Ketamine and serotonergic psychedelics both show promise as rapid-acting antidepressants, though through different primary mechanisms: ketamine modulates glutamate, while serotonergic psychedelics increase serotonin signaling. However, downstream effects like mTORC1 signaling and GABAA receptor activity appear similar, which may explain their shared antidepressant properties. Research on serotonergic psychedelics remains less advanced than on ketamine, and both face regulatory and methodological challenges, including difficulties with placebo controls in trials and the need for long-term observation.
In adult male rats exposed to repeated corticosterone (a model of depression), ketamine restored the expression of reelin, a protein implicated in depression, and both reelin and ketamine rescued synaptic levels of mTOR and its activated form p-mTOR in the hippocampus and cerebellum, which had been reduced by corticosterone. Reelin, but not ketamine, also normalized serotonin transporter clustering on peripheral lymphocytes. These results suggest ketamine modulates reelin expression and support exploring reelin itself as a potential fast-acting antidepressant.