Trial Outcomes & Findings for A Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression (NCT NCT02417064)

Last Updated: 2025-04-29

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

346 participants

Primary outcome timeframe

Baseline up to Day 28 of Double-blind Induction Phase

Results posted on

2025-04-29

Participant Flow

Participant milestones

Participant milestones
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 Induction Phase (4 Weeks) STARTED	117	116	113
Double-blind Induction Phase (4 Weeks) Full Analysis Set (FAS)	115	114	113
Double-blind Induction Phase (4 Weeks) Safety Analysis Set	115	116	113
Double-blind Induction Phase (4 Weeks) COMPLETED	111	97	107
Double-blind Induction Phase (4 Weeks) NOT COMPLETED	6	19	6
Follow-up Phase (24 Weeks) STARTED	47	52	69
Follow-up Phase (24 Weeks) COMPLETED	8	10	18
Follow-up Phase (24 Weeks) NOT COMPLETED	39	42	51

Reasons for withdrawal

Reasons for withdrawal
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 Induction Phase (4 Weeks) Adverse Event	1	7	2
Double-blind Induction Phase (4 Weeks) Lack of Efficacy	1	1	0
Double-blind Induction Phase (4 Weeks) Lost to Follow-up	0	1	0
Double-blind Induction Phase (4 Weeks) Protocol Violation	2	1	1
Double-blind Induction Phase (4 Weeks) Withdrawal by Subject	1	5	1
Double-blind Induction Phase (4 Weeks) Other	1	4	2
Follow-up Phase (24 Weeks) Lost to Follow-up	0	2	1
Follow-up Phase (24 Weeks) Protocol Violation	0	0	1
Follow-up Phase (24 Weeks) Withdrawal by Subject	3	9	2
Follow-up Phase (24 Weeks) PI Decision	34	29	44
Follow-up Phase (24 Weeks) Other	2	2	3

Baseline Characteristics

A Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed 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 56 mg Plus Oral Antidepressant n=115 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=116 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=113 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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=344 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	115 Participants n=5 Participants	115 Participants n=7 Participants	112 Participants n=5 Participants	342 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Continuous	46.4 years STANDARD_DEVIATION 11.18 • n=5 Participants	45.7 years STANDARD_DEVIATION 11.02 • n=7 Participants	46.8 years STANDARD_DEVIATION 11.36 • n=5 Participants	46.3 years STANDARD_DEVIATION 11.16 • n=4 Participants
Sex: Female, Male Female	81 Participants n=5 Participants	80 Participants n=7 Participants	81 Participants n=5 Participants	242 Participants n=4 Participants
Sex: Female, Male Male	34 Participants n=5 Participants	36 Participants n=7 Participants	32 Participants n=5 Participants	102 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	33 Participants n=5 Participants	27 Participants n=7 Participants	31 Participants n=5 Participants	91 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	74 Participants n=5 Participants	80 Participants n=7 Participants	71 Participants n=5 Participants	225 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	8 Participants n=5 Participants	9 Participants n=7 Participants	11 Participants n=5 Participants	28 Participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants
Race/Ethnicity, Customized Black or African American	7 Participants n=5 Participants	8 Participants n=7 Participants	5 Participants n=5 Participants	20 Participants n=4 Participants
Race/Ethnicity, Customized White	91 Participants n=5 Participants	86 Participants n=7 Participants	86 Participants n=5 Participants	263 Participants n=4 Participants
Race/Ethnicity, Customized More than one race	8 Participants n=5 Participants	11 Participants n=7 Participants	11 Participants n=5 Participants	30 Participants n=4 Participants
Race/Ethnicity, Customized Unknown or Not Reported	7 Participants n=5 Participants	9 Participants n=7 Participants	9 Participants n=5 Participants	25 Participants n=4 Participants
Region of Enrollment Belgium	8 Participants n=5 Participants	9 Participants n=7 Participants	12 Participants n=5 Participants	29 Participants n=4 Participants
Region of Enrollment Brazil	20 Participants n=5 Participants	19 Participants n=7 Participants	18 Participants n=5 Participants	57 Participants n=4 Participants
Region of Enrollment Canada	7 Participants n=5 Participants	7 Participants n=7 Participants	6 Participants n=5 Participants	20 Participants n=4 Participants
Region of Enrollment Estonia	3 Participants n=5 Participants	4 Participants n=7 Participants	3 Participants n=5 Participants	10 Participants n=4 Participants
Region of Enrollment France	11 Participants n=5 Participants	10 Participants n=7 Participants	10 Participants n=5 Participants	31 Participants n=4 Participants
Region of Enrollment Hungary	3 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	6 Participants n=4 Participants
Region of Enrollment Mexico	14 Participants n=5 Participants	16 Participants n=7 Participants	15 Participants n=5 Participants	45 Participants n=4 Participants
Region of Enrollment Slovakia	4 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	10 Participants n=4 Participants
Region of Enrollment United States	45 Participants n=5 Participants	46 Participants n=7 Participants	45 Participants n=5 Participants	136 Participants n=4 Participants

