A new study by Northwestern University shows how ketamine works to counteract the effects of depression on the brain.
We know by anecdotal, and with mounting clinical evidence, that psychedelics can have potentially pioneering effects in mental health conditions such as depression. But how does this process actually work?
Northwestern Medicine has published a new study outlining how ketamine works in a fast-acting way compared to traditional antidepressants. Ketamine can work within hours compared to several weeks for traditional SSRIs, and the new study (in mice) shows that ketamine works by increasing the activity of a very small number of newly generated neurons.
SSRIs work by increasing the number of neurons (neurogenesis), but this is a slow process. The new study shows that ketamine goes a different path – by increasing the activity of existing neurons, rather than waiting for new neurons to be generated. This stimulation can occur immediately when neurons are activated by ketamine treatments.
The study was published in the journal Nature Communications. See the full press release below.
The study is first to determine how it works; It can be adapted for use without many side effects
Peer review publications
- Scientists have discovered that ketamine increases the activity of newborn neurons
- Neonatal neurons act like a match to excite the activity of other neurons
- The knowledge will allow the design of a drug that targets only a small group of cells
Chicago – Ketamine is one of the most powerful antidepressants, working within hours compared to more common antidepressants which can take several weeks. But ketamine can only be given for a limited period of time due to its many side effects.
Now, a new study in Northwestern Medicine identifies for the first time exactly how ketamine works so quickly, and how it can be adapted for use as a drug without side effects.
The study in mice showed that ketamine acts as a rapid antidepressant by increasing the activity of a very small number of newborn neurons, which are part of the ongoing process of neurogenesis in the brain.
New neurons are always being formed at a slow rate. It is known that an increase in 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 new, existing neurons. This can happen immediately when the cells are activated by ketamine.
“We’ve narrowed the number of cells down to a small window involved,” said study lead author Dr. “This is important because when you give ketamine to patients now, it affects multiple areas of the brain and causes a lot of harmful side effects. But because we now know exactly which cells we want to target, we can design drugs to focus only on those cells.”
Side effects of ketamine include blurred or double vision, nausea, vomiting, insomnia, drowsiness, and addiction.
The study was recently published in Nature Communications.
The goal is to develop an antidepressant that works faster
“The goal is to develop an antidepressant that doesn’t take three to four weeks to work because people haven’t performed well during that time period,” Kessler said. “If you are severely depressed and start taking medication and nothing happens, that is frustrating in itself. Getting something that works right away will make a huge difference.”
Neonatal neurons act like matching to excite activity in neurons
“We demonstrated that neurogenesis is responsible for the behavioral effects of ketamine,” Kessler said. The reason is that these nascent neurons form synapses (connections) that activate other cells in the hippocampus. This small group of cells acts like a match, starting a fire that ignites a range of activity in a lot of other cells that produce the behavioral effects.”
“However, it is not understood that the same behavioral changes can be achieved by increasing the activity of new neurons without increasing their birth rate,” Kessler said. “Obviously, this is a much faster effect.”
For the study, Northwestern scientists created a mouse in which very few newborn neurons have receptors that allow these cells to be silenced or activated by a drug that does not affect any other cells in the brain. Scientists have shown that if they silence the activity of these cells, ketamine no longer works. But if they used the drug to activate this group of cells, the results mirror those of ketamine. This showed conclusively that the activity of these cells is responsible for ketamine’s effects, Kessler said.
This work was supported by grants F30MH124269, K99MH125016, and R01 MH114923 from the National Institute of Mental Health and T32GM008152 from the National Institute of General Medicine, all of the National Institutes of Health, and the Davee Foundation.