Patients with major depressive disorder (MDD) and active suicidal ideation with intent treated with esketamine experienced significantly reduced depressive symptoms, but not suicide severity, compared to those treated with placebo. These findings provide the first evidence for the potential use of esketamine as an acute treatment for depression associated with suicidal ideation in MDD, according to results published in the Journal of Clinical Psychiatry.1

The time between suicidal ideation with intent to a suicide attempt is often very short, frequently within the first 10 minutes.2 Early intervention is therefore of critical importance.

Don-Jing Fu, MD, PhD of  Neuroscience Clinical Development at Janssen Research & Development LLC, Titusville, New Jersey, and colleagues followed up a phase 2 double blind proof-of-concept study on esketamine in acutely suicidal MDD patients. For the ASPIRE I phase 3 clinical trial, the participants consisted of patients aged 18 to 64 years with a diagnosis of MDD without psychotic features. Eligible participants were evaluated at emergency departments or inpatient psychiatric units and indicated suicidal ideation with intent within 24 hours of randomization as assessed by the Mini International Neuropsychiatric Interview and a Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥28.

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The study consisted of a 24 to 48 hour screening period followed by 4 weeks of twice weekly 84 mg esketamine (n=114) or placebo (n=112) nasal treatment combined with comprehensive standard of care, including permitted benzodiazepine use. Patients were followed up for 9 weeks at the end of treatment. The primary endpoint was change in MADRS total score from baseline to 24 hours after the first dose, whereas the secondary endpoint was change in the Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r) score.

The group treated with esketamine showed significantly decreased depressive symptoms compared to patients in the placebo group (least-square mean difference [SE], -3.8; SD, 1.39; 95% CI, -6.56 to -1.09, P =.006). However, both groups experienced improvements, with the MADRS total score decreasing by -16.4±11.95 in the esketamine group and by -12.8±10.73 in the placebo group. The treatment effect of esketamine was observed 4 hours after administration and generally remained throughout 25 days.

However, the secondary endpoint was not met. While both groups experienced improvement in CGI-SS-r scores, there were no significant differences between treatment groups (P =.107). Some of the most common adverse events were dizziness, dissociations, nausea, and headache, the vast majority of which occurred the day of intranasal dosing and resolved the following day. A patient treated with esketamine in the double-blind phase died by suicide in follow-up.

Study limitations included potential expectancy bias from participation in clinical trials. Differences in global standard of care may have also provided a source of bias. Lastly, patients may have been unintentionally unblinded by the noticeable transient sedating and dissociative effects of esketamine.

The researchers noted that “our findings suggest 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.”

Disclosures: Several study authors reported relationships to pharmaceutical companies. Please see original papers for a full list of disclosures.


1. Fu DJ, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I) [published May 12, 2020]. J Clin Psychiatry. 2020;81(3):19m13191.

2. Deisenhammer EA, Ing CM, Strauss R, Kemmler G, Hinterhuber H, Weiss EM. The duration of the suicidal process: how much time is left for intervention between consideration and accomplishment of a suicide attempt?. J Clin Psychiatry. 2009;70(1):19‐24.