Repeated Dosing of Ketamine in the Forced Swim Test: Are Multiple Shots Better Than One?

The anesthetic drug ketamine has been repurposed as a rapid-acting antidepressant for major depressive disorder (MDD), including treatment-resistant cases, unlike slower monoaminergic antidepressants. Its fast onset suggests a unique mechanism studied in reverse translational rodent models. Most research examines single ketamine doses, but MDD often requires ongoing treatment. This review of rodent studies using repeated ketamine dosing in the forced swim test (FST) found that repeated dosing can paradoxically increase immobility at high doses (50 or 100 mg/kg). However, several studies show repeated dosing more effectively decreases immobility than a single dose, with longer-lasting behavioral effects. The findings indicate repeated ketamine has prominent depression-related effects in rodents, which may help optimize human MDD treatment.

Study at a glance

Abstract

The anesthetic drug ketamine has been successfully repurposed as an antidepressant in human subjects. This represents a breakthrough for clinical psychopharmacology, because unlike monoaminergic antidepressants, ketamine has rapid onset, including in Major Depressive Disorder (MDD) that is resistant to conventional pharmacotherapy. This rapid therapeutic onset suggests a unique mechanism of action, which continues to be investigated in reverse translational studies in rodents. A large fraction of rodent and human studies of ketamine have focused on the effects of only a single administration of ketamine, which presents a problem because MDD is typically a persistent illness that may require ongoing treatment with this drug to prevent relapse. Here we review behavioral studies in rodents that used repeated dosing of ketamine in the forced swim test (FST), with an eye toward eventual mechanistic studies. A subset of these studies carried out additional experiments with only a single injection of ketamine for comparison, and several studies used chronic psychosocial stress, where stress is a known causative factor in some cases of MDD. We find that repeated ketamine can in some cases paradoxically produce increases in immobility in the FST, especially at high doses such as 50 or 100 mg/kg. Several studies however provide evidence that repeated dosing is more effective than a single dose at decreasing immobility, including behavioral effects that last longer. Collectively, this growing literature suggests that repeated dosing of ketamine has prominent depression-related effects in rodents, and further investigation may help optimize the use of this drug in humans experiencing MDD.