Trial Outcomes & Findings for A Double-blind Study to Assess the Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Participants Who Are Assessed to be at Imminent Risk for Suicide (NCT NCT02133001)

Last Updated: 2025-04-29

Results Overview

The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The last observation carried forward (LOCF) approach was used for missing visit data in the ITT LOCF efficacy analyses.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

68 participants

Primary outcome timeframe

Baseline (Day 1-Predose) to Day 1: 4-hours post-dose

Results posted on

2025-04-29

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Double Blind (Day 1-25) STARTED	32	36
Double Blind (Day 1-25) Safety	31	35
Double Blind (Day 1-25) COMPLETED	22	27
Double Blind (Day 1-25) NOT COMPLETED	10	9
Follow-Up Phase (Day 26-81) STARTED	22	27
Follow-Up Phase (Day 26-81) COMPLETED	20	24
Follow-Up Phase (Day 26-81) NOT COMPLETED	2	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Double Blind (Day 1-25) Adverse Event	1	5
Double Blind (Day 1-25) Lack of Efficacy	4	1
Double Blind (Day 1-25) Lost to Follow-up	2	0
Double Blind (Day 1-25) Other	2	2
Double Blind (Day 1-25) Withdrawal by Subject	1	1
Follow-Up Phase (Day 26-81) Lost to Follow-up	1	1
Follow-Up Phase (Day 26-81) Withdrawal by Subject	1	1
Follow-Up Phase (Day 26-81) Other	0	1

Baseline Characteristics

A Double-blind Study to Assess the Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Participants Who Are Assessed to be at Imminent Risk for Suicide

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.	Total n=66 Participants Total of all reporting groups
Age, Continuous	36 years STANDARD_DEVIATION 12.82 • n=5 Participants	35.7 years STANDARD_DEVIATION 13.4 • n=7 Participants	35.8 years STANDARD_DEVIATION 13.03 • n=5 Participants
Sex: Female, Male Female	21 Participants n=5 Participants	22 Participants n=7 Participants	43 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	13 Participants n=7 Participants	23 Participants n=5 Participants
Region of Enrollment United States	31 Participants n=5 Participants	35 Participants n=7 Participants	66 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1-Predose) to Day 1: 4-hours post-dose

Population: Intent-To-Treat Analysis (ITT) analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Day 1: 4-Hour Post-dose in Montgomery Asberg Depression Rating Scale (MADRS) Total Score (Double-blind Phase)	-9.1 Units on a scale Standard Deviation 8.38	-13.4 Units on a scale Standard Deviation 9.03

SECONDARY outcome

Timeframe: Day 1 to Day 25

Population: ITT analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

Sustained response is defined as a reduction from baseline in MADRS total score of greater than or equal to 50 percent, with onset on Day 1 that is maintained through the end of the double-blind phase (Day 25). The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Percentage of Participants With Sustained Response Based on MADRS Total Score (Double-blind Phase)	6.7 Percentage of participants	11.8 Percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Day 2

The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Day 2 in MADRS Total Score (Double-blind Phase)	-12.8 Units on a scale Standard Deviation 9.77	-19.3 Units on a scale Standard Deviation 12.02

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Double-blind Phase-End Point (Day 25)

The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses. The last post baseline observation was carried forward as the "End Point" for the double-blind phase.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Double-blind Phase-End Point (Day 25) in MADRS Total Score (Double-blind Phase)	-23.0 units on a scale Standard Deviation 10.83	-26.4 units on a scale Standard Deviation 14.52

SECONDARY outcome

Timeframe: Day 1 (4 hours postdose), Day 2 (double blind phase), Double blind phase -Endpoint (Day 25)

Population: ITT analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4-hour post dose evaluation for the MADRS total score.

