A Game-Changing Treatment for Clinical Depression

Esketamine has shown promising results in major clinical trials and has been proven to be 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 of the Champalimaud Foundation and Portuguese National Coordinator of the study, said: “TRD, despite adequate administration of at least two different antidepressants, It is defined as persistent depressive symptoms.” Despite repeated treatment attempts, depressive symptoms persist in these patients.

Historically, TRDs have posed significant challenges. A National Institute of Mental Health (NIMH) study found that one-third of patients with depression found remission with the first treatment, but the effectiveness of subsequent treatments diminished, and remission was reached by the third trial. It was revealed that only 10-15% of This harsh reality reinforces the need for more effective intervention strategies.

Esketamine: a potential solution for TRD

Janssen has developed Esketamine Nasal Spray, a ketamine-derived formulation that has shown superior efficacy compared to placebo in several clinical trials. It has also received approval from the US Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) in Europe. But why do we need another drug in an already crowded antidepressant market and another study on esketamine NS?

Oliveira-Maia said: “Although there are many treatments available for depression, there is a dearth of drug options tailored for TRD.” , pharmaceutical companies need to demonstrate clear benefits over existing treatments, underscoring the rationale for this study.”

Direct comparison: esketamine and quetiapine

This study compared esketamine NS to oral quetiapine XR. Quetiapine XR is an atypical antipsychotic drug originally approved for conditions such as schizophrenia, but now with regulatory approval it is increasingly being used as an adjunctive treatment for difficult-to-treat depressive episodes . “Quetiapine is one of the few alternative drugs currently approved as an add-on for patients with major depressive episodes who have an inadequate response to ongoing antidepressant therapy,” Dr. Oliveira-Maia said. Says.

The study, designed to mimic real-world situations, was open-label, meaning both healthcare providers and patients were aware of the drugs being used. Additionally, esketamine NS has the potential for acute dissociative effects, making a double-blind design impractical. Importantly, however, the efficacy evaluation was conducted in the field by an independent evaluator who was blind to study group assignment. In this multicenter, international study, more than 800 patients were screened, of which more than 600 met the strict eligibility criteria of his TRD and subsequently participated in the study.

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 are currently using conventional antidepressants that are either selective serotonin reuptake inhibitors (SSRIs, e.g. fluoxetine) or serotonin and norepinephrine reuptake inhibitors (SNRIs, e.g. venlafaxine). continued on antidepressant regimen. “The study was conducted over 32 weeks, which is longer than typical clinical trials,” Oliveira-Maia says. “This allowed us to evaluate both short-term and long-term treatment outcomes. During this period, we carefully monitored participant responses, side effects, and the overall effectiveness of the drug.”

Oliveira-Maia elaborates. “We found that patients taking esketamine NS achieved remission (essentially equivalent to disappearance of symptoms) by the 8-week mark compared to patients taking quetiapine XR. We aimed to determine whether, among patients who achieved this remission at 2 months, the effect of continued treatment on preventing relapse in both arms until the end of the 32-week study. It was made.”

reveal the findings

result? After eight weeks, both groups exceeded the 10-15% remission rate noted in his NIMH study, as published in . New England Medical Journal. Of note, 27.1% of patients in the esketamine NS group achieved remission compared with 17.6% in the quetiapine ) treatment was continued. Long-term data were even more informative. The proportion of patients who achieved remission at week 8 and remained relapse-free through week 32 was 21.7% in the esketamine NS group and 14.1% in the quetiapine XR group.

Most notable to the authors was the significant increase in remission rates after the first 8-week initial period. Oliveira-Maia said: However, the 32-week data tells a different story. ” By this point, approximately half of the patients who continued esketamine NS treatment (including those who did not achieve remission by week 8) had achieved remission. In contrast, only one-third of her patients who continued on quetiapine XR reached this state.

In addition to treatment efficacy, safety parameters were also critically evaluated. Both treatments had very low rates of serious adverse events, including mortality and suicidal ideation. However, when looking at less severe side effects, patients in the esketamine NS group had a higher frequency compared to patients in the quetiapine XR group. “This was expected given the dissociative properties of esketamine,” Oliveira-Maia says. “Interestingly, the proportion of patients who discontinued treatment due to side effects was actually lower with esketamine NS than with quetiapine XR. This suggests that although esketamine NS may theoretically have more side effects, , suggesting that the side effects caused by quetiapine are poorly tolerated.”

The way forward: Implications and future directions

The findings are promising for patients battling TRD. But, as Oliveira-Maia points out, “The real challenge is to move from research to policy. The effectiveness of esketamine NS can only be realized if it is easily accessible to patients.” Currently, Portugal and others In many countries, there is limited access to approved evidence-based treatments for TRD, including esketamine as well as electroconvulsive therapy and transcranial magnetic stimulation (TMS). “Continued research and strong advocacy are needed to ensure that treatments reach the patients who need them.”

Oliveira-Maia remains optimistic about the future. “Our future research efforts will aim to precisely identify predictive markers of treatment response. Additionally, we will investigate ways to improve and maintain remission rates, including the potential role of psychotherapy.” TMS is also high on the list for future exploration. However, scientific advances must be matched with proactive policy measures and concrete government actions. Ultimately our goal is is about creating a health care environment where patients are not forced into substandard, non-evidence-based treatments because they lack access to more effective options.”

Reference: “Comparison of esketamine nasal spray and quetiapine for treatment-resistant depression” Andreas Reif, Istvan Bitter, Jozefien Buyze, Kerstin Cebulla, Richard Frey, Dong-Jing Fu, Tetsuro Ito, Yerkebulan Kambarov, Pierre-Michel Llorca, Written by Albino J. Oliveira – Maia, Thomas Messer, Siobhan Mulhern-Hoey, Benoît Rive, Christian von Holt, Alan H. Young, Jordan Godinoff, October 3, 2023. New England Medical Journal.
DOI: 10.1056/NEJMoa2304145