Researchers target brain mechanism to extend ketamine’s antidepressant effects

Researchers at Vanderbilt University have found that boosting a signaling pathway in the brain can prolong ketamine’s antidepressant effects, at least in mice. The team found that compared with mice that received only ketamine, mice who got the modified treatment showed less-pronounced depressive behaviors 8 weeks after the treatment (Science 2025, DOI: 10.1126/science.abb6748). Although the precise mechanism that ketamine uses to reduce depression symptoms isn’t fully understood, the drug has been shown to have remarkably fast and powerful antidepressant effects in people with depression that have resisted other treatments. Ketamine’s antidepressant effects persist even after the drug has exited the body. Previous work has suggested that this may be because it helps rebuild connections between neurons.

But it is not a one-dose miracle cure. People who undergo this treatment have to get an infusion about twice a week, which is a considerable burden, especially for this group. Additionally, greater numbers of infusions raise the risk for side effects like nausea, slight increases in blood pressure, and some dissociative experiences. Which is why the Vanderbilt researchers have tried to extend ketamine’s longevity to reduce these burdens.

To do that, the team boosted an extracellular signal–regulated kinase (ERK) pathway in neurons by targeting the DUSP6 protein with a commercially available inhibitor called BCI. Increasing the ERK pathway activity prolonged ketamine’s effectiveness in mouse models of depression.

This paper shows that targeting the downstream effects that ketamine causes in the brain can enhance the drug’s longevity, says Lisa Monteggia, the lead author of the study. This is possible only with an understanding, even an incomplete one, of ketamine’s mechanism of action, she says:
“ ‘Why’ is not trivial.”

John Krystal of Yale University, whose work first showed the antidepressant effects of the drug and who was not involved with this new research, says this “elegant” study could help more people access ketamine as an antidepressant.

“Most ketamine clinics are oversubscribed. They have a limited number of treatment bays or treatment rooms,” he says. “The more you reduce the number of treatments that people need, the more patients that can be treated with the same facility.”

The next logical step would be to try to translate this research to humans. BCI is not considered safe to use as a drug in people, but the work does show that activating the ERK pathway could be a new target for developing new antidepressants. “This is more of a proof of concept,” Monteggia says.