Percentage of participants with response (greater than or equal to (\>=) 50% improvement from baseline in MADRS total score) during the double- blind phase was assessed. The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Percentage of Participants With Response Based on MADRS Total Score During the Double-Blind Phase Day 1 (4 hours postdose)	12.9 Percentage of participants	25.7 Percentage of participants
Percentage of Participants With Response Based on MADRS Total Score During the Double-Blind Phase Day 2 (double blind phase)	29.0 Percentage of participants	54.3 Percentage of participants
Percentage of Participants With Response Based on MADRS Total Score During the Double-Blind Phase Double blind phase -Endpoint (Day 25)	54.8 Percentage of participants	74.3 Percentage of participants

SECONDARY outcome

Timeframe: Follow up phase-endpoint (Day 81)

Population: The ITT (Follow Up phase) analysis set was defined as all participants who had at least one measurement of MADRS total score during the follow up phase.

Percentage of participants with response (greater than or equal to (\>=) 50% improvement from baseline in MADRS total score) during the follow up was assessed. The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=27 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Percentage of Participants With Response Based on MADRS Total Score at Follow up Phase Endpoint	63.6 Percentage of participants	66.7 Percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Day 1: 4-hours Postdose

Population: ITT analysis set: all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score. Here N (overall number of participants analyzed)signifies number of participants who were evaluable for this endpoint.

SIBAT CGJ-SR: Module 8 operates numerous clinical global impression (CGI) severity scales used in other psychiatric studies. Changes in CGJ-SR designed to categorize clinically meaningful changes in clinician rated suicide risk from 'not at all suicidal' to 'participant is at imminent risk of suicide and immediate need for strong intervention (hospitalization with 24 hour 1:1 observation).' Patient scores for clinician-rated suicide risk: 0 (not suicidal); 1(occasional suicidal ideas, no intervention required);2(some clear suicidal ideas present),3(suicidal risk requires scheduled outpatient follow-up,no immediate intervention),4(suicidal risk requires immediate intervention, no hospitalization). 5( suicidal risk requires immediate hospitalization, no suicide precautions),6 (suicide risk requires hospitalization with suicide precautions). LOCF approach used for missing visit data in ITT LOCF efficacy analyses.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=33 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Day 1: 4-hours Post-dose in Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk (CGJ-SR) Module 8 Score (Double-blind Phase)	0 Units on a scale Interval -5.0 to 1.0	0 Units on a scale Interval -6.0 to 1.0

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Day 2

SIBAT CGJ-SR: Module 8 operates like numerous other CGI severity scales used in other psychiatric studies. Changes in CGJ-SR designed to categorize clinically meaningful changes in clinician rated suicide risk from 'not at all suicidal' to 'participant is at imminent risk of suicide and immediate need for strong intervention (hospitalization with 24 hour 1:1 observation).' Patient scores for clinician-rated suicide risk: 0 (not suicidal); 1(occasional suicidal ideas, no intervention required);2(some clear suicidal ideas present),3(suicidal risk requires scheduled outpatient follow-up,no immediate intervention),4(suicidal risk requires immediate intervention, no hospitalization). 5( suicidal risk requires immediate hospitalization, no suicide precautions),6 (suicide risk requires hospitalization with suicide precautions). LOCF approach used for missing visit data in ITT LOCF efficacy analyses.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Day 2 in Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk (SIBAT CGJ-SR) Module 8 Score (Double-blind Phase)	0 Units on a scale Interval -6.0 to 0.0	-1.0 Units on a scale Interval -6.0 to 1.0

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Double-blind Phase-Endpoint (Day 25)

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Double-blind Phase-Endpoint (Day 25) Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk (SIBAT CGJ-SR) Module 8 (Double-blind Phase)	-5.0 Units on a scale Interval -6.0 to 0.0	-5.0 Units on a scale Interval -6.0 to 0.0

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Follow-up Phase-Endpoint (Day 81)

Population: The ITT (Follow Up phase) analysis set was defined as all participants who had at least one measurement of MADRS total score during the follow up phase.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=27 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Follow-up Phase-Endpoint (Day 81) in Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk Score (Follow-up Phase)	-5.0 Units on a scale Interval -6.0 to -3.0	-5.0 Units on a scale Interval -6.0 to -2.0

