Participants in Panel A will self-administer intranasal esketamine 84 mg or placebo on Days 1, 4, 8, and 11 during the double-blind phase and intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60, and 74 during the optional open-label phase. During the optional open-label phase, all participants will start treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine can be adjusted if desired based on the Investigator's clinical judgment of efficacy and tolerability).

Participants in Panel A and B will self-administer intranasal placebo on Days 1 and 4 during the double-blind phase. Depending on response on Day 8, participants will receive intranasal placebo on Days 8 and 11 or be re-randomized to receive intranasal placebo or esketamine at a dose of 28 mg, 56 mg, or 84 mg (Panel A) or 14 mg or 56 mg (Panel B) on Day 8 and Day 11.

1 to 6 sprays of esketamine 28 mg self-administered as an intranasal formulation for 4 days (Days 1,4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days

1 to 6 sprays of esketamine 56 mg self-administered as an intranasal formulation for up to 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days

1 to 6 sprays of esketamine 84 mg self-administered as an intranasal formulation for up to 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days

1 to 6 sprays of placebo self-administered as an intranasal formulation for 2 days (Days 1 and 4) or depending on response on Day 8, for 4 days (Days 1,4, 8, 11) during the double-blind phase

Sustained response was defined as at least 50 percent (%) improvement from baseline in the MADRS total score with onset by Day 2 that is maintained to study Day 15. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.

A participant is defined a responder at a given time point if the percent improvement in MADRS is greater than or equal to (>=) 50%. Participant who do not meet such criterion, worsen or discontinue during the DB phase for any reason was considered as non-responders, that is, was assigned a value of 0. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.

A participant is defined a responder at a given time point if the percent improvement in MADRS is >=50%. Participant who do not meet such criterion, worsen or discontinue during the DB phase for any reason was considered as non-responders, that is, was assigned a value of 0. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.

Participants who had a MADRS total score of <=10 were considered remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.

Participants who had a MADRS total score of less than or equal to (<=10) were considered remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. A negative change in score indicates improvement.

QIDS-SR16 is self-rated scale assesses severity of depressive symptoms. Total scores range from 0-27. Higher score indicates greater severity of depression. Negative change in score indicates improvement. Total score obtained by adding scores for each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders-4th edition major depressive disorder (DSM-IV MDD) criteria: depressed mood, loss of interest/pleasure, concentration/decision making, self-outlook, suicidal ideation, energy/fatigability, sleep, weight/appetite change, psychomotor changes. 16 items used to rate 9 criterion domains: 4 items used to rate sleep disturbance (early/middle/late insomnia/hypersomnia); 2 items used to rate psychomotor disturbance (agitation, retardation); 4 items used to rate appetite/weight disturbance. 1 item used to rate 6 domains (depressed mood, decreased interest, decreased energy, worthlessness/guilt, concentration/decision making, suicidal ideation). Each item was rated 0-3.

QIDS-SR16 is self-rated scale assesses severity of depressive symptoms. Total scores range from 0-27. Higher score indicates greater severity of depression. Negative change in score indicates improvement. Total score obtained by adding scores for each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders-4th edition major depressive disorder (DSM-IV MDD) criteria: depressed mood, loss of interest/pleasure, concentration/decision making, self-outlook, suicidal ideation, energy/fatigability, sleep, weight/appetite change, psychomotor changes. 16 items used to rate 9 criterion domains: 4 items used to rate sleep disturbance (early/middle/late insomnia/hypersomnia); 2 items used to rate psychomotor disturbance (agitation, retardation); 4 items used to rate appetite/weight disturbance. 1 item used to rate 6 domains (depressed mood, decreased interest, decreased energy, worthlessness/guilt, concentration/decision making, suicidal ideation). Each item was rated 0-3.

CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. CGI-S permits global evaluation of participant's condition at given time. A negative change in score indicates improvement.

CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. CGI-S permits global evaluation of participant's condition at given time. A negative change in score indicates improvement.

GAD-7 is a brief and validated 7-item self-report 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).

GAD-7 is a brief and validated 7-item self-report 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).

PGI-S is a patient-rated scale that assesses the severity of their illness at the time of assessment, relative to participants past experience. It is a 4-point (1 to 4) scale in response to the question 'Considering all aspects of your depression right now would you say your depression is?' with scores as follows: 1: none; 2: mild; 3: moderate; 4: severe. A higher score implies a more severe condition.

