Adding esketamine to the start of a new antidepressant was associated with a small improvement in symptoms (effect size, 0.30), and this benefit did not continue to accrue further advantage past the original separation, which led to some skepticism from the author of an accompanying editorial (Am J Psychiatry. 2019 May. doi: 10.1176/appi.ajp.2019.19040423). “The question is, do you need to keep a patient on the drug past 48 hours? There is no statistically significant difference (in patient response) past the first 48 hours. That to me is a concern,” said Alan F. Schatzberg, MD, at the press conference.

Dr. Schatzberg, who is a professor of psychiatry at the Stanford (Calif.) University, also expressed concern about the potential for abuse with esketamine, as well as withdrawal after discontinuation. “I think the drug ought to be used, but it needs to be recommended with considerable caution. We have not answered the many questions that are needed in a drug of potential abuse,” Dr. Schatzberg added.

Study coauthor Michael E. Thase, MD, who also presented at the press conference, discussed the possibility of alterations to the treatment regimen. “I have a hunch you can see this (positive response) within first week or 2, and you can at least concentrate the resource on patients that gain the largest benefit. We can be smarter about it,” said Dr. Thase, who is a professor of psychiatry at the University of Pennsylvania, Philadelphia. He predicted that protocols eventually will be put in place to streamline intranasal ketamine treatment.

Regardless of the effect size, the study produced high remission and response rates in this difficult to treat population, which is welcome news to Gerard Sanacora, MD, PhD, a professor of psychiatry at Yale University, New Haven, Conn., and director of the Yale Depression Research Program. “The response rates that they were seeing are much higher than you would expect,” he said in an interview.

In the phase 3 study, researchers randomized 223 patients from five countries to receive esketamine or placebo, along with either an SSRI (escitalopram or sertraline) or a selective norepinephrine reuptake inhibitor (duloxetine or venlafaxine extended release), based on investigator choice.

To be eligible, participants had to have failed two previous trials of antidepressants. After a 4-week observation period, patients began a 4-week regimen of a new antidepressant combined with twice-weekly nasal esketamine or a placebo.

Subjects in the treatment arm received esketamine on day 1 of the treatment phase with a 56-mg dose. On day 4, 45.8% were increased to a dose of 84 mg, and 66.7% were at the 84-mg dose at the end of the treatment phase.

From baseline to day 28, the esketamine group had a greater decrease in Montgomery-Åsberg Depression Rating Scale (MADRS) score (difference of least square means, –4.0; P = .020; effect size, 0.30). A scatter plot of individual MADRS data during that period revealed rapid onset and increasing rapid response during repeated dosing 24 hours after dosing (least square mean between-group difference, –3.3), day 8 (–2.9), day 15 (–2.0), and day 22 (–4.0; P = .020).

Researchers also examined subjects who achieved at least a 50% reduction MADRS score at day 2 and maintained the improvement at day 28, and the difference was not significant between the two groups. At day 2, 16.5% of esketamine patients achieved a 50% or greater reduction in MADRS, compared with 10.8% in the placebo arm, though the significance of this difference could not be determined.

A post hoc analysis showed that 69.3% of participants in the esketamine group had responded by day 28, compared with 52.0% (odds ratio, 2.4; 95% confidence interval, 1.30-4.54; number needed to treat, 6). More subjects in the treatment group were in remission at day 28 (52.5% vs. 31.0%; NNT, 5).

The most common treatment-emergent adverse events in the esketamine group were dizziness (20.9%), dissociation (26.1%), dysgeusia (24.3%), vertigo (26.1%), and nausea (26.1%).

The study was funded by Janssen Research and Development. Dr. Sanacora was an investigator on previous Janssen-funded studies and has consulted for Janssen. Dr. Schatzberg has received research support from and consulted for Janssen, and has consulted for numerous other companies. Dr. Thase has received research support from Janssen and consulted for a wide range of pharmaceutical companies.

SOURCE: Popova V et al. APA 2019, Am J Psychiatry 2019 May. doi: 10.1176/appi.ajp.2019.19020172.

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