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

This is a randomized, double-blind (neither the researchers nor the subjects know what
treatment the subject is receiving), active-controlled, multicenter study (more than 1 study
site) in subjects with TRD to assess the efficacy, safety, and tolerability of flexible doses
of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly
initiated oral antidepressant (active comparator) plus intranasal placebo. The study will
consist of 3 phases: Screening/Prospective Observational Phase (4-7 weeks), Double-blind
Induction Phase (4-weeks), Follow-up Phase (24-weeks). Subjects who rollover into a long-term
maintenance study will not participate in the Follow-up Phase. The antidepressant treatment,
as well as any other ongoing medications being taken for depression at screening (including
adjunctive/ augmentation therapies), will continue unchanged, at the same dosage, from the
start of Week 1 through the end of Week 4 of the screening/prospective observational phase.
Subjects' safety will be monitored throughout the study.

Inclusion Criteria:

- At the time of signing the informed consent form (ICF), participant must be a man or
woman 18 (or older if the minimum legal age of consent in the country in which the
study is taking place is greater than [>]18) to 64 years of age, inclusive

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

- At the start of the screening/prospective observational phase, participant must have
an Inventory of Depressive Symptomatology-Clinician rated ( IDS-C30) total score of
greater than or equal to (>=) 34

- At the start of the screening/prospective observational phase, participant must have
had non-response (greater than or equal to [<=25] percent [%] improvement) to ≥1 but
less than or equal to (<=) 5 (if current episode is >2 years, 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 documented by medical
history and pharmacy/prescription records, for the current episode of depression. 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 MADRS total score >=28 required), and antidepressant treatment response in the
current depressive episode, must be confirmed using a Site Independent Qualification
Assessment

Exclusion Criteria:

- Participants who have previously demonstrated nonresponse of depressive symptoms to
esketamine or ketamine in the current major depressive episode, to all 4 of the oral
antidepressant treatment options available for the double-blind induction phase (ie,
duloxetine, escitalopram, sertraline, and venlafaxine extended release [XR]) in the
current major depressive episode (based on MGH-ATRQ), or 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
psychosis, bipolar or related disorders (confirmed by the MINI), comorbid obsessive
compulsive disorder, intellectual disability (DSM-5 diagnostic codes 317, 318.0,
318.1, 318.2, 315.8, and 319), 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)

- Participants with history of moderate or severe substance or alcohol use disorder
according to DSM-5 criteria