Randomised, double-blind Phase III trial (n=252) comparing flexible-dose intranasal esketamine (56–84 mg, twice weekly for 4 weeks, up to 8 doses) plus a newly initiated oral antidepressant versus oral antidepressant plus intranasal placebo in adults with treatment-resistant depression; primary outcome MADRS change at 28 days.
This randomised, double-blind, parallel-group study evaluated flexible-dose intranasal esketamine administered twice weekly for 4 weeks alongside a newly initiated oral antidepressant compared with oral antidepressant plus intranasal placebo in adults with treatment-resistant depression (MADRS ≥28).
Efficacy was assessed by change from baseline in MADRS total score to end of the 4-week double-blind phase; safety assessments included adverse events, vital signs, ECG and laboratory measures. The trial did not demonstrate significant benefit at 28 days.
Flexible-dose intranasal esketamine (start 56 mg, may be increased to 84 mg) plus a newly initiated oral antidepressant given twice weekly for 4 weeks.
Intranasal spray; start 56 mg on Day 1; may be increased to 84 mg per investigator discretion.
Newly initiated open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR) started Day 1; typical starting/therapeutic doses per protocol (e.g., duloxetine 60 mg/day; escitalopram 10→20 mg/day; sertraline 50→200 mg/day; venlafaxine XR 75→225 mg/day).
New oral antidepressant plus matching intranasal placebo twice weekly for 4 weeks.
Matching intranasal placebo spray.
Newly initiated open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR) as per investigator choice; dosing per protocol.