Towards Novel Antidepressant Strategies: A Comparative Study of Ketamine, Psilocybin, and Fluoxetine in a Chronic Stress Model
Małgorzata Domżalska, Joanna Kwiatkowska, Iwona Cichoń, Ewa Sokołowska
Research Square October 7, 2025 DOI: 10.21203/rs.3.rs-7269356/v1 via OpenAlex
Summary
AI-generated from the abstractIn a mouse model of depression using chronic social defeat stress, a single dose of either ketamine or psilocybin reversed social avoidance behavior within 24 hours, with effects lasting up to 14 days. By contrast, the SSRI fluoxetine showed no effect after a single dose or after 7 days of daily treatment; antidepressant-like effects appeared only after 14 days of continuous administration. These rapid and sustained effects of ketamine and psilocybin mirror clinical patterns and highlight their potential as fast-acting alternatives to conventional antidepressants like fluoxetine.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Male C57BL/6J mice subjected to chronic social defeat stress |
| Interventions | Fluoxetine Ketamine Psilocybin |
| Duration | 24 hours, 7 days, and 14 days post-treatment |
| Key finding | A single dose of ketamine or psilocybin produced rapid and durable antidepressant-like effects in mice, whereas fluoxetine required 14 days of continuous treatment to show similar effects. |
Abstract
Abstract Depression is a debilitating mental disorder affecting millions worldwide, yet current pharmacological treatments, such as selective serotonin reuptake inhibitors (SSRIs), often exhibit delayed onset and limited efficacy. The chronic social defeat (CSD) stress model in mice is a well-established preclinical paradigm for inducing depression-like behaviors and evaluating antidepressants effectiveness. This study compared the efficacy of both acute and chronic fluoxetine with acute ketamine and psilocybin treatment in male C57BL/6J mice subjected to CSD. Fluoxetine showed no significant effects 24 hours after a single dose or following 7 days of repeated administration; antidepressant-like effects only appeared after 14 days of continuous treatment. In contrast, a single dose of either ketamine or psilocybin significantly reversed social avoidance behavior at 24 hours, with sustained effects observed at 7- and 14-days post-treatment. These findings suggest that ketamine and psilocybin elicit rapid and durable, antidepressant-like responses in this preclinical model, in contrast to traditional SSRIs, like fluoxetine, which requires extended treatment duration, mirroring clinical efficacy patterns. The results support the utility of the CSD model in evaluating antidepressant efficacy and highlight the therapeutic potential of fast-acting agents such as ketamine and psilocybin as alternatives to conventional treatments for major depressive disorder.