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Acute antidepressant epigenetic therapy

After 4 weeks of blogposts on depression research, I hope that you understand that the field of depression faces two main challenges. The first one is that only 50% of patients respond well to widely used antidepressants like Prozac. The second challenge is that existing medications take a relatively long time (from 4 to 6 weeks) to have desired effects. Many people suffer vastly in those 6 weeks, give up on their treatment and some might even endanger their lives. Ketamine and psilocybin are two antidepressant remedies that tackle both of these challenges. In this blogpost, I want to introduce a potential new way to solve the second problem - the problem of the speed of antidepressant effects. A team at the University of São Paulo (USP) in Brazil is suggesting that future therapies could use epigenetic modulators that “erase” the consequences of stress [1].


Let me first explain key terms and the context before delving into the study. Epigenetics (see Figure 1) is the study of how behavior and environment might induce heritable changes without altering our DNA [2]. The Greek prefix “epi” means over or around, so it is useful to think of epigenetics as the study of everything that is “around” the double helical structure of DNA. Sometimes our bodies might want to not “read” all of the genes in our bodies, so they are “turned off”. This is done with the use of epigenetic modulators that are various chemicals that are modulating the cellular protein machinery that is needed to “read” genes.

Figure 1: Epigenetics visualized

It is a well documented correlation that stress can often trigger episodes of depression. It turns out that exposure to stress can trigger certain epigenetic markers in our brain as well. Many of the alterations occur in genes associated with neuroplasticity, the brain’s ability to change in response to experience. A specific type of epigenetic modulation called DNA methylation has been observed “around” crucial genes for neuroplasticity. DNA methylation “turns off” these genes either by not allowing the cellular machinery that reads genes to access these genes, or by itself recruiting proteins that will hide these genes from gene-reading proteins.


Let me sum up the context. In the cases of depression, stress causes our brains to “turn-off” key neuroplasticity genes by the use of an epigenetic marker called DNA methylation. That’s all the context you need to know to understand the brunt of this new development in depression research. Okay, so what did these scientists from São Paulo find?


Long-story short – they made mice stressed to the brink of hopelessness and then injected a drug that would interfere with how DNA methylation works [3]. To be more technical, the scientists inhibited an enzyme that catalyzes DNA methylation. They then measured the extent to which genes were suppressed in the hippocampus and the prefrontal cortex. The research group found that when mice were administered drugs that stop DNA methylation from working, the animals would show less hopelessness - it would take them longer to give up from swimming in the test where they are forced to swim for as long as possible. (look Figure 2). The effects of these epigenetic modifying-drugs was fast-acting. The mice were “less depressed” (as measured in the forced swimming test) one hour after the treatment. The findings also suggest that the mechanism through which the antidepressant effects occur was mediated through genes responsible for neuro plasticity.

Figure 2: The forced Swim Test (FST) that tests learned helplessness

Don’t get too excited yet. These sorts of antidepressant medications will need sometime to be fully developed. One of the reasons is that the drugs used are not “selective” enough. What I mean by this is that DNA methylation-targeting drug could also change the epigenetics of genes that we do not want to modulate. For example, one of the drugs is a cancer drug used to treat gliomas (specific type of brain tumor [4]). Cancer drugs usually want to kill all of the cells in the location where they are administered because they want to exterminate the fast replicating tumor cells. This sort of non-selective, “all-out war” is definitely not selective enough to target stress-induced epigenetic changes in our sensitive and delicate brains.


I think it is reasonable to take-away from this study that epigenetic modulation could be the next-next generation of drugs. My personal view is that we should be repurposing the currently used therapeutic substances such as ketamine or psychedelics or therapy to meet the immediate needs of depressed patients. However, there might be specific cases where epigenetic antidepressants might be useful.


This marks the end of the blogpost series on depression. I hope that those who have diligently read through this series (I hope you exist!!) will understand that depression research is a booming field that's full of miraculous discoveries almost on a weekly basis. The fact that about 264 million people around the globe suffer from depression [5] is a big motivator both for private philanthropists that invest into research and governmental programs. The future for the field is bright and so are the prospects of allowing more people achieve remission from depression through next-generation depression treatments.


The article was prepared on behalf of INA by Matas Vitkauskas


Sources:


[1] - https://neurosciencenews.com/epigenetics-depression-17527/

[2] - https://www.cdc.gov/genomics/disease/epigenetics.htm#:~:text=Epigenetics%20is%20the%20study%20of,body%20reads%20a%20DNA%20sequence.

[3] - https://link.springer.com/article/10.1007/s12035-020-02145-4

[4] -https://en.wikipedia.org/wiki/Glioma#:~:text=A%20glioma%20is%20a%20type,of%20all%20malignant%20brain%20tumours.

[5] - https://www.who.int/news-room/fact-sheets/detail/depression



Sources of images:


Cover image https://www.whatisepigenetics.com/new-link-found-between-dna-methyltransferase-and-antidepressants/

Figure 1 https://nugenis.eu/en/touchpoint-epigenetics/

Figure 2 https://www.neiglobal.com/Members/MonthInPsychopharmPost/tabid/509/topic/45/Default.aspx