Increased sensitivity to psychomotor effects of ketamine enantiomers in the Wistar-Kyoto depression model.
Kristian Elersič, Anamarija Banjac, Marko Živin, Maja Zorović
Journal of Psychiatric Research April 1, 2025 DOI: 10.1016/j.jpsychires.2025.02.061 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Wistar-Kyoto rats (depression model) and Wistar rats (control) |
| Interventions | R-ketamine S-ketamine |
| Dose | 10 mg/kg |
| Topics | Depression Ketamine Esketamine |
| Keywords | Depression mood disorder Clinical depression Ketamine ketalar Special k Dissociative anesthetic Psychopharmacology drug research Pharmaceutical studies Medication science Antidepressant Enantiomers Model of depression Psychomotor effects Wistar-kyoto |
| Citations | 3 |
| Key points | S-ketamine has stronger acute psychomotor effects than R-ketamine, and Wistar-Kyoto rats are more sensitive to these effects, but no persistent therapeutic changes were observed. |
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.