Esketamine Bests Quetiapine for Severe Depression in Head-to-Head Trial
BARCELONA — Intranasal esketamine (Spravato, Janssen) is superior to extended-release quetiapine (Seroquel, AstraZeneca), an atypical antipsychotic, for treatment-resistant depression (TRD), results of a large, multicenter, head-to-head phase 3 trial show.
Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission in comparison with quetiapine.
More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI).
Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates.
The findings were presented here at the 36th European College of Neuropsychopharmacology (ECNP) Congress and were published online October 5 in The New England Journal of Medicine.
The results provide "some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer," said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP.
"These patients are not resistant, they just have resistance to monoaminergic drugs," he added. Esketamine, he said, is a "new weapon in our armamentarium."
Reif said TRD is a serious condition that affects approximately 20% to 30% of those with major depressive disorder and has "substantial impact" on patients' lives, including quality of life and level of functioning.
"We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment," Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was "urgently needed."
For the trial, patients from 171 sites in 24 countries with TRD, defined as a <25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy.
Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery–Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32.
Reif said the study population was representative of a typical TRD population.
The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30.
Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8 compared to those treated with quetiapine (27.1% vs 17.6%; P = .003). This equated to an adjusted odds ratio (OR) for remission of 1.74 (P = .003).
Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% versus 14.1% with quetiapine; OR, 1.72 (P = .008).
At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, vs 37.0% (P < .001).
Reif noted that the definition of remission used in the study was a MADRS score of ≤10, but if the "more lenient" definition of ≤12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, vs 46.7%.
Reif also presented results on functional remission rates beyond 32 weeks ― data that were not included in the study as published in NEJM.
While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs 25.0%; OR, 1.88; P < .001).
The safety data revealed no new signals, Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs 11.0% with quetiapine.
Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover.
Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it "greatly improves patients' functional impairment" while achieving "generally lower" adverse event rates.
He added that they are currently running a significant number of secondary analyses "to give us a better grasp of which patient benefits most" from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection.
Session co-chair Mark Weiser, MD, chairman at the Department of Psychiatry, Sackler School of Medicine, Tel Aviv University, Israel, told Medscape Medical News the results are "very exciting" and offer "further proof of a tremendous advance in our field."
Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key.
"It's great to improve symptoms," he said, "but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that's of extreme importance and makes us feel very optimistic about the future."
Also commenting, Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, Barcelona, Spain, welcomed the findings.
"The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine," he said in a release. "This gives people with treatment-resistant depression more safe treatment options."
The study was funded by Janssen EMEA. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry.
36th European College of Neuropsychopharmacology (ECNP) Congress: Abstract S06.04. Presented October 8, 2023.