Preclinical toxicological study of prolonged exposure to ketamine as an antidepressant

Depression is one of the most common mentally debilitating diseases in the world. Ketamine has been recently identified as a potential novel antidepressant. Further animal model evaluations of the use of ketamine as an antidepressant are necessary to determine safety parameters for clinical use. Therefore, the objective of this study was to perform toxicological tests of prolonged treatment using three different doses of ketamine in adult male rats.

The animals were divided into four groups: three treated with 5, 10 or 20 mg/kg of ketamine and a control group treated with saline solution. Intraperitoneal route of treatment was administered daily for 3 weeks. Body weight, water and food intake were measured once a week, as well as evaluation of the functional observational battery, which includes methodic monitoring of motor activity, motor coordination, behavioral changes, and sensory/motor reflex responses. Upon completion of treatment period, all animals were euthanized by decapitation followed by immediate collection of samples, which included brain structures and blood for neurochemical, hematological and biochemical analyses.

Rats treated with the highest tested dosage (20 mg/kg) of ketamine had lower weight gain in the 1st and 2nd weeks of treatment and all experimental groups had measurable alterations in the serotoninergic system.

Our data indicate that the alterations observed are minor and due to a predicted mechanism of action, which implies that ketamine is a promising drug for repurposing as an antidepressant.