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Day 1: 4-hours postdose

SIBAT was specifically developed to measure rapid change in suicidality, based on concerns that existing scales such as Beck Scale for Suicidal Ideation (BSS) are not designed to discriminate differences associated with rapid change. Patient-rated section includes following modules: Module 1 (M-1)(demographic information,suicide history), M-2(current suicidal thinking),M-3 (protective factors), M-4 (suicide behavior),M-5(suicide risk),M-6(suicide-implicit association test).Patient-reported global assessment of suicide risk summarizes patient's judgment of suicide risk (Module 6). Scores: 0(None), 1(Very weak), 2(Weak), 3(Moderately weak), 4(Mild), 5(Moderate), 6 (Moderately strong), 7(Strong), 8(Extremely strong), 9(Extremely strong,constant). Negative change in score indicates improvement. LOCF approach used for missing visit data in the ITT LOCF efficacy analyses.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Day 1: 4- Hours Postdose in SIBAT-Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Double-blind Phase)	-1.0 Units on scale Interval -6.0 to 3.0	-1.0 Units on scale Interval -7.0 to 2.0

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Day 2

Population: Intent-To-Treat Analysis (ITT) analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and have both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

SIBAT was specifically developed to measure rapid change in suicidality, based on concerns that existing scales such as BSS are not designed to discriminate differences associated with rapid change. Patient-rated section includes following modules: Module 1 (M-1)(demographic information,suicide history), M-2(current suicidal thinking),M-3 (protective factors), M-4 (suicide behavior),M-5(suicide risk),M-6(suicide-implicit association test).Patient-reported global assessment of suicide risk summarizes patient's judgment of suicide risk (Module 6). Scores: 0(None), 1(Very weak), 2(Weak), 3(Moderately weak), 4(Mild), 5(Moderate), 6 (Moderately strong), 7(Strong), 8(Extremely strong), 9(Extremely strong,constant). Negative change in score indicates improvement. LOCF approach used for missing visit data in the ITT LOCF efficacy analyses.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Day 2 in Suicide Ideation and Behavior Assessment Tool Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Double-blind Phase)	-1.5 Units on a scale Interval -7.0 to 1.0	-2 Units on a scale Interval -8.0 to 0.0

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Double-blind Phase-Endpoint (Day 25)

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Double Blind Phase-Endpoint (Day 25) in Suicide Ideation and Behavior Assessment Tool Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Double-blind Phase)	-3.0 Units on a scale Interval -9.0 to 1.0	-4.0 Units on a scale Interval -8.0 to 0.0

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Follow-up Phase Endpoint (Day 81)

Population: The ITT (Follow Up phase) analysis set was defined as all participants who had at least one measurement of MADRS total score during the follow up phase.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=27 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Follow-up Phase-Endpoint (Day 81) in Suicide Ideation and Behavior Assessment Tool Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Follow-up Phase)	-4.0 Units on a scale Interval -9.0 to 0.0	-3.0 Units on a scale Interval -9.0 to 0.0

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Day 1: 4-hours postdose

Population: ITT analysis set: all randomized participants who received at least 1 dose of study medication during the double-blind phase and have both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score. Here 'N' signifies number of participants who were evaluable for this outcome measure.

BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation. BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide, level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes,attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=34 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Day 1: 4-Hours Postdose in Beck Scale for Suicidal Ideation (BSS) Total Score (Double-blind Phase)	-8.3 Units on a scale Standard Deviation 7.12	-10.2 Units on a scale Standard Deviation 9.74

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Day 2

Population: ITT analysis set: all randomized participants who received at least 1 dose of study medication during the double-blind phase and have both the baseline and the Day 1, 4-hour post dose evaluation for the MADRS total score. Here 'N' signifies number of participants who were evaluable for this outcome measure.

BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation. BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide,level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes, attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=34 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Day 2 in Beck Scale for Suicidal Ideation (BSS) Total Score (Double-blind Phase)	-10.7 Units on a scale Standard Deviation 7.73	-12.9 Units on a scale Standard Deviation 9.63

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Double-blind Phase-endpoint (Day 25)

BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation.BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide, level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes, attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses. Last post baseline observation was carried forward as "End Point" for double-blind phase.

