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.
Ketamine, an antidepressant, interacts with the HPA axis, but its behavioral effects' dependence on this axis is unknown. In male and female mice subjected to chronic unpredictable stress, ketamine (30 mg/kg) or vehicle was given with or without metyrapone to block corticosterone production. No significant drug effects on behavior were observed. Males had higher fecal corticosterone levels and stress-induced increases than females. Ketamine lowered the corticosterone response to a novel stressor only in males. Corticosterone levels correlated with immobility in a behavioral test across all mice, suggesting shared neural circuitry for endocrine and behavioral responses that may be ketamine-responsive only in males.