Discussion
TRD, treatment-resistant
This was the largest randomised controlled trial of racemic ketamine tested against placebo in participants with TRD, with cohort 2 alone being larger than total samples in previous trials. It showed the efficacy and safety of an adequately dosed 4-week treatment course given by subcutaneous injection, tested against an active control drug. The superior antidepressant efficacy of ketamine was evident only in cohort 2 (flexible-dose), which involved response-guided dose escalation from 0.5 mg/kg up to 0.9 mg/kg. However, it was not evident in cohort 1 (fixed-dose), which involved a dose of 0.5 mg/kg for all treatments. In this severely treatment-resistant population, of which 24% had failed to respond to treatment with electroconvulsive therapy, adequately dosed racemic ketamine produced benefits that were large, being both clinically and statistically superior to midazolam.