Esketamine Nasal Spray (Spravato) led to better remission rates compared with extended-release quetiapine (Seroquel XR) in patients with treatment-resistant depression when used in combination with ongoing treatment, the randomized phase IIIb ESCAPE-TRD trial showed.

Among patients who were taking a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), those who received adjunctive intranasal esketamine had better rates of remission at 8 weeks compared with adjunctive quetiapine (27.1% vs 17.6%; adjusted OR 1.74, 95% CI 1.20-2.52) based on the Montgomery-Åsberg Depression Rating Scale (MADRS), reported Andreas Reif, MD, of the University Hospital Frankfurt-Goethe University in Germany, and co-authors.

In addition, 21.7% of patients in the esketamine group had no relapse through 32 weeks after remission at week 8 versus 14.1% of those in the quetiapine group (aOR 1.72, 95% CI 1.15-2.57), they noted in the New England Journal of Medicine.

“Approximately one-third of people who suffer from major depressive disorder do not respond to treatment and are considered to have treatment-resistant depression,” Reif told MedPage Today in an email. “Research into treatments for treatment-resistant depression is essential, to help break the cycle of treatment failure and to combat the devastating impact that treatment-resistant depression has on people living with the condition.”

“Remission is the ultimate goal for the acute phase of antidepressive treatment, followed by preventing relapse once remission is achieved,” he noted. “The primary and key secondary endpoints represent major milestones in the course of treating depression for patients and clinicians and are even more significant and difficult to achieve in a treatment-resistant depression participant population.”

He noted that the rates of remission and relapse were in line with expectations based on previous studies, but that the continued increase in these rates all the way up to week 32 was unexpected. “This consolidates the importance of esketamine nasal spray as a long-term therapeutic option for adults with treatment-resistant depression,” he said.

“Given the different methods of administration of the two medicines … conducting the study open-label avoided the need to use a placebo, which reduced the burden on study patients in the quetiapine extended-release arm in terms of less frequent visits to treatment [centers],” he added.

In an accompanying editorial, Rupert McShane, MD, of the Oxford Health NHS Foundation Trust and the University of Oxford in England, noted that the trial provided positive progress in research on the use of esketamine nasal spray.

“Real-world experience with esketamine nasal spray has also been reassuring,” he wrote. “Cystitis and cognitive impairment remain theoretical, rather than actual, risks. Similarly, overuse is prevented because the nasal spray has to be administered in the clinic, which also enhances the opportunity for regular review.”

Despite the concerns around the use of esketamine in clinical settings, McShane said that this trial “supports the radical and disruptive idea that esketamine nasal spray has a place early in the sequence of antidepressant treatment.”

For this study, patients were recruited from August 2020 through November 2021 at 171 sites — including hospitals, inpatient and outpatient clinics, and research centers — across 24 countries.

Reif and colleagues randomized 336 patients to receive a flexible dose of esketamine nasal spray (median age 45, 67% women) and 340 patients to extended-release quetiapine (median age 47, 65.3% women) in combination with an SSRI or SNRI. The primary endpoint was remission at 8 weeks defined by a score of 10 or less on the MADRS (scores range from 0 to 60, with higher scores indicating more severe depression).

All enrolled patients were included in the analysis, with patients who discontinued treatment being counted as having an unfavorable outcome.

As for other secondary endpoints, patients in the esketamine group were more likely to be in remission at 32 weeks compared with those in the quetiapine group (49.1% vs 32.9%; OR 1.96, 95% CI 1.44-2.68). Similarly, 65.5% of patients in the esketamine group showed a treatment response at 32 weeks compared with 47.1% of those in the quetiapine group (OR 2.13, 95% CI 1.57-2.91).

Adverse events occurred in most patients in both the esketamine group (91.9%) and the quetiapine group (78%), but serious adverse events were far less common (5.7% vs 5.1%, respectively). The researchers noted that two patients in the esketamine group had serious adverse events — acute coronary syndrome at 21 weeks and dizziness at 2 weeks — that were considered to be related to the treatment. There were no serious adverse events considered to be related to treatment in the quetiapine group.