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
Carla M. Canuso, M.D., Jaskaran B. Singh, M.D., Maggie Fedgchin, Pharm.D., Larry Alphs, M.D., Ph.D., Rosanne Lane, M.A.S., Pilar Lim, Ph.D., Christine Pinter, M.S., David Hough, M.D., Gerard Sanacora, M.D., Ph.D., Husseini Manji, M.D., Wayne C. Drevets, M.D.
American Journal of Psychiatry, 2018, 175, 620–630
Objective : The authors compared the efficacy of standardof- care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk.
Method : In a double-blind, multicenter, proof-of-concept study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Åsberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary end points included these measures at 24 hours and double-blind endpoint at day 25.
Results : A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference= 25.3,SE=2.10; effect size=0.61) andat∼24hours (least-square mean difference=27.2, SE=2.85; effect size=0.65), but not at
day 25 (least-square mean difference=24.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group 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). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.
Conclusions : These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including somemeasures of suicidal ideation, among depressed patients at imminent risk for suicide.
Major depressive disorder is the most prevalentmental health condition (1), affecting 1 in 15 adults in the United States (2), and it is the psychiatric diagnosis most commonly associated with suicide (1, 3). Theincidence of attempted suicide is about 20-fold higher in patients with major depression compared with the general population (4). The Centers for Disease Control and Prevention estimated that over 44,000 individuals in the United States died by suicide in 2015; over 1 million persons reported having made a suicide attempt in the previous 12 months, and over 2 million adults reported having considered suicide in the previous 12 months (5, 6).
Suicidal ideation is a major risk factor for suicide in patients with major depression (7, 8). The interval between the onset of suicidal ideation and suicide attempt is often very short (9), highlighting the need for urgent intervention and development of novel antidepressant therapies with a rapid onset. While standard antidepressant medications have demonstrated efficacy in the treatment of mood symptoms, including suicidal ideation (10), they require 4–6 weeks for optimal effect. No medication has been approved for the emergency treatment of patients with major depression assessed to be at imminent risk for suicide (11, 12).
Research on mood disorder pathophysiology has implicated abnormalities in glutamatergic transmission, along with histopathological changes in neural circuits that modulate emotional behavior (13). This work contributed to the investigation of glutamatergic agents in treating major depression.
Several small studies reported that the NMDA receptor antagonist ketamine improved depressive symptoms (14–19) and reduced suicidal ideation within hours of intravenous administration (20–22). Likewise, pooled analyses of placebo-controlled single-dose studies of ketamine (23–25) suggested a substantial reduction in suicidal ideation in patients with treatment-resistant or bipolar depression. While most of the participants in these studies were not specifically selected for the presence or severity of suicidal ideation, a recent study of 80 depressed patients with clinically significant suicidal ideation found that ketamine produced a greater reduction in suicidal ideation within 24 hours compared with midazolam (26).
Esketamine, an NMDA receptor antagonist that modulates glutamatergic transmission (27), is being developed as an intranasal formulation for treatment-resistant depression and for rapid reduction of symptoms of major depressive disorder, including suicidal ideation, in patients at imminent risk for suicide. Rapid onset of antidepressant effects has been observed in patients with treatment-resistant depression as early as 2 hours (28) and 24 hours after single-dose intranasal esketamine administration (29).
Here, we report findings from a proof-of-concept study conducted in the context of comprehensive standard-of-care treatment. To explore the hypothesis that esketamine ismore efficacious than placebo, we compared standard-of-care treatment plus either intranasal esketamine or placebo for rapidly reducing depressive symptoms, including suicidality, among individuals with major depression who were assessed to be at imminent risk for suicide.