A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression

Abstract

The strategy of repeated ketamine in open-label and saline-control studies of treatment-resistant depression suggested greater antidepressant response beyond a single ketamine. However, consensus guideline stated the lack of evidence to support frequent ketamine administration. We compared the efficacy and safety of single vs. six repeated ketamine using midazolam as active placebo. Subjects received either six ketamine or five midazolam followed by a single ketamine during 12 days followed by up to 6-month post-treatment period. The primary end point was the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) score at 24 h after the last infusion. Fifty-four subjects completed all six infusions. For the primary outcome measure, there was no significant difference in change of MADRS scores between six ketamine group and single ketamine group at 24 h post-last infusion. Repeated ketamine showed greater antidepressant efficacy compared to midazolam after five infusions before receiving single ketamine infusion. Remission and response favored the six ketamine after infusion 4 and 5, respectively, compared to midazolam before receiving single ketamine infusion. For those who responded, the median time-to-relapse was nominally but not statistically different (2 and 6 weeks for the single and six ketamine group, respectively). Repeated infusions were relatively well-tolerated. Repeated ketamine showed greater antidepressant efficacy to midazolam after five infusions but fell short of significance when compared to add-on single ketamine to midazolam at the end of 2 weeks. Increasing knowledge on the mechanism of ketamine should drive future studies on the optimal balance of dosing ketamine for maximum antidepressant efficacy with minimum exposure.

Fig. 1. Mean Change in Severity of Depression between Six Ketamine versus Midazolam plus Single Ketamine Treatment within a 12-day Period.

Severity of depression scores measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 12 days between six ketamine and five midazolam plus single ketamine (last infusion) treatment groups in a randomized controlled trial in treatment-resistant major depression. Figure depicts mean MADRS scores in patients with treatment-resistant depression before and after 24 h of each ketamine (0.5 mg/kg) or single ketamine (0.5 mg/kg) preceded by five midazolam (0.045 mg/kg) infusion. * indicates significant difference in MADRS score between treatment condition (p = 0.01) before and at 24 h after infusion 5. ^¶Indicates significant difference in MADRS score between treatment conditions (p = 0.05) before infusion 6.

Fig. 2. Antidepressant Response and Remission Rates between Six Ketamine versus Midazolam plus Single Ketamine Treatment within a 12-day Period.

a Response rates over 12 days between six ketamine and five midazolam plus single ketamine (last infusion) treatment groups in a randomized controlled trial among subjects with treatment-resistant major depression. Response is defined as  > 50% decrease from baseline score measured by the Montgomery-Åsberg Depression Rating Scale. Figure depicts response in patients with treatment-resistant depression measured at 24h after each ketamine (0.5 mg/kg) or single ketamine (0.5 mg/kg) preceded by five midazolam (0.045 mg/kg) infusion. * indicates significant difference in response between treatment conditions (p = 0.007) at 24h after infusion 5 (Fig. 2b). Remission rates over 12 days between six ketamine and five midazolam plus single ketamine (last infusion) treatment groups in a randomized controlled trial among subjects with treatment-resistant major depression. Remission is defined as score < 10 in the Montgomery-Åsberg Depression Rating Scale. Figure depicts remission in patients with treatment-resistant depression measured at 24 h after each ketamine (0.5 mg/kg) or single ketamine (0.5 mg/kg) preceded by five midazolam (0.04 5mg/kg) infusion. * indicates significant difference in remission between treatment conditions (p = 0.006) at 24 h after infusion 4.

Fig. 3. Time-to-relapse between responders to single vs six ketamine infusions in treatment-resistant depression.

Figure depicts Kaplan–Meier analysis of responders for up 6 months of follow-up. Relapse was defined as <50% improvement in Montgomery–Åsberg Depression Rating Scale score at that visit compared with baseline.