a study to evaluate the efficacy, safety, and tolerability of fixed doses of intranasal esketamine plus an oral antidepressant in adult participants with treatment-resistant depression

Conditions: Treatment-resistant Depression

Summary: the purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (trd) participants 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.

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 participants with trd to assess the efficacy, safety, and tolerability of fixed 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: screening/prospective observational phase (4-7 weeks), double-blind induction phase (4-weeks), follow-up phase (24-weeks). participants who rollover into a long-term maintenance study will not participate in the follow-up phase. at the start of the screening/prospective observational phase, the participant must have had documented non-response to at least 1 antidepressant treatment (based on massachusetts general hospital - antidepressant treatment response questionnair \[mgh-atrq\]) in the current episode of depression, and 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, as well as any other ongoing medications being taken for depression at screening (including adjunctive/ augmentation therapies), will continue from the start of week 1 through the end of week 4 of the screening/prospective observational phase. participants will be randomly assigned to receive intranasal esketamine (56 milligrams \[mg\]), intranasal esketamine (84 mg), or intranasal placebo. 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.

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, participants must have had non-response (less than or equal to \[\ =1 but less than or equal to (\ 2 years, upper limit is applicable to only the last 2 years) 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 by medical history and pharmacy/prescription records, for the current episode of depression. 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 (i.e, 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 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/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

Keywords: treatment-resistant depression esketamine placebo oral antidepressant