Trial Outcomes & Findings for A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder (NCT NCT04338321)

Last Updated: 2025-04-29

Results Overview

Percentage of participants with remission as assessed by the MADRS at Week 8 was reported. The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. A participant was defined as being in remission if the MADRS total score was less than or equal to (\<=)10 and no treatment or study discontinuation before Week 8.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

676 participants

Primary outcome timeframe

Week 8

Results posted on

2025-04-29

Participant Flow

Participants who discontinued the treatment early still remained in the study and were followed up until the end of study.

Participant milestones

Participant milestones
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Overall Study STARTED	336	340
Overall Study Treated (Safety Analysis Set)	334	336
Overall Study Completed Treatment	258	203
Overall Study COMPLETED	274	232
Overall Study NOT COMPLETED	62	108

Reasons for withdrawal

Reasons for withdrawal
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Overall Study Adverse Event	4	10
Overall Study Death	1	1
Overall Study Lost to Follow-up	4	9
Overall Study Withdrawal by Subject	45	69
Overall Study Physician Decision	5	9
Overall Study Other	3	10

Baseline Characteristics

A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=336 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=340 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.	Total n=676 Participants Total of all reporting groups
Age, Continuous	44.3 years STANDARD_DEVIATION 13.6 • n=5 Participants	45.7 years STANDARD_DEVIATION 13.38 • n=7 Participants	45 years STANDARD_DEVIATION 13.5 • n=5 Participants
Sex: Female, Male Female	225 Participants n=5 Participants	222 Participants n=7 Participants	447 Participants n=5 Participants
Sex: Female, Male Male	111 Participants n=5 Participants	118 Participants n=7 Participants	229 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) White	137 Participants n=5 Participants	152 Participants n=7 Participants	289 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	185 Participants n=5 Participants	171 Participants n=7 Participants	356 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 8

Population: The full analysis set (FAS) included all randomized participants.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=336 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=340 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Percentage of Participants With Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) Score at Week 8	27.1 Percentage of participants	17.6 Percentage of participants

SECONDARY outcome

Timeframe: Week 32

Population: The FAS includes all randomized participants.

Percentage of participants with both remission at Week 8 and relapse-free until Week 32 were reported. A participant was defined as being in remission if the MADRS total score was \<= 10 and no treatment or study discontinuation before Week 8. A relapse was defined by any of following: a) Worsening of depressive symptoms as indicated by MADRS total score greater than or equal to (\>=) 22 confirmed by 1 additional assessment of MADRS total score \>= 22 within the next 5 to 15 days. The date of the second MADRS assessment was used for the date of relapse; b) Any psychiatric hospitalization for: worsening of depression, suicide prevention or suicide attempt, the start date of hospitalization was the date of relapse; c) Suicide attempt, completed suicide, or any other clinically relevant event determined by investigator's judgment to be indicative of a relapse of depressive illness, but without hospitalized. The onset of the event was used for the date of relapse.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=336 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=340 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Percentage of Participants With Both Remission at Week 8 and Relapse-free Until Week 32	21.7 Percentage of Participants	14.1 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32

Change from baseline in clinician-rated overall MADRS score was reported. The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed up for a total possible score range of 0 to 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=327 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=330 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Clinician-rated Overall MADRS Score Week 1	-5.3 Unit on scale Standard Deviation 5.71	-3.7 Unit on scale Standard Deviation 4.65
Change From Baseline in Clinician-rated Overall MADRS Score Week 2	-9.0 Unit on scale Standard Deviation 6.87	-6.1 Unit on scale Standard Deviation 6.52
Change From Baseline in Clinician-rated Overall MADRS Score Week 4	-12.8 Unit on scale Standard Deviation 7.50	-9.8 Unit on scale Standard Deviation 7.32
Change From Baseline in Clinician-rated Overall MADRS Score Week 6	-14.9 Unit on scale Standard Deviation 8.27	-12.2 Unit on scale Standard Deviation 8.11
Change From Baseline in Clinician-rated Overall MADRS Score Week 8	-16.4 Unit on scale Standard Deviation 8.67	-14.3 Unit on scale Standard Deviation 8.26
Change From Baseline in Clinician-rated Overall MADRS Score Week 10	-18.2 Unit on scale Standard Deviation 8.32	-16.2 Unit on scale Standard Deviation 7.38
Change From Baseline in Clinician-rated Overall MADRS Score Week 12	-18.4 Unit on scale Standard Deviation 8.26	-16.7 Unit on scale Standard Deviation 8.16
Change From Baseline in Clinician-rated Overall MADRS Score Week 14	-19.0 Unit on scale Standard Deviation 8.06	-17.1 Unit on scale Standard Deviation 8.06
Change From Baseline in Clinician-rated Overall MADRS Score Week 16	-19.6 Unit on scale Standard Deviation 8.16	-17.8 Unit on scale Standard Deviation 8.23
Change From Baseline in Clinician-rated Overall MADRS Score Week 18	-19.9 Unit on scale Standard Deviation 8.59	-18.1 Unit on scale Standard Deviation 8.36
Change From Baseline in Clinician-rated Overall MADRS Score Week 20	-20.1 Unit on scale Standard Deviation 8.75	-19.1 Unit on scale Standard Deviation 8.11
Change From Baseline in Clinician-rated Overall MADRS Score Week 22	-20.6 Unit on scale Standard Deviation 8.32	-19.5 Unit on scale Standard Deviation 8.04
Change From Baseline in Clinician-rated Overall MADRS Score Week 24	-21.0 Unit on scale Standard Deviation 8.58	-20.1 Unit on scale Standard Deviation 7.96
Change From Baseline in Clinician-rated Overall MADRS Score Week 26	-21.2 Unit on scale Standard Deviation 8.19	-20.0 Unit on scale Standard Deviation 8.18
Change From Baseline in Clinician-rated Overall MADRS Score Week 28	-21.5 Unit on scale Standard Deviation 8.33	-20.8 Unit on scale Standard Deviation 8.33
Change From Baseline in Clinician-rated Overall MADRS Score Week 30	-21.8 Unit on scale Standard Deviation 8.66	-20.6 Unit on scale Standard Deviation 8.39
Change From Baseline in Clinician-rated Overall MADRS Score Week 32	-22.2 Unit on scale Standard Deviation 8.12	-20.5 Unit on scale Standard Deviation 8.58

SECONDARY outcome

Timeframe: Baseline, LOCF at Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32

Population: The FAS included all randomized participants. Here, 'N' (number of participants analyzed) signifies participants evaluable for this outcome measure.

Change from baseline in clinician-rated overall MADRS score at LOCF was reported. The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed up for a total possible score range of 0 to 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=327 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=330 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 30	-19.2 Unit on scale Standard Deviation 10.10	-15.2 Unit on scale Standard Deviation 11.11
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 2	-9.0 Unit on scale Standard Deviation 6.86	-5.8 Unit on scale Standard Deviation 6.53
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 4	-12.6 Unit on scale Standard Deviation 7.63	-8.9 Unit on scale Standard Deviation 7.70
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 6	-14.5 Unit on scale Standard Deviation 8.47	-10.7 Unit on scale Standard Deviation 8.78
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 8	-15.7 Unit on scale Standard Deviation 9.07	-12.0 Unit on scale Standard Deviation 9.30
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 10	-16.9 Unit on scale Standard Deviation 9.15	-12.8 Unit on scale Standard Deviation 9.24
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 12	-17.1 Unit on scale Standard Deviation 9.22	-13.1 Unit on scale Standard Deviation 9.82
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 14	-17.6 Unit on scale Standard Deviation 9.08	-13.2 Unit on scale Standard Deviation 9.88
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 16	-18.1 Unit on scale Standard Deviation 9.24	-13.7 Unit on scale Standard Deviation 10.17
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 18	-18.1 Unit on scale Standard Deviation 9.60	-13.8 Unit on scale Standard Deviation 10.26
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 20	-18.2 Unit on scale Standard Deviation 9.80	-14.3 Unit on scale Standard Deviation 10.46
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 22	-18.7 Unit on scale Standard Deviation 9.83	-14.6 Unit on scale Standard Deviation 10.56
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 24	-18.8 Unit on scale Standard Deviation 9.88	-14.8 Unit on scale Standard Deviation 10.77
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 26	-19.0 Unit on scale Standard Deviation 9.76	-14.9 Unit on scale Standard Deviation 10.76
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 28	-19.1 Unit on scale Standard Deviation 9.88	-15.2 Unit on scale Standard Deviation 11.08
Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) Week 32	-19.6 Unit on scale Standard Deviation 9.94	-15.1 Unit on scale Standard Deviation 11.18

