Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial

TLDR

Subanesthetic ketamine produces rapid but transient antidepressant effects in treatment‑resistant depression, potentially lasting longer with repeated doses. The study aimed to evaluate the antidepressant effects of single, repeated, and maintenance ketamine infusions in patients with treatment‑resistant depression. Forty‑one patients were randomized to receive a single ketamine or midazolam infusion, and responders who relapsed received six open‑label ketamine infusions thrice weekly followed by four weekly maintenance infusions. A single ketamine infusion produced a greater 24‑hour reduction than midazolam, and repeated infusions yielded cumulative antidepressant effects with 59% responding after a median of three infusions, while weekly maintenance infusions maintained response without further change.

Abstract

Subanesthetic ketamine doses have been shown to have rapid yet transient antidepressant effects in patients with treatment-resistant depression, which may be prolonged by repeated administration. The purpose of this study was to evaluate the antidepressant effects of a single ketamine infusion, a series of repeated ketamine infusions, and prolongation of response with maintenance infusions.Forty-one participants with treatment-resistant depression completed a single-site randomized double-blind crossover comparison of single infusions of ketamine and midazolam (an active placebo control). After relapse of depressive symptoms, participants received a course of six open-label ketamine infusions administered thrice weekly over 2 weeks. Responders, classified as those participants who had a ≥50% decrease in their scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), received four additional infusions administered once weekly (maintenance phase).Compared with midazolam, a single ketamine infusion elicited a significantly greater reduction in depressive symptoms at the primary efficacy endpoint (24 hours postinfusion). Linear mixed models revealed cumulative antidepressant effects with repeated infusions and doubling of the antidepressant response rate. Fifty-nine percent of participants met response criteria after repeated infusions, with a median of three infusions required before achieving response. Participants had no further change in MADRS scores during weekly maintenance infusions.Repeated ketamine infusions have cumulative and sustained antidepressant effects. Reductions in depressive symptoms were maintained among responders through once-weekly infusions. These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression. Future studies should further expand on optimizing administration to better translate the use of ketamine into clinical settings.