A comparative assessment of the antidepressant efficacy of ketamine, psilocybin, and fluoxetine in a chronic stress model

In a mouse model of depression induced by chronic social defeat stress, a single dose of either ketamine or psilocybin reversed social avoidance within 24 hours, with effects lasting up to 14 days. In contrast, the SSRI fluoxetine showed no effect after a single dose or 7 days of repeated administration; antidepressant-like effects only appeared after 14 days of continuous treatment. These results mirror clinical patterns, where traditional SSRIs require weeks to work, while ketamine and psilocybin produce rapid and sustained effects. The findings highlight the potential of fast-acting agents as alternatives for treating major depressive disorder.

Study at a glance

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.