Clinical TrialParallelTreatment-Resistant Depression (TRD)EsketamineCompleted

A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/​Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder (ESCAPE-TRD)

This Phase III interventional trial (n=676) evaluated flexibly dosed esketamine nasal spray versus quetiapine XR, both with a continuing SSRI/SNRI, in participants with treatment-resistant major depressive disorder.

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Target Enrollment
676 participants
Study Type
Phase III interventional
Design
Randomized

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Related paper: Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant DepressionCompound research: EsketamineTopic research: Treatment-Resistant Depression (TRD)

Detailed Description

Randomized, parallel-group Phase III trial comparing flexibly dosed esketamine nasal spray (28/56/84 mg) plus continuing SSRI/SNRI against quetiapine XR augmentation of SSRI/SNRI in adults with treatment-resistant major depressive disorder.

Treatment included an 8-week acute phase (induction: twice-weekly dosing initially) followed by a 24-week maintenance phase with once-weekly or once-every-2-weeks dosing; safety assessments included AEs/SAEs, vitals, ECG, labs and C-SSRS monitoring.

Primary objective was efficacy for remission in participants with TRD; background SSRI/SNRI was continued and could be optimised per SmPC throughout the study.

Study Arms & Interventions

Esketamine 56–84 mg

experimental

Flexibly dosed esketamine nasal spray plus continuing SSRI/SNRI; induction then maintenance schedule.

Interventions

  • Esketamine56 - 84 mg
    via Other• twice-weekly (Day1–Week4), then weekly (Week5–8), then weekly or every 2 weeks (Week9–32)

    Nasal spray; doses 28, 56, or 84 mg; 28 mg initial option for elderly/Japanese ancestry; flexible uptitration per protocol.

Quetiapine XR 50–300 mg/day (active comparator)

active comparator

Quetiapine XR augmentation of continuing SSRI/SNRI per SmPC versus esketamine arm.

Interventions

  • Compound
    via Other• daily

    Quetiapine XR 50→150 mg (adults) with possible increase to 300 mg/day per investigator; elderly schedule differs; encoded as active comparator (name/doses in notes).

Participants

Ages
18 – 74
Sexes
Male & Female

Inclusion Criteria

  • At screening, participant must meet DSM-5 criteria for single-episode MDD or recurrent MDD without psychotic features confirmed by MINI.
  • IDS-C30 total score >=34 at screening and baseline.
  • On current SSRI/SNRI at screening with documented nonresponse (<25% improvement) after adequate dose/duration (>=6 weeks) and showing minimal clinical improvement at screening.
  • Current antidepressant treatment preceded by nonresponse to 1–5 different consecutive adequate AD treatments within current episode.
  • Treated with at least 2 different antidepressant substance classes at adequate dose/duration resulting in nonresponse in current episode.
  • Must be on a single oral SSRI/SNRI on Day 1 prior to randomization.

Exclusion Criteria

  • Received esketamine or ketamine in current episode.
  • Received quetiapine extended- or immediate-release >50 mg/day in current episode.
  • Depressive symptoms in current episode previously nonresponsive to adequate ECT course (>=7 unilateral/bilateral ECT treatments).
  • No signs of clinical improvement on current SSRI/SNRI as determined at screening.
  • Received vagal nerve stimulation or deep brain stimulation in current episode.
  • Current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders, current OCD, intellectual disability, autism spectrum disorder, borderline personality disorder, antisocial/histrionic/narcissistic personality disorder.
  • Age at onset of first MDD episode >=55 years.
  • Homicidal ideation or intent per investigator; suicidal ideation with some intent within 1 month prior to screening or C-SSRS Item 4 or 5 positive, or suicidal behaviour within past year.

