Ketamine-related drug gives better treatment for difficult to treat clinical depression
• Increases the number of patients likely to respond to treatment for major depression
IMAGE:
SHARE OF PEOPLE IN EU REPORTING CHRONIC DEPRESSION, 2019
view moreCREDIT: EUROSTAT
Type of work: peer-reviewed/clinical trial/people
A major clinical trial shows that the drug, esketamine, one of the two main forms of ketamine, outperforms one of the standard treatments for treatment-resistant major depression. This industry-funded work is presented for the first time at the 36th ECNP Congress in Barcelona, with publication in the peer-reviewed journal the New England Journal of Medicine (see Notes for details).
Clinical depression (also known as MDD, major depressive disorder) affects a significant number of people at any one time, giving them real life problems and increasing the health-related costs. Eurostat reports that 7% of the EU adult population had problems with depression in 2019, and around 20% to 30% of these patients do not respond to treatment. If these patients do not respond after two consecutive treatments, then they are classified as having treatment-resistant depression. Almost all MDD patients in hospital care suffer from treatment-resistant depression.
The antipsychotic drug quetiapine is commonly used in treatment-resistant depression (normally used together with an antidepressant). However, esketamine NS is the only specifically approved therapy for treatment-resistant depression in Europe (it is also given alongside other antidepressants). Esketamine NS is a nasal spray, approved in 2019.
Now the ESCAPE-TRD study describes the first large trial comparing esketamine with quetiapine. This study was funded by Janssen EMEA, the manufacturers of esketamine NS.
Researcher Andreas Reif (of Goethe University Frankfurt), first author of the study, said “The ESCAPE-TRD trial was an open-label, single-blind, randomised, controlled trial, conducted across 171 sites comprising hospitals, inpatient and outpatient clinics, and research centres in 24 countries. This is the first trial to compare this new treatment with a standard existing treatment for treatment-resistant depression, and so it’s a really necessary study. The results are very positive”.
The patients were aged between 18 and 74. All had treatment-resistant depression, in some cases the depression persisted after six different treatment attempts. All had been taking antidepressants, such as SSRI (selective serotonin reuptake inhibitor) or SNRI (serotonin and norepinephrine reuptake inhibitors). 336 patients then received esketamine nasal spray plus an SSRI or SNRI, while another 340 patients received quetiapine plus an SSRI or SNRI. Patients were treated for eight weeks, followed by 24 weeks of maintenance treatment.
Professor Reif continued, “We were testing patients at two endpoints (goals). The first major endpoint was to understand the proportion of patients who achieved remission after eight weeks. The second was determining the proportion of patients who met the first endpoint and who were relapse free at the end of the trial period (i.e. after 32 weeks). We measured the effects of treatment using a standard depression scale, the Montgomery‑Åsberg Depression Rating Scale”.
Results
After eight weeks, 28% patients taking esketamine plus antidepressants achieved remission, as against 18% remission in the group taking quetiapine (primary endpoint). At the 32-week mark (key secondary endpoint), 22% of patients taking it were still in remission, as opposed to 14% of patients who had taken quetiapine plus antidepressants.
“There were other differences we saw over time”, said researcher Professor Allan Young (of Kings College London who collaborated with the study). “For example the patients receiving the esketamine treatment had fewer depressive symptoms than those taking quetiapine. We found that patients receiving esketamine NS were around 1.5 times as likely to experience remission at Week 8 than those receiving quetiapine XR. In addition, esketamine NS‑treated patients were 1.5 times as likely to achieve the key secondary endpoint, remaining relapse free through Week 32. Indeed, by Week 32, approximately half of patients receiving esketamine NS were in remission, while two thirds were responders, emphasising the importance of continuing treatment in those who do not achieve remission in the acute phase”.
Commenting, Dr Josep Antoni Ramos-Quiroga from Vall Hebron University Hospital (CIBERSAM) and Autonomous University of Barcelona said: “The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine. This gives people with treatment-resistant depression more safe treatment options".
