Two phase 3 trials of esketamine nasal spray found that the treatment was significantly superior to placebo in rapidly reducing symptoms of major depressive disorder (MDD) in adult patients who have active suicidal ideation with intent. 

Esketamine (Spravato; Janssen) is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor and is currently approved for treatment-resistant depression in conjunction with an oral antidepressant. The two trials (ASPIRE I and II) enrolled over 450 patients with MDD who were assessed to have active suicidal ideation with intent. In both trials, patients were randomized to receive esketamine 84mg two times per week for 4 weeks or placebo in addition to standard of care (initial hospitalization and a newly initiated and/or optimized antidepressant regimen). The primary end point was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score 24 hours after the first dose.

Results from both studies showed that treatment with esketamine plus standard of care was clinically meaningful and statistically significantly superior to placebo plus standard of care (mean difference in MADRS total score: 3.8 points in ASPIRE I and 3.9 points in ASPIRE II; P=.006). Moreover, the magnitude of difference between the groups generally remained throughout the double-blind treatment phase (day 25). By the end of the double-blind period, 54% (ASPIRE I) and 47% (ASPIRE II) of patients in the esketamine group achieved remission (MADRS score ≤12). 

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With regard to safety, dizziness, dissociation, nausea, somnolence, blurred vision, vomiting, paresthesia, increased blood pressure and sedation were the most common treatment-emergent adverse events, with a frequency of ≥10%.

“These data are particularly important because patients with major depressive disorder presenting with active suicidal ideation with intent constitute a psychiatric emergency that requires immediate intervention,” said Carla Canuso, MD, Senior Director, Clinical Research, Janssen Research & Development, LLC, and clinical leader of the ASPIRE I and II studies. “Although currently available antidepressants are effective for many patients, their onset of effect can take 4 to 6 weeks, offering limited benefit to those in urgent need.”

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