NCT04599855

A Study of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants With Treatment-resistant Depression

Completed Phase 4 Results posted Last updated 25 April 2025

What this trial tests

Phase 4 trial testing Esketamine 56 mg in Depressive Disorder, Treatment-Resistant in 477 participants. Completed in 31 January 2024.

Timeline

4 November 2020

Primary endpoint
31 January 2024

31 January 2024

Quick facts

Lead sponsor	Janssen Research & Development, LLC
Phase	Phase 4
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	477
Start date	4 November 2020
Primary completion	31 January 2024
Estimated completion	31 January 2024
Sites	54 locations across United States

Drugs / interventions tested

• Esketamine 56 mg — full drug profile →
• Esketamine 84 mg — full drug profile →
• Placebo

Conditions studied

• Depressive Disorder, Treatment-Resistant — all drugs for Depressive Disorder, Treatment-Resistant →

Sponsor

Janssen Research & Development, LLC — full company profile →

Who can join

18 and older, any sex, with Depressive Disorder, Treatment-Resistant. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Double-blind Treatment Phase: Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Day 1 (Pre-randomization) to Day 28 Primary · Day 1 (pre-randomization) to Day 28 (end of DB treatment phase)

The MADRS was a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consisted of 10 items, each of which was scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score was the sum of scores from individual question items, which ranged from 0 to 60, higher scores represented a more severe condition. The MADRS evaluated apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and

Group	Value	95% CI
DB: Placebo	-7.0	± 10.07
DB: Esketamine 56 mg	-12.7	± 11.82
DB: Esketamine 84 mg	-13.9	± 11.89

Double-blind Treatment Phase: Change in MADRS Total Score From Day 1 (Pre-randomization) to Day 2 (24 Hours Post First Dose on Day 1) Secondary · Day 1 (pre-randomization) to Day 2 of DB treatment phase (24 hours post first dose on Day 1)

The MADRS was a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consisted of 10 items, each of which was scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score was the sum of scores from individual question items, which ranged from 0 to 60, higher scores represented a more severe condition. The MADRS evaluated apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and

Group	Value	95% CI
DB: Placebo	-9.7	± 10.27
DB: Esketamine 56 mg	-13.9	± 10.15
DB: Esketamine 84 mg	-13.0	± 9.68

Adverse events — posted to ClinicalTrials.gov

Time frame: Double-blind (DB) phase: From Day 1 (post-dose) to Day 28; Open-label (OL) phase: From Week 5 to Week 16; Follow-up (FU) phase: Up to 1 week after last dose of study drug in DB phase (Week 5) or OL treatment phase (Week 17). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

DB: Placebo

Serious: 3/250 (1%)

Deaths: 0/250

DB: Esketamine 56 mg

Serious: 1/105 (1%)

Deaths: 0/106

DB: Esketamine 84 mg

Serious: 2/121 (2%)

Deaths: 0/121

OL Treatment: Placebo to Esketamine

Serious: 6/237 (3%)

Deaths: 0/237

OL Treatment: Esketamine 56 mg to Esketamine

Serious: 3/99 (3%)

Deaths: 0/99

OL Treatment: Esketamine 84 mg to Esketamine

Serious: 0/105 (0%)

Deaths: 0/105

OL Observation Period

Serious: 0/1 (0%)

Deaths: 0/1

Follow up: All Participants

Serious: 1/476 (0%)

Deaths: 0/477

Serious adverse events (16 terms)

