A Study to Evaluate the Safety and Efficacy of Intranasal Esketamine in Treatment-resistant Depression

This will be a 2-panel, randomized ( participants are assigned different treatments based on
chance), double-blind (neither investigator nor participant knows which treatment the
participant receives), placebo-controlled (placebo is an inactive substance that is compared
with a drug to test whether the drug has a real effect in a clinical trial), multicenter
study. Approximately 100 male and female adult participants diagnosed with TRD will
participate in this study. For participants in both panels (Panel A and Panel B), there will
be 4 study phases: a 4-week screening phase, a double-blind treatment phase (Day 1 to Day
15), an optional open-label treatment phase (Panel A: Day 15 to 74; Panel B: Day 15 to 25),
and an 8-week post-treatment (follow-up) phase. Depending on the treatment Panel, patients
will be assigned to intranasal placebo or intranasal esketamine 14 mg, 28 mg, 56 mg, or 84
mg. Safety assessments will be performed throughout the study. The maximum study duration
for a participant will be 23 weeks for Panel A and 16 weeks for Panel B.

Inclusion Criteria:

--Participant must meet Diagnostic and Statistical Manual of Mental Disorders -Fourth
Edition -Text Revised (DSM-IV-TR) diagnostic criteria for Major Depressive Disorder (MDD),
without psychotic features, based upon clinical assessment, and confirmed by the Mini
International Neuropsychiatric Interview (MINI)-Participant's major depressive episode and
treatment response must be deemed "valid" by remote independent raters-Participant must
have had an inadequate response to at least 2 antidepressants, at least one of which is in
the current episode of depression; the antidepressant treatment response questionnaire
(ATRQ) will be used to assess antidepressant treatment response during the current
episode; prior medication history will be used to determine antidepressant treatment
response in prior episode(s) -Have an Inventory of Depressive Symptoms-Clinician rated,
30-item (IDS-C30) total score >=34 at Screening and predose at Day 1

Exclusion Criteria:

-Participant has a current DSM-IV-TR diagnosis of bipolar and related disorders,
intellectual disability, or cluster b personality disorder (e.g., borderline personality
disorder, antisocial personality disorder, histrionic personality disorder, and
narcissistic personality disorder) -Participant has a current or prior DSM-IV-TR diagnosis
of a psychotic disorder, MDD with psychosis, post-traumatic stress disorder (PTSD), or
obsessive compulsive disorder (OCD) -Anatomical or medical conditions that may impede
delivery or absorption of study medication (e.g., undergone facial reconstruction,
rhinoplasty, significant structural or functional abnormalities of the nose or upper
airway; obstructions or mucosal lesions of the nostrils or nasal passages; undergone sinus
surgery in the previous 2 years; signs and symptoms of rhinitis) -Has an abnormal or
deviated nasal septum with any 1 or more of the following symptoms: blockage of 1 or both
nostrils, nasal congestion (especially 1-sided), frequent nosebleeds, frequent sinus
infections, and at times has facial pain, headaches, and postnasal drip -Has a history of
substance abuse (drug or alcohol) or dependence (except nicotine or caffeine) within the
previous 1 year of the screening visit -Participant has known allergies, hypersensitivity,
intolerance, or contraindication to esketamine/ketamine or its excipients