Increased sensitivity to psychomotor effects of ketamine enantiomers in the Wistar-Kyoto depression model

Elersič, Kristian (author), Banjac, Anamarija (author), Živin, Marko (author), Zorović, Maja (author)

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.

• Language: English
• Keywords: antidepressant, depression, enantiomers, ketamine, model of depression, psychomotor effects, Wistar-Kyoto
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 307-317
• Numbering: Vol. 184
• PID: 20.500.12556/RUL-168110
• UDC: 616.89
• ISSN on article: 0022-3956
• DOI: 10.1016/j.jpsychires.2025.02.061
• COBISS.SI-ID: 230490371
• Publication date in RUL: 28.03.2025

Record is a part of a journal

• Title: Journal of psychiatric research
• Publisher: Elsevier
• ISSN: 0022-3956
• COBISS.SI-ID: 5639434

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: antidepresivi, depresija, enantiomeri, ketamin, model depresije, psihomotorični učinki, Wistar-Kyoto

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P3-0171
• Name: Plastičnost živčevja v fizioloških in patofizioloških razmerah

• Funder: ARIS - Slovenian Research and Innovation Agency
• Funding programme: Young researchers