PRIMARY outcome

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

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

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=111 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=98 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=108 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 of Double- Blind Induction Phase- Mixed- Effects Model Using Repeated Measures (MMRM) Analysis	-19.0 Units on a scale Standard Deviation 13.86	-18.8 Units on a scale Standard Deviation 14.12	-14.8 Units on a scale Standard Deviation 15.07

PRIMARY outcome

Timeframe: Baseline up to Double-blind Endpoint (Day 28)

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=115 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=113 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=113 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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])- ANCOVA Analysis	-18.3 Units on a scale Standard Deviation 14.21	-17.4 Units on a scale Standard Deviation 14.25	-14.3 Units on a scale Standard Deviation 15.00

SECONDARY outcome

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

Population: FAS: 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 was at least 50% improvement (decrease) from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained to Day 28. Participants were allowed one excursion (non-response) on Days 8, 15 or 22, however score must show at least 25% improvement. Participants who did not meet these criteria or discontinued during the study before Day 28 were considered as non-responders and were assigned the value of 0 (that is no). MADRS is clinician-rated scale that 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), for total possible score of 0 to 60. Higher scores represent more severe condition.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=115 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=114 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=113 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 by Day 2 and Day 8 Day 2 up to Day 28	10.4 Percentage of Participants	8.8 Percentage of Participants	1.8 Percentage of Participants
Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8 Day 8 up to Day 28	13.0 Percentage of Participants	11.4 Percentage of Participants	3.5 Percentage of Participants

SECONDARY outcome

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

Population: FAS: 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' (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. The first 3 items assess disruption of 1) work/school, 2) social life, and 3) family life/home responsibilities using 0 (not at all) to 10 (extremely) rating scale. Score for first 3 items are summed to create total score of 0 (unimpaired) to 30 (highly impaired), where higher score indicates greater impairment.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=88 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=87 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=90 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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	-11.0 Units on a scale Standard Deviation 9.32	-11.1 Units on a scale Standard Deviation 10.04	-8.4 Units on a scale Standard Deviation 9.70

SECONDARY outcome

Timeframe: Baseline up to Double-blind Endpoint (Day 28)

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=91 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=99 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=95 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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	-10.7 Units on a scale Standard Deviation 9.39	-10.2 Units on a scale Standard Deviation 10.00	-8.1 Units on a scale Standard Deviation 9.57

SECONDARY outcome

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

PHQ-9 is 9-item, self-reported scale assessing 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria. Each item is rated on 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half days, 3 = Nearly every day). The scores are summed for a total score ranging from 0-27. Higher score indicates greater severity of depression. 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 recall period is 2 weeks.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=110 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=99 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=108 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis	-11.0 Units on a scale Standard Deviation 8.07	-11.7 Units on a scale Standard Deviation 7.74	-9.1 Units on a scale Standard Deviation 8.35

SECONDARY outcome

Timeframe: Baseline up to Double-blind Endpoint (Day 28)

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=113 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=112 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=113 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis	-10.9 Units on a scale Standard Deviation 8.26	-10.9 Units on a scale Standard Deviation 7.81	-8.9 Units on a scale Standard Deviation 8.37

SECONDARY outcome

Timeframe: At Day 28 of Double-blind Induction phase

A participant was defined as a responder (yes=1 and no=0) at a given time point if the percent reduction from baseline in MADRS total score is at least 50 percent (%). The percentage of participants who achieved at least 50% reduction from baseline were reported. 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.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=111 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=98 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=108 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 at Least 50% Reduction From Baseline in MADRS Total Score at Day 28 of Double-blind Induction Phase (Observed Data)	54.1 Percentage of Participants	53.1 Percentage of Participants	38.9 Percentage of Participants

SECONDARY outcome

Timeframe: At Day 28 (Double-blind Endpoint)

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=115 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=113 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=113 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 at Least 50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data)	53.0 Percentage of Participants	47.8 Percentage of Participants	37.2 Percentage of Participants

