Esketamine Nasal Spray Bests Quetiapine XR in Difficult-to-Treat Depression

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The trial compared Spravato (esketamine nasal spray) to quetiapine extended-release, both in combination with a continuing SSRI or SNRI.

Topline results were announced from a phase 3b trial that compared the short- and long-term efficacy, safety, and tolerability of esketamine nasal spray to quetiapine extended-release (XR) in adults with treatment-resistant major depressive disorder.

In the ESCAPE-TRD trial ( Identifier: NCT04338321), patients with treatment-resistant major depressive disorder were randomly assigned 1:1 to receive either esketamine nasal spray (n=336) or quetiapine XR (n=340), in combination with a continuing selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) for up to a maximum of 36 weeks. 

The primary endpoint was the percentage of patients with remission as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) at week 8. The key secondary endpoint was the percentage of patients with remission at week 8 without relapse until the end of week 32.

Results showed that a significantly greater percentage of patients in the esketamine nasal spray arm achieved remission at week 8 compared with the quetiapine XR arm (27.1% vs 17.6%, respectively; P =.003). Among those who achieved remission at week 8, 21.7% of patients administered esketamine nasal spray remained relapse free until week 32 vs 14.1% of patients on quetiapine XR (P =.008). Remission rates continued to increase in both arms after week 8, with a significantly greater proportion of patients treated with esketamine nasal spray in remission at week 32 compared with quetiapine XR-treated patients (55% vs 37%, respectively; P <.001).

As for safety, the most common treatment-emergent adverse events with esketamine nasal spray were dizziness, nausea, dissociation, headache, vertigo, somnolence, dysgeusia, paresthesia, and vomiting. The rates of treatment discontinuation were 23.2% in the esketamine nasal spray arm and 40.3% in the quetiapine XR arm.

“The ESCAPE-TRD findings showed that esketamine nasal spray enabled a significantly greater percentage of patients to achieve remission at week 8 and remain relapse free in the longer term up to week 32 compared to quetiapine extended-release,” said Professor Andreas Reif, principal investigator for the ESCAPE-TRD trial and Head of Department, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy at University Hospital Frankfurt, Germany. “This provides further evidence for the use of esketamine nasal spray in this difficult-to-treat population and offers hope for the millions of people affected by [treatment-resistant depression].”

Esketamine nasal spray is currently marketed under the brand name Spravato® for use, in conjunction with an oral antidepressant, in the treatment of adults with treatment-resistant depression or depressive symptoms of major depressive disorder with acute suicidal ideation or behavior.


Spravato® (esketamine nasal spray) data from the phase 3b ESCAPE-TRD study demonstrate superior efficacy compared to quetiapine extended-release in treatment-resistant major depressive disorder. News release. Janssen Pharmaceutical Companies of Johnson & Johnson. Accessed November 23, 2022.