In the double-blind (DB) phase, participants received placebo nasal spray (matching to esketamine) twice a week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25. After completion of the DB phase (including Day 28 visit), participants opted to enter the open-label (OL) phase (treatment/observation phase). Participants who opted OL treatment phase received esketamine 56 milligrams (mg) nasal spray on Day 28 regardless of the treatment assignment in the DB phase and received subsequent doses at the same or adjusted (56 mg or 84 mg) dose level based on efficacy and tolerability with dosing frequency: twice weekly from Weeks 5 to 8 followed by once weekly from Weeks 9 to 12 and then weekly or every other week from Weeks 13 to 16 based on clinical judgment and was individualized to the least frequent dosing to maintain remission/response. During this period participants were given the option to receive standard-of-care treatment for depression. Participants who opted OL observation phase were only observed without esketamine nasal spray treatment but received standard-of-care treatment for depression. All participants underwent 1-week follow-up phase for safety assessment after their last dose of study treatment in DB or OL treatment phase.

In the DB phase, participants received esketamine 56 mg nasal spray twice a week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25. After completion of the DB phase (including Day 28 visit), participants opted to enter the OL phase (treatment/observation phase). Participants who opted OL treatment phase received esketamine 56 mg nasal spray on Day 28 regardless of the treatment assignment in the DB phase and received subsequent doses at the same or adjusted (56 mg or 84 mg) dose level based on efficacy and tolerability with dosing frequency: twice weekly from Weeks 5 to 8 followed by once weekly from Weeks 9 to 12 and then weekly or every other week from Weeks 13 to 16 based on clinical judgment and was individualized to the least frequent dosing to maintain remission/response. During this period participants were given the option to receive standard-of-care treatment for depression. Participants who opted OL observation phase were only observed without esketamine nasal spray treatment but received standard-of-care treatment for depression. All participants underwent 1-week follow-up phase for safety assessment after their last dose of study treatment in DB or OL treatment phase.

In the DB phase, participants received esketamine 84 mg nasal spray twice a week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25. After completion of the DB phase (including Day 28 visit), participants opted to enter the OL phase (treatment/observation phase). Participants who opted OL treatment phase received esketamine 56 mg nasal spray on Day 28 regardless of the treatment assignment in the DB phase and received subsequent doses at the same or adjusted (56 mg or 84 mg) dose level based on efficacy and tolerability with dosing frequency: twice weekly from Weeks 5 to 8 followed by once weekly from Weeks 9 to 12 and then weekly or every other week from Weeks 13 to 16 based on clinical judgment and was individualized to the least frequent dosing to maintain remission/response. During this period participants were given the option to receive standard-of-care treatment for depression. Participants who opted OL observation phase were only observed without esketamine nasal spray treatment but received standard-of-care treatment for depression. All participants underwent 1-week follow-up phase for safety assessment after their last dose of study treatment in DB or OL treatment phase.

Total of all reporting groups

In the double-blind (DB) phase, participants received placebo nasal spray (matching to esketamine) twice a week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25.

In the DB phase, participants received esketamine 56 mg nasal spray twice a week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25.

In the DB phase, participants received esketamine 84 mg nasal spray twice a week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25.

Participants who received placebo in DB phase were given a choice either to receive esketamine nasal spray treatment or were observed only without nasal spray treatment. Participants who opted OL treatment phase received esketamine 56 mg nasal spray on Day 28 regardless of the treatment assignment in the DB phase and received subsequent doses at the same or adjusted (56 mg or 84 mg) dose level based on efficacy and tolerability with dosing frequency: twice weekly from Weeks 5 to 8 followed by once weekly from Weeks 9 to 12 and then weekly or every other week from Weeks 13 to 16 based on clinical judgment and was individualized to the least frequent dosing to maintain remission/response. During this period participants were given the option to receive standard-of-care treatment for depression. As planned, OL phase adverse events analysis was performed by treatment groups assigned in the DB phase, irrespective of the OL phase adjusted doses.

Participants who received esketamine 56 mg in DB phase were given a choice either to receive esketamine nasal spray treatment or were observed only without nasal spray treatment. Participants who opted OL treatment phase received esketamine 56 mg nasal spray on Day 28 regardless of the treatment assignment in the DB phase and received subsequent doses at the same or adjusted (56 mg or 84 mg) dose level based on efficacy and tolerability with dosing frequency: twice weekly from Weeks 5 to 8 followed by once weekly from Weeks 9 to 12 and then weekly or every other week from Weeks 13 to 16 based on clinical judgment and was individualized to the least frequent dosing to maintain remission/response. During this period participants were given the option to receive standard-of-care treatment for depression. As planned, OL phase adverse events analysis was performed by treatment groups assigned in the DB phase, irrespective of the OL phase adjusted doses.

Participants who received esketamine 84 mg in DB phase were given a choice either to receive esketamine nasal spray treatment or were observed only without nasal spray treatment. Participants who opted OL treatment phase received esketamine 56 mg nasal spray on Day 28 regardless of the treatment assignment in the DB phase and received subsequent doses at the same or adjusted (56 mg or 84 mg) dose level based on efficacy and tolerability with dosing frequency: twice weekly from Weeks 5 to 8 followed by once weekly from Weeks 9 to 12 and then weekly or every other week from Weeks 13 to 16 based on clinical judgment and was individualized to the least frequent dosing to maintain remission/response. During this period participants were given the option to receive standard-of-care treatment for depression. As planned, OL phase adverse events analysis was performed by treatment groups assigned in the DB phase, irrespective of the OL phase adjusted doses.

After completion of DB treatment phase, participants who opted OL observation phase were only observed without esketamine nasal spray treatment but received standard-of-care treatment for depression.

Participants who received at least 1 dose of study treatment in the DB or OL treatment phase entered into 1- week follow-up phase after their last dose of study treatment.