Study Protocol, Arms & Participants

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Study Details

Study Team

Sponsors & Collaborators

Locations

Fundacion para el Estudio y Tratamiento de las Enfermedades Mentales — Buenos Aires, Argentina
FunDaMos — Buenos Aires, Argentina
CEN Consultorios Especializados en Neurociencias — Córdoba, Argentina
Fundacion Lennox — Córdoba, Argentina
Instituto Medico DAMIC — Córdoba, Argentina
Sanatorio Prof Leon S Morra S A — Córdoba, Argentina
Instituto de Neurociencias San Agustin — La Plata, Argentina
C I A P Centro de investigacion y Asistencia en Psiquiatria — Rosario, Argentina
Medical University Graz — Graz, Austria
Schmitz and Schmitz — Vienna, Austria
Medical University Vienna MUV — Vienna, Austria
Anima — Alken, Belgium
Pz Duffel — Duffel, Belgium
Clinique Psychiatrique des Frères Alexiens — Henri-Chapelle, Belgium
Sint-Franciskusziekenhuis — Heusden-Zolder, Belgium
ARIADNE — Lede, Belgium
CHU de Liege — Liège, Belgium
CPN - Centro de Pesquisa em Neurociências Ltda — Belo Horizonte, Brazil
Trial Tech Tecnologia em Pesquisas com Medicamentos — Curitiba, Brazil
Ruschel Medicina e Pesquisa Clínica Ltda — Rio de Janeiro, Brazil
C J S Carvalho & Carvalho LTDA (Viver - Centro De Desospitalizacao Humana) — São Paulo, Brazil
BR Trials — São Paulo, Brazil
State Psychiatric Hospital Kardzhali — Kardzhali, Bulgaria
UMHAT 'Dr. Georgi Stranski', EAD — Pleven, Bulgaria
Mental Health Center - Plovdiv — Plovdiv, Bulgaria
Mental Health Center - Rousse — Rousse, Bulgaria
Multiprofile Hospital for Active Treatment in Neurology and Psychiatry Sveti Naum — Sofia, Bulgaria
MHC - Sofia, EOOD — Sofia, Bulgaria
Centre for Mental Health Prof.N.Shipkovenski EOOD — Sofia, Bulgaria
University Multiprofile Hospital for Active Treatment - UMHAT Alexandrovska EAD — Sofia, Bulgaria
Psychiatricka ambulance Saint Anne s.r.o. — Brno, Czechia
Psychiatricka ambulance, MUDr. Marta Holanova — Brno, Czechia
NeuropsychiatrieHK, s.r.o. — Hradec Kralove-Vekose, Czechia
A Shine S R O — Pilsen, Czechia
Clintrial s r o — Prague, Czechia
AD71 s.r.o. — Prague, Czechia
Medical Services Prague S R O — Prague, Czechia
Institut Neuropsychiatricke pece — Prague, Czechia
Aalborg University Hospital — Aalborg, Denmark
Psykiatrien i Region Syddanmark — Esbjerg N, Denmark
Mederon LTD at ARTES — Helsinki, Finland
Psykiatrinen Palvelukeskus Solvum Oy — Helsinki, Finland
Savon Psykiatripalvelu — Kuopio, Finland
Universitaetsklinikum der RWTH Aachen — Aachen, Germany
Rheinhessen Fachklinik Alzey — Alzey, Germany
Emovis GmbH — Berlin, Germany
Charite Campus Benjamin Franklin — Berlin, Germany
Medizinisches Versorgungszentrum LiO GmbH — Berlin, Germany
Alexander Schulze - Germany — Berlin, Germany
Praxis Dr. med. Kirsten Hahn — Berlin, Germany
Vivantes Klinikum Spandau — Berlin, Germany
Universitatsklinikum Bonn — Bonn, Germany
Klinikum Chemnitz gGmbH — Chemnitz, Germany
Carl-Thiem-Klinikum Cottbus gGmbH — Cottbus, Germany
Klinikum Dortmund gGmbH — Dortmund, Germany
Universitatsklinikum Carl Gustav Carcus Dresden — Dresden, Germany
Universitatsklinikum Frankfurt — Frankfurt am Main, Germany
Universitätsklinikum Freiburg - Abteilung für Psychiatrie u. Psychotherapie mit Poliklinik — Freiburg im Breisgau, Germany
