A Study of Esketamine Nasal Spray Versus Placebo Spray in Adult Participants With Treatment-resistant Depression

DB Treatment Phase: Change From Baseline in MADRS Total Score From Day 1 to Day 2

The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Baseline (Day 1 [prerandomization]) up to Day 2 (approximately 24 hours after the first dose)

DB Treatment Phase: Percentage of Responders in MADRS Over Time to the End of the 4-Week DB Treatment Phase

Percentage of responders (greater than or equal to \[\>=\] 50 percent \[%\] reduction from baseline in MADRS total score) over time to the end of the 4-week DB treatment phase will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Up to end of the 4-Week DB treatment phase (Day 28)

DB Treatment Phase: Percentage of Participants in Remission in MADRS Over Time to the End of the 4-Week DB Treatment Phase

Percentage of participants in remission (MADRS less than or equal to \[\<=\] 10 and MADRS \<= 12) over time to the end of the 4-week DB treatment phase will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Up to end of the 4-Week DB treatment phase (Day 28)

DB Treatment Phase: Change From Baseline in Clinical Global Impression-Severity (CGI-S) Over Time to the End of the 4-Week DB Treatment Phase

Change from baseline in CGI-S over time to the end of the 4-week DB treatment phase will be reported. The CGI-S is a clinician-rated scale that measures illness severity. The CGI has proved to be a robust measure of efficacy in many clinical drug trials and is easy and quick to administer. The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (among the most severely ill participants).

Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)

DB Treatment Phase: Change From Baseline in MADRS Total Score Over Time to the End of the 4-Week DB Treatment Phase

Change from baseline in MADRS total score over time to the end of the 4-week DB treatment phase will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)

DB Treatment Phase: Change From Baseline in Individual MADRS Item Scores Over Time to the End of the 4-Week DB Treatment Phase

Change from baseline in individual MADRS item scores over time to the end of the 4-week DB treatment phase will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)

DB Treatment Phase: Change From Baseline in Anhedonia Symptoms Over Time to the End of the 4-Week DB Treatment Phase As Assessed by MADRS Anhedonia Factor Score

Change from baseline in anhedonia symptoms over time to the end of the 4-week DB treatment phase as assessed by MADRS anhedonia factor score will be reported. The MADRS anhedonia factor is a widely used 5-item subscale of the MADRS used to specifically measure the lack of pleasure (anhedonia) in depression, combining items for apparent sadness, reported sadness, concentration difficulties, lassitude (tiredness), and inability to feel. The sum of these five items (each scored 0-6), resulting in a score from 0 to 30, with higher scores indicating more severe anhedonia. This score helps assess treatment effectiveness for anhedonia, correlates with functional improvement, and provides a deeper look beyond the total depression score, showing significant clinical relevance in major depressive disorder (MDD) trials.

Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)

DB Treatment Phase: Change From Baseline in Patient-Reported Anhedonia Symptoms Over Time to the End of the 4-Week DB Treatment Phase As Assessed by Patient Health Questionnaire 9-item (PHQ-9) Item 1 Score

Change from baseline in patient-reported anhedonia symptoms over time to the end of the 4-week DB treatment phase as assessed by PHQ-9 item 1 score (little interest/pleasure in things) will be reported. The PHQ-9 is a participant-reported outcome measure that will be used to assess depressive symptoms. The scale scores each of the 9 symptom domains of the diagnostic and statistical manual of mental disorders (5th edition) (DSM-5) MDD criteria and it has been used both as a screening tool and a measure of response to treatment for depression. 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).

Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)

DB Treatment Phase: Change From Baseline in PHQ-9 Total Score Over Time to the End of the 4-Week DB Treatment Phase

Change from baseline in PHQ-9 total score over time to the end of the 4-week DB treatment phase will be reported. The PHQ-9 is a participant-reported outcome measure that will be used to assess depressive symptoms. The scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and it has been used both as a screening tool and a measure of response to treatment for depression. 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.

Time frame: Baseline up to end of the 4-Week DB treatment phase (Day 28)

DB Treatment Phase: Percentage of Responders in PHQ-9 Over Time to the End of the 4-Week DB Treatment Phase

Percentage of responders (\>= 50% reduction from baseline in PHQ-9 total score) over time to the end of the 4-week DB treatment phase will be reported. The PHQ-9 is a participant-reported outcome measure that will be used to assess depressive symptoms. The scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and it has been used both as a screening tool and a measure of response to treatment for depression. 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.