Reaction	System	DB: Placebo	DB: Esketamine 56 mg	DB: Esketamine 84 mg	OL Treatment: Placebo to E…	OL Treatment: Esketamine 5…	OL Treatment: Esketamine 8…	OL Observation Period	Follow up: All Participants
Breast Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—	—
Acute Myocardial Infarction	Cardiac disorders	—	—	—	—	—	—	—	—
Abdominal Hernia Obstructive	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Peritonitis	Infections and infestations	—	—	—	—	—	—	—	—
Ankle Fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—	—	—
Hip Fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—	—	—
Colon Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—	—
Endometrial Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—	—
Loss of Consciousness	Nervous system disorders	—	—	—	—	—	—	—	—
Ophthalmic Migraine	Nervous system disorders	—	—	—	—	—	—	—	—
Syncope	Nervous system disorders	—	—	—	—	—	—	—	—
Self-Injurious Ideation	Psychiatric disorders	—	—	—	—	—	—	—	—
Suicidal Ideation	Psychiatric disorders	—	—	—	—	—	—	—	—
Suicide Attempt	Psychiatric disorders	—	—	—	—	—	—	—	—

Other adverse events (15 terms — click to expand)

Reaction	System	DB: Placebo	DB: Esketamine 56 mg	DB: Esketamine 84 mg	OL Treatment: Placebo to E…	OL Treatment: Esketamine 5…	OL Treatment: Esketamine 8…	OL Observation Period	Follow up: All Participants
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—	—	—
Dissociation	Psychiatric disorders	—	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Hypoaesthesia	Nervous system disorders	—	—	—	—	—	—	—	—
Dysgeusia	Nervous system disorders	—	—	—	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—	—	—	—
Feeling Drunk	General disorders	—	—	—	—	—	—	—	—
Throat Irritation	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Upper Respiratory Tract Infection	Infections and infestations	—	—	—	—	—	—	—	—
Somnolence	Nervous system disorders	—	—	—	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—	—	—	—

Most-reported serious reactions: Breast Cancer, Acute Myocardial Infarction, Abdominal Hernia Obstructive, Constipation, Vomiting, Peritonitis, Ankle Fracture, Hip Fracture.

Data from ClinicalTrials.gov NCT04599855 adverse events section.

Sponsor's own description

The purpose of this study is to evaluate the efficacy of each individual dose of esketamine nasal spray, 56 milligram (mg) and 84 mg, compared with placebo nasal spray in improving depressive symptoms in participants with treatment resistant depression (TRD), as assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 (prerandomization) to the end of the 4 week double-blind treatment phase (Day 28).

Publications & conference data

7 peer-reviewed publications reference this trial (live from Europe PMC):

1. Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial.
   Janik A, Qiu X, Lane R, Popova V, et al · · 2025 · cited 19× · PMID 40601310 · DOI 10.1001/jamapsychiatry.2025.1317
2. Ketamine and Esketamine in Clinical Trials: FDA-Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations.
   Vekhova KA, Namiot ED, Jonsson J, Schiöth HB. · · 2025 · cited 17× · PMID 39428602 · DOI 10.1002/cpt.3478
3. Emerging Therapeutics Based on the Amino Acid Neurotransmitter System: An Update on the Pharmaceutical Pipeline for Mood Disorders.
   Hecking J, Davoudian PA, Wilkinson ST. · · 2021 · cited 13× · PMID 34124495 · DOI 10.1177/24705470211020446
4. Safety in treatment: Classical pharmacotherapeutics and new avenues for addressing maternal depression and anxiety during pregnancy.
   Dagher M, Cahill CM, Andrews AM. · · 2025 · cited 5× · PMID 40056793 · DOI 10.1016/j.pharmr.2025.100046
5. Pharmacological Monotherapy for Depressive Disorders: Current and Future-A Narrative Review.
   Gao K, Oruc EB, Koparal B. · · 2025 · cited 3× · PMID 40282849 · DOI 10.3390/medicina61040558
6. Efficacy and safety of esketamine for "treatment resistant depression": registered report for a systematic review with an individual patient data meta-analysis of randomized, double-blind, placebo-controlled trials.
   Naudet F, Pellen C, Fodor LA, Gastaldon C, et al · · 2025 · cited 2× · PMID 41310599 · DOI 10.1186/s12916-025-04435-x
7. ACNP 63rd Annual Meeting: Poster Abstracts P1-P304
   · 2024