A Study of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants With Treatment-resistant Depression

Inclusion Criteria:

• Participant must meet the Diagnostic and Statistical Manual of Mental Disorders (5thedition) (DSM-5) diagnostic criteria for single-episode MDD or recurrent MDD,without psychotic features, based upon clinical assessment and confirmed by theMINI. Participants 65 years of age or older must have had the first onset ofdepression prior to 55 years of age

• Participant must have had nonresponse (<=25% improvement) to >=2 oral antidepressanttreatments in the current episode of depression, assessed using the MGH-ATRQ, andconfirmed by documented records (example, medical/pharmacy/prescription records or aletter from a treating physician)

• Participant must have an Inventory of Depressive Symptomatology-Clinician rated, 30-item (IDS-C30) total score of >=34

• The participant's current major depressive episode, depression symptom severity, andantidepressant treatment response in the current depressive episode, must beconfirmed by the State vs. Trait, Assessibility, Face Validity, Ecological Validity,Rule of Three P's (SAFER) Interview

• Participant must be medically stable on the basis of physical examination, medicalhistory, vital signs (including blood pressure), and 12-lead electrocardiogram (ECG)performed in the screening phase. If there are any abnormalities that are notspecified in the inclusion and exclusion criteria, the determination of theirclinical significance must be determined by the investigator and recorded in theparticipant's source documents and initiated by the investigator

• Participant must be medically stable on the basis of clinical laboratory testsperformed in the screening phase. If the results of the serum chemistry panel,hematology, or urinalysis are outside the normal reference ranges, the participantmay be included only if the investigator judges the abnormalities or deviations fromnormal to be not clinically significant or to be appropriate and reasonable for thepopulation under study. This determination must be recorded in the participant'ssource documents and initialed by the investigator: (a) Participants with apre-existing history of thyroid disease/disorder who are treated with thyroidhormones must be on a stable dosage for 3 months prior to the start of the screeningphase; (b) For any participant (regardless of thyroid history), if thethyroid-stimulating hormone (TSH) value is out of range, a free thyroxine (FT4) willbe conducted. If the FT4 value is abnormal and considered to be clinicallysignificant (after discussion with the medical monitor), the participant is noteligible

• Participant must be comfortable with self-administration of nasal spray medicationand be able to follow the nasal spray administration instructions provided

Exclusion Criteria:

• The participant has used ketamine/esketamine (lifetime)

• The participant's depressive symptoms have previously demonstrated nonresponse to anadequate course of treatment with electroconvulsive therapy (ECT) in the currentmajor depressive episode, defined as at least 7 treatments with unilateral/bilateralECT

• Participant has received vagal nerve stimulation (VNS) or has received deep brainstimulation (DBS) in the current episode of depression

• Participant has a current or history of seizures (uncomplicated childhood febrileseizures with no sequelae are not exclusionary)

• Participant has any anatomical or medical condition that, per the investigator'sclinical judgment based on assessment, may impede delivery or absorption of nasalspray study drug