Time frame: Up to end of the 4-Week DB treatment phase (Day 28)

DB Treatment Phase: Percentage of Participants in Remission in PHQ-9 Over Time to the End of the 4-Week DB Treatment Phase

Percentage of participants in remission (PHQ-9 total score \< 5) over time to the end of the 4-week DB treatment phase will be reported. The PHQ-9 is a participant-reported outcome measure that will be used to assess depressive symptoms. The scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and it has been used both as a screening tool and a measure of response to treatment for depression. 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.

Time frame: Up to end of the 4-Week DB treatment phase (Day 28)

Open-Label (OL) Treatment Phase: Percentage of Responders in MADRS Over Time to the End of the OL Treatment Phase

Percentage of responders (\>= 50% reduction from baseline in MADRS total score) over time to the end of the OL treatment phase will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Up to 12 Weeks

OL Treatment Phase: Percentage of Participants in Remission in MADRS Over Time to the End of the OL Treatment Phase

Percentage of participants in remission (MADRS \<= 10 and MADRS \<= 12) over time to the end of the OL treatment phase will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Up to 12 Weeks

OL Treatment Phase: Change From Baseline in CGI-S Over Time to the End of the OL Treatment Phase

Change from baseline in CGI-S over time to the end of the OL treatment phase will be reported. The CGI-S is a clinician-rated scale that measures illness severity. The CGI has proved to be a robust measure of efficacy in many clinical drug trials and is easy and quick to administer. The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (among the most severely ill participants).

Time frame: Baseline (Day 28) up to 12 Weeks

OL Treatment Phase: Change From Baseline in MADRS Total Score Over Time to the End of the OL Treatment Phase

Change from baseline in MADRS total score over time to the end of the OL treatment phase will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Baseline (Day 28) up to 12 Weeks

OL Treatment Phase: Change From Baseline in Individual MADRS Item Scores Over Time to the End of the OL Treatment Phase

Change from baseline in individual MADRS item scores over time to the end of the OL treatment phase will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Baseline (Day 28) up to 12 Weeks

OL Treatment Phase: Change From Baseline in Anhedonia Symptoms Over Time to the End of the OL Treatment Phase As Assessed by MADRS Anhedonia Factor Score

Change from baseline in anhedonia symptoms over time to the end of the OL treatment phase as assessed by MADRS anhedonia factor score will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Baseline (Day 28) up to 12 Weeks

OL Treatment Phase: Change From Baseline in Patient-Reported Anhedonia Symptoms Over Time to the End of the OL Treatment Phase As Assessed by PHQ-9 Item 1 Score

Change from baseline in patient-reported anhedonia symptoms over time to the end of the OL treatment phase as assessed by PHQ-9 item 1 score will be reported. The PHQ-9 is a participant-reported outcome measure that will be used to assess depressive symptoms. The scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and it has been used both as a screening tool and a measure of response to treatment for depression. 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.

Time frame: Baseline (Day 28) up to 12 Weeks

OL Treatment Phase: Change From Baseline in PHQ-9 Total Score Over Time to the End of the OL Treatment Phase

Change from baseline in PHQ-9 total score over time to the end of the OL treatment phase will be reported. The PHQ-9 is a participant-reported outcome measure that will be used to assess depressive symptoms. The scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and it has been used both as a screening tool and a measure of response to treatment for depression. 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.

Time frame: Baseline (Day 28) up to 12 Weeks

OL Treatment Phase: Percentage of Responders in PHQ-9 Over Time to the End of the OL Treatment Phase

Percentage of responders (\>= 50% reduction from baseline in PHQ-9 total score) over time to the end of the OL treatment phase will be reported. The PHQ-9 is a participant-reported outcome measure that will be used to assess depressive symptoms. The scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and it has been used both as a screening tool and a measure of response to treatment for depression. 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.

Time frame: Up to 12 Weeks

OL Treatment Phase: Percentage of Participants in Remission in PHQ-9 Over Time to the End of the OL Treatment Phase

Percentage of participants in remission (PHQ-9 total score \< 5) over time to the end of the OL treatment phase will be reported. The PHQ-9 is a participant-reported outcome measure that will be used to assess depressive symptoms. The scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and it has been used both as a screening tool and a measure of response to treatment for depression. 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.

Time frame: Up to 12 Weeks