Fedgchin 2019.

Study characteristics
Methods	Phase 3 randomised, double‐blind, active‐controlled multicentre trial
Participants	Diagnosis: DSM‐5 single episode or recurrent major depressive disorder without psychotic features N: 346 randomised (342 included in analysis) Age: esketamine 56 mg = 46.4 (SD=11.8); esketamine 84 mg = 45.7 (SD = 11.10); Placebo = 46.8 (SD=11.36). Sex: esketamine 56 mg group 70.4% female ; esketamine 84 mg 69.3% female; Placebo = 71.7% female. Baseline depression severity: esketamine 56 mg group MADRS 37.4 (SD = 4.76); esketamine 84 mg group MADRS 37.8 (SD = 5.58); Placebo group MADRS 37.5 (SD = 6.16).
Interventions	Participants were randomised to receive the following intranasal treatments twice weekly for four weeks: Esketamine 56 mg Esketamine 84 mg Placebo nasal spray (with bittering agent to simulate the taste of esketamine solution. Participants also initiated one of the following oral antidepressants to take alongside the randomised treatment: Duloxetine Escitalopram Sertraline Venlafaxine Extended Release (XR) Concomitant treatment: Yes
Outcomes	MADRS CADSS CGADR CGI‐S PHQ‐9 Response (≥50% improvement on MADRS from baseline) Remission (MADRS total score ≤12)
Notes	Authors kindly provided additional data for remission rates according to this review's definition and MADRS mean scores
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Patients were randomised to interventions in a 1:1:1 sequence.
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was balanced by using randomly permuted blocks and stratified by country and class of oral antidepressant"
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Stated but not tested.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	MADRS assessments were completed by independent, blinded, remote raters, however not tested.
Incomplete outcome data (attrition bias) All outcomes	High risk	Higher rates of withdrawal and AEs in treatment group
Selective reporting (reporting bias)	Low risk	Trial registered (NCT02417064) outcomes reported as expected.
Other bias	High risk	Authors are associated with and receive payments from pharmaceutical companies.