Ketamine, an NMDA receptor antagonist, produces rapid and robust antidepressant effects in patients with treatment-resistant major depressive disorder and bipolar depression. Sub-anesthetic dose infusions (0.5 mg/kg for 40 minutes) show efficacy within 24 hours, with relapse often within one week. Ketamine also rapidly reduces suicidal thinking. The drug's mechanism involves blocking NMDA receptors on inhibitory interneurons, leading to increased glutamate release and activation of AMPA receptors, which triggers intracellular signaling cascades that stimulate synaptic plasticity. Challenges include lack of FDA approval, need for standardized dosing and administration, and risks of abuse and long-term side effects with repeated use. Future research requires better control conditions, identification of enriched subgroups, and development of glutamate biomarkers.
A single low-dose infusion of the anesthetic ketamine produces rapid antidepressant effects in people with treatment-resistant major depressive disorder. In this trial, depressed individuals with a family history of alcohol use disorder showed a longer-lasting antidepressant response to ketamine compared to those without such a family history. Adding the drug riluzole did not extend or enhance ketamine's antidepressant durability. The findings suggest that family history of alcohol use disorder may predict a more durable ketamine response, which should be accounted for in future ketamine depression studies.