In patients with major depressive disorder at high risk for suicide, the rapid onset of action and reduction of depressive symptoms reported with intranasal esketamine may be beneficial, according to the results of a double-blind, placebo-controlled study published in the American Journal of Psychiatry.

Major depressive disorder affects approximately 7% of American adults and is the psychiatric disorder most often associated with suicide. In 2015, 44,000 Americans died by suicide, more than 1 million made a suicide attempt, and 2 million Americans reported they had considered suicide. Standard antidepressants can be effective in treating mood disorders, including suicidal ideation, but it may take up to 6 weeks to achieve maximum effect.

For this proof-of-concept study, Carla M. Canuso, MD, of Janssen Research and Development in Titusville, New Jersey, and colleagues randomly assigned 68 patients to esketamine 84 mg or placebo twice weekly for 4 weeks, plus standard-of-care treatment in both groups. The primary outcome was a change in score on the Montgomery-Asberg Depression Rating Scale (MADRS) between baseline and 4 hours after the initial dose. The investigators also assessed clinician global judgment of suicide risk. These measures at 24 hours and double-blind end point at day 25 constituted secondary outcomes.

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Patients in the esketamine group saw significantly greater improvement in MADRS score than those in the placebo group at 4 hours (least-square mean difference=-5.3, SE=2.10; effect size=0.61) as well as at 24 hours (least-square mean difference=-7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=-4.5, SE=3.14; effect size=0.35). Those in the esketamine group also demonstrated significantly greater improvement on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67) but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). The investigators found no statistically significant difference between the groups for clinician global judgment of suicide risk scores. Adverse events observed in the esketamine group included nausea, dizziness, dissociation, unpleasant taste, and headache.

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The authors noted that there was a nearly 35% between-group difference for esketamine in the number of patients whose suicide risk resolved 24 hours after the initial dose. These results mirror those achieved with ketamine infusion in clinical trials.

Although there were no indications of esketamine dependence, misuse, diversion, or withdrawal symptoms in this trial, this is a possible concern, and the authors call for further evidence from clinical trials to evaluate the drug’s potential for abuse. In a recent article published in the American Journal of Psychiatry, Robert Freedman, MD, and colleagues, all of whom sit on the Editorial Board of the journal, noted that “ketamine drug-seeking behavior has already appeared as a clinical issue, with some patients shopping infusion clinics to obtain repeated injections for mood elevation.” They add that to date, trials have investigated only short-term safety and efficacy. Given the devastating consequences of the ongoing opioid epidemic, caution is warranted.


  1. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study [published online April 16, 2018]. Am J Psychiatry. doi:10.1176/appi.ajp.2018.17060720
  2. Freedman R, Brown AS, Cannon TD, et al. Can a framework be established for the safe use of ketamine? [published online April 16, 2018] Am J Psychiatry. doi:10.1176/appi.ajp.2018.18030290