SECONDARY outcome

Timeframe: Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in clinician-rated overall severity of depressive illness as assessed by CGI-S scale score was reported. The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 1 = normal (not at all ill); 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=327 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=331 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 1	-0.3 Units on scale Standard Deviation 0.58	-0.2 Units on scale Standard Deviation 0.53
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 2	-0.7 Units on scale Standard Deviation 0.79	-0.5 Units on scale Standard Deviation 0.77
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 3	-1.0 Units on scale Standard Deviation 0.88	-0.7 Units on scale Standard Deviation 0.83
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 4	-1.3 Units on scale Standard Deviation 0.94	-1.0 Units on scale Standard Deviation 0.95
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 8	-1.7 Units on scale Standard Deviation 0.98	-1.4 Units on scale Standard Deviation 1.05
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 12	-1.9 Units on scale Standard Deviation 1.00	-1.7 Units on scale Standard Deviation 1.07
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 16	-2.1 Units on scale Standard Deviation 1.05	-1.9 Units on scale Standard Deviation 1.15
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 20	-2.2 Units on scale Standard Deviation 1.04	-2.0 Units on scale Standard Deviation 1.22
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 24	-2.3 Units on scale Standard Deviation 1.06	-2.1 Units on scale Standard Deviation 1.22
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 28	-2.4 Units on scale Standard Deviation 1.02	-2.2 Units on scale Standard Deviation 1.19
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score Week 32	-2.5 Units on scale Standard Deviation 1.05	-2.3 Units on scale Standard Deviation 1.21

SECONDARY outcome

Timeframe: Baseline, LOCF at Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 32

Population: The FAS included all randomized participants. Here, 'N' (number of participants analyzed) signifies participants evaluable for this outcome measure.

Change from Baseline in clinician-rated overall severity of depressive illness as assessed by CGI-S scale score at LOCF was reported. The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. A participant is assessed on severity of mental illness at the time of rating according to: 1 = normal (not at all ill); 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=327 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=331 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF Week 2	-0.7 Units on scale Standard Deviation 0.79	-0.5 Units on scale Standard Deviation 0.75
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF Week 3	-1.0 Units on scale Standard Deviation 0.88	-0.7 Units on scale Standard Deviation 0.84
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF Week 4	-1.3 Units on scale Standard Deviation 0.95	-0.9 Units on scale Standard Deviation 0.96
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF Week 8	-1.6 Units on scale Standard Deviation 1.02	-1.2 Units on scale Standard Deviation 1.10
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF Week 12	-1.8 Units on scale Standard Deviation 1.09	-1.3 Units on scale Standard Deviation 1.18
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF Week 16	-1.9 Units on scale Standard Deviation 1.16	-1.4 Units on scale Standard Deviation 1.26
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF Week 20	-2.0 Units on scale Standard Deviation 1.17	-1.5 Units on scale Standard Deviation 1.32
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF Week 24	-2.1 Units on scale Standard Deviation 1.22	-1.5 Units on scale Standard Deviation 1.35
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF Week 28	-2.1 Units on scale Standard Deviation 1.22	-1.6 Units on scale Standard Deviation 1.36
Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF Week 32	-2.2 Units on scale Standard Deviation 1.27	-1.6 Units on scale Standard Deviation 1.40

SECONDARY outcome

Timeframe: Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32

Clinician-rated overall severity of depressive illness as assessed by CGI-C scale score was reported. The CGI-C evaluates the total improvement whether or not entirely due to drug treatment on a scale of 1 to 7. Compared to the condition at baseline, a participant is assessed on how much he/she has changed, according to: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. Higher scores indicate more severity.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=327 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=331 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 1	3.3 Units on scale Standard Deviation 0.77	3.6 Units on scale Standard Deviation 0.72
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 2	2.9 Units on scale Standard Deviation 0.87	3.3 Units on scale Standard Deviation 0.85
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 3	2.7 Units on scale Standard Deviation 0.83	3.1 Units on scale Standard Deviation 0.84
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 4	2.4 Units on scale Standard Deviation 0.85	2.9 Units on scale Standard Deviation 0.96
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 8	2.1 Units on scale Standard Deviation 0.84	2.4 Units on scale Standard Deviation 0.93
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 12	2.0 Units on scale Standard Deviation 0.85	2.3 Units on scale Standard Deviation 0.89
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 16	1.9 Units on scale Standard Deviation 0.87	2.2 Units on scale Standard Deviation 0.99
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 20	1.8 Units on scale Standard Deviation 0.85	2.1 Units on scale Standard Deviation 0.92
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 24	1.8 Units on scale Standard Deviation 0.85	2.0 Units on scale Standard Deviation 0.84
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 28	1.7 Units on scale Standard Deviation 0.84	2.0 Units on scale Standard Deviation 0.91
Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score Week 32	1.6 Units on scale Standard Deviation 0.81	1.9 Units on scale Standard Deviation 0.88

SECONDARY outcome

Timeframe: Baseline, LOCF at Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 32

Population: The FAS included all randomized participants. Here, 'N' (number of participants analyzed) signifies participants evaluable for this outcome measure.

Number of participants with clinician-rated overall severity of depressive illness as assessed by CGI-C scale score at LOCF was reported. The CGI-C evaluates the total improvement whether or not entirely due to drug treatment on a scale of 1 to 7. Compared to the condition at baseline, a participant is assessed on how much he/she has changed, according to: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. Higher scores indicate more severity. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=327 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=331 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF No change at Week 28	24 Participants	48 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much worse at Week 24	1 Participants	0 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much improved at Week 28	127 Participants	71 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much improved at Week 28	121 Participants	104 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much improved at Week 2	6 Participants	4 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much improved at Week 2	97 Participants	39 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally improved at Week 2	141 Participants	149 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF No change at Week 2	75 Participants	108 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally worse at Week 2	6 Participants	26 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much worse at Week 2	1 Participants	5 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much worse at Week 2	1 Participants	0 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much improved at Week 3	14 Participants	8 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much improved at Week 3	126 Participants	57 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally improved at Week 3	135 Participants	159 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF No change at Week 3	45 Participants	81 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally worse at Week 3	6 Participants	20 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much worse at Week 3	0 Participants	6 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much worse at Week 3	1 Participants	0 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much improved at Week 4	41 Participants	17 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much improved at Week 4	150 Participants	83 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally improved at Week 4	102 Participants	152 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF No change at Week 4	29 Participants	52 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally worse at Week 4	4 Participants	17 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much worse at Week 4	0 Participants	10 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much worse at Week 4	1 Participants	0 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much improved at Week 8	68 Participants	38 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much improved at Week 8	165 Participants	118 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally improved at Week 8	68 Participants	105 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF No change at Week 8	18 Participants	44 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally worse at Week 8	5 Participants	16 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much worse at Week 8	2 Participants	10 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much worse at Week 8	1 Participants	0 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much improved at Week 12	83 Participants	45 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much improved at Week 12	156 Participants	120 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally improved at Week 12	53 Participants	92 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF No change at Week 12	24 Participants	47 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally worse at Week 12	9 Participants	18 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much worse at Week 12	1 Participants	9 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much worse at Week 12	1 Participants	0 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much improved at Week 16	100 Participants	55 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much improved at Week 16	136 Participants	111 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally improved at Week 16	58 Participants	84 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF No change at Week 16	25 Participants	49 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally worse at Week 16	5 Participants	23 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much worse at Week 16	2 Participants	9 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much worse at Week 16	1 Participants	0 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much improved at Week 20	106 Participants	61 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much improved at Week 20	137 Participants	110 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally improved at Week 20	55 Participants	83 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF No change at Week 20	19 Participants	49 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally worse at Week 20	7 Participants	19 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much worse at Week 20	2 Participants	9 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much worse at Week 20	1 Participants	0 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much improved at Week 24	123 Participants	64 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much improved at Week 24	123 Participants	109 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally improved at Week 24	48 Participants	86 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF No change at Week 24	25 Participants	44 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally worse at Week 24	6 Participants	19 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much worse at Week 24	1 Participants	9 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally improved at Week 28	46 Participants	80 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally worse at Week 28	7 Participants	19 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much worse at Week 28	1 Participants	9 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much worse at Week 28	1 Participants	0 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much improved at Week 32	148 Participants	82 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much improved at Week 32	103 Participants	96 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally improved at Week 32	42 Participants	81 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF No change at Week 32	28 Participants	43 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Minimally worse at Week 32	4 Participants	20 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Much worse at Week 32	1 Participants	9 Participants
Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF Very much worse at Week 32	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32

Change from baseline in participant-reported depressive symptoms as assessed by PHQ 9-item total score was reported. The PHQ-9 is a validated 9-item, patient-reported outcome (PRO) measure to assess depressive symptoms. Each item is rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19) and Severe (20-27).