PGI-S is a patient-rated scale that assesses the severity of their illness at the time of assessment, relative to participants past experience. It is a 4-point (1 to 4) scale in response to the question 'Considering all aspects of your depression right now would you say your depression is?' with scores as follows: 1: none; 2: mild; 3: moderate; 4: severe. A higher score implies a more severe condition. A negative change in score indicates improvement.

Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1 in Panel A.

Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1 in Panel A.

Participants self administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1 in Panel B.

Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1 in Panel B.

Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1 in Panel B.

Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score greater than or equal to [>=] 11) were re-randomized to receive Placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.

Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel A continued to receive placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.

Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were re-randomized to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2.

Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were re-randomized to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2.

Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were re-randomized to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.

Participants who received esketamine 28 mg in Period 1 of Panel A continued to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2.

Participants who received esketamine 56 mg in Period 1 of Panel A continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2.

Participants who received esketamine 84 mg in Period 1 of Panel A continued to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.

Participants who were non-responders with QIDS-SR16 score >=11 at the end of Period 1 were re-randomized to receive placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes using 4 separate devices) on Days 8 and 11 of Period 2 in Panel B.

Participants who were responders with QIDS-SR16 score <11 at the end of Period 1 continued to receive placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes using 4 separate devices) on Days 8 and 11 in Period 2.

Participants who received placebo in Period 1 and were non-responders with QIDS-SR16 score >=11 at the end of Period 1 were re-randomized to receive esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo in other nostril at 0 minute and 1 spray of placebo in each nostril at 5 minutes using 4 separate devices) on Days 8 and 11 in Period 2.

Participants who received placebo in Period 1 and were non-responders (with QIDS-SR16 score >=11) at the end of Period 1 in Panel B were re-randomized to receive esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2.

Participants who received esketamine 14 mg in Period 1 of Panel B continued to receive esketamine 14 mg (1 spray of esketamine 14 mg to one nostril and 1 spray of placebo into other nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 in Period 2.

Participants who received esketamine 56 mg in Period 1 of Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2.

Participants who received Placebo in Period 1 and 2 of Panel A and elected to continue with open label phase received up to 9 single doses of intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60 and 74. The doses for the optional open-label treatment phase included 28, 56, and 84 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22, 25, 32, 39, and 46 could be adjusted to the next lower or higher dose, based on the investigator's clinical judgment. The same dose administered on Day 46 was administered on Day 60 and Day 74.

Participants who received Placebo in Period 1 and esketamine in Period 2 of Panel A and elected to continue with open label phase received up to 9 single doses of intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60 and 74. The doses for the optional open-label treatment phase included 28, 56, and 84 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22, 25, 32, 39, and 46 could be adjusted to the next lower or higher dose, based on the investigator's clinical judgment. The same dose administered on Day 46 was administered on Day 60 and Day 74.

Participants who received esketamine in Period 1 and 2 of Panel A and elected to continue with open label phase received up to 9 single doses of intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60 and 74. The doses for the optional open-label treatment phase included 28, 56, and 84 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22, 25, 32, 39, and 46 could be adjusted to the next lower or higher dose, based on the investigator's clinical judgment. The same dose administered on Day 46 was administered on Day 60 and Day 74.

Participants who received Placebo in Period 1 and 2 of Panel A and elected to continue with open label phase received up to 4 single doses of intranasal esketamine on Days 15, 18, 22 and 25. The doses for the optional open-label treatment phase included 14, 28 and 56 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22 and 25 could be adjusted to the next lower or higher dose, based on the investigator's clinical judgment.

Participants who received Placebo in Period 1 and esketamine in Period 2 of Panel A and elected to continue with open label phase received up to 4 single doses of intranasal esketamine on Days 15, 18, 22 and 25. The doses for the optional open-label treatment phase included 14, 28 and 56 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22 and 25 could be adjusted to the next lower or higher dose, based on the investigator's clinical judgment.

Participants who received esketamine in Period 1 and 2 of Panel A and elected to continue with open label phase received up to 4 single doses of intranasal esketamine on Days 15, 18, 22 and 25. The doses for the optional open-label treatment phase included 14, 28 and 56 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22 and 25 could be adjusted to the next lower or higher dose, based on the investigator's clinical judgment.

All participants whose last dose was Placebo in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks.

All participants whose last dose was esketamine 14 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks.

All participants whose last dose was esketamine 28 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks.

All participants whose last dose was esketamine 56 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks.

All participants whose last dose was esketamine 84 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks.