A Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Participants With Treatment-resistant Depression
Condition: Depressive Disorder, Treatment-Resistant
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) (New Antidepressant)
Intervention description: All participants will start with first dose (Day 1 as 28 milligram [mg]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability.; 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 given at a dose of 10 mg/day throughout the Double-Blind Induction Phase. This dose (10 mg/day) is the also the minimum therapeutic dose.; 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 may 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 may 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
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 139.0
Sex: All
Minimum age: 65 Years
Healthy volunteers: No
Keywords: Depressive Disorder, Treatment-Resistant; Esketamine; Oral Antidepressant; Elderly Participants

Summary:

      The purpose of this study is to evaluate the efficacy and safety of switching elderly
      participants with treatment-resistant depression (TRD) 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 65 years of age or older

          -  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 (>=) 31

          -  At the start of the Screening/Prospective observational Phase, participants must have
             had nonresponse (less than or equal to 25% improvement) to >=1 but less than or equal
             to (<=) 8 oral antidepressant treatments taken at adequate dosage and for adequate
             duration, as assessed using the Massachusetts General Hospital - Antidepressant
             Treatment Response Questionnaire (MGH-ATRQ) and documented records by medical and
             pharmacy/prescription records, or a letter from the treating physician, for the
             current episode of depression

          -  Participant must be taking one of the oral antidepressant treatment with nonresponse
             that is documented on the MGH-ATRQ at the start of the screening/prospective
             observational phase

          -  The participant's current major depressive episode, depression symptom severity (Week
             1 MADRS total score greater than or equal to 24 required) and treatment response to
             antidepressant treatments used in the current depressive episode (retrospectively
             assessed) must be confirmed for participation in a clinical study based on a
             Site-Independent Qualification Assessment

          -  Participant must be medically stable on the basis of clinical laboratory tests
             performed in the screening/prospective observational phase

        Exclusion Criteria:

          -  The participant's depressive symptoms have previously demonstrated nonresponse to:
             Esketamine or ketamine in the current major depressive episode per clinical judgment,
             or all of the 4 oral antidepressant treatment options available for the double-blind
             induction Phase (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 ECT

          -  Participants who has received vagal nerve stimulation (VNS) or who 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), obsessive compulsive
             disorder (current episode only), intellectual disability ( 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) and also
             includes history of suicidal behavior within the past year prior to start of the
             screening/prospective observational phase

          -  Participant has a history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid
             diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related
             use disorder\

          -  Participant has a Mini Mental State Examination (MMSE) < 25 or <22 for those
             participants with less than an equivalent of high school education

          -  Participant has neurodegenerative disorder (eg, Alzheimer's Disease, Vascular
             dementia, Parkinson's disease with clinical evidence of cognitive impairment) or
             evidence of mild cognitive impairment (MCI)

          -  Participant has a history of uncontrolled hypertension; current or past history of
             significant pulmonary insufficiency/condition;clinically significant ECG
             abnormalities; current or past history of seizures; clinically significant
             cardiovascular disorders including cerebral and cardiac vascular disease