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

The purpose of this study is to evaluate the efficacy of switching adult participants with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal esketamine (56 milligram \[mg\] or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms. Efficacy will be assessed by the change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score from Day 1 (before randomization) to the end of the 4-week double-blind treatment phase.


Eligibility Criteria:
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, 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 Clinical-Validation Inventory for Study Admission (C-VISA)
* 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