SECONDARY outcome

Timeframe: At Day 28 of Double-blind Induction Phase

Participants who had a MADRS total score of less than or equal to (\<=) 12 were considered as remitters. 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.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=111 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=98 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=108 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 Day 28 of Double-blind Induction Phase (Observed Data)	36 Percentage of participants	38.8 Percentage of participants	30.6 Percentage of participants

SECONDARY outcome

Timeframe: At Day 28 (Double-blind Endpoint)

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=115 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=113 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=113 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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])- ANCOVA Analysis (LOCF Data)	34.8 Percentage of participants	35.4 Percentage of participants	29.2 Percentage of participants

SECONDARY outcome

Timeframe: Baseline up to Double-blind Endpoint (Day 28)

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 (a decrease in score indicates improvement). Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as "End Point" for that phase.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=115 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=113 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=113 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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) 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	-1.0 Units on a scale Interval -6.0 to 3.0

SECONDARY outcome

Timeframe: Baseline up to Double-blind Endpoint (Day 28)

GAD-7 is a brief and validated 7-item self-reported assessment of overall anxiety. Participants responded 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). Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as "End Point" for that phase.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=111 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=109 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=111 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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-7 Item (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])	-7.4 Units on a scale Standard Deviation 5.94	-7.7 Units on a scale Standard Deviation 5.72	-6.0 Units on a scale Standard Deviation 6.01

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=113 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=112 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=113 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Health Status Index	0.224 Units on a scale Standard Deviation 0.2481	0.243 Units on a scale Standard Deviation 0.2395	0.181 Units on a scale Standard Deviation 0.2495

SECONDARY outcome

Timeframe: Baseline up to end of Double-blind induction phase (Day 28)

EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine).

Outcome measures

Outcome measures
Measure	Intranasal Esketamine 56 mg Plus Oral Antidepressant n=113 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=112 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=113 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): EQ-VAS	20.9 Units on a scale Standard Deviation 25.04	19.1 Units on a scale Standard Deviation 26.86	14.9 Units on a scale Standard Deviation 27.15

SECONDARY outcome

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

EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). The descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). The responses are used to generate Health Status Index (HSI). HSI range is -0.148 to 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 scale of 0 (the worst health you can imagine) to 100 (the 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 56 mg Plus Oral Antidepressant n=113 Participants Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Intranasal Esketamine 84 mg Plus Oral AD n=112 Participants Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Oral AD Plus Intranasal Placebo n=113 Participants Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Sum Score	-19.0 Units on a scale Standard Deviation 18.84	-19.4 Units on a scale Standard Deviation 18.43	-14.6 Units on a scale Standard Deviation 19.78

Adverse Events

DB Phase: Intranasal Esk 56 mg + Oral AD

Serious events: 2 serious events

Other events: 93 other events

Deaths: 0 deaths

DB Phase: Intranasal Esk 84 mg + Oral AD

Serious events: 0 serious events

Other events: 92 other events

Deaths: 0 deaths

DB Phase: Oral AD + Intranasal Placebo

Serious events: 0 serious events

Other events: 64 other events

Deaths: 0 deaths

FU Phase: Intranasal Esk 56 mg + Oral AD

Serious events: 2 serious events

Other events: 7 other events

Deaths: 0 deaths

FU Phase: Intranasal Esk 84 mg + Oral AD

Serious events: 2 serious events

Other events: 4 other events

Deaths: 0 deaths

FU Phase: Oral AD + Intranasal Placebo

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	DB Phase: Intranasal Esk 56 mg + Oral AD n=115 participants at risk Participants self-administered 56 mg of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 \[milligram\] mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase.	DB Phase: Intranasal Esk 84 mg + Oral AD n=116 participants at risk Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase.	DB Phase: Oral AD + Intranasal Placebo n=113 participants at risk Participants self-administered intranasal matching placebo, intranasally, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase.	FU Phase: Intranasal Esk 56 mg + Oral AD n=47 participants at risk Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up (FU) phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug and for collection of additional informative data to assess the course of the participant's major depressive episode over a 24-week period.	FU Phase: Intranasal Esk 84 mg + Oral AD n=52 participants at risk Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug and for collection of additional informative data to assess the course of the participant's major depressive episode over a 24-week period.	FU Phase: Oral AD + Intranasal Placebo n=69 participants at risk Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 to assess safety and tolerability including withdrawal symptoms of study drug and for collection of additional informative data to assess the course of the participant's major depressive episode over a 24-week period.
Nervous system disorders Headache	0.87% 1/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Psychiatric disorders Anxiety	0.00% 0/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.9% 1/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Psychiatric disorders Depression	0.87% 1/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	4.3% 2/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.9% 1/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Psychiatric disorders Insomnia	0.00% 0/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.9% 1/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Psychiatric disorders Suicidal Ideation	0.00% 0/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.4% 1/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.