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=322 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=316 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 2	-4.9 Units on scale Standard Deviation 4.90	-3.1 Units on scale Standard Deviation 4.62
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 4	-6.7 Units on scale Standard Deviation 5.25	-5.0 Units on scale Standard Deviation 5.06
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 6	-8.1 Units on scale Standard Deviation 5.37	-6.1 Units on scale Standard Deviation 5.64
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 8	-8.9 Units on scale Standard Deviation 5.74	-7.4 Units on scale Standard Deviation 5.58
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 10	-9.6 Units on scale Standard Deviation 5.37	-8.4 Units on scale Standard Deviation 5.58
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 12	-9.8 Units on scale Standard Deviation 5.78	-8.7 Units on scale Standard Deviation 5.65
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 14	-10.2 Units on scale Standard Deviation 5.49	-8.5 Units on scale Standard Deviation 5.76
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 16	-10.5 Units on scale Standard Deviation 5.50	-9.2 Units on scale Standard Deviation 5.77
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 18	-10.6 Units on scale Standard Deviation 5.79	-9.3 Units on scale Standard Deviation 5.74
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 20	-10.4 Units on scale Standard Deviation 5.64	-9.4 Units on scale Standard Deviation 5.97
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 22	-10.7 Units on scale Standard Deviation 5.74	-9.5 Units on scale Standard Deviation 5.87
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 24	-10.6 Units on scale Standard Deviation 5.84	-9.7 Units on scale Standard Deviation 6.08
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 26	-10.9 Units on scale Standard Deviation 5.88	-9.7 Units on scale Standard Deviation 6.21
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 28	-10.9 Units on scale Standard Deviation 6.16	-10.0 Units on scale Standard Deviation 6.23
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 30	-11.2 Units on scale Standard Deviation 6.39	-10.1 Units on scale Standard Deviation 6.08
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score Week 32	-11.4 Units on scale Standard Deviation 6.40	-10.5 Units on scale Standard Deviation 6.01

SECONDARY outcome

Timeframe: Baseline, LOCF at Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32

Change from baseline in participant-reported depressive symptoms as assessed by PHQ 9-item total score at LOCF was reported. The PHQ-9 is a validated 9-item, PRO measure to assess depressive symptoms. Each item is rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19) and Severe (20-27). LOCF is defined as participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=322 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=316 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 2	-4.9 Units on scale Standard Deviation 4.90	-3.1 Units on scale Standard Deviation 4.62
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 4	-6.6 Units on scale Standard Deviation 5.33	-4.7 Units on scale Standard Deviation 5.06
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 6	-7.8 Units on scale Standard Deviation 5.51	-5.6 Units on scale Standard Deviation 5.69
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 8	-8.5 Units on scale Standard Deviation 5.94	-6.3 Units on scale Standard Deviation 5.86
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 10	-9.0 Units on scale Standard Deviation 5.75	-7.0 Units on scale Standard Deviation 5.90
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 12	-9.1 Units on scale Standard Deviation 6.13	-7.1 Units on scale Standard Deviation 6.07
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 14	-9.3 Units on scale Standard Deviation 5.93	-6.9 Units on scale Standard Deviation 6.12
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 16	-9.6 Units on scale Standard Deviation 5.98	-7.4 Units on scale Standard Deviation 6.20
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 18	-9.5 Units on scale Standard Deviation 6.26	-7.3 Units on scale Standard Deviation 6.21
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 20	-9.4 Units on scale Standard Deviation 6.12	-7.4 Units on scale Standard Deviation 6.32
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 22	-9.7 Units on scale Standard Deviation 6.27	-7.5 Units on scale Standard Deviation 6.31
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 24	-9.5 Units on scale Standard Deviation 6.35	-7.5 Units on scale Standard Deviation 6.47
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 26	-9.7 Units on scale Standard Deviation 6.46	-7.5 Units on scale Standard Deviation 6.56
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 28	-9.7 Units on scale Standard Deviation 6.66	-7.6 Units on scale Standard Deviation 6.64
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 30	-9.9 Units on scale Standard Deviation 6.85	-7.6 Units on scale Standard Deviation 6.61
Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF Week 32	-10.1 Units on scale Standard Deviation 6.94	-8.0 Units on scale Standard Deviation 6.70

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in participant-reported functional impairment and associated disability as assessed by SDS total score was reported. The SDS is a validated PRO measure consisting of a 5-item questionnaire that has been widely used and accepted 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 a rating scale from 0 to 10. It also has 1 item assessing days lost from school or work and 1 item assessing days of underproductivity. The scores for the first 3 items are summed to create a total score of 0 to 30, where higher score indicates greater impairment. Scores \<=2 for each item and \<= 6 for the total score are considered functional remission.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=310 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=303 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score Week 4	-5.9 Units on scale Standard Deviation 6.58	-4.1 Units on scale Standard Deviation 5.89
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score Week 8	-8.6 Units on scale Standard Deviation 7.03	-6.8 Units on scale Standard Deviation 7.63
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score Week 12	-9.7 Units on scale Standard Deviation 7.54	-8.6 Units on scale Standard Deviation 6.94
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score Week 16	-10.6 Units on scale Standard Deviation 7.29	-9.0 Units on scale Standard Deviation 7.50
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score Week 20	-10.9 Units on scale Standard Deviation 7.57	-9.0 Units on scale Standard Deviation 7.41
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score Week 24	-11.2 Units on scale Standard Deviation 7.88	-10.1 Units on scale Standard Deviation 7.76
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score Week 28	-11.9 Units on scale Standard Deviation 7.84	-10.8 Units on scale Standard Deviation 8.03
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score Week 32	-12.6 Units on scale Standard Deviation 8.09	-11.1 Units on scale Standard Deviation 8.06

SECONDARY outcome

Timeframe: Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in participant-reported functional impairment and associated disability as assessed by SDS total score at LOCF was reported. The SDS is a validated PRO measure consisting of a 5-item questionnaire 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 a rating scale from 0 to 10. It also has 1 item assessing days lost from school or work and 1 item assessing days of underproductivity. The scores for the first 3 items are summed to create a total score of 0 to 30, where higher score indicates greater impairment. Scores \<=2 for each item and \<= 6 for the total score are considered functional remission. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=310 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=303 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF Week 4	-5.9 Units on scale Standard Deviation 6.58	-4.1 Units on scale Standard Deviation 5.89
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF Week 8	-8.2 Units on scale Standard Deviation 7.06	-5.8 Units on scale Standard Deviation 7.45
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF Week 12	-9.0 Units on scale Standard Deviation 7.59	-6.8 Units on scale Standard Deviation 7.59
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF Week 16	-9.8 Units on scale Standard Deviation 7.47	-7.0 Units on scale Standard Deviation 7.99
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF Week 20	-9.9 Units on scale Standard Deviation 7.75	-7.0 Units on scale Standard Deviation 7.97
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF Week 24	-10.0 Units on scale Standard Deviation 8.13	-7.6 Units on scale Standard Deviation 8.37
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF Week 28	-10.4 Units on scale Standard Deviation 8.21	-7.9 Units on scale Standard Deviation 8.69
Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF Week 32	-11.1 Units on scale Standard Deviation 8.56	-8.2 Units on scale Standard Deviation 8.78

