 This is a randomized, double-blind neither the researchers nor the participants know what treatment the participant is receiving, active-controlled, multicenter study more than 1 study site in elderly participants with TRD to assess the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant active comparator plus intranasal placebo. The study will consist of 3 phases: ScreeningProspective Observational Phase 4 to 7 weeks, Double-blind induction Phase 4 weeks, Follow up Phase 2 weeks. Participants who rollover into a long-term open-label safety study will not participate in the Follow-up Phase. At the start of the ScreeningProspective observational Phase, participant must have had documented nonresponse to at least one antidepressant treatment based on Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire MGH-ATRQ criteria in the current episode of depression, and 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. This antidepressant treatment will be discontinued prior to the double-blind induction Phase. Participants taking benzodiazepines at dosages equal to or less than the equivalent of 6 mgday of lorazepam andor permitted non-benzodiazepine sleep medications example, zolpidem, zaleplon during the screeningprospective observational phase can continue these medications. 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. In addition, each participant will be assigned to receive 1 of 4 oral antidepressant medications from 2 different classes of antidepressant treatments, a Selective Serotonin Reuptake Inhibitor SSRI escitalopram or sertraline or a Serotonin and Norepinephrine Reuptake Inhibitor SNRI duloxetine or venlafaxine extended release XR, initiated on Day 1 and continued through the double-blind induction Phase. Participants will be primarily evaluated for improvement in depressive symptoms as assessed by change in Montgomery Asberg Depression Rating Scale MADRS total score at Week 4. Participants safety will be monitored throughout the study. 