Fava 2018.

Study characteristics
Methods	Double‐blind placebo‐controlled trial
Participants	Diagnosis: DSM‐IV‐TR major depressive disorder, confirmed by the Structured Clinical Interview for DSM‐IV‐Patient Edition (SCID‐I/P) N: 99 Age: ketamine 0.1 mg/kg group M = 43.1 (SD = 11.9); ketamine 0.2 mg/kg group M = 45.5 (SD = 14.6); ketamine 0.5 mg/kg group M = 48.6 (SD = 12.9); ketamine 1.0 mg/kg group M = 47.4 (SD = 10.1); midazolam group M = 45.6 (SD = 13.8) Sex: ketamine 0.1 mg/kg group 55.6% female; ketamine 0.2 mg/kg group 45% female; ketamine 0.5 mg/kg group 50% female; ketamine 1.0 mg/kg group 40% female; midazolam group 57.9% female Baseline depression severity: ketamine 0.1 mg/kg group HAM‐D‐6 M = 12.6 (SD = 1.8); ketamine 0.2 mg/kg group HAM‐D‐6 M = 12.8 (SD = 2.5); ketamine 0.5 mg/kg group HAM‐D‐6 M = 12.6 (SD = 1.5); ketamine 1.0 mg/kg group HAM‐D‐6 13.1 (SD 2.3); midazolam group HAM‐D‐6 M = 13.1 (SD = 2.3)
Interventions	Five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). Concomitant medications: patients on exclusionary concomitant psychotropic medications (e.g. opioids, tramadol, valproic acid, lamotrigine, carbamazepine, barbiturates, eszopiclone, stimulants, NMDA receptor antagonists such as memantine) were included only if they had been free of the exclusionary medication post‐taper for five half lives within the maximum screening period (28 days).
Outcomes	HAM‐D‐6 MADRS CGI‐S CGI‐I SDQ PAS
Notes	Authors kindly provided additional data which has been used in this review.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomly assigned to one of five 40 min infusion arms in a 1:1:1:1:1 fashion. Prior to randomization, patients were grouped by body mass index (BMI) (group I: BMI ≤ 30; group II: BMI > 30), and were block randomized into each arm of the study, with the mg/kg ratio being maintained across all BMIs."
Allocation concealment (selection bias)	Low risk	Quote: "Randomly assigned to one of five 40 min infusion arms in a 1:1:1:1:1 fashion. Prior to randomization, patients were grouped by body mass index (BMI) (group I: BMI ≤ 30; group II: BMI > 30), and were block randomized into each arm of the study, with the mg/kg ratio being maintained across all BMIs."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding tested and largely uneffective: quote: "Regarding unblinding, both clinicians’ and participants’ guesses of treatment assignment were significantly related to actual treatment group (p < 0.01 for both), where both groups were able to correctly guess assignment to ketamine for the 0.5 mg/kg (100% and 77% guessed correctly by clinicians and participants, respectively) and the 1.0 mg/kg (95% correctly guessed by both) ketamine doses, but not for the 0.1 mg/kg (50%, 56%, respectively) and 0.2 mg/kg doses (55%, 45%, respectively). Assignment to placebo was guessed correctly 42% by clinicians and 37% by participants."
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding tested and largely uneffective, which may have impacted upon outcome assessments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	CONSORT diagram published (p3)
Selective reporting (reporting bias)	Low risk	Protocol available online, outcomes reported as expected.
Other bias	High risk	Extensive links with pharmaceutical industry creates potential for bias.