This was a Phase II, randomised, double-blind, multi-site trial in TRD patients with the benzodiazepine, Midazolam, used as the active placebo comparator to reduce the risk of unblinding of the trial due to its similar adverse psychotropic effects as ketamine.
99 participants were randomised into one of five study arms in a 1:1:1:1:1 ratio. These arms included a single dose of ketamine at 0.1 mg/kg (n = 18),0.2 mg/kg (n = 20), 0.5 mg/kg (n = 22), 1.0 mg/kg (n = 20), or a single dose of midazolam 0.045 mg/kg (n = 19). After receiving their intravenous infusion, patients were given assessments for up to 30 days at days 0, 1, 3, 5, 7, 14, and 30 to gauge the safety and efficacy of ketmaine compared to midazolam - with the 0-3 day period being the acute phase[3] .
The 6-Item Hamilton Depression Rating Scale (HAM-D6) was used as the primary outcome measure, with a lower score indicating a better depressive state.
Secondary measures of depression included the (MADRS) (not administered at day 1), the self-rated Symptoms of Depression Questionnaire (SDQ); the self-rated Positive Affect Scale (PAS); the self-rated Snaith-Hamilton Pleasure Scale (SHAPS); the global severity and improvement scales of the Clinical Global Impressions (CGI-S and CGI-I respectively). Other secondary measures included the Clinician-Administered Dissociative States Scale (CADSS); Columbia Suicide Severity Rating Scale (CSSRS) for suicidal ideation and behaviour; response rates (HAM-D-6 reduction from baseline score ≥50%); blood pressure and heart rates measured at 15-20 minute intervals for two hours following infusion [3].
For the primary endpoint, there was a statistically significant improvement on the 6-Item Hamilton Depression Rating Scale (HAM-D6) score for ketamine compared to the active placebo using 2-group analysis (comparison between those that took any ketamine dose and placebo)(p=0.0278)[3]. After adjustment for multiple comparisons, only 0.5mg/kg and 1.0mg/kg doses were statistically superior to placebo and only at day 1. The Cohen’s d effect sizes were above 0.8 at day 1 for doses 0.1mg/kg, 0.5mg/kg, and 1.0mg/kg and remained above 0.4 on day 3, showing a medium to large effect size throughout the acute phase wire these doses[3].
For the secondary endpoints, 0.5mg/kg dosage was statistically superior to placebo on all secondary outcomes but only at day 1 (excluding the MADRS which was not assessed at day 1 but did show a significant difference on day 3). The 1.0mg/kg dose was statically superior to placebo on day 1 on the CGI-S. All secondary outcomes for 0.5mg/kg and 1.0mg/kg had a Cohen’s d between 0.94-1.27. Response rates were 53% for 1.0mg/kg and 57% for 0.5mg/kg compared to 11% for placebo[3].
Despite there being higher rates of adverse effects in ketamine-treated patients there was no significant difference in the combined ketamine group rates of adverse effects compared to those in placebo: headache (11.3% vs. 0%), nausea (10% vs. 0%), vomiting (5% vs. 0%), and depression (3.8% vs. 0%)[3]. Two cases of suicidal ideation were reported but CSSRS scores showed no significantly higher rates of suicidal ideations in ketamine-treated patients compared to placebo.
Statistically, significant comparisons on both the primary and secondary outcomes for individual ketamine doses with placebo suggest clinical antidepressant efficacy for standard doses of 0.5kg/mg and high doses of 1.0kg/mg for subanaesthetic intravenous ketamine. Rapid loss of efficacy was shown following the 3-day acute phase after a single intravenous dose during the 30 day follow-ups. 1.0mg/kg did show a more sustained effect as far out as days 15-30, though this effect was modest it may warrant further investigation.
A dose-response curve for dissociative symptoms was shown via the CADSS which may have caused unblinding of the trial at higher doses of ketamine. This may account for the higher numerical efficacy of 0.5mg/kg compared to 0.1mg/kg for example but does not account for 0.5mg/kg consistent higher numerical effects over 1.0mg/kg.