A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant Depression

This is a randomized, double-blind (neither the researchers nor the participant know what
treatment the participants is receiving), active-controlled, multicenter (more than 1 study
site) study in participants with TRD to assess the efficacy of intranasal esketamine plus an
oral antidepressant compared with an oral antidepressant (active comparator) plus intranasal
placebo in delaying relapse of depressive symptoms. The study will consist of 5 phases:
Screening/Prospective Observational Phase (4-7weeks) for direct-entry participants only,
Open-label Induction Phase (4-weeks) for direct-entry participants only, Optimization Phase
(12-weeks; open-label for direct-entry participants and double-blind for transferred-entry
participants), Maintenance Phase (variable duration; double-blind for all participants) and
Follow-up Phase (2-weeks). Participants' safety will be monitored throughout the study.

Inclusion Criteria:

For Direct-Entry Participants

- 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 nonresponse (less than or equal to 25 percent [%] improvement) to greater than or
equal to (>=1) but less than or equal to (<=) 5 oral antidepressant treatments taken
at adequate dosage and for adequate duration, as assessed using the Massachusetts
General Hospital (MGH-ATRQ )

- MGH-ATRQ and documented by medical history and pharmacy/prescription records, for the
current episode of depression. In addition, the participant is taking different
ongoing oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2
weeks at or above the minimal therapeutic dose

- The participant's current major depressive episode, depression symptom severity (Week
1 MADRS total score >=28 required), and treatment response to antidepressant
treatments used in the current depressive episode (retrospectively assessed) must be
deemed valid for participation in a clinical study based on a Site-Independent
Qualification Assessment For Transferred-Entry Participants

- The participant must have completed the double-blind induction phase in ESKETINTRD3001
or ESKETINTRD3002 and must have demonstrated response at the end of that phase (>=50%
reduction in the MADRS total score from baseline [Day 1 pre-randomization] at the end
of the 4-week double-blind induction phase)

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
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