Esketamine produces antidepressant effects in mice subjected to chronic restraint stress by activating glutamatergic neurons in the medial prefrontal cortex. In a study of 150 male C57BL/6J mice, those treated with esketamine showed reduced immobility in tail suspension and forced swim tests and increased sucrose preference compared with saline-treated controls. Immunofluorescence staining indicated higher c-Fos expression in glutamatergic neurons after esketamine treatment. Chemogenetic activation of these neurons mimicked the antidepressant effects, while their inhibition blocked esketamine's benefits.
Classic psychedelics, especially psilocybin, show promise for treating depression, with several randomized controlled trials indicating that one or a few sessions of psychedelic-assisted psychotherapy can produce rapid and lasting antidepressant effects in patients with treatment-resistant depression. Mechanistically, these substances quickly increase neurotrophic factors, enhance neuroplasticity, and reorganize brain networks, creating a window for psychotherapy. However, the specific molecular and circuit-level mechanisms remain unclear, with debate between the 5-HT2A receptor-dependent hypothesis and the TrkB neurotrophic pathway-dependent hypothesis. Key challenges include psychedelic-related risks, incomplete mechanistic understanding, lack of standardized protocols, and insufficient long-term safety data.