In the double blind (DB) phase, participants received 3 intranasal doses of placebo (matched to esketamine nasal spray) using 3 devces, each device at time points 0, 5 and 10 minutes (min) respectively. For each device, 1 spray was administered into each nostril (that is total of 2 sprays/device). An oral solution of midazolam 0.125 milligrams per kilogram (mg/kg) was administered immediately before the first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During the study, all participants were treated with Standard of care (SOC): antidepressant treatment (either fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated, or optimized on Day 1 or up to 7 days after first dose of study drug administration (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB treatment phase, participants entered post-treatment follow-up (FU) phase and received no study drug.

In DB phase, participants received 1 intranasal dose of esketamine 28 mg nasal spray using a device, at 0 min, followed by 2 intranasal doses of placebo (matched to esketamine) using 2 devices, 1 at 5 min and another at 10 min, respectively. For each device, 1 spray (esketamine 14 mg/placebo) was administered into each nostril (that is total of 2 sprays = esketamine 28 mg/placebo). Placebo oral solution (matched to midazolam 0.125 mg/kg) was administered immediately before first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During study, all participants received SOC: antidepressant treatment (fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after first dose (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB phase, participants entered post-treatment FU phase and received no study drug.

In DB phase, participants received 2 intranasal doses of esketamine 56 mg nasal spray using 2 devices, 1 at 0 min and another at 5 min, followed by 1 intranasal dose of placebo (matched to esketamine) using 1 device at 10 min. For each device, 1 spray (esketamine 14 mg/placebo) was administered into each nostril (that is total of 2 sprays = esketamine 28 mg/placebo). Placebo oral solution (matched to midazolam 0.125 mg/kg) was administered immediately before first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During study, all participants received SOC: antidepressant treatment (fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after first dose (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB phase, participants entered post-treatment FU phase and received no study drug.

In DB phase, participants received 3 intranasal doses of esketamine 84 mg nasal spray using 3 devices, each device at 0, 5 and 10 min, respectively. For each device, 1 spray (esketamine 14 mg/placebo) was administered into each nostril (that is total of 2 sprays = esketamine 28 mg/placebo). Placebo oral solution (matched to midazolam 0.125 mg/kg) was administered immediately before first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During study, all participants received SOC: antidepressant treatment (fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after first dose (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB phase, participants entered post-treatment FU phase and received no study drug.

Total of all reporting groups

In the double blind (DB) phase, participants received 3 intranasal doses of placebo (matched to esketamine nasal spray) using 3 devces, each device at time points 0, 5 and 10 minutes (min) respectively. For each device, 1 spray was administered into each nostril (that is total of 2 sprays/device). An oral solution of midazolam 0.125 milligrams per kilogram (mg/kg) was administered immediately before the first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During the study, all participants were treated with Standard of care (SOC): antidepressant treatment (either fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated, or optimized on Day 1 or up to 7 days after first dose of study drug administration (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB treatment phase, participants entered post-treatment FU phase and received no study drug.

In DB phase, participants received 1 intranasal dose of esketamine 28 mg nasal spray using a device, at 0 min, followed by 2 intranasal doses of placebo (matched to esketamine) using 2 devices, 1 at 5 min and another at 10 min, respectively. For each device, 1 spray (esketamine 14 mg/placebo) was administered into each nostril (that is total of 2 sprays = esketamine 28 mg/placebo). Placebo oral solution (matched to midazolam 0.125 mg/kg) was administered immediately before first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During study, all participants received SOC: antidepressant treatment (fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after first dose (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB phase, participants entered post-treatment FU phase and received no study drug.

In DB phase, participants received 2 intranasal doses of esketamine 56 mg nasal spray using 2 devices, 1 at 0 min and another at 5 min, followed by 1 intranasal dose of placebo (matched to esketamine) using 1 device at 10 min. For each device, 1 spray (esketamine 14 mg/placebo) was administered into each nostril (that is total of 2 sprays = esketamine 28 mg/placebo). Placebo oral solution (matched to midazolam 0.125 mg/kg) was administered immediately before first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During study, all participants received SOC:antidepressant treatment (fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after first dose (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB phase, participants entered post-treatment FU phase and received no study drug.

In DB phase, participants received 3 intranasal doses of esketamine 84 mg nasal spray using 3 devices, each device at time points 0, 5 and 10 minutes respectively. For each device, 1 spray (esketamine 14 mg/placebo) was administered into each nostril (that is total of 2 sprays = esketamine 28 mg/placebo). Placebo oral solution (matched to midazolam 0.125 mg/kg) was administered immediately before first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During study, all participants received SOC:antidepressant treatment (fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after first dose (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB phase, participants entered post-treatment FU phase and received no study drug.

After completion of DB treatment phase, participants entered post-treatment follow-up phase and received no study drug. During the study, all participants were treated with SOC: antidepressant treatment (either fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after 1st dose of study drug administration (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy.

After completion of DB treatment phase, participants entered post-treatment follow-up phase and received no study drug. During the study, all participants were treated with SOC: antidepressant treatment (either fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after 1st dose of study drug administration (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy.

After completion of DB treatment phase, participants entered post-treatment follow-up phase and received no study drug. During the study, all participants were treated with SOC: antidepressant treatment (either fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after 1st dose of study drug administration (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy.).

After completion of DB treatment phase, participants entered post-treatment follow-up phase and received no study drug. During the study, all participants were treated with SOC: antidepressant treatment (either fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after 1st dose of study drug administration (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy.