Breaking the Chains of Treatment-Resistant Depression With Esketamine Nasal Spray

Treatment-resistant depression (TRD) is a particularly difficult form of severe depression. "TRD is defined as the persistence of depressive symptoms despite adequate courses of at least two different antidepressant medications," explains Albino Oliveira-Maia, chairman of the Champalimaud Foundation's Neuropsychiatry Unit and the study's national coordinator for Portugal (1^✔ ✔Trusted Source
Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression

Go to source). These patients' depressed symptoms persist despite multiple therapy attempts. TRD has historically been a considerable challenge. According to research conducted by the National Institute of Mental Health (NIMH), while one-third of individuals with depression achieved remission with their first treatment, subsequent treatments experienced diminishing effects, with just 10-15% achieving remission by their third trial. This sobering truth highlights the critical need for more effective intervention options.

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Finding a Treatment for Treatment-Resistant Depression with Esketamine

Janssen created esketamine nasal spray, a formulation that has outperformed placebo in multiple clinical trials. It has also received approval from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in Europe. But why is there a need for another antidepressant in an already saturated market, as well as another trial on esketamine NS?

"While there are many treatments available for depression, there is a paucity of drug options tailored for TRD," says Oliveira-Maia. Furthermore, to aid physicians and patients in their decision-making, as well as to be embraced by health insurance companies and governments, drug producers must demonstrate a clear advantage over existing treatment methods, highlighting the purpose of this study."

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Comparison of Esketamine and Quetiapine for the Treatment of Depression

The trial compared esketamine NS to oral quetiapine XR, an atypical antipsychotic originally approved for disorders such as schizophrenia but now widely utilized as an adjuvant treatment for difficult-to-treat episodes of depression with regulatory permission. It is noted that "Quetiapine is currently one of the few alternative medications approved as an add-on for patients with a major depressive episode and inadequate response to ongoing antidepressant treatment".

The open-label trial was designed to simulate real-world situations so that both healthcare providers and patients were aware of the drugs being administered. Furthermore, considering the potential for immediate dissociative effects of esketamine NS, a double-blind strategy seemed unfeasible. Importantly, efficacy assessments were carried out on-site by independent raters who were unaware of the study group allocations. Over 800 patients were assessed in the multi-center worldwide investigation, with over 600 meetings the tight eligibility criteria for TRD and being subsequently included in the study.

Participants were divided into two groups: those who self-administered quetiapine XR at home and those who got esketamine NS under hospital supervision. Both groups continued their previous antidepressant regimen with a standard antidepressant, either a selective serotonin reuptake inhibitor (SSRI, such as fluoxetine) or a serotonin and norepinephrine reuptake inhibitor (SNRI, such as venlafaxine). "The study lasted 32 weeks, which is longer than most trials," Oliveira-Maia explains. "We were able to assess both short-term and long-term treatment outcomes as a result of this." Throughout this time, we meticulously examined individuals' responses, side effects, and the overall efficacy of the drugs."

"We wanted to see if patients on esketamine NS were more likely to achieve remission—essentially, elimination of symptoms—by the eight-week mark, compared to those on quetiapine XR," Oliveira-Maia explains. We intended to investigate the impact of continuous treatment on avoiding recurrence in both arms up to the trial's conclusion at 32 weeks among those who achieved this remission at two months."

What were the outcomes? After 8 weeks, both groups had exceeded the NIMH study's 10-15% remission rate, which was published in the New England Journal of Medicine. Notably, 27.1% of esketamine NS patients achieved remission, compared to 17.6% of quetiapine XR patients, with both groups continuing treatment with a traditional antidepressant (either an SSRI or an SNRI). Long-term data was even more useful. The proportion of patients who achieved remission at week 8 and maintained it without recurrence through week 32 in the esketamine NS group was 21.7% and 14.1% in the quetiapine XR group, respectively.

What were the outcomes? After 8 weeks, both groups had exceeded the NIMH study's 10-15% remission rate, which was published in the New England Journal of Medicine. Notably, 27.1% of esketamine NS patients achieved remission, compared to 17.6% of quetiapine XR patients, with both groups continuing treatment with a traditional antidepressant (either an SSRI or an SNRI). Long-term data was even more useful. The proportion of patients who achieved remission at week 8 and maintained it without recurrence through week 32 in the esketamine NS group was 21.7% and 14.1% in the quetiapine XR group, respectively.

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Prolonged Remission Trends with Esketamine NS and Quetiapine XR

The authors found the most significant increase in remission rates after the initial eight-week period. "Had this trial ended at eight weeks," Oliveira-Maia observed, "the results would have been quite interesting but not remarkable." The 32-week data, on the other hand, presents a different narrative." By this point, over half of the patients who had continued with esketamine NS treatment - including those who had not achieved remission by week eight - had achieved remission. In comparison, just one-third of individuals who continued using quetiapine XR reached this point.

Aside from therapeutic efficacy, safety criteria were evaluated. Both treatment choices had extremely low incidences of serious adverse events such as death or suicide ideation. When looking at less significant side effects, patients in the esketamine NS group had a higher frequency than those in the quetiapine XR group. "Given esketamine's dissociative properties, this was expected," explains Oliveira-Maia. "Interestingly, the rate of patients discontinuing treatment due to side effects was lower for esketamine NS than for quetiapine XR, which suggests that while esketamine NS may have more side effects on paper, those caused by quetiapine were less tolerable".

Encouraging Trends in Treatment of TRD (Treatment-Resistant Depression)

The findings are encouraging for those suffering from TRD. However, as Oliveira-Maia observes, "the real challenge is shifting from research to policy." The full impact of esketamine NS can be realized only if patients have easy access to it." There is currently limited access to licensed, evidence-based treatments for TRD in Portugal and many other countries, including esketamine, but also electroconvulsive therapy and transcranial magnetic stimulation (TMS). "Continued research and strong advocacy are needed to make sure treatments reach the patients who need them".

Looking ahead, Oliveira-Maia stays upbeat. "Our future research efforts will focus on identifying predictive markers for treatment responsiveness." We also want to look for measures to increase and maintain remission rates, including the potential role of psychotherapy. TMS is also on our list of potential future explorations. However, scientific advancement must be accompanied by aggressive policy initiatives and tangible government action. Our ultimate goal is to create a healthcare landscape in which patients are not forced to accept inferior, non-evidence-based therapies due to a lack of access to more effective options."

Reference:

1. Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression - (https:pubmed.ncbi.nlm.nih.gov/37792613/ )