Other adverse events

Other adverse events
Measure	DB Phase: Intranasal Esk 56 mg + Oral AD n=115 participants at risk Participants self-administered 56 mg of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 \[milligram\] mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase.	DB Phase: Intranasal Esk 84 mg + Oral AD n=116 participants at risk Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase.	DB Phase: Oral AD + Intranasal Placebo n=113 participants at risk Participants self-administered intranasal matching placebo, intranasally, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] 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 MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase.	FU Phase: Intranasal Esk 56 mg + Oral AD n=47 participants at risk Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up (FU) phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug and for collection of additional informative data to assess the course of the participant's major depressive episode over a 24-week period.	FU Phase: Intranasal Esk 84 mg + Oral AD n=52 participants at risk Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug and for collection of additional informative data to assess the course of the participant's major depressive episode over a 24-week period.	FU Phase: Oral AD + Intranasal Placebo n=69 participants at risk Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) 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 to assess safety and tolerability including withdrawal symptoms of study drug and for collection of additional informative data to assess the course of the participant's major depressive episode over a 24-week period.
Ear and labyrinth disorders Vertigo	20.9% 24/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	20.7% 24/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.8% 2/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Eye disorders Vision Blurred	7.0% 8/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	7.8% 9/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Gastrointestinal disorders Diarrhoea	7.0% 8/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	4.3% 5/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	2.7% 3/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.9% 1/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	2.9% 2/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Gastrointestinal disorders Hypoaesthesia Oral	13.9% 16/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	10.3% 12/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.8% 2/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Gastrointestinal disorders Nausea	27.0% 31/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	31.9% 37/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	10.6% 12/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	4.3% 2/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.9% 1/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.4% 1/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Gastrointestinal disorders Paraesthesia Oral	7.8% 9/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.86% 1/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.8% 2/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Gastrointestinal disorders Vomiting	6.1% 7/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	12.1% 14/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.8% 2/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	2.1% 1/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
General disorders Fatigue	10.4% 12/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	6.9% 8/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	4.4% 5/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.4% 1/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
General disorders Feeling Drunk	6.1% 7/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	2.6% 3/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Investigations Blood Pressure Increased	7.0% 8/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	9.5% 11/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	4.4% 5/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Dizziness	27.8% 32/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	22.4% 26/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	8.8% 10/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.9% 1/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.4% 1/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Dizziness Postural	6.1% 7/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	6.0% 7/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Dysgeusia	14.8% 17/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	17.2% 20/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	15.0% 17/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Headache	20.0% 23/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	20.7% 24/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	16.8% 19/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	8.5% 4/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	3.8% 2/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	4.3% 3/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Hypoaesthesia	12.2% 14/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	13.8% 16/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.8% 2/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.9% 1/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Lethargy	6.1% 7/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	4.3% 5/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.88% 1/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Mental Impairment	5.2% 6/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	2.6% 3/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.88% 1/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Paraesthesia	16.5% 19/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	9.5% 11/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	2.7% 3/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Sedation	5.2% 6/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	6.9% 8/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.88% 1/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Somnolence	20.9% 24/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	18.1% 21/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	11.5% 13/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Nervous system disorders Tremor	3.5% 4/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	5.2% 6/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.8% 2/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	2.1% 1/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.4% 1/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Psychiatric disorders Anxiety	8.7% 10/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	7.8% 9/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	6.2% 7/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	2.1% 1/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	2.9% 2/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Psychiatric disorders Dissociation	26.1% 30/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	27.6% 32/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	3.5% 4/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Psychiatric disorders Euphoric Mood	7.0% 8/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.7% 2/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.8% 2/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Psychiatric disorders Insomnia	8.7% 10/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	6.9% 8/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	9.7% 11/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.9% 1/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Renal and urinary disorders Pollakiuria	5.2% 6/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	1.7% 2/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.88% 1/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Respiratory, thoracic and mediastinal disorders Nasal Discomfort	3.5% 4/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	4.3% 5/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	6.2% 7/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.
Respiratory, thoracic and mediastinal disorders Throat Irritation	4.3% 5/115 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	7.8% 9/116 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	3.5% 4/113 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/47 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/52 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.	0.00% 0/69 • Up to follow up phase (Week 24) The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase and were evaluated for the safety.

Additional Information

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