September 09, 2019
COPENHAGEN, Denmark — Patients who have major depressive disorder (MDD) and who are at imminent risk for suicide may experience rapid benefit from esketamine nasal spray (Spravato, Janssen Pharmaceuticals) used in conjunction with the standard of the care, new research suggests.
In the phase 3 Aspire I and Aspire II trials, more than 450 patients who had MDD and were at risk for suicide were randomly assigned to receive esketamine, a rapidly acting S-enantiomer of racemic ketamine that was recently approved by the US Food and Drug Administration for treatment-resistant depression, or placebo. Both groups also received comprehensive standard of care that included antidepressants.
Pooled results of the two trials showed that use of esketamine led to significant reductions in scores on the Montgomery–Åsberg Depression Rating Scale (MADRS). The differences between the treatment group and the placebo group emerged as early as 4 hours after initiation of treatment and lasted for 25 days.
However, these differences were not significant, and there were no significant reductions on the Clinical Global Impression of Severity of Suicidality (Revised) (CGI-SS-R) with either intervention.
Further analysis did show that esketamine had a greater effect than placebo with regard to depressive and suicidality scores for more severely depressed patients and for those who had already attempted suicide.
Above all else, the findings show that "we can actually study these patients safely and effectively in clinical trials," Carla Canuso, MD, senior director in neuroscience clinical development at Janssen Research and Development, told attendees here at the 32nd European College of Neuropsychopharmacology (ECNP) Congress.
"Importantly, in both of the studies, esketamine plus standard of care demonstrated a clinically meaningful and statistically significant reduction of symptoms of depression at 24 hours after the first dose," she added. "This treatment numerically favored esketamine as early as 4 hours and through to the end of the double-blind treatment period."
Canuso said that suicide is a "highly unmet medical need," with almost 1 million suicides occurring worldwide every year.
Canuso noted that although MDD is the condition most commonly associated with suicide, patients with active suicidal ideation and intent are excluded from antidepressant trials.
Moreover, the majority of antidepressants take up to 6 weeks to work — and the window to intervene is small, inasmuch as hospitalization to protect patients from self-harm is temporary.
With phase 2 data showing that esketamine plus standard of care was associated with reduced depressive symptoms, including reductions in some measures of suicidal ideation, 4 hours after administration, the researchers embarked on a phase 3 analysis.
ASPIRE I and II had the same design and objectives, which were to assess the efficacy of intranasal esketamine 85 mg vs placebo in reducing MDD symptoms, including suicidal ideation, in individuals regarded as being at high risk for suicide.
Patients were screened within 48 hours of arriving in the emergency department or for an inpatient visit. A total of 451 patients with MDD and active suicidal ideation and intent were enrolled in the trials.
All participants were randomly assigned in a double-blind fashion at a 1:1 ratio to receive standard of care with antidepressant treatment plus either esketamine or placebo. They were treated with two doses per week for 25 days.
It was recommended that the patients spend at least 5 of the first 14 days after enrollment in an inpatient psychiatric unit. They could then be seen at the outpatient psychiatric clinic.
Following the 25-day treatment period, the participants were followed to day 90 from baseline with the standard of care antidepressant therapy.
The mean age of the patients was between 38 and 41 years, and the majority (58% to 65%) were women.
The mean MADRS score was 40 to 51, and approximately 90% of patients were moderately to extremely suicidal, as demonstrated on the CGI-SS-R. Between 60% and 66% had a lifetime suicide attempt, and 21% to 32% had made a suicide attempt in the past month.
Results showed that treatment with esketamine plus standard of care was associated with significant reductions in MADRS total scores over baseline. The mean reduction at 24 hours after the first dose was 16.4 in ASPIRE I and 15.7 in ASPIRE II (P = .006 for both comparisons).
Placebo plus standard of care was associated with a significant, albeit lower, reduction in MADRS total scores over baseline at 24 hours, with an average reduction of 12.8 in ASPIRE I and 12.4 in ASPIRE II.
A numerical difference between the esketamine and placebo groups emerged as early as 4 hours after initial treatment. A difference in least squares means was maintained for the whole of the double-blind period, at an average of 3.8 in ASPIRE I and 3.9 in ASPIRE II.
Overall, the difference between the treatment groups was not significant.
However, subgroup analysis indicated that esketamine plus standard of care had a greater effect for individuals whose baseline MADRS total score was greater than the median and for those who had a prior suicide attempt.
There was no overall significant reduction in CGI-SS-R scores from baseline to 24 hours after the first dose across the two studies.
Nevertheless, there was a notable reduction in the number of patients with marked or severe suicidality from baseline to day 5, and a corresponding increase in the proportion of individuals considered normal (44.4% for placebo vs 51.8% for esketamine).
Again, subgroup analysis suggested that esketamine plus standard of care had a greater effect on risk for suicide in patients whose baseline MADRS total score was greater than the median and in those who had a prior suicide attempt.
In terms of safety, there were more treatment-emergent adverse events (AEs) with esketamine than with placebo during the double-blind phase (89.9% vs 75.8%, respectively), and there were more events that led to discontinuation (6.2% vs 3.6%).
During follow-up, the two groups were broadly comparable in terms of AEs (53.7% for esketamine vs 50.8% for placebo). The groups were also comparable in terms of serious AEs (11.6% vs 11.9%, respectively).
There was one death from suicide across both studies; it occurred in a patient who was being treated with esketamine plus standard of care.
Although the main differences between esketamine and placebo were not significant, experts noted that achieving a durable numerical reduction with the active drug was "encouraging."
The ECNP session was chaired by Mark Weiser, MD, Sackler School of Medicine, Tel Aviv University Israel Medical Practice, and Andreas Reif, MD, PhD, University Hospital of Frankfurt, Frankfurt am Main, Germany, both of whom treated two or three patients as part of ASPIRE II.
Reif told Medscape Medical News that the results show "how good the standard of care is" and that, in the context of the studies, "this is not usual 'treatment as usual.'
"They are within a clinical randomized controlled trial, with all the bells and whistles, so these are probably those patients that are treated the best, actually," he added. "To still see a separation from the standard of care with esketamine is not at all disappointing. I think this is what you can expect from this kind of study."
However, Reif noted that one thing that "is a bit problematic with this type of study is that the patients are repetitively asked very intensively about their suicidal thoughts."
Consequently, the study framework itself "keeps reminding patients about their severity of illness, which for these patients is probably not a very good thing," he said.
Weiser also emphasized that clinical trials such as ASPIRE I and II "do not represent all suicidal patients.
"In a study like this, you cannot take people with severe medical illnesses. Some of these patients are very suicidal," he said.
"You cannot take patients with psychosis, because esketamine has a psychogenic potential, and many of our most suicidal patients are psychotic...and it does not include patients who are involuntary, because you have to sign on a consent form," Weiser added.
Reif noted that the studies also excluded patients who had substance use disorders, "which in our department is almost half of the patients with suicide attempts."
Still, "taking all that into account, the results are quite encouraging in my mind," Weiser concluded.
The study was sponsored by Janssen. Canuso is a full-time employee of Janssen Research and Development and holds shares of stock in Johnson & Johnson.