This is an independent comment, Dr Ramos-Quiroga was not involved in this work.
Notes
Funding: This study was funded by Janssen EMEA, manufacturers of esketamine NS.
This press release is developed from work presented at the 36th ECNP Congress in Barcelona, 7-10 October 2023 (listed below). All press releases from the ECNP congress are produced independently of any sponsorship or external interest.
ECNP Presentation
Andreas Reif will present this work during the ECNP New Medications symposium on 8 October, https://www.ecnp.eu/congress2023/ECNPcongress/programme/programme#!sessiondetails/0000122610_0
Relevant Posters from the ECNP Congress, presented Sunday 8 October.
- P.0149 Duration and impact of adverse events with esketamine nasal spray and quetiapine extended release in the ESCAPE‑TRD phase IIIb trial E. Vieta1, P.M. Llorca2, A.J. Oliveira-Maia3,4, L. Häggström5, W. Cubała6, J. Buyze7, Y. Godinov8, B. Rive9, A. Reif10
- P.0146 Remission/response with esketamine nasal spray versus quetiapine extended release in treatment resistant depression using the Clinical Global Impression‑Severity scale A. Reif1, A. Fagiolini2, A.J. Oliveira-Maia3,4, A. Luts5, N. Cardoner6, J. Buyze7, S. Mulhern-Haughey8, Y. Kambarov7, A.H. Young9,10
This work is presented at the 36th ECNP Congress, which takes place in Barcelona and online on 7-10 October 2023, see https://www.ecnp.eu/Congress2023/ECNPcongress. With more than 5,300 participants the ECNP Congress is Europe’s leading platform for the latest research in disease-related neuroscience.
This work is also published on 5 October, in the New England Journal of Medicine. “Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression”: Andreas Reif et al. DOI: 10.1056/NEJMoa2304145 Embargo as indicated above.
JOURNAL
New England Journal of Medicine
COI STATEMENT
Full COI and funding details are listed in the NEJM publication. All press releases from the ECNP congress are produced independently of any sponsorship or external interest
Esketamine nasal spray: an option for patients with treatment-resistant depression
IMAGE:
ESKETAMINE NASAL SPRAY
view moreCREDIT: JANSSEN PHARMACEUTICA NV
Understanding Treatment-Resistant Depression
Treatment-resistant depression (TRD) is a particularly challenging form of major depressive disorder. As Albino Oliveira-Maia, head of the Champalimaud Foundation’s Neuropsychiatry Unit and the study’s national coordinator for Portugal, explains, “TRD is defined as the persistence of depressive symptoms despite adequate courses of at least two different antidepressant medications”. Despite repeated therapeutic attempts, these patients’ depressive symptoms remain.
Historically, TRD has posed a significant challenge. A study from the National Institute of Mental Health (NIMH) revealed that while a third of patients with depression found remission with their initial treatment, subsequent treatments saw diminishing returns, with only 10-15% attaining remission by their third trial. This stark reality amplifies the need for more effective intervention strategies.
Esketamine: Finding a Treatment for TRD
Janssen developed esketamine nasal spray, a formulation which has shown superior efficacy compared to placebo in several clinical trials. It has also secured approvals from 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?
As Oliveira-Maia puts it, “While there are many treatments available for depression, there is a paucity of drug options tailored for TRD. Moreover, in order to guide clinicians and patients in their decision-making, and to be adopted by health insurance companies and governments, drug manufacturers need to demonstrate a distinct advantage over existing treatment modalities, underscoring the rationale for this study”.
Head-to-Head: Esketamine Versus Quetiapine
The study compared esketamine NS with oral quetiapine XR, an atypical antipsychotic originally authorised for conditions like schizophrenia but increasingly used, with regulatory approval , as an adjunctive treatment for difficult-to-treat episodes of depression. Oliveira-Maia notes, “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”.