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in participant-reported HRQoL and health status as assessed by SF-36 scale score was reported. The SF-36 consists of 8 subscales (physical function, role limitations due to physical problems, pain, general health perception, vitality, social function, role limitations due to emotional problems, and mental health). Participants self-report on items in a subscale that have between 2-6 choices per item using likert-type responses (for example: none of the time, some of the time, etc.). Summations of item scores of the same subscale give the subscale scores, which are transformed into a range from 0 to 100; 0= worst HRQoL, 100=best HRQoL. Higher scores indicate better health status.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=319 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=308 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Vitality Week 20	13.2 Units on scale Standard Deviation 10.67	12.6 Units on scale Standard Deviation 10.64
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Vitality Week 24	13.4 Units on scale Standard Deviation 10.83	12.9 Units on scale Standard Deviation 11.26
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Physical Functioning Week 4	3.5 Units on scale Standard Deviation 7.16	2.2 Units on scale Standard Deviation 6.85
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Physical Functioning Week 8	5.4 Units on scale Standard Deviation 7.64	3.8 Units on scale Standard Deviation 8.19
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Physical Functioning Week 12	5.8 Units on scale Standard Deviation 8.29	4.7 Units on scale Standard Deviation 8.00
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Physical Functioning Week 16	6.2 Units on scale Standard Deviation 8.36	5.2 Units on scale Standard Deviation 8.42
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Physical Functioning Week 20	6.1 Units on scale Standard Deviation 8.62	5.1 Units on scale Standard Deviation 8.87
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Physical Functioning Week 24	6.2 Units on scale Standard Deviation 9.01	5.9 Units on scale Standard Deviation 9.23
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Physical Functioning Week 28	6.4 Units on scale Standard Deviation 8.68	6.2 Units on scale Standard Deviation 9.51
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Physical Functioning Week 32	6.8 Units on scale Standard Deviation 8.79	6.4 Units on scale Standard Deviation 9.58
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Physical Week 4	5.7 Units on scale Standard Deviation 9.57	3.1 Units on scale Standard Deviation 9.75
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Physical Week 8	7.5 Units on scale Standard Deviation 10.49	6.1 Units on scale Standard Deviation 11.67
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Physical Week 12	8.8 Units on scale Standard Deviation 10.59	7.1 Units on scale Standard Deviation 11.38
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Physical Week 16	10.0 Units on scale Standard Deviation 11.60	8.3 Units on scale Standard Deviation 12.47
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Physical Week 20	10.0 Units on scale Standard Deviation 11.75	8.2 Units on scale Standard Deviation 12.34
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Physical Week 24	10.4 Units on scale Standard Deviation 11.97	9.2 Units on scale Standard Deviation 12.50
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Physical Week 28	10.9 Units on scale Standard Deviation 11.92	8.8 Units on scale Standard Deviation 12.62
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Physical Week 32	11.7 Units on scale Standard Deviation 11.97	9.4 Units on scale Standard Deviation 12.39
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Body Pain Week 4	3.7 Units on scale Standard Deviation 9.05	2.3 Units on scale Standard Deviation 8.50
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Body Pain Week 8	4.5 Units on scale Standard Deviation 10.04	4.0 Units on scale Standard Deviation 8.85
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Body Pain Week 12	5.1 Units on scale Standard Deviation 9.93	5.3 Units on scale Standard Deviation 9.71
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Body Pain Week 16	5.6 Units on scale Standard Deviation 10.05	5.5 Units on scale Standard Deviation 10.52
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Body Pain Week 20	5.7 Units on scale Standard Deviation 11.14	6.0 Units on scale Standard Deviation 10.41
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Body Pain Week 24	6.2 Units on scale Standard Deviation 10.68	6.1 Units on scale Standard Deviation 10.64
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Body Pain Week 28	6.2 Units on scale Standard Deviation 11.32	6.3 Units on scale Standard Deviation 11.34
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Body Pain Week 32	6.7 Units on scale Standard Deviation 11.03	7.2 Units on scale Standard Deviation 11.62
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score General Health Week 4	5.3 Units on scale Standard Deviation 7.85	3.3 Units on scale Standard Deviation 7.45
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score General Health Week 8	7.2 Units on scale Standard Deviation 8.63	5.7 Units on scale Standard Deviation 8.50
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score General Health Week 12	7.9 Units on scale Standard Deviation 8.79	6.4 Units on scale Standard Deviation 9.02
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score General Health Week 16	8.8 Units on scale Standard Deviation 9.09	7.3 Units on scale Standard Deviation 9.55
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score General Health Week 20	9.0 Units on scale Standard Deviation 9.30	7.2 Units on scale Standard Deviation 9.71
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score General Health Week 24	9.5 Units on scale Standard Deviation 9.73	7.7 Units on scale Standard Deviation 10.05
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score General Health Week 28	10.1 Units on scale Standard Deviation 9.71	8.8 Units on scale Standard Deviation 10.38
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score General Health Week 32	10.6 Units on scale Standard Deviation 10.25	9.7 Units on scale Standard Deviation 10.33
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Vitality Week 4	8.7 Units on scale Standard Deviation 9.13	5.2 Units on scale Standard Deviation 7.75
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Vitality Week 8	11.3 Units on scale Standard Deviation 10.04	9.2 Units on scale Standard Deviation 9.44
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Vitality Week 12	12.4 Units on scale Standard Deviation 10.36	10.8 Units on scale Standard Deviation 9.79
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Vitality Week 16	13.1 Units on scale Standard Deviation 10.69	12.1 Units on scale Standard Deviation 9.88
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Vitality Week 28	14.2 Units on scale Standard Deviation 11.25	13.9 Units on scale Standard Deviation 11.19
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Vitality Week 32	15.2 Units on scale Standard Deviation 11.64	14.0 Units on scale Standard Deviation 11.34
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Social Functioning Week 4	7.1 Units on scale Standard Deviation 10.32	5.0 Units on scale Standard Deviation 8.83
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Social Functioning Week 8	11.2 Units on scale Standard Deviation 11.42	8.7 Units on scale Standard Deviation 9.59
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Social Functioning Week 12	12.4 Units on scale Standard Deviation 11.29	10.2 Units on scale Standard Deviation 10.45
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Social Functioning Week 16	13.5 Units on scale Standard Deviation 10.92	11.2 Units on scale Standard Deviation 11.24
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Social Functioning Week 20	13.6 Units on scale Standard Deviation 11.65	11.7 Units on scale Standard Deviation 10.73
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Social Functioning Week 24	14.3 Units on scale Standard Deviation 11.55	12.5 Units on scale Standard Deviation 11.75
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Social Functioning Week 28	15.3 Units on scale Standard Deviation 11.26	13.3 Units on scale Standard Deviation 11.15
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Social Functioning Week 32	16.1 Units on scale Standard Deviation 11.34	13.8 Units on scale Standard Deviation 11.47
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Emotional Week 4	8.6 Units on scale Standard Deviation 9.62	5.3 Units on scale Standard Deviation 9.53
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Emotional Week 8	12.7 Units on scale Standard Deviation 10.67	10.1 Units on scale Standard Deviation 11.30
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Emotional Week 12	13.8 Units on scale Standard Deviation 10.70	12.2 Units on scale Standard Deviation 11.48
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Emotional Week 16	15.4 Units on scale Standard Deviation 11.30	13.2 Units on scale Standard Deviation 12.07
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Emotional Week 20	15.8 Units on scale Standard Deviation 11.26	13.4 Units on scale Standard Deviation 11.14
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Emotional Week 24	16.0 Units on scale Standard Deviation 11.79	14.7 Units on scale Standard Deviation 11.71
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Emotional Week 28	17.3 Units on scale Standard Deviation 12.44	15.0 Units on scale Standard Deviation 11.58
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Role-Emotional Week 32	18.1 Units on scale Standard Deviation 12.49	14.9 Units on scale Standard Deviation 12.62
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Mental Health Week 4	9.8 Units on scale Standard Deviation 9.77	6.7 Units on scale Standard Deviation 9.34
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Mental Health Week 8	13.5 Units on scale Standard Deviation 10.37	11.6 Units on scale Standard Deviation 10.78
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Mental Health Week 12	15.0 Units on scale Standard Deviation 10.50	13.3 Units on scale Standard Deviation 10.84
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Mental Health Week 16	16.1 Units on scale Standard Deviation 11.04	14.3 Units on scale Standard Deviation 11.01
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Mental Health Week 20	16.5 Units on scale Standard Deviation 10.90	14.7 Units on scale Standard Deviation 11.36
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Mental Health Week 24	16.6 Units on scale Standard Deviation 11.69	15.3 Units on scale Standard Deviation 11.45
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Mental Health Week 28	17.6 Units on scale Standard Deviation 11.40	16.5 Units on scale Standard Deviation 12.16
Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score Mental Health Week 32	18.4 Units on scale Standard Deviation 11.89	17.0 Units on scale Standard Deviation 12.05

SECONDARY outcome

Timeframe: Baseline, LOCF at Weeks 8, 12, 16, 20, 24, 28, 32

Population: The FAS included all randomized participants. Here, 'N' (number of participants analyzed) signifies participants evaluable for this outcome measure. Here, 'n' (number analyzed) signifies participants evaluable for this outcome measure at specified categories with time points. LOCF was applied only for participants whose questionnaire was completely missing. No LOCF imputation was done on partially completed questionnaire.

