A new study from Northwestern Medicine has identified for the first time how ketamine works so quickly, and how it might be adapted for use as a drug without side effects.
Ketamine is one of the fastest-acting antidepressants. The compound works within hours of administration compared to traditional antidepressants, which can take up to several weeks to kick in.
Researchers at Northwestern Medicine have completed a new study, published in Nature Communications, in mice investigating how the compound works so quickly. The team discovered that the compound increases the activity of the very small number of newborn neurons, which are part of ongoing neurogenesis in the brain.
Neurons are always being made in the brain at a slow rate, and it is commonly understood that increasing the number of neurons leads to behavioural changes in an individual. Other antidepressants work by increasing the rate of neurogenesis, in other words, increasing the number of neurons, however this takes weeks to happen.
The team have discovered that ketamine produces behavioural changes simply by increasing the activity of the existing new neurons, which can happen immediately when the cells are activated by ketamine.
Lead author of the study, 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, commented: “We narrowed down the population of cells to a small window that is involved.
“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.
Kessler continued: “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 of time. 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 behavioural effects of ketamine. The reason is these newborn neurons form synapses (connections) that activate the other cells in the hippocampus. This small population of cells acts like a match, starting a fire that ignites a bunch of activity in a lot of other cells that produce the behavioural effects.
“However, it has not been understood that the same behavioural changes can be accomplished by increasing the activity of the new neurons without increasing the rate at which they are born. This obviously is a much more rapid effect.”
For the study, the team 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.
They demonstrated that if they silenced the activity of these cells, ketamine didn’t work anymore 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.
The team
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