Outcome measures

Outcome measures
Measure	Placebo n=31 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=34 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Double-blind Phase-Endpoint (Day 25) in Beck Scale for Suicidal Ideation Total Score (Double-blind Phase)	-16.0 Units on a scale Standard Deviation 10.54	-19.3 Units on a scale Standard Deviation 9.61

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Follow-up Phase-Endpoint (Day 81)

Population: The ITT (Follow Up phase) analysis set was defined as all participants who had at least one measurement of MADRS total score during the follow up phase. Here 'N' signifies number of participants who were evaluable for this outcome measure.

BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation. BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide, level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes, attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses, last post baseline observation was carried forward as the "End Point" follow up phase.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=26 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Follow-up Phase-Endpoint (Day 81) in Beck Scale for Suicidal Ideation Total Score (Follow-up Phase)	-18.0 Units on a scale Standard Deviation 9.92	-20.3 Units on a scale Standard Deviation 8.02

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Day 1: 4-hours Postdose

BHS is paper-based self-reported measure to assess one's level of negative expectations or pessimism regarding future. Consists of 20 true-false items that examine the respondent's attitude over past week by either endorsing a pessimistic statement or denying an optimistic statement; 9 are keyed false and 11 are keyed true. Items fall within 3 domains: feelings about future; loss of motivation; future expectations. each response is assigned a score of 0 or 1. Total BHS score is sum of item responses, with range from 0 to 20, with a higher score representing higher level of hopelessness. Total scores that range from 0 to 3 are (normal range), scores 4 to 8 (mild hopelessness, scores 9 to 14 (moderate hopelessness), scores \<14 (severe hopelessness). Negative change in score indicates improvement. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Day 1: 4-Hours Postdose in Beck Hopelessness Scale (BHS) Total Score (Double-blind Phase)	-3.1 Units on a scale Standard Deviation 5.71	-4.1 Units on a scale Standard Deviation 5.63

SECONDARY outcome

Timeframe: Baseline (Day 1-predose) to Double-blind Phase-Endpoint (Day 25)

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Esketamine 84 mg n=35 Participants Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Change From Baseline to Double-blind Phase-Endpoint (Day 25) in Beck Hopelessness Scale Total Score (Double-blind Phase)	-7.7 Units on a scale Standard Deviation 7.81	-10.3 Units on a scale Standard Deviation 5.51

Adverse Events

Double Blind (Day 1-25): Placebo

Serious events: 0 serious events

Other events: 25 other events

Deaths: 0 deaths

Double Blind (Day 1-25): Esketamine 84 mg

Serious events: 4 serious events

Other events: 30 other events

Deaths: 0 deaths

Follow Up Phase (Day 26-81): Placebo

Serious events: 5 serious events

Other events: 6 other events

Deaths: 0 deaths

Follow Up Phase (Day 26-81): Esketamine 84 mg

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Double Blind (Day 1-25): Placebo n=31 participants at risk Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment determined by the treating physician based on clinical judgment on Day 1 and continued for the duration of the double-blind treatment phase.	Double Blind (Day 1-25): Esketamine 84 mg n=35 participants at risk Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment determined by the treating physician based on clinical judgment on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.	Follow Up Phase (Day 26-81): Placebo n=22 participants at risk Participants who completed the double blind treatment phase were continued to follow-up phase for 81 days.	Follow Up Phase (Day 26-81): Esketamine 84 mg n=27 participants at risk Participants who completed the double blind treatment phase were continued to follow-up phase for 81 days.
Infections and infestations Cellulitis	0.00% 0/31 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	0.00% 0/35 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	4.5% 1/22 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	0.00% 0/27 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.
Psychiatric disorders Agitation	0.00% 0/31 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	2.9% 1/35 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	0.00% 0/22 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	0.00% 0/27 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.
Psychiatric disorders Depressive Symptom	0.00% 0/31 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	2.9% 1/35 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	0.00% 0/22 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	0.00% 0/27 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.
Psychiatric disorders Suicidal Ideation	0.00% 0/31 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	5.7% 2/35 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	4.5% 1/22 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	3.7% 1/27 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.
Psychiatric disorders Suicide Attempt	0.00% 0/31 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	0.00% 0/35 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	13.6% 3/22 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.	0.00% 0/27 • Up to Day 81 Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.

Other adverse events

Additional Information

Senior Medical Director

Janssen Research & Development, LLC

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.
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