Change from baseline in participant-reported HRQoL and health status as assessed by SF-36 domain scores at LOCF was reported. The SF-36 consists of 8 subscales (physical function, role limitations due to physical problems, pain, general health perception, vitality, social function, role limitations due to emotional problems, and mental health). Participants self-report on items in a subscale that have between 2-6 choices per item using likert-type responses (for example: none of the time, some of the time, etc.). Summations of item scores of the same subscale give the subscale scores, which are transformed into a range from 0 to 100; 0= worst HRQoL, 100=best HRQoL. Higher scores indicate better health status. LOCF is defined as participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=319 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=308 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Physical Functioning Week 8	5.1 Units on scale Standard Deviation 7.61	3.2 Units on scale Standard Deviation 8.15
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Physical Functioning Week 12	5.3 Units on scale Standard Deviation 8.22	3.9 Units on scale Standard Deviation 7.96
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Physical Functioning Week 16	5.6 Units on scale Standard Deviation 8.33	4.2 Units on scale Standard Deviation 8.27
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Physical Functioning Week 20	5.5 Units on scale Standard Deviation 8.63	4.0 Units on scale Standard Deviation 8.48
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Physical Functioning Week 24	5.6 Units on scale Standard Deviation 8.83	4.4 Units on scale Standard Deviation 8.84
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Physical Functioning Week 28	5.6 Units on scale Standard Deviation 8.71	4.5 Units on scale Standard Deviation 8.97
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Physical Functioning Week 32	6.0 Units on scale Standard Deviation 8.77	4.6 Units on scale Standard Deviation 9.05
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Physical Week 8	7.4 Units on scale Standard Deviation 10.51	5.3 Units on scale Standard Deviation 11.50
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Physical Week 12	8.3 Units on scale Standard Deviation 10.87	5.7 Units on scale Standard Deviation 11.31
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Physical Week 16	9.3 Units on scale Standard Deviation 11.49	6.2 Units on scale Standard Deviation 12.23
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Physical Week 20	9.1 Units on scale Standard Deviation 11.69	6.3 Units on scale Standard Deviation 12.09
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Physical Week 24	9.2 Units on scale Standard Deviation 11.93	6.9 Units on scale Standard Deviation 12.48
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Physical Week 28	9.4 Units on scale Standard Deviation 12.00	6.8 Units on scale Standard Deviation 12.36
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Physical Week 32	10.2 Units on scale Standard Deviation 12.21	7.2 Units on scale Standard Deviation 12.29
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Body Pain Week 8	4.4 Units on scale Standard Deviation 9.84	3.5 Units on scale Standard Deviation 8.79
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Body Pain Week 12	4.8 Units on scale Standard Deviation 9.99	4.2 Units on scale Standard Deviation 9.51
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Body Pain Week 16	5.2 Units on scale Standard Deviation 10.14	4.3 Units on scale Standard Deviation 10.02
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Body Pain Week 20	5.2 Units on scale Standard Deviation 10.85	4.5 Units on scale Standard Deviation 10.05
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Body Pain Week 24	5.6 Units on scale Standard Deviation 10.45	4.4 Units on scale Standard Deviation 10.26
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Body Pain Week 28	5.4 Units on scale Standard Deviation 11.01	4.5 Units on scale Standard Deviation 10.78
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Body Pain Week 32	6.0 Units on scale Standard Deviation 10.93	5.0 Units on scale Standard Deviation 11.10
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF General Health Week 8	6.9 Units on scale Standard Deviation 8.85	4.9 Units on scale Standard Deviation 8.19
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF General Health Week 12	7.4 Units on scale Standard Deviation 9.19	5.1 Units on scale Standard Deviation 8.68
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF General Health Week 16	8.0 Units on scale Standard Deviation 9.41	5.6 Units on scale Standard Deviation 9.20
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF General Health Week 20	8.1 Units on scale Standard Deviation 9.60	5.5 Units on scale Standard Deviation 9.37
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF General Health Week 24	8.2 Units on scale Standard Deviation 10.08	5.6 Units on scale Standard Deviation 9.57
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF General Health Week 28	8.6 Units on scale Standard Deviation 10.19	6.1 Units on scale Standard Deviation 10.01
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF General Health Week 32	9.2 Units on scale Standard Deviation 10.78	6.7 Units on scale Standard Deviation 10.18
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Vitality Week 8	11.1 Units on scale Standard Deviation 10.08	7.8 Units on scale Standard Deviation 9.46
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Vitality Week 12	11.7 Units on scale Standard Deviation 10.48	8.7 Units on scale Standard Deviation 9.98
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Vitality Week 16	12.3 Units on scale Standard Deviation 10.81	9.5 Units on scale Standard Deviation 10.26
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Vitality Week 20	12.3 Units on scale Standard Deviation 10.94	9.6 Units on scale Standard Deviation 10.77
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Vitality Week 24	12.2 Units on scale Standard Deviation 11.04	9.6 Units on scale Standard Deviation 11.34
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Vitality Week 28	12.8 Units on scale Standard Deviation 11.43	10.1 Units on scale Standard Deviation 11.53
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Vitality Week 32	13.8 Units on scale Standard Deviation 11.99	10.4 Units on scale Standard Deviation 11.65
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Social Functioning Week 8	10.7 Units on scale Standard Deviation 11.31	7.6 Units on scale Standard Deviation 9.72
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Social Functioning Week 12	11.4 Units on scale Standard Deviation 11.29	8.6 Units on scale Standard Deviation 10.47
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Social Functioning Week 16	12.2 Units on scale Standard Deviation 11.24	9.0 Units on scale Standard Deviation 11.22
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Social Functioning Week 20	12.3 Units on scale Standard Deviation 11.91	9.1 Units on scale Standard Deviation 10.92
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Social Functioning Week 24	12.7 Units on scale Standard Deviation 11.81	9.5 Units on scale Standard Deviation 11.63
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Social Functioning Week 28	13.0 Units on scale Standard Deviation 12.09	9.8 Units on scale Standard Deviation 11.49
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Social Functioning Week 32	14.0 Units on scale Standard Deviation 12.35	10.3 Units on scale Standard Deviation 11.71
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Emotional Week 8	12.0 Units on scale Standard Deviation 10.75	8.6 Units on scale Standard Deviation 11.30
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Emotional Week 12	12.7 Units on scale Standard Deviation 10.89	9.8 Units on scale Standard Deviation 11.82
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Emotional Week 16	14.2 Units on scale Standard Deviation 11.53	10.3 Units on scale Standard Deviation 12.32
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Emotional Week 20	14.3 Units on scale Standard Deviation 11.77	10.4 Units on scale Standard Deviation 11.67
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Emotional Week 24	14.3 Units on scale Standard Deviation 12.15	11.2 Units on scale Standard Deviation 12.22
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Emotional Week 28	15.2 Units on scale Standard Deviation 12.91	11.2 Units on scale Standard Deviation 12.30
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Role-Emotional Week 32	16.0 Units on scale Standard Deviation 13.16	11.2 Units on scale Standard Deviation 12.96
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Mental Health Week 8	12.9 Units on scale Standard Deviation 10.76	9.8 Units on scale Standard Deviation 11.04
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Mental Health Week 12	14.0 Units on scale Standard Deviation 11.09	10.6 Units on scale Standard Deviation 11.44
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Mental Health Week 16	14.7 Units on scale Standard Deviation 11.63	10.9 Units on scale Standard Deviation 11.85
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Mental Health Week 20	15.0 Units on scale Standard Deviation 11.64	11.2 Units on scale Standard Deviation 12.07
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Mental Health Week 24	14.8 Units on scale Standard Deviation 12.24	11.5 Units on scale Standard Deviation 12.23
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Mental Health Week 28	15.5 Units on scale Standard Deviation 12.35	12.2 Units on scale Standard Deviation 13.01
Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF Mental Health Week 32	16.3 Units on scale Standard Deviation 12.90	12.6 Units on scale Standard Deviation 13.08

