COPENHAGEN – Esketamine nasal spray achieved rapid reduction of major depressive disorder symptoms in patients at imminent risk for suicide in a pair of pivotal phase 3 clinical trials known as ASPIRE-1 and ASPIRE-2, Carla M. Canuso, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
Bruce Jancin/MDedge News
Dr. Carla M. Canuso
These were groundbreaking studies, which addressed a major unmet need familiar to every mental health professional, given that more than 800,000 suicides per year occur worldwide. Standard antidepressants are of only limited value during the period of acute suicidal crisis because they take 4-6 weeks to work. Moreover, this population of seriously depressed and suicidal patients has been understudied.
“Patients with active suicidal ideation and intent are routinely excluded from antidepressant trials,” observed Dr. Canuso, a psychiatrist who serves as senior director of neuroscience clinical development at Janssen Research and Development in Titusville, N.J.
It’s very important for the field to know that we can actually study these patients safely and effectively in clinical trials,” she said.
ASPIRE-1 and -2 were identically designed, randomized, double-blind, placebo-controlled, multinational studies conducted in patients with moderate to severe major depressive disorder as evidenced by a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score of about 40, along with moderate to extreme active suicidal ideation and intent as assessed using the Clinical Global Impression-Severity of Suicidality-Revised (CGI-SS-R).
“These were all patients in psychiatric crisis seeking clinical care,” according to Dr. Canuso.
All 456 participants in the two phase 3 studies underwent an initial 5-14 days of psychiatric hospitalization, during which they began treatment with esketamine nasal spray at 84 mg twice weekly or placebo coupled with comprehensive standard of care, which included a newly initiated and/or optimized oral antidepressant regimen.
The primary endpoint in the two clinical trials was the change in MADRS total score 24 hours after the first dose of study medication. The esketamine-treated patients demonstrated a mean reduction of 16.4 and 15.7 points, respectively, in the two trials, which was 3.82 points greater than in the pooled placebo group. This represents a clinically meaningful and statistically significant between-group difference.
The treatment effect size was even larger in some of the prespecified patient subgroups. Dr. Canuso drew attention to two key groups: In the roughly 60% of ASPIRE participants with a prior suicide attempt, esketamine resulted in a mean 4.81-point greater reduction in MADRS total score than placebo, and in the nearly 30% of participants with a suicide attempt during the past month, the difference was 5.22 points.
A word on the study design: Patients received intranasal esketamine at 84 mg per dose or placebo in double-blind fashion twice weekly for 4 weeks, thereby giving time for their oral antidepressant therapy to kick in, and were then followed on the conventional therapy out to 90 days.
A between-group difference in MADRS total score in favor of the esketamine group was evident as early as 4 hours after the first dose and continued through day 25, the end of the double-blind treatment period, at which point 54% and 47% of the esketamine-plus-conventional-antidepressant groups in the two trials had achieved remission as defined by a MADRS score of 12 or less, as had about one-third of the control group.
The prespecified key secondary efficacy endpoint in ASPIRE-1 and -2 was change in the CGI-SS-R 24 hours after the first dose. Both the esketamine and placebo-treated patients experienced significant improvement in this domain, with a disappointing absence of between-group statistical significance.
“We think that this may be due to the effect of acute hospitalization in diffusing the suicidal crisis,” Dr. Canuso said.
She noted, however, that other suicidality indices did show significant improvement in the esketamine-treated group during assessments at 4 hours, 24 hours, and 25 days after the first dose. For example, the double-blind esketamine-treated patients were 2.62-fold more likely than controls to show a significant improvement in MADRS Suicidal Thoughts at 4 hours after dose number one, and 6.15 times more likely to do so 4 hours after their day-25 dose. The CGI structured physician assessments of suicide risk and frequency of suicidal thinking, as well as patient-reported frequency of suicidal thinking, showed consistent favorable numeric trends for improvement with esketamine, with odds ratios of 1.46-2.11 from 4 hours through 25 days, although those results generally failed to achieve statistical significance.
In terms of safety, the rate of serious adverse events was just under 12% in both the esketamine and placebo arms. As in earlier studies, the most common adverse events associated with the novel antidepressant were dizziness, dissociation, nausea, and sleepiness, all several-fold more frequent than with placebo.
Esketamine is the S-enantiomer of racemic ketamine. It’s a noncompetitive N-methyl-D-aspartate receptor antagonist.
Janssen, which already markets intranasal esketamine as Spravato in the United States for treatment-resistant depression, plans to file for an expanded indication on the basis of the ASPIRE-1 and -2 results. The Food and Drug Administration already has granted Breakthrough Therapy designation for research on esketamine for reduction of major depression symptoms in patients with active suicidal ideation.
The ASPIRE studies were funded by Janssen.