KETAMINE OPTIMIZED TO WORK LONGER

 KETAMINE OPTIMIZED TO WORK LONGER

For the millions of people living with major depressive disorder (MDD), standard treatments often fall short. About one in ten Americans deals with MDD at any given time, and up to a fifth will experience it at some point. The usual antidepressants don’t work for roughly 30 percent of patients, leaving a massive gap in care.

Ketamine has been a rare bright spot. Given at low doses, it can lift depression within hours, even for people who haven’t responded to anything else. The catch? Its effects fade quickly, so patients need regular infusions. That means more trips to the clinic, a higher risk of side effects like dissociation, and the looming possibility of addiction or relapse if treatments stop.

Now, a research team at Vanderbilt University may have found a way to stretch out ketamine’s benefits. In experiments led by neuroscientists Lisa Monteggia and Ege Kavalali, they figured out how to push a single dose’s antidepressant action from about a week to as long as two months.

The breakthrough came from understanding how ketamine works in the brain. It turns out that ketamine’s rapid antidepressant effects depend on a signaling pathway called ERK, which helps drive changes in the brain’s synapses. Earlier research showed that blocking ERK erases the long-term effects of ketamine, but not the initial lift. Monteggia’s team wondered: What if you could keep that ERK pathway switched on for longer?

They tested a drug called BCI, which boosts ERK activity by inhibiting a specific protein in the brain. When used with ketamine, BCI extended the antidepressant effects for up to two months in lab models. While BCI isn’t ready for clinical use, the results prove it can prolong ketamine’s benefits by targeting these signaling pathways.

“This study was built around a testable model for how ketamine acts so quickly,” said Monteggia, who leads the Vanderbilt Brain Institute. She and Kavalali hope their work will spark further research into molecules that might safely extend the life of a single ketamine dose.

If these findings translate to patients, they could make life a lot easier for people with stubborn depression, potentially reducing both the need for frequent treatments and the risk of side effects.

The study, published in Science, included contributions from graduate student Natalie Guzikowski and postdoc Ji-Woon Kim. It’s early days, but this research could lead to longer-lasting depression relief and a lighter treatment burden for those who need it most.