University of New South Wales
Dr. Colleen Loo
“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,” report the researchers, led by Colleen Loo, MD, MBBS, with Black Dog Institute, University of New South Wales, Sydney.
The study was published online in the British Journal of Psychiatry.
Individualized dosing
“Previously, most studies of racemic ketamine [administered] it by intravenous infusion over half an hour to several hours, which is a much more medically complex and expensive procedure,” Dr. Loo said in an interview.
The fact that subcutaneously administered ketamine was “highly effective” given by this practical and feasible route is a “major contribution to the field,” said Dr. Loo.
The Ketamine for Adult Depression trial assessed the acute efficacy and safety of a 4-week course of twice-weekly subcutaneous injections of racemic ketamine or midazolam (active control) in 174 adults with TRD.
Initially, the trial tested a fixed dose of 0.5 mg/kg ketamine vs. 0.025 mg/kg midazolam (cohort 1; 68 patients). Dosing was subsequently revised, after the data safety monitoring board recommended flexible-dose ketamine (0.5-0.9 mg/kg) or midazolam (0.025-0.045 mg/kg) with response-guided dosing increments (cohort 2; 106 patients).
The primary outcome was remission defined as Montgomery-Åsberg Rating Scale for Depression (MADRS) score ≤ 10 at week 4.
On this outcome, in the fixed-dose cohort, there was no statistically significant difference in remission rates between ketamine and midazolam (6.3% and 8.8%; odds ratio, 1.34; 95% CI, 0.22-8.21; P = .76).
However, there was a significant difference in remission in the flexible-dose cohort, with remission rates 19.6% for ketamine vs. just 2% for midazolam (OR, 12.11; 95% CI, 2.12-69.17; P = .005).
“The study showed that individualized dose adjustment, based on clinical response, was very important in optimizing the benefit of ketamine,” said Dr. Loo.
“It meant that one, you are more likely to respond as you receive a higher dose if needed, and two, you don’t receive a higher dose than needed, given that side effects are also dose-related,” she said.
Results also favored flexible-dose ketamine over midazolam for the secondary outcomes of response (≥ 50% reduction in MADRS: 29% vs. 4%; P = .001) and remission defined by a less rigid definition (MADRS ≤ 12: 22% vs. 4%; P = .007).
The results also confirm that the antidepressant effects of ketamine are not sustained when treatment stops.
“The study included careful follow-up for 4 weeks after the end of treatment. This is an important contribution to the literature, as it shows that ongoing treatment beyond the 4 weeks will be necessary for most people to maintain the benefits of ketamine treatment if you respond to the treatment. This study provided clear evidence of this, for racemic ketamine,” said Dr. Loo.
Overall, ketamine was well-tolerated, with the well-established acute effects of ketamine observed in both cohorts. The acute effects resolved or returned to pretreatment levels within the 2-hour observation period. No one required medical intervention, and there was no evidence of cognitive impairment.