Esketamine outperforms quetiapine in head-to-head depression trial

In patients with treatment-resistant depression, esketamine nasal spray appears to have superior efficacy compared with extended-release quetiapine when used in combination with conventional antidepressants.

Data from the phase IIIb ESCAPE-TRD trial showed that participants who received esketamine were 54 percent more likely to achieve remission (Montgomery–Åsberg Depression Rating Scale [MADRS] score ≤10) at week 8—the primary endpoint—than those who received quetiapine (27.1 percent vs 17.6 percent; p=0.003; adjusted relative risk [aRR], 1.54, 95 percent confidence interval [CI], 1.15–2.06). All participants had ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). [N Engl J Med 2023;389:1298-1309]

More esketamine-treated participants did not experience relapse through week 32 after remission at week 8 (21.7 percent vs 14.1 percent; aRR, 1.55, 95 percent CI, 1.12–2.16).

These data, according to the investigators, were clinically relevant and aligned with treatment goals, that is remission and prevention of relapse.

“If a patient does not show any improvement after two different antidepressant therapies over several weeks, we call this treatment-resistant depression. Studies have shown that administering an additional drug can then be effective,” said principal investigator Prof Andreas Reif of the Department of Psychiatry, Psychosomatics and Psychotherapy at University Hospital Frankfurt, Frankfurt, Germany, in a statement.

“In the first instance, such an added drug does not need to have an antidepressant effect, but it can often improve or enhance the effect in combination with the previous SSRI or SNRI therapy. This is what was done in the comparison arm, using quetiapine extended release in addition to ongoing SSRI/SNRI treatment,” Reif explained.

The benefit of esketamine nasal spray in treatment-resistant depression has been previously shown in a study that used placebo nasal spray as a comparator, with both study drugs given in addition to a newly initiated SSRI or SNRI. ESCAPE-TRD provided data on direct comparisons of esketamine with an augmentation strategy. [Am J Psychiatry 2019;176:428-438; Depress Anxiety 2021;38:1120-1130; JAMA Psychiatry 2019;76:893-903]

Study details

A total of 676 adult patients with treatment-resistant depression were included, of whom 336 (mean age 44.3 years, 67.0 percent women) were assigned to the esketamine group and 340 to the quetiapine group (mean age 45.7 years, 65.3 percent women). The mean duration of current depressive episode was 68.8 and 64.6 weeks in the respective groups, with the mean MADRS score at baseline being 31.

Aside from the key primary and secondary endpoints, results for other endpoints also favoured esketamine. Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline were better in the esketamine than in the quetiapine group.

“The adverse events were consistent with the established safety profiles of the trial treatments,” with no new safety signals identified, the investigators said.

Serious adverse events occurred in 19 participants in the esketamine group and in 17 participants in the quetiapine group. Acute coronary syndrome in one patient and dizziness in another were deemed related to esketamine treatment.

Adverse events led to treatment discontinuation in 4.2 percent of participants in the esketamine group and in 11.0 percent of those in the quetiapine group. Suicide attempts were documented in two and one participants, respectively. One case of death was recorded in each group. None of these events were related to treatment.

“As a 32-week head-to-head comparison of esketamine nasal spray with an active control, our trial appears to be an important addition to the phase III clinical program of esketamine nasal spray. In the previous phase III trials, another commonly used remission threshold—a MADRS score of 12 or less—was used,” according to the investigators. [J Clin Psychiatry 2020;81:19m12891; Int J Neuropsychopharmacol 2019;22:616-630; Am J Geriatr Psychiatry 2020;28:121-141; J Affect Disord 2023;321:153-160]

When remission was defined as MADRS score ≤12 in ESCAPE-TRD, similar results were obtained. A greater proportion of patients in the esketamine group than in the quetiapine group had remission at week 8 (38.7 percent vs 22.9 percent) and had no relapse through week 32 (32.1 percent vs 17.6 percent), which reinforces the superiority of esketamine nasal spray to extended-release quetiapine, as the investigators pointed out.

“Existing guidelines for the treatment of patients with treatment-resistant depression lack uniformity; collectively, these data provide support for the use of esketamine nasal spray in treatment-resistant depression and may be of value for informing future guidelines,” they said.