Trial Outcomes & Findings for A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression (NCT NCT02418585)

NCT ID: NCT02418585

Last Updated: 2025-04-29

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

236 participants

Primary outcome timeframe

Baseline up to Day 28 of Double-blind Induction Phase

Results posted on

2025-04-29

Participant Flow

Total 236 participants were enrolled, out of which 227 were randomized and 9 participants were excluded due to Good Clinical Practice (GCP) violations.

Participant milestones

Participant milestones
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Double Blind (DB) Phase (4 Weeks) STARTED	116	111
Double Blind (DB) Phase (4 Weeks) Safety Analysis Set	115	109
Double Blind (DB) Phase (4 Weeks) Full Analysis Set	114	109
Double Blind (DB) Phase (4 Weeks) COMPLETED	98	99
Double Blind (DB) Phase (4 Weeks) NOT COMPLETED	18	12
Follow-up Phase (24 Weeks) STARTED	34	52
Follow-up Phase (24 Weeks) COMPLETED	16	27
Follow-up Phase (24 Weeks) NOT COMPLETED	18	25

Reasons for withdrawal

Reasons for withdrawal
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Double Blind (DB) Phase (4 Weeks) Lost to Follow-up	1	1
Double Blind (DB) Phase (4 Weeks) Protocol Violation	2	2
Double Blind (DB) Phase (4 Weeks) Withdrawal by Subject	4	7
Double Blind (DB) Phase (4 Weeks) Lack of Efficacy	2	0
Double Blind (DB) Phase (4 Weeks) Adverse Event	9	1
Double Blind (DB) Phase (4 Weeks) Other	0	1
Follow-up Phase (24 Weeks) Lost to Follow-up	3	3
Follow-up Phase (24 Weeks) Withdrawal by Subject	6	3
Follow-up Phase (24 Weeks) Investigator Decision	6	17
Follow-up Phase (24 Weeks) Other	3	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=115 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=109 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Total n=224 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	115 Participants n=5 Participants	109 Participants n=7 Participants	224 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	45 years STANDARD_DEVIATION 12.56 • n=5 Participants	46.4 years STANDARD_DEVIATION 11.14 • n=7 Participants	45.7 years STANDARD_DEVIATION 11.89 • n=5 Participants
Sex: Female, Male Female	76 Participants n=5 Participants	63 Participants n=7 Participants	139 Participants n=5 Participants
Sex: Female, Male Male	39 Participants n=5 Participants	46 Participants n=7 Participants	85 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	109 Participants n=5 Participants	99 Participants n=7 Participants	208 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Race (NIH/OMB) White	107 Participants n=5 Participants	102 Participants n=7 Participants	209 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment CZECH REPUBLIC	30 Participants n=5 Participants	28 Participants n=7 Participants	58 Participants n=5 Participants
Region of Enrollment GERMANY	10 Participants n=5 Participants	10 Participants n=7 Participants	20 Participants n=5 Participants
Region of Enrollment POLAND	20 Participants n=5 Participants	18 Participants n=7 Participants	38 Participants n=5 Participants
Region of Enrollment SPAIN	9 Participants n=5 Participants	9 Participants n=7 Participants	18 Participants n=5 Participants
Region of Enrollment UNITED STATES	46 Participants n=5 Participants	44 Participants n=7 Participants	90 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up to Day 28 of Double-blind Induction Phase

Population: Full analysis set (FAS) defined as all randomized participants who received at least 1 dose of intranasal study medication, 1 dose of oral antidepressant (AD) medication during double-blind induction phase (D-BIP). Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=101 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=100 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 in the Double-blind Induction Phase- Mixed-Effects Model Using Repeated Measures (MMRM) Analysis	-21.4 Units on a scale Standard Deviation 12.32	-17.0 Units on a scale Standard Deviation 13.88

PRIMARY outcome

Timeframe: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Population: FAS defined as all randomized participants who received at least 1 dose of intranasal study medication, 1 dose of AD medication during double-blind induction phase (D-BIP). Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The last post baseline observation during the phase was carried forward as "End Point" for that phase.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=112 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=109 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (ANCOVA) Analysis	-19.6 Units on a scale Standard Deviation 13.58	-16.3 Units on a scale Standard Deviation 14.24

SECONDARY outcome

Timeframe: Day 2 up to Day 28 and Day 8 up to Day 28

Population: FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase.

A participant was defined as having a clinical response if there is at least 50 percent (%) improvement from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained to Day 28. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Participants who did not meet such criterion or discontinue during the study before Day 28 for any reason were considered as non-responders.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=114 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=109 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8 Onset of Clinical response on Day 2	7.9 Percentage of participants	4.6 Percentage of participants
Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8 Onset of Clinical response on Day 8	10.5 Percentage of participants	6.4 Percentage of participants

SECONDARY outcome

Timeframe: Baseline up to Day 28 of Double-blind Induction phase

Population: FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

The SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=86 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=85 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis	-13.6 Units on a scale Standard Deviation 8.31	-9.4 Units on a scale Standard Deviation 8.43

SECONDARY outcome

Timeframe: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=95 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=89 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis	-12.5 Units on a scale Standard Deviation 8.85	-9.3 Units on a scale Standard Deviation 8.39

SECONDARY outcome

Timeframe: Baseline up to Day 28 of Double-blind Induction phase

Population: FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' signifies overall number of participants who were evaluable for this outcome measure.

PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day. Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27).

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=104 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=100 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis	-13.0 Units on a scale Standard Deviation 6.42	-10.2 Units on a scale Standard Deviation 7.80

SECONDARY outcome

Timeframe: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Population: FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' signifies overall number of participants who were evaluable for this outcome measure.

PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day). Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27). The last post baseline observation during the phase was carried forward as "End Point" for that phase.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=111 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=105 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis	-12.2 Units on a scale Standard Deviation 6.87	-10.1 Units on a scale Standard Deviation 7.87

SECONDARY outcome

Timeframe: At Endpoint (Double-blind Induction Phase [Day 28])

Population: FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The percentage of participants with greater than or equal to (\>=) 50 % reduction from baseline in MADRS total score was reported. The last post baseline observation during the phase was carried forward as "End Point" for that phase.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=112 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=109 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28])	63.4 Percentage of participants	49.5 Percentage of participants

SECONDARY outcome

Timeframe: At Endpoint (Double-blind Induction Phase [Day 28])

Remission was defined as participants who had a MADRS total score of less than or equal to (=\<) 12. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The last post baseline observation during the phase was carried forward as "End Point" for that phase.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=112 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=109 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])	48.2 Percentage of participants	30.3 Percentage of participants

SECONDARY outcome

Timeframe: At Day 28 [end of Double-blind Induction Phase]

Response defined as SDS total score \<= 12 and individual item scores each \<= 4. SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=86 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=86 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Percentage of Participants in Response (SDS Total Score <=12 and Individual Item Scores Each <=4) at the End of 4-Week Double-blind Induction Phase (Day 28)	57.0 Percentage of participants	39.5 Percentage of participants

SECONDARY outcome

Timeframe: At Day 28 (End of Double-blind Induction Phase)

Remission defined as SDS total score \<= 6 and individual item scores each \<= 2. SDS is a participant reported outcome measure and is a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items were summed to create a total score of 0-30 where a higher score indicates greater impairment. It also has one item on days lost from school or work and one item on days when under productive.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=86 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=86 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Percentage of Participants in Remission (SDS Total Score <=6 and Individual Item Scores Each <=2) at the End of 4-Week Double-blind Induction Phase (Day 28)	39.5 Percentage of participants	20.9 Percentage of participants

SECONDARY outcome

Timeframe: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Population: FAS defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. CGI-S permits global evaluation of participant's condition at given time. The last post baseline observation during the phase was carried forward as "End Point" for that phase.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=111 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=109 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])	-2.0 Units on a scale Interval -5.0 to 1.0	-2.0 Units on a scale Interval -5.0 to 1.0

SECONDARY outcome

Timeframe: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21). The last post baseline observation during the phase was carried forward as "End Point" for that phase.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=110 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=102 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in Generalized Anxiety Disorder (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])	-7.9 Units on a scale Standard Deviation 6.12	-6.8 Units on a scale Standard Deviation 5.75

SECONDARY outcome

Timeframe: Baseline up to End of Double-blind Induction Phase (Day 28)

European Quality of Life Group-5 Dimension-5-Level (EQ-5D-5L) is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health).

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=111 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=105 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in EQ 5D-5L-Health Status Index to End of Double-blind Induction Phase (Day 28)	0.288 Units on a Scale Standard Deviation 0.2317	0.231 Units on a Scale Standard Deviation 0.2506

SECONDARY outcome

Timeframe: Baseline up to End of Double-blind Induction Phase (Day 28)

Population: FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine).

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=111 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=105 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in EQ 5D-5L- European Quality of Life - Visual Analogue Scale (EQ-VAS) to End of Double-blind Induction Phase (Day 28)	29.1 Units on a scale Standard Deviation 26.32	20.9 Units on a scale Standard Deviation 26.60

SECONDARY outcome

Timeframe: Baseline up to End of Double-blind Induction Phase (Day 28)

EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health). EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) n=111 Participants Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Placebo Plus Oral AD n=105 Participants Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Change From Baseline in EQ 5D-5L- Sum Score to End of Double-blind Induction Phase (Day 28)	-23.2 Units on a scale Standard Deviation 16.64	-17.1 Units on a scale Standard Deviation 19.66

Adverse Events

DB Phase: Intranasal Esk + Oral AD

Serious events: 1 serious events

Other events: 90 other events

Deaths: 1 deaths

DB Phase: Oral AD + Intranasal Placebo

Serious events: 1 serious events

Other events: 53 other events

Deaths: 0 deaths

FU Phase: Intranasal Esk + Oral AD

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

FU Phase: Oral AD + Intranasal Placebo

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	DB Phase: Intranasal Esk + Oral AD n=115 participants at risk Participants self-administered (under direct supervision by health care professional \[HCP\]) esketamine either 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1, 4, 8, 11, 15, 18, 22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral antidepressant (AD) with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase.	DB Phase: Oral AD + Intranasal Placebo n=109 participants at risk Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1, 4, 8, 11, 15, 18, 22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase.	FU Phase: Intranasal Esk + Oral AD n=34 participants at risk Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk+ Oral AD in DB induction phase were followed in posttreatment follow-up (FU) phase for up to 24 weeks.	FU Phase: Oral AD + Intranasal Placebo n=52 participants at risk Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Ear and labyrinth disorders Vertigo Positional	0.00% 0/115 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.92% 1/109 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.00% 0/34 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.00% 0/52 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.
Injury, poisoning and procedural complications Multiple Injuries	0.87% 1/115 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.00% 0/109 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.00% 0/34 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.00% 0/52 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.
Injury, poisoning and procedural complications Road Traffic Accident	0.87% 1/115 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.00% 0/109 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.00% 0/34 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.00% 0/52 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.
Nervous system disorders Cerebral Haemorrhage	0.00% 0/115 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.00% 0/109 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	2.9% 1/34 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.	0.00% 0/52 • Approximately up to 2.2 Years The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.

Other adverse events

Additional Information

Senior 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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Restriction type: OTHER