A Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression
Condition: Treatment-resistant Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
Intervention: Esketamine (Intranasal Spray); Duloxetine (Oral Antidepressant); Escitalopram (Oral Antidepressant); Sertraline (Oral Antidepressant); Venlafaxine Extended Release (XR) (Oral Antidepressant)
Intervention description: Open-Label Induction Phase: Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen (56 mg or 84 mg for those < 65 years; 28 mg, 56 mg or 84 mg for those >= 65 years). Participants >= 65 years old will start at a dose of 28 mg on Day 1. Optimization/Maintenance Phase: Participants will self-administer esketamine intranasally (56 mg or 84 mg for those < 65 years; 28 mg, 56 mg or 84 mg for those >= 65 years) once weekly then individualized to either once weekly or once every other week based on the severity of depressive symptoms. Transferred-entry responder participants from ESKETINTRD3005 >= 65 years old will start at a dose of 28 mg in Week 5.; 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. The minimum therapeutic dose is 10 mg/day. Participants >= 65 years of age will be titrated up to 20 mg/day, but can lower the dose to 10 mg/day for tolerability.; 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 up to 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 for participants < 65 years of age up to a dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day. For participants >= 65, it can be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 75 mg/day.
Intervention MeSH terms: Duloxetine Hydrochloride; Venlafaxine Hydrochloride; Sertraline; Antidepressive Agents; Esketamine; Escitalopram
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 802.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Treatment-resistant Depression; Esketamine; Oral Antidepressant

Summary:

      The purpose of this open-label, multicenter study is to assess the long term safety and
      efficacy of intranasal esketamine plus an oral antidepressant in participants with
      treatment-resistant depression (TRD).
    

Eligibility criteria:

        Inclusion Criteria:

        A). 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)

          -  At the start of the screening 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 screening, participant must have a MADRS total score of >=22

          -  At the start of the screening phase, participants must have had nonresponse to >=2
             oral antidepressant treatments in the current episode of depression, as assessed using
             the the MGHATRQ and confirmed by documented records (example
             medical/pharmacy/prescription records or a letter from treating a physician, etc,) B).
             For Transferred-entry Participants

          -  All participants who completed the double-blind induction phase of ESKETINTRD3005
             study, regardless of their response status, will be eligible to participate in this
             study, if they meet the study specific eligibility criteria

        Exclusion Criteria:

        A). For Direct-Entry Participants

          -  Participant's depressive symptoms have previously not responded to: Esketamine or
             ketamine in the current major depressive episode per clinical judgment or All of the 4
             oral antidepressant treatment options available in the respective country for the
             open-label induction phase (that is, duloxetine, escitalopram, sertraline, and
             venlafaxine XR) in the current major depressive episode (based on Massachusetts
             General Hospital - Antidepressant Treatment Response Questionnaire [ MGH-ATRQ])

          -  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 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

          -  Participants who has a Mini Mental State Examination (MMSE) <25; Has neurodegenerative
             disorder (example, Alzheimer's disease, vascular dementia, Parkinson's disease), or
             evidence of mild cognitive impairment (MCI) B). Transferred-Entry Participants

          -  Participant has taken any prohibited therapies that would not permit dosing on Day 1