Esketamine has shown promising results in a major clinical trial, proving more effective than standard treatments for treatment-resistant depression.
Treatment-resistant depression (TRD) is a particularly challenging form of major depressive disorder. Albino Oliveira-Maia, head of the Neuropsychiatry Unit at the Champalimaud Foundation and national coordinator of the study in Portugal, explains: “TRD is defined as the persistence of depressive symptoms despite adequate treatment with at least two different antidepressants. Despite repeated therapeutic attempts, these patients’ depressive symptoms persist.
Historically, TRD has been a significant challenge. A study by the National Institute of Mental Health (NIMH) found that while one-third of patients with depression achieved remission with their first treatment, subsequent treatments showed diminishing returns, with only 10-15% achieving remission by their third trial. This stark reality reinforces the need for more effective intervention strategies.
Esketamine: A potential solution for TRD
Janssen has developed esketamine nasal spray, a formulation derived from ketamine that has shown superior efficacy over placebo in several clinical trials. It has also been approved by the US Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) in Europe. But why is there a need for another drug in the already crowded antidepressant market, and another study on esketamine NS?
Oliveira-Maia says: “While there are many treatments available for depression, there is a paucity of drug options tailored for TRD. In addition, in order to guide clinicians and patients in their decision making, and to be adopted by health insurance companies and governments, drug companies need to demonstrate a clear advantage over existing treatment modalities, which underlines the rationale for this study”.
Head-to-head comparison: Esketamine vs. quetiapine
The trial compared esketamine NS with oral quetiapine XR, an atypical antipsychotic originally approved for conditions such as schizophrenia, but increasingly used as an adjunctive treatment for difficult-to-treat episodes of depression. Oliveira-Maia notes: “Quetiapine is currently one of the few alternative drugs approved as an adjunct for patients with a major depressive episode and an inadequate response to ongoing antidepressant treatment.
Designed to mimic real-world conditions, the study was open-label, meaning that both healthcare providers and patients were aware of the drugs being used. In addition, the potential for acute dissociative effects of esketamine NS made a double-blind approach impractical. Importantly, however, efficacy assessments were conducted on site by independent assessors who were blinded to the allocation of study groups. The multi-centre, international study screened over 800 patients, of whom over 600 met the strict eligibility criteria for TRD and were subsequently enrolled in the study.
Participants were divided into two cohorts: one self-administered quetiapine XR at home and the other received esketamine NS under hospital supervision. At the same time, both groups continued their most recent antidepressant treatment with a conventional antidepressant, either a selective serotonin reuptake inhibitor (SSRI, such as fluoxetine) or a serotonin and norepinephrine reuptake inhibitor (SNRI, such as venlafaxine). “The trial lasted 32 weeks, which is longer than typical trials,” says Oliveira-Maia. “This allowed us to measure both short-term and long-term treatment outcomes. Throughout this time, we closely monitored participants’ responses, side effects and the overall efficacy of the drugs.”
Oliveira-Maia continues: “We wanted to see if patients taking esketamine NS were more likely to achieve remission – essentially the elimination of symptoms – at the eight-week mark, compared to those taking quetiapine XR. For those who achieved remission at two months, we sought to determine the effect of continued treatment on preventing relapse in both arms until the end of the trial at 32 weeks.
Unveiling the results
The results? After 8 weeks, both groups exceeded the 10-15% remission rate reported in the NIMH study, published in the New England Journal of Medicine. Specifically, 27.1% of patients on esketamine NS achieved remission, compared with 17.6% on quetiapine XR, with both groups continuing treatment with a conventional antidepressant (either an SSRI or SNRI). The long-term data were even more revealing. The proportion of patients who achieved remission at week 8 and maintained it without relapse to week 32 was 21.7% in the esketamine NS group and 14.1% in the quetiapine XR group.
The authors were particularly struck by the marked increase in remission rates after the initial eight-week period. Oliveira-Maia commented: “If this study had stopped at eight weeks, the results would have been interesting but not remarkable. But the 32-week data tell a different story. At that point, about half of the patients who continued on esketamine NS – including those who were not in remission at week eight – had achieved remission. By contrast, only a third of those continuing on quetiapine XR had achieved remission.
In addition to therapeutic efficacy, safety parameters were critically assessed. Both treatment options had very low rates of serious adverse events, such as mortality or suicidal thoughts. However, when it came to less serious side effects, patients in the esketamine NS group had a higher incidence than those in the quetiapine XR group. “This was expected, given the dissociative properties of esketamine,” says Oliveira-Maia. “Interestingly, the rate of patients discontinuing treatment due to side effects was actually lower for esketamine NS than for quetiapine XR, suggesting that while esketamine NS may have more side effects on paper, those caused by quetiapine were less tolerable.”
The road ahead: Implications and future directions
The results are promising for patients with TRD. However, as Oliveira-Maia points out, “the real challenge is to move from research to policy. The impact of esketamine NS can only be realised if patients have easy access to it. Currently, in Portugal and many other countries, there is limited access to approved, evidence-based treatments for TRD, including esketamine, but also electroconvulsive therapy and transcranial magnetic stimulation (TMS). “Continued research and strong advocacy are needed to ensure that treatments reach the patients who need them.”
Looking ahead, Oliveira-Maia remains optimistic. “Our future research efforts aim to identify predictive markers of treatment response. We also want to investigate ways to improve and maintain remission rates, including the potential role of psychotherapy. TMS is also high on our list for future research. However, scientific progress must be matched by proactive policy and concrete government action. Ultimately, our goal is to create a healthcare landscape where patients are not relegated to inferior, non-evidence-based treatments for lack of access to more effective options.
