Ochs‐Ross 2020.

Study characteristics
Methods	Randomised, double‐blind, active controlled, multicentre trial
Participants	Diagnosis: DSM‐5 single episode or recurrent major depressive disorder without psychotic features N: 138 randomised (137 included in analysis) Age: esketamine = 70.6 (SD = 4.79); placebo = 69.4 (SD = 4.15). Sex: esketamine group 62.5% female; placebo = 61.5% female. Baseline depression severity: esketamine group MADRS 35.5 (SD = 5.91); Placebo group MADRS 34.8 (SD = 6.44).
Interventions	Patients were randomised to receive either flexibly dosed esketamine (28 mg, 56 mg, or 84 mg) plus a newly initiated antidepressant, or a placebo plus newly initiated antidepressant for four weeks. Concomitant treatment: Yes
Outcomes	MADRS CGI‐S Response (≥ 50% improvement on MADRS from baseline) Remission (MADRS total score ≤12)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Eligible patients were randomized in a 1:1 ratio to one of two treatments: ESK+AD (N=72) or AD+PBO (N=66). Randomization was stratified by country and class of oral AD (SNRI or SSRI)".
Allocation concealment (selection bias)	Low risk	Quote: "A computer‐generated randomization schedule was used to randomize patients (1:1)!".
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	Quote: "MADRS scores were obtained remotely by telephone by independent rates using a structured clinical interview guide (SIGMA) for additional (triple) blinding in this study. The raters had no knowledge of the patient's response to treatment including adverse or dissociative effects". Effectiveness of patient or personnel blinding not tested.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Numbers of withdrawn participants and reasons for withdrawal listed.
Selective reporting (reporting bias)	Low risk	Trial registered (NCT02422186), outcomes reported as planned.
Other bias	High risk	Authors are associated with and receive payments from pharmaceutical companies.