A Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed 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 participants know what
treatment the participant is receiving), active-controlled, multicenter study (more than 1
study site) in participants with TRD to assess the efficacy, safety, and tolerability of
fixed 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). Participants who rollover into a
long-term maintenance study will not participate in the Follow-up Phase. At the start of the
screening/prospective observational phase, the participant must have had documented
non-response to at least 1 antidepressant treatment (based on Massachusetts General Hospital
- Antidepressant Treatment Response Questionnair [MGH-ATRQ]) in the current episode of
depression, and 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. This
antidepressant treatment, as well as any other ongoing medications being taken for depression
at screening (including adjunctive/ augmentation therapies), will continue from the start of
Week 1 through the end of Week 4 of the screening/prospective observational phase.
Participants will be randomly assigned to receive Intranasal esketamine (56 milligrams [mg]),
Intranasal esketamine (84 mg), or Intranasal placebo. In addition, each participant will be
assigned to receive 1 of 4 oral antidepressant medications from 2 different classes of
antidepressant treatments, a Selective Serotonin Reuptake Inhibitor (SSRI) (escitalopram or
sertraline) or a Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) (duloxetine or
venlafaxine extended release [XR]), initiated on Day 1 and continued through the double-blind
induction phase. Participants will be primarily evaluated for improvement in depressive
symptoms as assessed by change in Montgomery-Asberg Depression Rating Scale (MADRS) total
score at Week 4. Participants' 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, participants must have
had non-response (less 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 taken at adequate
dosage and for adequate duration, as 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.

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 (i.e,
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
psychotic features bipolar or related disorders (confirmed by the MINI), obsessive
compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes
317, 318.0, 318.1, 318.2, 315.8, 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)

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