SRH Waldklinikum Gera GmbH — Gera, Germany
Georg August Universitat Universitatsmedizin Gottingen — Göttingen, Germany
Evangelisches Krankenhaus Bethanien gGmbH — Greifswald, Germany
Universitaetsklinik Hamburg-Eppendorf — Hamburg, Germany
Klinische Forschung Hamburg — Hamburg, Germany
Klinische Forschung Hannover-Mitte GmbH — Hanover, Germany
Medizinische Hochschule Hannover — Hanover, Germany
Universität Heidelberg — Heidelberg, Germany
Oberhavel Kliniken GmbH — Hennigsdorf, Germany
Universitätsklinikum des Saarlandes — Homburg, Germany
Universitatsklinikum Jena — Jena, Germany
Panakeia - Arzneimittelforschung GmbH — Leipzig, Germany
Universitaetsklinikum Magdeburg A.oe.R — Magdeburg, Germany
Universitatsmedizin der Johannes Gutenberg Universitat Mainz — Mainz, Germany
Pharmakologisches Studienzentrum Chemnitz GmbH — Mittweida, Germany
Universitatsklinikum Munster — Münster, Germany
Ruppiner Kliniken — Neuruppin, Germany
Praxis Prof. Steinwachs — Nuremberg, Germany
Johanniter Krankenhaus Oberhausen — Oberhausen, Germany
Danuvius Klinik Pfaffenhofen Fachklinik für Psychiatrie, Psychotherapie und Psychosomatik — Pfaffenhofen, Germany
Somni Bene GmbH — Schwerin, Germany
Klinische Forschung Schwerin GmbH — Schwerin, Germany
Klinikum der Hansestadt Stralsund GmbH-Ambulanz-Klinik für Psychiatrie und Psychotherapie - Germany — Stralsund, Germany
Aiginition Hospital of Athens — Athens, Greece
'Dafni' Psychiatric Hospital of Attica — Athens, Greece
Venizeleio General Hospital — Crete, Greece
Psychiatric Clinic 'Agios Charalampos' — Heraklion, Greece
University General Hospital of Ioannina — Ioannina, Greece
University General Hospital of Rio Patras — Pátrai, Greece
424 Military Hospital of Thessaloniki — Thessaloniki, Greece
Psychiatric Hospital of Thessaloniki — Thessaloniki, Greece
G Papanikolaou Hospital of Thessaloniki — Thessaloniki, Greece
Semmelweis Egyetem — Budapest, Hungary
Eszak Kozep budai Centrum Uj Szent Janos Korhaz es Szakrendelo Budai Csaladkozpontu — Budapest, Hungary
Processus Kft — Budapest, Hungary
Debreceni Egyetem, Kenézy Gyula Egyetemi Oktatókórház — Debrecen, Hungary
Bugat Pal Korhaz — Gyöngyös, Hungary
Petz Aladar Megyei Oktato Korhaz — Győr, Hungary
Bács-Kiskun Megyei Kórház a Szegedi Tudományegyetem Általános Orvostudományi Kar Oktató Kórháza — Kalocsa, Hungary
Szabolcs-Szatmar-Bereg Megyei Korhazak es Egyetemi Oktatokorhaz — Nyíregyháza, Hungary
Pecsi Tudomanyegyetem Klinikai Kozpont — Pécs, Hungary
Rambam Medical Center — Haifa, Israel
Shalvata Mental Health Center — Hod HaSharon, Israel
Beer Yaakov Mental Health Center — Lod, Israel
Geha Mental Health Center — Petah Tikva, Israel
Sheba Medical Center — Ramat Gan, Israel
Tel Aviv Sourasky Medical Center — Telaviv, Israel
Republican Scientific and Practical Center of Mental Health — Almaty, Kazakhstan
Medical Center for Psychological Healt SME — Nur-Sultan, Kazakhstan
East-Kazakhstan Regional Centre of Mental Health — Ust-Kamenogorsk, Kazakhstan
Hospital Raja Permaisuri Bainun — Ipoh, Malaysia
Hospital Kuala Lumpur — Kuala Lumpur, Malaysia
University Malaya Medical Centre — Kuala Lumpur, Malaysia
Hospital Pengajar Universiti Putra Malaysia — Serdang, Malaysia
Hospital Tuanku Jaafar — Seremban, Malaysia
