Esketamine nasal spray may rapidly reduce depressive symptoms, suicidal ideation with intent
Esketamine nasal spray appeared to rapidly reduce depressive symptoms among severely ill patients with major depressive disorder who had active suicidal ideation with intent, according to a study published in Journal of Clinical Psychiatry.
“The ASPIRE I and II trials are part of the first global pivotal program for patients with MDD who have active suicidal ideation with intent,” Dong-Jing Fu, MD, PhD, director of clinical research at Janssen Research & Development and ASPIRE I investigator, told Healio Psychiatry. “This severely ill patient population has typically been excluded from antidepressant treatment trials, and it is important to note that the severity of these patients’ disease is a psychiatric emergency. Therefore, our findings suggest that esketamine nasal spray may address the unmet need for a rapid-acting antidepressant in patients with MDD and active suicidal ideation with intent, for which there is no approved pharmacologic treatment.”
The FDA has approved esketamine — the S-enantiomer of ketamine racemate and an N-methyl-d-aspartate receptor antagonist — as a nasal spray for patients with treatment-resistant depression. Results of four small trials that included patients with MDD suggested that IV ketamine may rapidly decrease suicidal ideation. In a phase 2 double-blind, proof-of-concept study, the investigators of the current study found that compared with placebo nasal spray, esketamine nasal spray plus comprehensive standard-of-care treatment significantly reduced depressive symptoms at 4 and 24 hours after the first dose among patients with depression who were at imminent risk for suicide.
In the double-blind, randomized phase 3 ASPIRE I study, Fu and colleagues sought to compare esketamine with placebo, each combined with standard-of-care treatment, for rapid reduction of MDD symptoms, including suicidal ideation. They enrolled 226 adults with MDD diagnosis according to DSM-5 criteria, active suicidal ideation with intent and need for psychiatric hospitalization.
The researchers randomly assigned patients 1:1 to 84 mg of esketamine or placebo nasal spray twice weekly for 4 weeks, in addition to initial psychiatric hospitalization and newly initiated or optimized oral antidepressant therapy. Using analysis of covariance (ANCOVA), they analyzed change from baseline to 24 hours following first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score. Further, they used an ANCOVA model to analyze change in Clinical Global Impression of Severity of Suicidality Revise version score, with treatment difference calculated using the Hodges-Lehmann estimate.
The investigators observed greater improvement in MADRS total score with esketamine plus standard of care vs. placebo plus standard of care at 24 hours (least-squares mean difference = 3.8; 95% CI, 6.56 to 1.09), as well as at 4 hours and later time points during 4-week double-blind treatment. They observed no statistically significant difference between groups in the severity of suicidality, and reported dizziness, dissociation, headache, nausea and somnolence as the most common adverse events among esketamine-treated patients.
“The results observed in patients treated with esketamine are particularly notable given the difference in outcomes between the groups, despite all participants receiving truly comprehensive standard-of-care,” Fu said. “It was also notable that the improvement in the MADRS total score was greater for the esketamine-treated group compared with those given placebo as soon as 4 hours after the first dose and continuing through the end of the double-blind portion of the study, when the newly initiated or optimized antidepressant therapy had enough time to achieve an effect.” – by Joe Gramigna
Disclosures: Fu is an employee of Janssen Research & Development. Please see the study for all other authors’ relevant financial disclosures.