The Food and Drug Administration (FDA) has approved Spravato® (esketamine nasal spray; Janssen), in conjunction with an oral antidepressant, for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

The approval was based on 2 identical phase 3 trials (ASPIRE I and II) that compared the efficacy and safety of esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, to placebo in 449 adults with moderate to severe MDD who had active suicidal ideation and intent. Patients were randomized to receive esketamine nasal spray 84mg twice weekly 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 the change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score 24 hours after the first dose. 

Results from both studies showed that esketamine nasal spray plus standard of care was found to be statistically superior on the primary end point compared with placebo plus standard of care (mean difference in MADRS total score: 3.8 points in ASPIRE I and 3.9 points in ASPIRE II). In both studies, the treatment difference between esketamine nasal spray and placebo was observed as early as 4 hours with continued improvement for both groups through day 25; the difference between both groups generally remained but did not appear to increase over time. 

Additionally, 41% and 43% of patients treated with esketamine nasal spray plus standard of care achieved clinical remission of depression (minimal or no symptoms) in ASPIRE I and II, respectively, compared with 34% and 27% for placebo plus standard of care by the end of the double-blind period, respectively.

“The clinical trials supporting this new indication provide compelling evidence that esketamine may offer clinicians a new way to provide support to patients quickly in the midst of an urgent depressive episode and help set them on the path to remission,” said Gerard Sanacora, PhD, MD, Director, Yale Depression Research Program, Co-Director, Yale New Haven Hospital Interventional Psychiatry Service, and esketamine clinical trial investigator.

The safety profile of esketamine was consistent with that seen in previous studies. The most common adverse reactions included dissociation, dizziness, sedation, increased blood pressure, hypoesthesia, vomiting, euphoric mood and vertigo.

Spravato carries a Boxed Warning regarding the risk for sedation, dissociation, abuse/misuse, and suicidal thoughts and behaviors that may result from use of the product. It is only available through a restricted program called the Spravato REMS.

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Spravato is also approved for the treatment of adult patients with treatment-resistant depression in conjunction with oral antidepressants.

Each Spravato nasal spray device delivers 2 sprays containing a total of 28mg of esketamine; the product is classified as a Schedule III controlled substance. Spravato must be administered under the direct supervision of a healthcare provider; a treatment session consists of nasal administration and post-administration observation under supervision.

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1. Janssen announces US FDA approval of Spravato® (esketamine) CIII nasal spray to treat depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Accessed August 3, 2020. 

2. Spravato [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2020.