The Hidden Key to Beating Depression?
Ketamine, a well-known sedative, has gained a lot of attention in the world of neuroscience and psychiatry for its ability to reduce depressive symptoms rapidly and effectively, even in those who have not gained relief from typical antidepressants. Indeed, here on Inspire The Mind (ITM), we’ve published articles on the drug and the effects it has on mental health, and have relayed evidence from a King’s College London research team demonstrating it may even be beneficial in other mental health disorders like anorexia.
You might be surprised to learn that ketamine offers these benefits. In addition to its sedative effects, ketamine is also known for its mind-altering, or psychotomimetic, properties (hallucinations, confusion and sensory disturbances can occur), which have made it a popular party drug in recent years. The same sensations that fuel its recreational use also contribute to its potential for psychological addiction.
For these reasons, ketamine itself is clearly not the perfect antidepressant. Therefore, it is important that steps are taken to uncover exactly how ketamine can produce antidepressant effects, so that new drugs may be developed which replicate its antidepressant effects, but do not induce psychotomimetic changes nor have addictive potential.
This was the purpose of a study which was undertaken here at the Stress Psychiatry and Immunology lab (SPI lab; the team that brings you ITM) and recently published in the International Journal of Neuropsychopharmacology. In this article, I will explain to you what we did, what we found, and what this means for antidepressant research.
What did we do and why did we do it?
To begin to understand how ketamine may be producing antidepressant effects, we used our well-established model of ‘depression in a dish’. This involves the use of human brain cells, derived from the hippocampus (a region of the brain thought to produce new brain cells). The hippocampus plays a role in depression, with research suggesting that people with depression may have a reduced ability to produce new neurons in this region of the brain.
There is now a lot of research to support the notion that having chronically high levels of inflammation – essentially the body’s natural response to injury or infection – can increase the risk of depression. Inflammation involves the release of various substances, including proteins called cytokines. These cytokines act like messengers, helping immune cells communicate and respond to threats. When your body has an injury or infection, this response is helpful because it promotes healing. But when inflammation lasts for a long time, like in some people with depression, these cytokine levels stay high, leading to negative effects on brain and mood. This is why many people with depression have been found to have elevated levels of these inflammation-related proteins in their blood.
In many studies published from our group, we have demonstrated that when you treat our hippocampal cells with cytokines, they have reduced levels of growth and maturation. Furthermore, we have previously shown that treating the cells with antidepressants at the same time as a cytokine prevents these changes from happening. This suggests that classic antidepressants protect the brain from the negative effects of inflammation, and this may be one of the ways in which they reduce depressive symptoms.
Based on this, we wanted to see if ketamine could have the same effect. Therefore, we gave the cells treatment with cytokines as we have done before, but this time we also gave them some ketamine. Within our bodies, we produce an abundance of cytokines – under names like interleukin 1-beta (IL-1b), IL-6, IL-10, tumour necrosis factor alpha (TNF-a), and many more. In our experiment, we focused on two specific cytokines, IL-6 and IL-1β (as our previous work showed that these reduce growth of brain cells), to see if ketamine could stop the negative effects caused by each of them.
We then looked at how the cells grew and matured, as well as looking at what genes they were expressing and what proteins they were producing.
What did we find?
Using this model, we revealed that just like antidepressants, ketamine protects the cells from the negative effects of cytokines. In other words, ketamine prevents cytokines from reducing the number of new neurons which are generated. This is the case for both IL-6 and IL-1b.
As we looked closer at how genes and proteins were affected, we were able to figure out how ketamine might be working on a molecular level. Interestingly, we discovered that ketamine protects the cells from inflammation in different ways, depending on which cytokine we used.
When looking at cells which were given IL-1b, we saw that ketamine prevents the production of neurotoxic (meaning, poisonous to the brain) components of a biological pathway called the kynurenine pathway. However, this was not the case for IL-6. Indeed, our study was unable to reveal exactly how ketamine is protecting against IL-6.
What does this all mean?
This study essentially uncovers that ketamine can protect the brain from the detrimental effects of inflammation. Since antidepressants produce the same outcome, this could be one of the reasons underlying ketamine’s ability to reduce depressive symptoms.
The fact that ketamine works through different mechanisms depending on the type of inflammation suggests that depression can be approached from multiple angles to achieve the same result. Ketamine’s ability to protect against different types of inflammation, and via different mechanisms, also highlights its versatility as a treatment.
While ketamine seems to have a broad approach, this opens the door to the possibility of treating patients differently based on their specific inflammatory profile (for example, which specific cytokines are elevated in their blood). Although more research is needed, our study offers insights into how ketamine shields the brain from inflammation, leading to more personalized treatments for depression in the future.
Comments