A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression
Condition: Treatment-resistant Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
Intervention: Esketamine; Placebo; Duloxetine (Oral Antidepressant); Escitalopram (Oral antidepressant); Sertraline (Oral Antidepressant); Venlafaxine Extended Release (XR) (Oral Antidepressant)
Intervention description: Participants will self-administer either 56 mg or 84 mg of esketamine, intranasally, twice per week as a flexible dose regimen in the Double-Blind Induction Phase.; Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a flexible dose regimen in the Double-Blind Induction Phase.; Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).; Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be titrated upto a dose of 20 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 10 mg/day.; Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline will be titrated upto a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.; Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release will be titrated upto a dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day.
Intervention MeSH terms: Duloxetine Hydrochloride; Venlafaxine Hydrochloride; Sertraline; Antidepressive Agents; Esketamine; Escitalopram
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 236.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: Treatment-resistant Depression; Esketamine; Placebo; Oral Antidepressant

Summary:

      The purpose of this study is to compare the efficacy and safety of switching
      treatment-resistant depression (TRD) subjects from a prior antidepressant treatment (to which
      they have not responded) to either intranasal esketamine plus a new oral antidepressant or
      switching to a new oral antidepressant plus intranasal placebo.
    

Eligibility criteria:

        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, participant must have
             had non-response (greater 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 in the current
             episode of depression, 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. In
             addition, the 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 (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
             psychosis, bipolar or related disorders (confirmed by the MINI), comorbid obsessive
             compulsive disorder, intellectual disability (DSM-5 diagnostic codes 317, 318.0,
             318.1, 318.2, 315.8, and 319), 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