In male mice exposed to , ketamine and psilocybin produced faster and longer-lasting antidepressant-like effects than fluoxetine.
Evidence
This preclinical treatment comparison in male C57BL/6J mice found single-dose ketamine or psilocybin reversed social avoidance at 24 h and through 14 days, while fluoxetine needed 14 days.
Caveat
Because this was a mouse chronic social defeat model measuring social avoidance, the findings suggest antidepressant potential but do not prove benefit in people with major depressive disorder.
Simplified
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 (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.
Key numbers
51%
Social Avoidance Reversal
Percentage of C57BL/6J mice exhibiting social avoidance after chronic stress.
14 days
Fluoxetine Treatment Duration
Duration of fluoxetine administration needed to elicit significant behavioral changes.
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