Brain Research Center — Amsterdam, Netherlands
AMC — Amsterdam, Netherlands
LUMC — Leiden, Netherlands
Haukeland University Hospital — Hordaland, Norway
Sykehuset Ostfold — Moss, Norway
St Olav University Hospital — Trondheim, Norway
Mlynowamed Specjalistyczny Psychiatryczny Gabinet Lekarski Joanna Lazarczyk — Bialystok, Poland
Osrodek Badan Klinicznych CLINSANTE S C — Bydgoszcz, Poland
Uniwersyteckie Centrum Kliniczne — Gdansk, Poland
Centrum Badan Klinicznych PI House sp z o o — Gdansk, Poland
Centrum Medyczne Care Clinic Katowice — Katowice, Poland
Niepubliczny Zaklad Opieki Psychiatrycznej MENTIS — Leszno, Poland
Specjalistyczny Psychiatryczny Zespol Opieki Zdrowotnej w Lodzi Szpital im. J. Babinskiego — Lodz, Poland
SPZOZ CSK UM w Lodzi Klinika Zaburzen Afektywnych i Psychotycznych — Lodz, Poland
Centrum Medyczne Luxmed Sp z o o — Lublin, Poland
Osrodek Badan Klinicznych CLINSANTE S C — Torun, Poland
Hospital de Braga — Braga, Portugal
Centro Hospitalar do Tâmega e Sousa, EPE - Hospital Padre Americo, Vale do Sousa — Guilhufe - Penafiel, Portugal
Hosp. Cuf Tejo — Lisbon, Portugal
Fund. Champalimaud — Lisbon, Portugal
Centro Hospitalar de Lisboa Norte Hospital Santa Maria — Lisbon, Portugal
Uls Loures Odivelas - Hosp. Loures — Loures, Portugal
Cape Town Clinical Research Centre — Cape Town, South Africa
Flexivest 14 Research — Cape Town, South Africa
Gert Bosch Pretoria South Africa — Garsfontein, South Africa
Chonnam National University Hospital — Gwangju, South Korea
Wonkwang University Hospital — Iksan, South Korea
KyungHee University Hospital — Seoul, South Korea
Korea University Anam Hospital — Seoul, South Korea
Severance Hospital Yonsei University Health System — Seoul, South Korea
Samsung Medical Center — Seoul, South Korea
Psykiatriska kliniken — Gothenburg, Sweden
Affecta Pskyiatrimottagning — Halmstad, Sweden
Psykiatriska kliniken — Luleå, Sweden
ProbarE i Lund AB — Lund, Sweden
ONE LIFETIME Lakarmottagning — Skövde, Sweden
ProbarE i Stockholm AB — Stockholm, Sweden
Changhua Christian Hospital — Changhua, Taiwan
Hualien Tzu Chi Hospital — Hualien City, Taiwan
Kai-Syuan Psychiatric Hospital — Kaohsiung City, Taiwan
Chang Gung Memorial Hospital — Kaohsiung City, Taiwan
National Cheng Kung University Hospital — Tainan, Taiwan
National Taiwan University Hospital — Taipei, Taiwan
Mackay Memorial Hospital — Taipei, Taiwan
Taipei Medical University — Taipei, Taiwan
Taipei Veterans General Hospital — Taipei, Taiwan
Chang Gung Memorial Hospital — Taoyuan District, Taiwan
Hacettepe University Medical Faculty — Ankara, Turkey (Türkiye)
Bursa Yuksek Ihtisas Training and Research Hospital — Bursa, Turkey (Türkiye)
Uludag University Medical Faculty — Bursa, Turkey (Türkiye)
Bakirkoy Mental Health Training and Research Hospital — Istanbul, Turkey (Türkiye)
Erenkoy Mental Health Hospital — Istanbul, Turkey (Türkiye)
Uskudar University Neuropsychiatry Hospital — Istanbul, Turkey (Türkiye)
Ege Universitesi Tip Fakultesi — Izmir, Turkey (Türkiye)
Selcuk University Medical Faculty — Konya, Turkey (Türkiye)
Liv Hospital — Samsun, Turkey (Türkiye)
Namik Kemal University — Tekirdağ, Turkey (Türkiye)
American Center for Psychiatry and Neurology — Abu Dhabi, United Arab Emirates