Designed to mimic real-world conditions, the study was open-label, meaning both healthcare providers and patients were aware of the medications being used. Furthermore, given esketamine NS’s potential for acute dissociative effects, a double-blind approach was impractical. Importantly, however, efficacy assessments were conducted on site by independent raters who were blind to the trial group allocations. The multi-centre international study screened over 800 patients, of whom over 600 met the strict eligibility criteria for TRD and were subsequently included in the study.
Study participants were split into two cohorts: one self-administered quetiapine XR at home, while the other received esketamine NS under hospital supervision. Concurrently, both groups continued their most recent antidepressant regimen with a conventional antidepressant, either a selective serotonin reuptake inhibitor (SSRI, for example fluoxetine) or a serotonin and norepinephrine reuptake inhibitor (SNRI, for example venlafaxine). “The study spanned 32 weeks, which is longer than typical trials”, says Oliveira-Maia. “This allowed us to gauge both short-term and long-term treatment outcomes. Throughout this time, we closely monitored participants’ responses, side effects, and the medications’ overall efficacy”.
Oliveira-Maia elaborates, “We aimed to ascertain whether patients on esketamine NS were more likely to achieve remission— essentially corresponding to elimination of symptoms—by the eight-week mark, compared to those on quetiapine XR. Among those who achieved this remission at two months, we sought to determine the effects of continued treatment on preventing relapse in both arms up to the trial’s conclusion at 32 weeks”.
Unveiling the Findings
The results? After 8 weeks, both groups surpassed the 10-15% remission rate noted in the NIMH study, as published in the New England Journal of Medicine. Notably, 27.1% of patients on esketamine NS achieved remission, compared to 17.6% on quetiapine XR, with both groups continuing treatment with a conventional antidepressant (either an SSRI or SNRI). Long-term data was even more informative. The proportion of patients who achieved remission at week 8 and sustained it without relapse through week 32 was 21.7% for the esketamine NS group and 14.1% for the quetiapine XR group.
Most noteworthy for the authors was the marked uptick in remission rates after the initial eight-week initial period. As Oliveira-Maia remarked, “Had this trial concluded at eight weeks, the results would be quite interesting but not remarkable. However, the 32-week data tells a different story”. By this juncture, around half of the patients persisting with esketamine NS treatment - encompassing those not in remission by week eight - had achieved remission. In contrast, only a third of those continuing with quetiapine XR reached this state.
In addition to therapeutic efficacy, safety parameters were critically assessed. Both treatment options recorded very low rates of severe adverse events such as mortality or suicidal ideation. However, when examining less serious side effects, patients in the esketamine NS group presented a higher frequency compared to those in the quetiapine XR group. “This was anticipated, given esketamine’s dissociative properties,” says Oliveira-Maia. “Interestingly, the rate of patients discontinuing treatment due to side effects was actually 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”.
The Road Ahead: Clinical and Policy Implications
The findings are promising for patients grappling with TRD. Yet, as Oliveira-Maia points out, “The real challenge is shifting from research to policy. The impact of esketamine NS can only be realised if patients can readily access it”. At present, 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 make sure treatments reach the patients who need them”.
Looking forward, Oliveira-Maia remains optimistic. “Our future research endeavours aim to pinpoint predictive markers for treatment responsiveness. Additionally, we want to investigate ways to improve and sustain remission rates, including the potential role of psychotherapy. TMS is also high on our list for future exploration. However, scientific progress must be matched with proactive policy measures and concrete governmental action. Ultimately, our goal is to construct a healthcare landscape where patients are not relegated to subpar, non-evidence-based treatments due to lack of access to more effective options”.
JOURNAL
New England Journal of Medicine
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Esketamine Nasal Spray versus Quetiapine for Treatment Resistant Depression
ARTICLE PUBLICATION DATE
5-Oct-2023
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