Procedures
Ketamine and midazolam were given subcutaneously into the abdominal wall twice per week for 4 weeks, with at least 3 days between treatments. The initial trial protocol (cohort 1) involved fixed doses at 0.5 mg/kg ketamine and 0.025 mg/kg midazolam (identical injection volume). At a routine Data Safety Monitoring Board meeting reviewing data from the first completed 51 participants, a revisiting of drug dosage was recommended as no participants in the entire masked sample had remitted and the safety profile was good. No interim analyses were planned or conducted. Thus, for cohort 2, flexible response-guided dosing was implemented. If participants had not improved by 50% from pretreatment baseline in MADRS scores at sessions 2, 4 and 6, dose escalation steps comprised 0.6, 0.75 and 0.9 mg/kg ketamine and 0.03, 0.0375 and 0.045 mg/kg midazolam (i.e. identical injection volumes between drugs at each dose level). After the 4-week treatment period, participants continued on any antidepressant medications that were established prior to study entry, with dosage unchanged prior to and during the trial, and were followed up 4 weeks later (RCT 4-week follow-up, at week 8). Those who had relapsed at this follow-up were eligible to enter an open-label treatment phase. See Supplementary material and the trial protocol for further details.