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


Objective: This study aimed to assess the antidepressant effects of subanesthetic doses of ketamine in patients with treatment-resistant depression (TRD), focusing on the impact of a single ketamine infusion, a series of repeated infusions, and the maintenance of response with ongoing infusions.

Methods: Forty-one participants with TRD completed a randomized, double-blind crossover trial comparing single infusions of ketamine and midazolam (an active placebo). Following a relapse of depressive symptoms, participants underwent six open-label ketamine infusions administered thrice weekly over a 2-week period. Responders, defined as those achieving ≥50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores, received an additional four infusions weekly during a maintenance phase.

Results: Compared to midazolam, a single ketamine infusion significantly reduced depressive symptoms at the primary endpoint (24 hours post-infusion). Linear mixed models demonstrated cumulative antidepressant effects with repeated ketamine infusions, leading to a doubling of the antidepressant response rate. Fifty-nine percent of participants met response criteria following repeated infusions, typically requiring three infusions to achieve response. MADRS scores remained stable during weekly maintenance infusions among responders.

Conclusions: Repeated ketamine infusions exhibit cumulative and sustained antidepressant effects in patients with TRD. Responders maintained reduced depressive symptoms through weekly maintenance infusions. These findings highlight effective administration strategies for ketamine in TRD and suggest avenues for optimizing clinical application in future studies.

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