Antidepressant, anxiolytic and procognitive effects of subacute and chronic ketamine in the chronic mild stress model of depression
In the chronic mild stress rat model, daily ketamine (optimal ~10 mg/kg) produced sustained antidepressant effects with onset at about one week—faster than imipramine—and both subacute and chronic regimens fully reversed CMS-induced anxiety-like behaviour and cognitive deficits. This demonstrates ketamine’s long-term antidepressant, anxiolytic and procognitive efficacy with notable translational potential.
Authors
- Papp, M.
- Gruca, P.
- Lason-Tyburkiewicz, M.
Published
Abstract
Ketamine is the prototype of a new generation of antidepressant drugs, which is reported in clinical studies to be effective in treatment-resistant patients, with an effect that appears within hours and lasts for a few days. Chronic mild stress (CMS) is a well-established and widely used animal model of depression, in which anhedonia, anxiogenesis and cognitive dysfunction can be observed reliably. Studies using acute or brief ketamine treatment following withdrawal from CMS have replicated the clinical finding of a rapid onset of antidepressant action. However, there have been no CMS studies of chronic daily ketamine treatment or continued stress following ketamine treatment, which would have greater translational potential in relation to the long-term maintenance of antidepressant effects. Wistar rats were drug treated following an initial 2 weeks of CMS exposure, which continued alongside daily drug treatment. A first experiment tested a range of chronic (5 weeks) ketamine doses (5–30 mg/kg); a second compared the effects of subacute (3–5 days) and chronic (5 weeks) treatment. CMS-induced anhedonic, anxiogenic and dyscognitive effects, as measured, respectively, by decreased sucrose intake, avoidance of open arms in the elevated plus maze and loss of discrimination in the novel object recognition test. A sustained antidepressant-like effect of ketamine in the sucrose intake test was observed in both experiments, with an onset at around 1 week, faster than imipramine, and an optimum dose of 10 mg/kg. Anxiogenic and dyscognitive effects of CMS, in the elevated plus maze and novel object recognition test, respectively, were fully reversed by both subacute and chronic ketamine treatment. Daily treatment with ketamine in the CMS model causes sustained long-term antidepressant, anxiolytic and procognitive effects. The demonstration of a procognitive effect of ketamine may have particular translational value.
Research Summary of 'Antidepressant, anxiolytic and procognitive effects of subacute and chronic ketamine in the chronic mild stress model of depression'
Introduction
Over the past decades, conventional antidepressant drugs have shown limited gains in overall efficacy and remain slow to act, typically requiring 4–6 weeks for clinical benefit. The discovery that a single infusion of the NMDA-receptor antagonist ketamine produces rapid antidepressant effects in some treatment‑resistant patients prompted extensive preclinical and clinical investigation. In animal work using the chronic mild stress (CMS) model of depression, which models anhedonia (decreased responsiveness to reward) and also produces anxiogenesis and cognitive deficits, prior studies have largely examined single or brief ketamine treatments given after withdrawal from stress and have reported rapid but short-lived antidepressant-like effects. Papp and colleagues designed the present study to address four gaps in that literature. They sought to determine whether repeated daily ketamine treatment could sustain antidepressant-like effects during ongoing stress, to characterise dose–response relationships, to compare the time of onset of ketamine effects with conventional antidepressant treatment (imipramine), and to test whether chronic or subacute ketamine could reverse CMS‑induced anxiety and cognitive deficits. Two experiments are reported: one exploring a range of ketamine doses over chronic administration, and a second comparing subacute versus chronic treatment with a single dose on behavioural endpoints including sucrose intake, elevated plus maze (EPM) performance and novel object recognition (NORT).
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- APA Citation
Papp, M., Gruca, P., Lason-Tyburkiewicz, M., & Willner, P. (2017). Antidepressant, anxiolytic and procognitive effects of subacute and chronic ketamine in the chronic mild stress model of depression. Behavioural Pharmacology, 28(1), 1-8. https://doi.org/10.1097/FBP.0000000000000259
References (3)
Papers cited by this study that are also in Blossom
Abdallah, C. G., Averill, L. A., Krystal, J. H. · Annals of the New York Academy of Sciences (2015)
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Permoda-Osip, A., Kisielewski, J., Bartkowska- Sniatkowska, A. et al. · Pharmacopsychiatry (2014)
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