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in participant-reported quality of life as assessed by QLDS total score was reported. The QLDS is a disease-specific validated PRO measure which assesses the impact that depression has on a participant's quality of life. It is a 34-item self-rated questionnaire which consists of dichotomous response questions, with the response being either True/Not True. Each statement on the QLDS is given a score of "1" or "0". A score of "1" is indicative of adverse quality of life. All item scores are summed to give a total score that ranges from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=318 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=305 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score Week 4	-8.9 Units on Scale Standard Deviation 8.83	-5.6 Units on Scale Standard Deviation 7.43
Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score Week 8	-12.0 Units on Scale Standard Deviation 9.36	-9.1 Units on Scale Standard Deviation 9.31
Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score Week 12	-13.5 Units on Scale Standard Deviation 9.30	-10.9 Units on Scale Standard Deviation 9.52
Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score Week 16	-14.2 Units on Scale Standard Deviation 9.39	-11.6 Units on Scale Standard Deviation 9.39
Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score Week 20	-14.3 Units on Scale Standard Deviation 9.50	-12.1 Units on Scale Standard Deviation 9.74
Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score Week 24	-14.9 Units on Scale Standard Deviation 9.44	-12.8 Units on Scale Standard Deviation 9.64
Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score Week 28	-15.6 Units on Scale Standard Deviation 9.42	-13.7 Units on Scale Standard Deviation 9.51
Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score Week 32	-16.0 Units on Scale Standard Deviation 9.55	-14.2 Units on Scale Standard Deviation 9.96

SECONDARY outcome

Timeframe: Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in participant-reported quality of life as assessed by QLDS total score at LOCF was reported. The QLDS is a disease-specific validated PRO measure which assesses the impact that depression has on a participant's quality of life. It is a 34-item self-rated questionnaire which consists of dichotomous response questions, with the response being either True/Not True. Each statement on the QLDS is given a score of "1" or "0". A score of "1" is indicative of adverse quality of life. All item scores are summed to give a total score that ranges from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=318 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=305 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF Week 4	-8.9 Units on Scale Standard Deviation 8.83	-5.6 Units on Scale Standard Deviation 7.43
Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF Week 8	-11.3 Units on Scale Standard Deviation 9.59	-8.1 Units on Scale Standard Deviation 9.22
Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF Week 12	-12.3 Units on Scale Standard Deviation 9.73	-9.0 Units on Scale Standard Deviation 9.62
Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF Week 16	-13.0 Units on Scale Standard Deviation 9.86	-9.3 Units on Scale Standard Deviation 9.80
Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF Week 20	-13.0 Units on Scale Standard Deviation 9.93	-9.5 Units on Scale Standard Deviation 10.02
Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF Week 24	-13.3 Units on Scale Standard Deviation 9.98	-9.8 Units on Scale Standard Deviation 10.18
Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF Week 28	-13.6 Units on Scale Standard Deviation 10.06	-10.3 Units on Scale Standard Deviation 10.26
Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF Week 32	-14.1 Units on Scale Standard Deviation 10.29	-10.5 Units on Scale Standard Deviation 10.59

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in participant-reported health-related quality of Life as assessed by EQ-5D-5L score: health status index was reported. The EQ-5D-5L is a standardized 2-part instrument used to measure health outcomes, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and the EQ Visual Analogue Scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems (level 1 = no problem, level 2 = slight problems, level 3 = moderate problems, level 4 = severe problems, level 5 = extreme problems). The participant selects an answer for each of the 5 dimensions considering the response that best matches his or her health "today." Responses were used to generate health status index which ranges from 0 (dead) and 1 (full health), a lower score indicates worse health.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=320 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=308 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index Week 4	0.177 Units on Scale Standard Deviation 0.2354	0.124 Units on Scale Standard Deviation 0.2280
Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index Week 8	0.234 Units on Scale Standard Deviation 0.2655	0.206 Units on Scale Standard Deviation 0.2463
Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index Week 12	0.276 Units on Scale Standard Deviation 0.2405	0.227 Units on Scale Standard Deviation 0.2367
Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index Week 16	0.284 Units on Scale Standard Deviation 0.2445	0.232 Units on Scale Standard Deviation 0.2431
Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index Week 20	0.294 Units on Scale Standard Deviation 0.2399	0.238 Units on Scale Standard Deviation 0.2423
Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index Week 24	0.297 Units on Scale Standard Deviation 0.2498	0.259 Units on Scale Standard Deviation 0.2489
Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index Week 28	0.303 Units on Scale Standard Deviation 0.2584	0.262 Units on Scale Standard Deviation 0.2492
Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index Week 32	0.317 Units on Scale Standard Deviation 0.2636	0.279 Units on Scale Standard Deviation 0.2581

SECONDARY outcome

Timeframe: Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in participant-reported health-related quality of Life as assessed by EQ-5D-5L score: health status index at LOCF was reported. The EQ-5D-5L is a standardized 2-part instrument used to measure health outcomes, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems (level 1 = no problem, level 2 = slight problems, level 3 = moderate problems, level 4 = severe problems, level 5 = extreme problems). The participant selects an answer for each of the 5 dimensions considering the response that best matches his or her health "today." LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=320 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=308 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF Week 4	0.177 Units on Scale Standard Deviation 0.2354	0.124 Units on Scale Standard Deviation 0.2280
Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF Week 8	0.221 Units on Scale Standard Deviation 0.2681	0.175 Units on Scale Standard Deviation 0.2510
Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF Week 12	0.247 Units on Scale Standard Deviation 0.2552	0.187 Units on Scale Standard Deviation 0.2523
Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF Week 16	0.255 Units on Scale Standard Deviation 0.2580	0.188 Units on Scale Standard Deviation 0.2595
Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF Week 20	0.261 Units on Scale Standard Deviation 0.2600	0.187 Units on Scale Standard Deviation 0.2590
Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF Week 24	0.264 Units on Scale Standard Deviation 0.2627	0.196 Units on Scale Standard Deviation 0.2671
Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF Week 28	0.266 Units on Scale Standard Deviation 0.2739	0.195 Units on Scale Standard Deviation 0.2664
Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF Week 32	0.280 Units on Scale Standard Deviation 0.2806	0.207 Units on Scale Standard Deviation 0.2739

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in participant-reported health status as assessed by EQ-5D-5L Score: VAS was reported. The EQ-5D-5L is a standardized 2-part instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It essentially consists of the EQ-5D-5L descriptive system and the EQ-VAS. EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Positive change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=318 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=310 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS Week 4	13.3 Units on Scale Standard Deviation 18.43	9.7 Units on Scale Standard Deviation 17.83
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS Week 8	18.9 Units on Scale Standard Deviation 19.84	16.1 Units on Scale Standard Deviation 19.64
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS Week 12	20.9 Units on Scale Standard Deviation 20.98	17.2 Units on Scale Standard Deviation 20.73
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS Week 16	21.9 Units on Scale Standard Deviation 20.14	20.2 Units on Scale Standard Deviation 22.14
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS Week 20	22.3 Units on Scale Standard Deviation 21.20	19.6 Units on Scale Standard Deviation 21.59
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS Week 24	23.6 Units on Scale Standard Deviation 20.95	21.8 Units on Scale Standard Deviation 21.60
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS Week 28	25.2 Units on Scale Standard Deviation 20.95	23.2 Units on Scale Standard Deviation 22.11
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS Week 32	24.9 Units on Scale Standard Deviation 21.65	24.5 Units on Scale Standard Deviation 22.64

SECONDARY outcome

Timeframe: Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in participant-reported health status as assessed by EQ-5D-5L score: VAS at LOCF was reported. The EQ-5D-5L is a standardized 2-part instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It essentially consists of the EQ-5D-5L descriptive system and the EQ-VAS. EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Positive change in score indicates improvement. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=318 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=310 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF Week 32	22.3 Units on Scale Standard Deviation 22.47	18.0 Units on Scale Standard Deviation 23.59
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF Week 4	13.3 Units on Scale Standard Deviation 18.43	9.7 Units on Scale Standard Deviation 17.83
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF Week 8	18.2 Units on Scale Standard Deviation 19.94	14.0 Units on Scale Standard Deviation 20.42
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF Week 12	19.4 Units on Scale Standard Deviation 21.04	14.4 Units on Scale Standard Deviation 21.19
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF Week 16	20.2 Units on Scale Standard Deviation 20.37	16.1 Units on Scale Standard Deviation 22.42
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF Week 20	20.4 Units on Scale Standard Deviation 21.34	15.4 Units on Scale Standard Deviation 22.19
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF Week 24	21.3 Units on Scale Standard Deviation 21.34	16.9 Units on Scale Standard Deviation 22.64
Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF Week 28	21.9 Units on Scale Standard Deviation 21.78	17.3 Units on Scale Standard Deviation 23.10

