A Study to Evaluate the Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression

Inclusion Criteria:

- At the start of the screening/prospective observational phase, participant must meet
the Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5)
diagnostic criteria for recurrent major depressive disorder (MDD) or single-episode
MDD (if single-episode MDD, the duration must be greater than or equal to [>=] 2
years), without psychotic features, based upon clinical assessment and confirmed by
the Mini-International Neuropsychiatric Interview (mental status questionnaire) (MINI)

- At the start of the screening/prospective observational phase, participant must have
had non-response (less than or equal to [<=] 25 percent [%] improvement) to >=1 but
<=5 (if current episode is greater than (>) 2 years or not definable, upper limit is
applicable to only the last 2 years) oral antidepressant treatments in the current
episode of depression, assessed using the Massachusetts General Hospital -
Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and confirmed by documented
records (for example, medical/ pharmacy/prescription records or letter from a treating
physician). In addition, the participant is taking a different oral antidepressant
treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum
therapeutic dose

- The participant's current major depressive episode, depression symptom severity (Week
1 Montgomery-Asberg Depression Rating Scale [MADRS] total score >=28 required), and
antidepressant treatment response in the current depressive episode, must be confirmed
using a Site Independent Qualification Assessment

- Participant must be medically stable on the basis of physical examination, medical
history, vital signs (including blood pressure), pulse oximetry, and 12-lead
electrocardiogram (ECG) performed in the screening/prospective observational phase. If
there are any abnormalities that are not specified in the inclusion and exclusion
criteria, they must be consistent with the underlying illness in the study population.
This determination must be recorded in the participant's source documents and
initialed or signed by the investigator

- Participant must be medically stable on the basis of clinical laboratory tests
performed in the screening/prospective observational phase. If the results of the
serum chemistry panel, hematology, or urinalysis are outside the normal reference
ranges, the participant may be included only if the investigator judges the
abnormalities or deviations from normal to be not clinically significant or to be
appropriate and reasonable for the population under study. This determination must be
recorded in the participant's source documents and initialed or signed by the
investigator

Exclusion Criteria:

- The participant's depressive symptoms have previously demonstrated non-response to:

1. Esketamine or ketamine in the current major depressive episode per clinical
judgment, or

2. All of the oral antidepressant treatment options available in the respective
country for the double-blind phase (that is, duloxetine, escitalopram,
sertraline, and venlafaxine XR) in the current major depressive episode (based on
MGH-ATRQ), or

3. An adequate course of treatment with electroconvulsive therapy (ECT) in the
current major depressive episode, defined as at least 7 treatments with
unilateral/bilateral ECT

- Participant has received vagal nerve stimulation (VNS) or has received deep brain
stimulation (DBS) in the current episode of depression

- Participant has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with
psychotic features, bipolar or related disorders (confirmed by the MINI), obsessive
compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes
315.8, 317, 318.0, 318.1, 318.2 and 319), autism spectrum disorder, borderline
personality disorder, antisocial personality disorder, histrionic personality
disorder, or narcissistic personality disorder

- Participant has homicidal ideation/intent, per the investigator's clinical judgment,
or has suicidal ideation with some intent to act within 6 months prior to the start of
the screening/prospective observational phase, per the investigator's clinical
judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS),
corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some
intent to act, without specific plan) or Item 5 (active suicidal ideation with
specific plan and intent) for suicidal ideation on the C-SSRS, or a history of
suicidal behavior within the past year prior to the start of the screening/prospective
observational phase. Participants reporting suicidal ideation with intent to act or
suicidal behavior prior to the start of the double-blind treatment phase should be
excluded

- Participant has a history of moderate or severe substance or alcohol use disorder
according to DSM-5 criteria, except nicotine or caffeine, within 6 months before the
start of screening/prospective observational phase a. A history (lifetime) of
ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3,
4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is
exclusionary