Treatment-resistant depression affects 10-30% of patients with major depressive disorder (MDD). These patients have trialled two or more pharmacologic treatments that have been given adequate duration for a response, at an adequate dose. This is associated with increased hospitalization, higher mortality and suicide rates.
Esketamine nasal spray (Spravato), the newest agent to be approved by both the United States Food Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of treatment-resistant depression, has fulfilled a long-standing need for additional agents to treat this serious condition. In its phase 3 trials, Esketamine nasal spray combined with an oral antidepressant significantly reduced the risk of relapse compared to a placebo plus an oral antidepressant. Before the approval of Esketamine nasal spray, extended-release Quetiapine, in addition to oral antidepressants, is a commonly used agent to treat treatment-resistant depression. Since approval, there has not been a head-to-head comparison between Esketamine nasal spray and another augmentation strategy.
The ESCAPE-TRD trial aims to determine if Esketamine nasal spray, in addition to selective serotonin reuptake inhibitors (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) will result in greater remission rates and freedom from relapse compared to extended-release Quetiapine. This open-label trial recruited 676 adult patients with treatment-resistant depression who are currently on antidepressant treatment, which included an SSRI or SNRI. All augmentation agents were discontinued – patients who were already receiving Quetiapine 50mg or less once a day had to undergo a washout period of at least 7 days. Patients were randomly assigned 1:1 to receive Esketamine nasal spray or extended-release quetiapine for an initial treatment phase of 8 weeks and maintenance phase of 24 weeks – doses of both agents were flexible. They followed the product characteristics of each agent. Subsequently, patients underwent a safety follow-up of 2 weeks. The investigators decided on an open-label trial to minimise patient burden with the need for additional placebo since the trial drugs had different route of administration.
The primary endpoint of remission, defined as a Montgomery–Åsberg Depression Rating Scale (MADRS) score of 10 or less at week 8, occurred in significantly more patients in the Esketamine group compared to the Quetiapine group (27.1% vs 17.6%), with the Esketamine group achieving a greater reduction in depressive symptoms from baseline. More patients (21.7%) in the Esketamine group had no relapse through week 32 after remission at week eight compared to the Quetiapine group (14.1%), which was a key secondary endpoint. Remission at week 32 occurred in more patients in the Esketamine group than in the Quetiapine group.
The adverse events detected during the trial period were consistent with the established safety profile of Esketamine and extended-release Quetiapine. Adverse events that led to discontinuation occurred in 14 patients in the Esketamine group and 37 patients in the quetiapine group, with two patients in the Esketamine group having a serious adverse event considered to be due to study drug – one had acute coronary syndrome at week 21, and one had dizziness at week 2.
Based on the efficacy results, patients treated with Esketamine nasal spray were 1.54 times more likely to achieve remission at week 8, a goal that is difficult to achieve in patients with treatment-resistant depression. This provides sufficient evidence to show the superiority of Esketamine nasal spray over extended release Quetiapine in helping patients with treatment-resistant depression achieve remission, while also reducing the risk of relapse. Almost half of the patients in the Esketamine group achieve remission by week 32, despite only 27.1% achieving remission at week 8, which emphasises the need to persist on treatment despite not having remission initially. Although these findings will provide new breakthroughs for the treatment of treatment-resistant depression, the generalizability may be limited given the fact that in real-world practice, there is no guideline consensus on the treatment algorithm for patients with treatment-resistant depression. Patients may already receive multiple augmenting agents on top of their regular antidepressants, and it is unknown if Esketamine nasal spray use will be superior to these other agents. Nonetheless, these results may give clinicians more confidence in selecting between Esketamine and Quetiapine as an augmentation strategy when managing treatment-resistant depression, and it will provide a new lifeline for patients struggling with this complicated condition.
References
- Reif A, Bitter I, Buyze J, Cebulla K, Frey R, Fu D-J, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression. New England Journal of Medicine. 2023;389(14):1298–309. doi:10.1056/nejmoa2304145
