This double-blind, placebo-controlled study compared the efficacy and safety of repeated versus single subanesthetic ketamine infusions for treatment-resistant depression (TRD). Fifty-four participants received either six ketamine infusions or five midazolam (active placebo) infusions followed by a single ketamine infusion over 12 days. The primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at 24 hours post-last infusion. No significant difference was found between groups for the primary outcome. However, remission and response rates favored the six-ketamine group after infusions 4 and 5. Time-to-relapse was not significantly different between groups. Repeated ketamine showed better efficacy than midazolam after five infusions but not compared to the single ketamine add-on at the study's end. The study suggests that repeated ketamine may offer benefits, but further research is needed to optimize dosing.

Paulo R. Shiroma, Paul Thuras, Joseph Wels, C. Sophia Abbott, Christopher Erbes, Susannah Tye, Kelvin O. Lim