Increased sensitivity to psychomotor effects of ketamine enantiomers in the Wistar-Kyoto depression model.
Journal of psychiatric research – April 01, 2025
Source: PubMed
Summary
Groundbreaking research reveals that depressed subjects may be more sensitive to ketamine's effects than previously thought. Scientists compared two forms (enantiomers) of this promising antidepressant in a depression model using specialized Wistar-Kyoto rats. The S-form showed stronger immediate psychomotor effects than its R-counterpart, particularly in depressed subjects. However, with repeated treatment, tolerance developed, suggesting side effects may decrease over time.
Abstract
Ketamine, a fast-acting antidepressant, is a racemic mixture, composed of equal amounts of R- and S-ketamine. Preclinical studies are comparing them to better understand their role in therapeutic and undesirable effects. An important research gap is that studies do not use long clinically relevant protocols to compare the desired and undesired effects of ketamine enantiomers in modeled and control animals. In our preclinical study, we explored the behavioral effects of R- and S-ketamine at 10 mg/kg in clinically relevant treatment protocol using Wistar-Kyoto rats as a depression model and Wistar rats as a control. Undesirable psychomotor effects were evaluated with locomotor stimulation and sensitization, ataxia, and stereotypy. Persistent effects associated with therapeutic outcomes were evaluated by measuring working memory, anxiety, and behavioral despair. We found that S-ketamine has stronger acute psychomotor effects compared to R-ketamine and that Wistar-Kyoto rats are more sensitive to these effects compared to Wistar rats. After repeated treatment, sensitization to locomotor stimulating effects, and tolerance to ataxic effects of S-ketamine develops. We found no persistent changes due to ketamine treatments. Taken together, our results may indicate that depressed patients would be more prone to negative side effects of ketamine, compared to healthy controls. However, after repeated treatment, tolerance to side effects may develop and make the treatment more tolerable. Future preclinical and clinical studies are needed to address neurobiological mechanisms and clinical relevance of higher sensitivity to the psychomotor effects of ketamine, and the development of tolerance to psychomotor effects of ketamine in depressed individuals.