Kanherkar, 2018 The Effect of Citalopram on Genome-Wide DNA Methylation of Human Cells

[Rhiannon]

Int J Genomics 2018, 8929057

The Effect of Citalopram on Genome-Wide DNA Methylation of Human Cells

Riya R Kanherkar  1 , Bruk Getachew  2 , Joseph Ben-Sheetrit  3 , Sudhir Varma  4 , Thomas Heinbockel  1 , Yousef Tizabi  2 , Antonei B Csoka  1

DOI: 10.1155/2018/8929057

Quote

 

Abstract

Commonly used pharmaceutical drugs might alter the epigenetic state of cells, leading to varying degrees of long-term repercussions to human health. To test this hypothesis, we cultured HEK-293 cells in the presence of 50 μM citalopram, a common antidepressant, for 30 days and performed whole-genome DNA methylation analysis using the NimbleGen Human DNA Methylation 3x720K Promoter Plus CpG Island Array. A total of 626 gene promoters, out of a total of 25,437 queried genes on the array (2.46%), showed significant differential methylation (p < 0.01); among these, 272 were hypomethylated and 354 were hypermethylated in treated versus control. Using Ingenuity Pathway Analysis, we found that the chief gene networks and signaling pathways that are differentially regulated include those involved in nervous system development and function and cellular growth and proliferation. Genes implicated in depression, as well as genetic networks involving nucleic acid metabolism, small molecule biochemistry, and cell cycle regulation were significantly modified. Involvement of upstream regulators such as BDNF, FSH, and NFκB was predicted based on differential methylation of their downstream targets. The study validates our hypothesis that pharmaceutical drugs can have off-target epigenetic effects and reveals affected networks and pathways. We view this study as a first step towards understanding the long-term epigenetic consequences of prescription drugs on human health.

 

 

Free full text https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083487/

 

https://www.hindawi.com/journals/ijg/2018/8929057/

 

Epigenetics is a new hot sexy topic, so there are a lot of papers speculating that ADs work their beneficent wonders via epigenetic mechanisms, yada yada (very little evidence of the beneficent wonders, and these people should be alarmed rather than tickled that their drugs are causing changes to our genes, so I don't have much time for that nonsense). The usual pharmaceutical industry spin doctor scienceyness.

 

This paper is strictly about an experiment that demonstrated that cells cultured with citalopram did, yes, end up showing a lot of epigenetic changes, and they actually (hallelujah) mention the possibility that maybe this might not always have results on ONLY the desired targets, whatever those are.

 

I like it because it supports my hypothesis that the delayed AD withdrawal syndrome that we so often see is probably due to adaptive alterations, epigenetic and otherwise, which are not quickly reversible. I also think it's probably harder to fix and reverse those changes when the nervous system is struggling with the aftermath of rapid discontinuation, while a slow taper allows those processes to reverse at a more do-able pace.

Edited February 15, 2020 by Altostrata
Journals format

[India]

@Rhiannon Thank you for this.  Would you be able to  speculate on how this intersects with the concept of   kindling and those of us that CTed , then to reinstate at lower doses much later and are now tapering at a slower rate.

 

I came across this study:

 “it has been shown that chronic SSRIs can reduce the 5-HT tissue levels reflecting decreased intraneuronal 5-HT concentrations.“ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547473/

 

Can you comment on what any of this means for the possibility of recovery in respect to reversing those adaptations? 

[Caspur]

Hi Rhiannon,

This is very interesting and I agree strongly with your conclusions. Thanks for posting it.

 

In my mind it also suggests people must have different degrees of susceptibility to these cellular-level impacts. Some really struggle to taper even when they go super slow. It almost seems that for them, the impacts are very slow to reverse and as you say, if they have already had their CNS thrown into complete disarray by a doctor led taper, things are even worse for them.

 

For me its evidence that people must, must, must taper slowly to avoid harm. It just seems some don't want to listen :- ( I see this time and again (I am an Admin in a venlafaxine withdrawal group on Fb - we have nearly 6000 members now and we only accept those wanting to taper due to the overwhelming numbers that want to join - 35% of applicants are not admitted - we just don't have the time and knowledge to deal with everyone).

