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.
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
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.
Compound
via Other• daily
Continuing SSRI/SNRI (background treatment; dose optimised per SmPC).
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
Quetiapine XR augmentation of continuing SSRI/SNRI per SmPC versus esketamine arm.
Interventions
Placebo
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).
Compound
via Other• daily
Continuing SSRI/SNRI (background treatment; dose optimised per SmPC).
Participants
Ages
18 – 74
Sexes
Male & Female
BMI
-
Psychosis History
-
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.
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
Open AccessindividualSecondary analysis
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.
Published
Journal
British Journal of Psychiatry
Authors
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.