What do recent ketamine findings mean for depression treatment?

Psychiatrist Dr Tiago Reis Marques discusses what new research findings on ketamine mean for treatment-resistant mental conditions such as major depressive disorder.

Ketamine is currently administered intravenously in clinical settings as a fast-acting antidepressant for treatment-resistant depression. Recent findings from researchers at Karolinska Institutet in Sweden uncovered the mechanisms behind ketamine’s antidepressant effects, demonstrating that ketamine directly stimulates AMPA receptors – part of the nerve cell that receives signals – leading to the increased release of adenosine (a neurotransmitter) which inhibits presynaptic glutamate release.

The researchers said the findings are new knowledge that can explain some of the rapid effects of the medicine and suggest that the “antidepressant action of ketamine can be regulated by a feedback mechanism.”

Dr Tiago Reis Marques, psychiatrist and researcher with over 15 years of experience studying and treating psychiatric disorders, and CEO of Pasithea Therapeutics, which has ketamine clinics in the UK and Us to treat depression and post-traumatic stress disorder (PTSD), explains why these new findings provide hope for new treatment options for major depressive disorder in the future.

“It is a very interesting study because our understanding of how ketamine works from its basic action has been that ketamine works on the NMDA receptor which is a glutamatergic receptor, so, there is basically a rapid release of a neurotransmitter called glutamate.  

“This is why everyone thought that ketamine is a fast-acting antidepressant, it increases the levels of glutamate in the brain. This was a bit contradictory as the literature shows that in patients with depression, there was already an increase of glutamate levels. The question now was that, if patients already have an increase in glutamate levels, how can a drug that further increases this have an antidepressant property?

“Then research progressed which showed that ketamine also works on a receptor called AMPA, which is also a glutamatergic receptor. Research shows that blockage of the AMPA receptor was fundamental for ketamine’s antidepressant properties. 

“What this new study shows is that, when ketamine blocks the AMPA receptor, it actually induced an increase of substance called adenosine which is a neurotransmitter – which then binds to adenosine receptors. There’s two types of adenosine receptor – A1 and A2. In this case, when it binds to the A1 receptor it causes a reduction in glutamate levels. So, basically, ketamine can bind to two glutamatergic receptors.

“Therefore, what the study shows is that ketamine has a complex mechanism of action with region-specific changes on glutamate levels in the brain.”

Dr Marques says the animal study is well designed, but that, as it is hard to conduct this type of experiment in humans, and because of the complexity of human psychiatric disorders, the findings need to be extrapolated from the animal study.

“As the study was done in rodents – in terms of its regional actions on the brain – a rat brain is very different from the human brain, but that is something that will be further explored in future studies. 

“The findings of this study will not change the way that ketamine is administered. But, they show the action through the AMPA receptor and that the A1 receptor is also involved. So, if we are trying to find future antidepressant drugs we might not look to other NMDA blockers but instead look for drugs that act on AMPA or on the downstream A1 receptor.

“By elucidating a method of action, it will allow us to produce more, and eventually better antidepressants and possibly, without the negative aspects of ketamine – such as the side effects and the potential for abuse. We are always trying to produce drugs with more efficacy and fewer side effects and we can only do that when we understand how these how drugs work, and what the mechanisms are that are involved in depression. So, the next step for this research will be to try to relate these findings into a human antidepressant effect.”

Marques highlights that the efficacy of ketamine treatment in patients with treatment-resistant depression is between 50 to 70 per cent.

“It is not a miracle drug but it is definitely a revolution in terms of having a new drug as a treatment for depression, as it has a completely different mechanism of action to other antidepressants. The study is another piece of the puzzle for what seems to be a very complex drug.”

Dr Marques, CEO at Pasithea