A comparative assessment of the antidepressant efficacy of ketamine, psilocybin, and fluoxetine in a chronic stress model
Małgorzata Domżalska, Joanna Kwiatkowska, Iwona Cichoń, Ewa Sokołowska
Scientific Reports November 26, 2025 DOI: 10.1038/s41598-025-29642-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Male C57BL/6J mice subjected to chronic social defeat stress |
| Interventions | fluoxetine ketamine psilocybin |
| Duration | 14 days post-treatment |
| Topics | Depression Ketamine Psilocybin Serotonin Esketamine |
| Keywords | Fluoxetine Chronic stress Depression economics Serotonin reuptake inhibitor Pharmacology Paroxetine Tricyclic antidepressant Clinical trial Imipramine Therapeutic effect Clinical efficacy Social defeat Serotonin uptake inhibitors |
| Citations | 2 |
| Key points | A single dose of ketamine or psilocybin rapidly and durably reversed social avoidance behavior in mice, whereas fluoxetine required 14 days of continuous treatment to show effects. |
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 h 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 h, 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.