A flexibly dosed, twice-weekly subcutaneous injection of ketamine over four weeks led to higher levels of clinical remission compared to midazolam in patients with treatment-resistant depression, according to a new phase III trial.
The trial by Australian researchers, which was published in the British Journal of Psychiatry, compared racemic ketamine with midazolam in two patient cohorts: one with fixed dosing and a second with a more flexible regimen.
The trial was initially designed to compare twice-weekly subcutaneous racemic ketamine (0.5 mg/kg) or midazolam (0.025 mg/kg) for four weeks, with at least three days between treatments. Data for these findings were referred to in the study as cohort one.
The dosing schedule was revised after a Data Safety Monitoring Board recommendation to flexible-dose ketamine 0.5–0.9 mg/kg or midazolam 0.025–0.045 mg/kg, with response-guided dosing increments. Data for these findings were referred to in the study as cohort two.
The primary outcome was remission, characterised by a Montgomery-Åsberg Rating Scale for Depression score of less than 10, after four weeks of treatment.
Subcutaneous ketamine and treatment outcomes
The final analysis comprised 68 patients in the fixed-dose cohort one and 106 in the flexible-dose cohort two.
Ketamine was found to be significantly more efficacious than midazolam in cohort two at achieving remission (odds ratio, OR = 12.1, 95% CI 2.1 – 69.2, p = 0.005). However, there was no significant different between the two treatments when given as a fixed dose in cohort one (OR = 1.3, 95% CI 0.2 – 8.2, p = 0.76).
In terms of safety, serious adverse events were rare and most were unrelated to the study drug. For instance, in cohort one, there were two serious adverse events in the midazolam group – a suicide attempt and mood deterioration – but both unrelated to the study medications. There were no serious adverse events in the ketamine group.
Among those in cohort two, there were three serious adverse events in the midazolam group: a suicide attempt, increased suicidal ideation and a wrist injury, which, again, were unrelated to the study treatments. In contrast, there were two serious adverse events in the ketamine group: one major dissociative episode and auditory hallucination, both of which were deemed to be related to treatment. No deaths were reported throughout the study.
Failing to respond to an adequate course of two or more treatments is referred to as treatment-resistant depression, and ketamine is a novel highly effective and rapidly acting treatment. It is available as an intravenous infusion of a racemic mixture and as a commercially developed single enantiomeric intranasal spray containing S-ketamine.