Participants will self-administer 84 mg of esketamine as intranasal spray.

Participants will self-administer matching placebo as intranasal spray.

Duloxetine can be selected as the oral antidepressant medication based on investigator's discretion. The minimum therapeutic dose is 60 milligram per day (mg/day).

Escitalopram can be selected as the oral antidepressant medication based on investigator's discretion. Escitalopram will be started at a dose of 10 mg/day and up-titrated to a maximum dose of 20 mg/day.

Sertraline can be selected as the oral antidepressant medication based on investigator's discretion. Sertraline will be started at a dose of 50 mg/day and up-titrated to a maximum dose of 200 mg/day.

Venlafaxine XR can be selected as the oral antidepressant medication based on investigator's discretion. Venlafaxine XR will be started at a dose of 75 mg/day and up-titrated to a maximum dose of 225 mg/day.

The SDS is a subject-reported outcome measure that consists of a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items are summed to create a total score of 0-30, where a higher score indicates greater impairment. It also has one item on days lost from school or work and one item on days when underproductive.

Onset of clinical response is defined as greater than or equal to (>=) 50 percent (%) improvement from baseline in MADRS total score with onset by Day 2 that was maintained through Day 28. The MADRS scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

Percentage of responders at the end of double-blind treatment phase (Day 28) were assessed. A participant was defined as a responder at a given time point if the percent improvement from baseline in MADRS total score is at least 50%. The MADRS scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

Percentage of participants in remission at the end of double-blind treatment phase (Day 28) were assessed. A participant was considered as a remitter if participant had a MADRS total score of less than or equal to [<=] 12 at a visit. MADRS scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

Sustained remission is defined as the first occurrence of remission (MADRS Total score <=12) that was maintained through the Day 28 assessment with one excursion prior to Day 28. The MADRS scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

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 patients. The CGI-S permits a global evaluation of the participant's condition at a given time. Negative change in score indicates improvement. The last post-baseline observation during the double-blind phase was carried forward as Endpoint.

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

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 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 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a HSI. Health Status Index ranges from -0.148 to 0.949, and is anchored at 0 (dead) and 1 (full health), a lower score indicates worse health.

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.

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

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.

Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.