Study: Ketamine acts as a speedster of antidepressants

According to a new study from Northwestern University, ketamine operates as an antidepressant sprinter, functioning in hours rather than weeks like other antidepressants. For the first time, the Northwestern Medicine study has pinpointed exactly how ketamine works so swiftly, and how it could be altered for use as a medicine without the negative side effects. Ketamine acts as a fast antidepressant in mice by enhancing the activity of a limited number of newborn neurons that are part of the brain’s ongoing neurogenesis.

New neurons are always being made at a slow rate. It’s been known that increasing the number of neurons leads to behavioral changes. Other antidepressants work by increasing the rate of neurogenesis, in other words, increasing the number of neurons. But this takes weeks to happen. By contrast, ketamine produces behavioral changes simply by increasing the activity of the existing new neurons. This can happen immediately when the cells are activated by ketamine. “We narrowed down the population of cells to a small window that is involved,” said lead study author Dr. John Kessler, a professor of neurology at Northwestern University Feinberg School of Medicine and the Ken and Ruth Davee Professor of Stem Cell Biology. “That’s important because when you give ketamine to patients now, it affects multiple regions of the brain and causes a lot of adverse side effects. But since we now know exactly which cells we want to target, we can design drugs to focus only on those cells.”

The side effects of ketamine include blurred or double vision, nausea, vomiting, insomnia, drowsiness, and addiction. The study was published recently in Nature Communications. “The goal is to develop an antidepressant that doesn’t take three to four weeks to work because people don’t do well during that period,” Kessler said. “If you are badly depressed and start taking your drug and nothing is happening, that is depressing in itself. To have something that works right away would make a huge difference.”

“We prove neurogenesis is responsible for the behavioral effects of ketamine,” Kessler said. “The reason is these newborn neurons form synapses (connections) that activate the other cells in the hippocampus. This small population of cells acts as a match, starting a fire that ignites a bunch of activity in a lot of other cells that produce the behavioral effects.” “However, it has not been understood that the same behavioral changes can be accomplished by increasing the activity of the new neurons without increasing the rate at which they are born,” Kessler said. “This is a much more rapid effect.”

For the study, Northwestern scientists created a mouse in which only the very small population of newborn neurons had a receptor that allowed these cells to be silenced or activated by a drug that did not affect any other cells in the brain. Scientists showed if they silenced the activity of these cells, ketamine didn’t work anymore. But if they used the drug to activate this population of cells, the results mirrored those of ketamine. This showed conclusively that it is the activity of these cells that is responsible for the effects of ketamine, Kessler said.