A Study of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants With Treatment-resistant Depression
A Study of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants With Treatment-resistant Depression
The purpose of this study is to evaluate the efficacy of each individual dose of esketamine
 nasal spray, 56 milligram (mg) and 84 mg, compared with placebo nasal spray in improving
 depressive symptoms in participants with treatment resistant depression (TRD), as assessed by
 the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score
 from Day 1 (prerandomization) to the end of the 4 week double-blind treatment phase (Day 28).
Inclusion Criteria:

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

 -  Participant must have had nonresponse (<=25% improvement) to >=2 oral antidepressant
 treatments in the current episode of depression, assessed using the MGH-ATRQ, and
 confirmed by documented records (example, medical/pharmacy/prescription records or a
 letter 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, and
 antidepressant treatment response in the current depressive episode, must be confirmed
 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, medical
 history, vital signs (including blood pressure), and 12-lead electrocardiogram (ECG)
 performed in the screening phase. If there are any abnormalities that are not
 specified in the inclusion and exclusion criteria, the determination of their clinical
 significance must be determined by the investigator and recorded in the participant's
 source documents and initiated by the investigator

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

 -  Participant must be comfortable with self-administration of nasal spray medication and
 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 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 history of seizures (uncomplicated childhood febrile
 seizures with no sequelae are not exclusionary)

 -  Participant has any anatomical or medical condition that, per the investigator's
 clinical judgment based on assessment, may impede delivery or absorption of nasal
 spray study drug