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32

Change from baseline in participant-reported work productivity as assessed by WPAI: depression questionnaire was reported. The WPAI-D questionnaire is a validated short instrument that assesses impairment in work and other regular activities over the past 7 days. The WPAI yields four types of scores: (a) Absenteeism (work time missed); (b) Presenteeism (impairment at work / reduced on-the-job effectiveness); (c) Work productivity loss (overall work impairment / absenteeism plus presenteeism); (d) Activity Impairment. The first three scores were derived only for respondents who were working (should be missing for non-working), but the last score was applicable for all respondents. Each score ranges from 0 to 100 with higher scores indicating greater impairment and less productivity.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=310 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=307 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Activity Impairment Week 20	-33.88 Units on scale Standard Deviation 28.770	-30.93 Units on scale Standard Deviation 27.698
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Absenteeism Week 4	-11.95 Units on scale Standard Deviation 20.745	-8.37 Units on scale Standard Deviation 25.790
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Absenteeism Week 8	-19.02 Units on scale Standard Deviation 30.205	-13.62 Units on scale Standard Deviation 31.059
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Absenteeism Week 12	-21.87 Units on scale Standard Deviation 34.711	-17.25 Units on scale Standard Deviation 31.340
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Absenteeism Week 16	-22.85 Units on scale Standard Deviation 33.023	-14.24 Units on scale Standard Deviation 37.823
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Absenteeism Week 20	-27.88 Units on scale Standard Deviation 32.107	-18.70 Units on scale Standard Deviation 35.310
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Absenteeism Week 24	-26.83 Units on scale Standard Deviation 32.909	-21.03 Units on scale Standard Deviation 34.459
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Absenteeism Week 28	-27.16 Units on scale Standard Deviation 35.825	-17.90 Units on scale Standard Deviation 31.254
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Absenteeism Week 32	-28.90 Units on scale Standard Deviation 32.066	-16.68 Units on scale Standard Deviation 29.394
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Presenteeism Week 4	-21.75 Units on scale Standard Deviation 25.558	-9.13 Units on scale Standard Deviation 21.948
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Presenteeism Week 8	-31.70 Units on scale Standard Deviation 25.144	-16.86 Units on scale Standard Deviation 27.140
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Presenteeism Week 12	-35.46 Units on scale Standard Deviation 27.998	-23.22 Units on scale Standard Deviation 29.942
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Presenteeism Week 16	-36.96 Units on scale Standard Deviation 28.556	-24.50 Units on scale Standard Deviation 31.898
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Presenteeism Week 20	-39.80 Units on scale Standard Deviation 26.263	-26.34 Units on scale Standard Deviation 33.389
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Presenteeism Week 24	-42.83 Units on scale Standard Deviation 27.332	-31.60 Units on scale Standard Deviation 30.922
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Presenteeism Week 28	-43.00 Units on scale Standard Deviation 28.762	-33.29 Units on scale Standard Deviation 34.445
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Presenteeism Week 32	-47.58 Units on scale Standard Deviation 26.691	-33.88 Units on scale Standard Deviation 33.621
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Work productivity loss Week 4	-20.94 Units on scale Standard Deviation 25.759	-9.46 Units on scale Standard Deviation 23.374
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Work productivity loss Week 8	-32.91 Units on scale Standard Deviation 26.244	-18.21 Units on scale Standard Deviation 29.156
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Work productivity loss Week 12	-36.68 Units on scale Standard Deviation 29.247	-25.62 Units on scale Standard Deviation 35.135
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Work productivity loss Week 16	-38.13 Units on scale Standard Deviation 30.490	-24.50 Units on scale Standard Deviation 34.089
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Work productivity loss Week 20	-41.11 Units on scale Standard Deviation 28.643	-26.57 Units on scale Standard Deviation 32.885
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Work productivity loss Week 24	-45.31 Units on scale Standard Deviation 29.000	-30.63 Units on scale Standard Deviation 34.087
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Work productivity loss Week 28	-44.40 Units on scale Standard Deviation 32.098	-32.61 Units on scale Standard Deviation 33.836
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Work productivity loss Week 32	-50.20 Units on scale Standard Deviation 29.176	-35.48 Units on scale Standard Deviation 35.915
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Activity Impairment Week 4	-20.29 Units on scale Standard Deviation 23.702	-13.43 Units on scale Standard Deviation 20.846
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Activity Impairment Week 8	-30.31 Units on scale Standard Deviation 27.410	-24.25 Units on scale Standard Deviation 24.187
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Activity Impairment Week 12	-33.96 Units on scale Standard Deviation 27.218	-28.28 Units on scale Standard Deviation 25.555
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Activity Impairment Week 16	-35.07 Units on scale Standard Deviation 27.291	-30.95 Units on scale Standard Deviation 27.444
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Activity Impairment Week 24	-36.69 Units on scale Standard Deviation 29.742	-36.84 Units on scale Standard Deviation 27.000
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Activity Impairment Week 28	-40.00 Units on scale Standard Deviation 29.828	-37.62 Units on scale Standard Deviation 28.500
Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire Activity Impairment Week 32	-41.92 Units on scale Standard Deviation 30.299	-39.59 Units on scale Standard Deviation 27.190

SECONDARY outcome

Timeframe: Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32

Population: The FAS included all randomized participants. Here, 'N' (number of participants analyzed) signifies participants evaluable for this outcome measure. Here, 'n' (number analyzed) signifies participants evaluable for this outcome measure at specified time points. LOCF was applied only for participants whose questionnaire was completely missing. No LOCF imputation was done on partially completed questionnaire.

Change from baseline in participant-reported work productivity as assessed by WPAI: depression questionnaire at LOCF was reported. The WPAI-D questionnaire is a validated short instrument that assesses impairment in work and other regular activities over the past 7 days. The WPAI yields four types of scores: (a) Absenteeism (work time missed); (b) Presenteeism (impairment at work / reduced on-the-job effectiveness); (c) Work productivity loss (overall work impairment / absenteeism plus presenteeism); (d) Activity Impairment. The first three scores were derived only for respondents who were working (should be missing for non-working), but the last score was applicable for all respondents. Each score ranges from 0 to 100 with higher scores indicating greater impairment and less productivity. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=310 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=307 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Absenteeism Week 12	-20.23 Units on scale Standard Deviation 33.590	-15.17 Units on scale Standard Deviation 31.835
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Absenteeism Week 16	-21.35 Units on scale Standard Deviation 31.806	-14.14 Units on scale Standard Deviation 37.534
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Absenteeism Week 20	-25.45 Units on scale Standard Deviation 31.628	-16.04 Units on scale Standard Deviation 37.769
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Absenteeism Week 24	-24.41 Units on scale Standard Deviation 32.403	-16.28 Units on scale Standard Deviation 37.672
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Absenteeism Week 28	-23.88 Units on scale Standard Deviation 34.623	-14.14 Units on scale Standard Deviation 35.849
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Absenteeism Week 32	-26.10 Units on scale Standard Deviation 31.903	-13.90 Units on scale Standard Deviation 36.104
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Presenteeism Week 4	-21.75 Units on scale Standard Deviation 25.558	-9.13 Units on scale Standard Deviation 21.948
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Presenteeism Week 8	-29.45 Units on scale Standard Deviation 26.437	-14.84 Units on scale Standard Deviation 27.067
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Presenteeism Week 12	-33.57 Units on scale Standard Deviation 28.745	-17.44 Units on scale Standard Deviation 29.997
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Presenteeism Week 16	-35.00 Units on scale Standard Deviation 29.075	-19.84 Units on scale Standard Deviation 31.322
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Presenteeism Week 20	-36.08 Units on scale Standard Deviation 28.598	-21.41 Units on scale Standard Deviation 32.862
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Presenteeism Week 24	-36.87 Units on scale Standard Deviation 29.641	-22.19 Units on scale Standard Deviation 32.189
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Presenteeism Week 28	-37.40 Units on scale Standard Deviation 30.924	-23.83 Units on scale Standard Deviation 34.757
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Presenteeism Week 32	-40.53 Units on scale Standard Deviation 30.700	-23.44 Units on scale Standard Deviation 35.526
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Work productivity loss Week 4	-20.94 Units on scale Standard Deviation 25.759	-9.46 Units on scale Standard Deviation 23.374
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Work productivity loss Week 8	-30.59 Units on scale Standard Deviation 26.789	-15.35 Units on scale Standard Deviation 30.059
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Work productivity loss Week 12	-34.46 Units on scale Standard Deviation 29.333	-19.27 Units on scale Standard Deviation 33.905
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Work productivity loss Week 16	-36.35 Units on scale Standard Deviation 30.531	-20.75 Units on scale Standard Deviation 33.545
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Work productivity loss Week 20	-37.59 Units on scale Standard Deviation 30.354	-22.58 Units on scale Standard Deviation 34.117
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Work productivity loss Week 24	-39.02 Units on scale Standard Deviation 31.482	-22.54 Units on scale Standard Deviation 34.635
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Work productivity loss Week 28	-39.09 Units on scale Standard Deviation 33.271	-23.85 Units on scale Standard Deviation 35.152
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Work productivity loss Week 32	-43.42 Units on scale Standard Deviation 32.638	-24.89 Units on scale Standard Deviation 37.870
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Activity Impairment Week 4	-20.29 Units on scale Standard Deviation 23.702	-13.43 Units on scale Standard Deviation 20.846
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Activity Impairment Week 8	-28.84 Units on scale Standard Deviation 27.412	-20.39 Units on scale Standard Deviation 24.599
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Activity Impairment Week 12	-31.10 Units on scale Standard Deviation 27.778	-22.81 Units on scale Standard Deviation 26.264
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Activity Impairment Week 16	-31.84 Units on scale Standard Deviation 28.413	-23.68 Units on scale Standard Deviation 28.014
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Activity Impairment Week 20	-30.84 Units on scale Standard Deviation 29.983	-23.62 Units on scale Standard Deviation 28.185
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Activity Impairment Week 24	-32.45 Units on scale Standard Deviation 31.207	-26.71 Units on scale Standard Deviation 28.821
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Activity Impairment Week 28	-34.87 Units on scale Standard Deviation 31.804	-27.07 Units on scale Standard Deviation 29.965
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Activity Impairment Week 32	-36.65 Units on scale Standard Deviation 32.357	-28.40 Units on scale Standard Deviation 29.930
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Absenteeism Week 4	-11.95 Units on scale Standard Deviation 20.745	-8.37 Units on scale Standard Deviation 25.790
Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF Absenteeism Week 8	-18.28 Units on scale Standard Deviation 29.417	-12.38 Units on scale Standard Deviation 30.369

