Discovery reveals how low-dose ketamine, a 'lifesaving' drug for major depression, alleviates symptoms withing hours

University at Buffalo neuroscientists have identified the binding site of low-dose ketamine, providing critical insight into how the medication, often described as a wonder drug, alleviates symptoms of major depression in ...

Published in Molecular Psychiatry , the UB discovery will also help scientists identify how depression originates in the brain, and will stimulate research into using ketamine and ketamine-like drugs for other brain disorders. A lifesaving drug Ketamine has been used since the 1960s as an anesthetic, but in 2000, the first trial of far lower doses of ketamine proved its rapid efficacy in treating major depression and suicidal ideation.

"Due to its fast and long-lasting effects, low-dose ketamine proved to be literally a lifesaving medicine," says Gabriela K. Popescu, Ph.D., senior author on the research and professor of biochemistry in the Jacobs School of Medicine and Biomedical Sciences at UB. Traditional antidepressants take months to kick in, which increases the risk for some patients to act on suicidal thoughts during the initial period of treatment. Ketamine provides almost instant relief from depressive symptoms and remains effective for several days and up to a week after administration. Since this observation was published in the early 2000s, ketamine clinics, where the drug is administered intravenously to treat depression, have been established in cities nationwide.

These images demonstrate the different binding sites in NMDA receptors that the UB team has discovered are responsible for ketamine's distinct clinical effects, as an anesthetic at high doses and as an anti-depressant at very low doses. The image on the left shows ketamine bound in the central pore of the receptor, which results in anesthetic action; the one on the right shows ketamine bound in the lateral sites, which results in anti-depressive action. Credit: Jamie Abbott Read more

Extended dose-response relationships. Credit: Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02729-9 Read more

Putative interactions between S-KET+ and NMDA receptors. Credit: Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02729-9 Read more