Escaping Treatment-Resistant Depression with Esketamine

Patients with major depressive disorder (MDD) often require multiple medications trials to achieve remission. Treatment-resistant depression (TRD) — defined as lack of response to two or more medication trials — affects up to 30% of patients with MDD. Patients with TRD not only have significantly lower quality of life and impaired functional status than patients without TRD, but also have higher mortality and suicide rates.

TRD is notoriously difficult to treat. The relapse rate is approximately 70% among patients who are fortunate enough to experience a response. Augmentation with the antipsychotic quetiapine has been used for decades in patients who have failed first-line treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs). However, remission rates remain suboptimal, and quetiapine is associated with serious adverse effects, including sedation and extrapyramidal effects.

Esketamine, a ketamine derivative, was approved by the FDA for treatment of TRD in 2019. Multiple placebo-controlled trials have demonstrated its efficacy as an augmentative agent in reducing depressive symptoms in TRD. Until now, no major long-term studies have directly compared the efficacy of esketamine augmentation to existing treatments for TRD.

Researchers of the open-label, single-blind ESCAPE-TRD study addressed this knowledge gap by randomizing 676 patients with TRD to receive esketamine nasal spray or extended-release quetiapine in addition to their SSRI or SNRI. Patients had already failed two to six consecutive treatment trials and were taken off all non-SSRI or SNRI antidepressant medications for the study.

The results were promising. Based on blinded rating of depression symptoms, significantly more esketamine recipients than quetiapine recipients (27% vs.18%, respectively) reached the primary endpoint of remission (defined as a Montgomery–Åsberg Depression Rating Scale [MADRS] score ≤10) by week 8. At 32 weeks, remission rates were even higher (49% vs. 33%, respectively).

However, esketamine was associated with more adverse effects than quetiapine (92% vs. 78%), mostly dizziness, nausea, and dissociation. The most common adverse effects among quetiapine recipients were somnolence, headache, and weight gain. Serious adverse events related to the study treatment (including acute coronary syndrome) were reported in 6% of esketamine recipients and no quetiapine recipients. Nevertheless, fewer patients in the esketamine group discontinued treatment (23% vs. 40%) but more patients who discontinued quetiapine did so because of adverse effects or lack of efficacy.

This was the first head-to-head comparison of esketamine versus a guideline-recommended treatment for TRD. The findings affirm its role as an important adjunctive agent for TRD treatment. However, several limitations should temper our enthusiasm about these results. Due to the open-label design, patients knew which medication they were receiving, which could have affected dropout rates. Further, many patients with TRD receive medications other than SSRIs or SNRIs, raising questions about esketamine’s efficacy in heterogeneous treatment regimens. Adherence could also be an issue since administration of esketamine requires one to two clinic visits per week. Finally, a sobering result is that even at 32 weeks, a majority of patients with TRD still had not achieved remission.

Read the following NEJM Journal Watch summary for more details of this study.

Peter Roy-Byrne, MD, reviewing Reif A et al. N Engl J Med 2023 Oct 5

Esketamine, an antagonist of N-methyl-D-aspartate receptors, is a U.S. FDA-approved medication for patients with treatment-resistant depression. It is available as a nasal spray that is administered in a healthcare facility (not at home) and is approved for use only in conjunction with an oral antidepressant.

In a 32-week randomized trial, 676 patients with major depressive disorder and minimal response to two different antidepressants received esketamine nasal spray (initially twice weekly) or daily oral extended-release quetiapine; patients continued the antidepressant (i.e., selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor) that they already were taking. (Note: The comparator, quetiapine, is an atypical antipsychotic drug that is approved as adjunctive therapy for patients with inadequate response to antidepressants.)

Remission at 8 weeks was significantly more likely with esketamine than quetiapine (27% vs. 18%). Remission rates increased over time in both groups, continuing to favor esketamine at 32 weeks (49% vs. 33%). The incidence of serious adverse events was ≈5% in both groups. Side effect–related dropouts were more common with quetiapine (11% vs. 4%), mostly due to weight gain and sedation.

Comment: Many second-step treatment strategies — all roughly equal in efficacy — are available after initial antidepressant failure. In this study, short-term remission rates were low initially but doubled over another 6 months — highlighting the importance of watchful waiting rather than changing a potentially effective treatment prematurely. The modestly greater efficacy of esketamine likely is offset by the required twice-weekly clinic visits and uncertain insurance coverage. Because quetiapine has a greater side effect burden than some other atypical antipsychotic drugs used as adjunctive agents, it might have been a less-than-ideal comparator in this study.

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Suellen Li, MD, is a 2023–2024 NEJM Editorial Fellow. She is a hospitalist at Massachusetts General Hospital, where she also completed her internal medicine residency.