SECONDARY outcome

Timeframe: Up to Week 35

Population: The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.

An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. TEAEs were those events if they started after administration of the first dose until 14 days after the last dose of study medication for other TEAEs except serious; and first dose until 30 days after the last dose of study medication for serious TEAEs.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=334 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=336 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	307 Participants	262 Participants

SECONDARY outcome

Timeframe: Up to Week 35

Population: The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.

Number of participants with TEAEs of special interest were reported. It included significant TEAEs that were judged to be of special interest because of clinical importance, known or suspected class effects, or based on nonclinical signals. Events such as sedation, depersonalization/derealization disorder, depression suicidal, aggression, allergic cystitis, cholestasis and jaundice of hepatic origin, and many more were considered as TEAEs of special interest.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=334 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=336 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Number of Participants With TEAEs of Special Interest	223 Participants	140 Participants

SECONDARY outcome

Timeframe: Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32

Population: The safety analysis set included all randomized participants who received at least 1 dose of any study intervention. Here, 'N' (number of participants analyzed) signifies participants evaluable for this outcome measure. Here, 'n' (number analyzed) signifies participants evaluable for this outcome measure at specified time points.

Number of participants with suicidal ideation or behavior as assessed by C-SSRS score was reported. The C-SSRS is an assessment tool that evaluates suicidal ideation and behavior. Suicidal ideation consists of 5 items: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intention to act, active suicidal ideation with some intent to act without specific plan, and active suicidal ideation with specific plan and intent. Suicidal behavior consists of 5 items: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt (non-fatal), and completed suicide. The maximum score (from the 10 categories) assigned for each participant was summarized into one of three broad categories: No suicidal ideation or behavior (0), Suicidal ideation (1 - 5), Suicidal behavior (6 - 10). Total score ranges from 1 to 10. Higher scores indicate more severe suicidal ideation and behavior.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=317 Participants Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=295 Participants Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 1	22 Participants	25 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 2	21 Participants	32 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 2	0 Participants	1 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 3	19 Participants	17 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 3	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 4	22 Participants	27 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 4	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 8	21 Participants	18 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 8	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 12	13 Participants	14 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 12	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 16	12 Participants	12 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 16	1 Participants	1 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 20	15 Participants	14 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 20	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 24	14 Participants	9 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 24	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 28	8 Participants	5 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 28	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Ideation Week 32	7 Participants	4 Participants
Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Suicidal Behavior Week 32	0 Participants	1 Participants

Adverse Events

Esketamine Nasal Spray + Oral Antidepressant (AD)

Serious events: 19 serious events

Other events: 289 other events

Deaths: 1 deaths

Quetiapine Extended Release (XR) + Oral AD

Serious events: 17 serious events

Other events: 216 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Europe, Middle East, Africa (EMEA) Medical Advisor Spravato

Janssen-Cilag International NV

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days to allow for filing of a patent application.
Publication restrictions are in place

Restriction type: OTHER

Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=334 participants at risk Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=336 participants at risk Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Blood and lymphatic system disorders Lymphadenopathy mediastinal	0.00% 0/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Cardiac disorders Acute coronary syndrome	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Cardiac disorders Atrial fibrillation	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Eye disorders Retinal detachment	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Gastrointestinal disorders Abdominal pain	0.00% 0/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Gastrointestinal disorders Pancreatitis	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
General disorders Death	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Infections and infestations Bronchitis	0.00% 0/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Infections and infestations COVID-19	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Infections and infestations Cystitis	0.00% 0/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Infections and infestations Pilonidal disease	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Injury, poisoning and procedural complications Tendon rupture	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Nervous system disorders Cerebrovascular accident	0.00% 0/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Nervous system disorders Dizziness	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Nervous system disorders Generalised tonic-clonic seizure	0.00% 0/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Psychiatric disorders Alcoholism	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Psychiatric disorders Anxiety	0.00% 0/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.60% 2/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Psychiatric disorders Conversion disorder	0.00% 0/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Psychiatric disorders Depression	0.60% 2/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.89% 3/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Psychiatric disorders Major depression	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Psychiatric disorders Somatic symptom disorder	0.60% 2/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Psychiatric disorders Suicidal ideation	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.89% 3/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Psychiatric disorders Suicide attempt	0.60% 2/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Renal and urinary disorders Nephrolithiasis	0.30% 1/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.00% 0/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Respiratory, thoracic and mediastinal disorders Nasal turbinate hypertrophy	0.00% 0/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.

Measure	Esketamine Nasal Spray + Oral Antidepressant (AD) n=334 participants at risk Participants received treatment with esketamine nasal spray (28 milligrams \[mg\] \[initial dose for elderly participants aged 65 to 74 years and adults of Japanese ancestry\], 56 mg \[initial dose for adult participants aged 18 to 64 years\], or 84 mg \[maximum dose esketamine nasal spray\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Quetiapine Extended Release (XR) + Oral AD n=336 participants at risk Participants continued to take their current SSRI/SNRI augmented with quetiapine XR as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable) at an initial dose of 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 (lowest effective dose) in adult participants aged 18 to 64 years; a further dose increase to 300 mg/day on Day 5 and onward were based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose was 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day were based on individual participant evaluation no earlier than Day 22.
Ear and labyrinth disorders Vertigo	18.9% 63/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.89% 3/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Eye disorders Vision blurred	6.3% 21/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.89% 3/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Gastrointestinal disorders Dry mouth	0.90% 3/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	6.5% 22/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Gastrointestinal disorders Nausea	29.3% 98/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	3.6% 12/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Gastrointestinal disorders Vomiting	10.8% 36/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	1.5% 5/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
General disorders Fatigue	5.7% 19/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	10.1% 34/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Infections and infestations COVID-19	7.2% 24/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	8.6% 29/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Infections and infestations Nasopharyngitis	6.3% 21/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	3.3% 11/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Investigations Blood pressure increased	8.4% 28/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	1.2% 4/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Investigations Weight increased	2.7% 9/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	12.5% 42/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Musculoskeletal and connective tissue disorders Back pain	5.1% 17/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	2.7% 9/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Nervous system disorders Dizziness	46.7% 156/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	8.3% 28/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Nervous system disorders Dysgeusia	12.0% 40/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Nervous system disorders Headache	24.6% 82/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	12.8% 43/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Nervous system disorders Hypoaesthesia	5.7% 19/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Nervous system disorders Paraesthesia	11.1% 37/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.60% 2/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Nervous system disorders Sedation	6.6% 22/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	8.6% 29/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Nervous system disorders Somnolence	15.0% 50/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	23.2% 78/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Psychiatric disorders Confusional state	6.0% 20/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.30% 1/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.
Psychiatric disorders Dissociation	28.1% 94/334 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.	0.60% 2/336 • All-cause mortality and serious adverse events: until 30 days after last dose (up to Week 35); other AEs: until 14 days after last dose (up to Week 33) The safety analysis set included all randomized participants who received at least 1 dose of any study intervention.