Ketamine is an NMDA antagonist, meaning it blocks the NMDA receptor, which is involved in neuroplasticity. Originally licensed by the FDA for use as an anesthetic, ketamine exists in two forms: R-ketamine and S-ketamine. R-ketamine and S-ketamine are enantiomers–two different molecules that are mirror images of each other. S-ketamine, also known as esketamine, comprises the majority of ketamine research, especially in clinical trials. It is FDA-approved for the treatment of depression as a nasal spray, though R-ketamine is not. However, R-ketamine has shown promise in early clinical trials since it may possess stronger antidepressant effects while also inducing fewer side effects. Some ketamine metabolites (broken-down products of ketamine by metabolism) have also shown promise as antidepressants in preliminary research.
Ketamine’s response rate for patients with treatment resistant depression is 25% to 85% at 24 hours after infusion. This demonstrates two main benefits of ketamine over traditional antidepressants. Firstly, as previously mentioned, one-third of patients with depression do not respond to treatment with traditional antidepressants, so ketamine’s ability to treat a large percentage of them is noteworthy. Secondly, traditional antidepressants often take weeks or months to take effect, whereas ketamine is generally able to show benefits within hours or days. Ketamine is also able to treat symptoms that are typically treatment-refractive under traditional antidepressants, such as anhedonia, amotivation, and suicidality.
Ketamine’s mechanisms of action for its antidepressant effects are still ambiguous and multi-faceted, but researchers primarily attribute ketamine’s therapeutic effects to upregulated neuroplasticity induced via glutamatergic modulation. By dissecting the molecular mechanisms of action in which Ketamine affects depression, scientists are hoping to find novel and more effective medications that target these pathways.
Inside the Mind 