Clinical TrialTreatment-Resistant Depression (TRD)EsketaminePlaceboCompleted

A Study to Evaluate the Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression

Randomised, double-blind Phase III trial (n=252) comparing flexible-dose intranasal esketamine (56–84 mg, twice weekly for 4 weeks, up to 8 doses) plus a newly initiated oral antidepressant versus oral antidepressant plus intranasal placebo in adults with treatment-resistant depression; primary outcome MADRS change at 28 days.

Target Enrollment
252 participants
Study Type
Phase III interventional
Design
Randomized, double Blind

Detailed Description

This randomised, double-blind, parallel-group study evaluated flexible-dose intranasal esketamine administered twice weekly for 4 weeks alongside a newly initiated oral antidepressant compared with oral antidepressant plus intranasal placebo in adults with treatment-resistant depression (MADRS ≥28).

Efficacy was assessed by change from baseline in MADRS total score to end of the 4-week double-blind phase; safety assessments included adverse events, vital signs, ECG and laboratory measures. The trial did not demonstrate significant benefit at 28 days.

Study Protocol

Preparation

sessions

Dosing

8 sessions

Integration

sessions

Study Arms & Interventions

Esketamine + AD

experimental

Flexible-dose intranasal esketamine (start 56 mg, may be increased to 84 mg) plus a newly initiated oral antidepressant given twice weekly for 4 weeks.

Interventions

  • Esketamine56 - 84 mg
    via Other• twice per week• 8 doses total

    Intranasal spray; start 56 mg on Day 1; may be increased to 84 mg per investigator discretion.

  • Compound
    via Oral• daily

    Newly initiated open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR) started Day 1; typical starting/therapeutic doses per protocol (e.g., duloxetine 60 mg/day; escitalopram 10→20 mg/day; sertraline 50→200 mg/day; venlafaxine XR 75→225 mg/day).

Antidepressant + placebo

active comparator

New oral antidepressant plus matching intranasal placebo twice weekly for 4 weeks.

Interventions

  • Placebo
    via Other• twice per week• 8 doses total

    Matching intranasal placebo spray.

  • Compound
    via Oral• daily

    Newly initiated open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR) as per investigator choice; dosing per protocol.

Participants

Ages
18 – 64
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • At the start of screening, participant must meet DSM-5 criteria for recurrent or single-episode MDD without psychotic features, confirmed by MINI.
  • Non-response (≤25% improvement) to ≥1 but ≤5 oral antidepressant treatments in the current episode (if episode >2 years upper limit applies to last 2 years), assessed by MGH-ATRQ and documented.
  • Taking a different oral antidepressant for at least the previous 2 weeks at or above the minimum therapeutic dose.
  • Current MADRS total score ≥28 confirmed by C-VISA.
  • Medically stable per physical exam, vital signs, pulse oximetry and ECG.
  • Medically stable laboratory tests or judged not clinically significant by the investigator.

Exclusion Criteria

  • Exclusion Criteria:
  • Non-response to esketamine or ketamine in the current major depressive episode, or non-response to all oral antidepressant options available for the double-blind phase (duloxetine, escitalopram, sertraline, venlafaxine XR) in the current episode, or inadequate ECT (fewer than 7 treatments).
  • Prior vagal nerve stimulation (VNS) or deep brain stimulation (DBS) in the current episode.
  • Current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar disorder, current OCD, intellectual disability, autism spectrum disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder.
  • Homicidal ideation/intent or suicidal ideation with intent within 6 months per investigator or C-SSRS Item 4 or 5, or history of suicidal behaviour within the past year; such participants are excluded.
  • History of moderate or severe substance or alcohol use disorder within 6 months (except nicotine or caffeine); lifetime hallucinogen-related use disorder (ketamine, PCP, LSD, MDMA) is exclusionary.

Study Details

Locations

Atlanta Center for Medical Research — Atlanta, Georgia, United States
Biomedical Research Foundation of Northwest Louisiana — Shreveport, Louisiana, United States
CBH Health — Gaithersburg, Maryland, United States
Adams Clinical — Watertown, Massachusetts, United States
The Medical Research Network, LLC — New York, New York, United States
IPS Research Company — Oklahoma City, Oklahoma, United States
Beijing Anding Hospital of Capital Medical University — Beijing, China
Beijing HuiLong Guan Hospital — Beijing, China
Peking University Sixth Hospital — Beijing, China
The Second People's Hospital of Hunan Province / Brian Hospital of Hunan Province — Changsha, China
The second Xiangya Hospital of Central South University — Changsha, China
West China Hospital Sichuan University — Chengdu, China
Chongqing Mental Health Center — Chongqing, China
the 3rd Affiliated Hospital,Sun Yansen University — Guangzhou, China
Guangdong Provincial People's Hospital — Guangzhou, China
Hangzhou Seventh People's Hospital — Hangzhou, China
First Hospital, Zhejiang University Medical College — Hangzhou, China
The Second Affiliated Hospital of Zhejiang University — Hangzhou, China
Huzhou third people's Hospital — Huzhou, China
First Affiliated Hospital of Kunming Medical Unversity — Kunming, China
Nanjing Brain Hospital Affilicated to Nanjing Medical University — Nanjing, China
The First Hospital of Hebei Medical University — Shijiazhuang, China
Tianjin Anding Hospital — Tianjin, China
Urumqi fourth Hospital — Ürümqi, China
The first affiliated hospital of Xinjiang medical university — Ürümqi, China
Renmin Hospital of Wuhan University — Wuhan, China
The First Affiliated Hospital of Xian Jiaotong University — Xi'an, China
Xi'an Mental Health Center — Xi'an, China
Xiamen Xianyue Hospital — Xiamen, China
The First Affiliated Hospital of Zhengzhou University — Zhengzhou, China

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