Related Publications

PaywallindividualPrimary

Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression

This open-label Phase IIIb trial (n=676) compared the efficacy of esketamine nasal spray and extended-release quetiapine, combined with an SSRI or SNRI, in patients with treatment-resistant depression (TRD). The study found that a significantly higher percentage of patients in the esketamine group achieved remission at week 8 (27.1% vs 17.6%) and had no relapse through week 32 after remission at week 8 (21.7% vs 14.1%). Adverse events were consistent with the established safety profiles of the trial treatments.

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New England Journal of Medicine
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Reif, A., Bitter, I., Buyze, J., Cebulla, K., Frey, R., Ito, T., Kambarov, Y., Llorca, P-M., Oliveira-Maia, A. J., Messer, T., Mulhern-Haughey, S., Fu, D. J.
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Efficacy of esketamine nasal spray over quetiapine extended release over the short and long term: sensitivity analyses of ESCAPE-TRD, a randomised phase IIIb clinical trial

Sensitivity analyses of the randomised ESCAPE‑TRD trial confirmed that adjunctive esketamine nasal spray was consistently superior to quetiapine extended release for achieving remission at Week 8 and remaining relapse‑free to Week 32 (relative risks 1.46–1.84, all p<0.05). Esketamine also shortened time to first and confirmed remission (hazard ratios ≈1.66–1.71), supporting the robustness of the original findings.

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British Journal of Psychiatry
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Young, A. H., Llorca, P. M., Fagiolini, A., Falkai, P., Cardoner, N., Nielsen, R. E., Blomqvist, O., Godinov, Y., Rive, B., Diels, J., Mulhern-Haughey, S., Reif, A.
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Esketamine nasal spray versus quetiapine XR in adults with treatment-resistant depression: a secondary analysis of the ESCAPE-TRD randomized clinical trial

In a secondary analysis of ESCAPE-TRD (n=636), esketamine nasal spray plus an oral antidepressant, dosed according to US prescribing information, produced significantly higher remission rates from week 8 to week 32 and greater, earlier reductions in MADRS scores (from day 8) than quetiapine XR, with fewer discontinuations due to adverse events.

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Esketamine Nasal Spray vs Quetiapine Extended-Release: Examining Work Productivity Loss and Related Costs in Patients With Treatment-Resistant Depression

This secondary analysis (n=321) of the ESCAPE-TRD trial compared work productivity loss (WPL) and related costs in patients with treatment-resistant depression (TRD) receiving esketamine nasal spray (56mg or 84mg) versus quetiapine (atypical antipsychotic) extended release, both combined with an oral antidepressant. By week 8, WPL decreased by 30.3% with esketamine and 17.3% with quetiapine, leading to a cost savings difference of $156 per week. By week 32, WPL reductions were 45.3% (esketamine) and 32.5% (quetiapine), with a weekly cost savings difference of $153.

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Trajectory of response to esketamine nasal spray for treatment resistant depression: findings from ESCAPE-TRD

This analysis of the randomised, open-label Phase IIIb ESCAPE-TRD study (n=676) compared esketamine nasal spray with extended-release quetiapine in treatment-resistant depression, tracking response to Week 32. Most esketamine-treated patients improved continuously, with early response linked to better long-term outcomes, and symptom resolution was greater and earlier than with quetiapine across most rated symptoms.

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