 

Cheers

Casper

[drugged]

@Rhiannon

 

I was just looking at a paper on epigenetic changes induced by fluoroquinolones and the role they play in renal toxicity and inhibiting the repair of damaged collagen.  My very first thought when I read about the targets of this class of drugs, DNA gyrase and topoisomerase IV, was "what could possibly go wrong?"  The assumption that there are significant differences between said enzymes in bacteria and eukaryotic cells, not even taking into account the hypothesized origin of mitochondria.  The same hubris that thought tinkering with serotonin metabolism would somehow only effect the brain, specifically the "mood."  All of this is fascinating stuff scientifically speaking but to carry out an experiment of global scale on unsuspecting living beings?  

 

It seems it is our nature to mess about with processes of which we have little understanding.  

[Rhiannon]

On 2/1/2020 at 4:49 AM, drugged said:

@Rhiannon

 

I was just looking at a paper on epigenetic changes induced by fluoroquinolones and the role they play in renal toxicity and inhibiting the repair of damaged collagen.  My very first thought when I read about the targets of this class of drugs, DNA gyrase and topoisomerase IV, was "what could possibly go wrong?"  The assumption that there are significant differences between said enzymes in bacteria and eukaryotic cells, not even taking into account the hypothesized origin of mitochondria.  The same hubris that thought tinkering with serotonin metabolism would somehow only effect the brain, specifically the "mood."  All of this is fascinating stuff scientifically speaking but to carry out an experiment of global scale on unsuspecting living beings?  

 

It seems it is our nature to mess about with processes of which we have little understanding.  

Well, somebody's nature, anyway. There's a lot of greed and stupidity and sheer self-interest and not caring about other people involved, I think.

[Rhiannon]

On 1/31/2020 at 2:33 AM, Caspur said:

Hi Rhiannon,

This is very interesting and I agree strongly with your conclusions. Thanks for posting it.

 

In my mind it also suggests people must have different degrees of susceptibility to these cellular-level impacts. Some really struggle to taper even when they go super slow. It almost seems that for them, the impacts are very slow to reverse and as you say, if they have already had their CNS thrown into complete disarray by a doctor led taper, things are even worse for them.

 

For me its evidence that people must, must, must taper slowly to avoid harm. It just seems some don't want to listen :- ( I see this time and again (I am an Admin in a venlafaxine withdrawal group on Fb - we have nearly 6000 members now and we only accept those wanting to taper due to the overwhelming numbers that want to join - 35% of applicants are not admitted - we just don't have the time and knowledge to deal with everyone).

 

Cheers

Casper

Wow, Casper, that sounds like a challenging job! And so needed. 

 

One of the most frustrating things about working with people on this forum (among the many things that are hard) is when people come in and just ignore our advice because they assume they are an exception, or that we don't really know what we're talking about since it's not the same thing their doctor says. After the first couple dozen times that happens and you see them crash and burn it's easy to get a little cynical. That's when I know it's time to step back from this work for a while. 

 

The individual variations are interesting, I agree. I think there are large scale trends that are pretty consistent: when people are started on these drugs in childhood or youth while the brain is still forming, when people are on them for a long time like say 5 years or longer and especially after decades, and when people have a history of past going on and off and on and off various doses of various drugs, that's when it's going to be trickier to taper and they really need to go slow and be prepared for the process taking years and maybe not getting all the way off everything. (That's another thing that's hard--it's a process of realization and acceptance and you can't really push that, but you know where it's going to end up.)

 

Anyway, glad you're doing that work.

 

 

[Rhiannon]

On 1/31/2020 at 2:15 AM, India said:

@Rhiannon Thank you for this.  Would you be able to  speculate on how this intersects with the concept of   kindling and those of us that CTed , then to reinstate at lower doses much later and are now tapering at a slower rate.

 

I came across this study:

 “it has been shown that chronic SSRIs can reduce the 5-HT tissue levels reflecting decreased intraneuronal 5-HT concentrations.“ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547473/

 

Can you comment on what any of this means for the possibility of recovery in respect to reversing those adaptations? 

India, I can only speculate like I have before, in all my other posts on this subject. I don't really have anything new.

[Caspur]

On 2/7/2020 at 7:06 PM, Rhiannon said:

Wow, Casper, that sounds like a challenging job! And so needed. 

 

One of the most frustrating things about working with people on this forum (among the many things that are hard) is when people come in and just ignore our advice because they assume they are an exception, or that we don't really know what we're talking about since it's not the same thing their doctor says. After the first couple dozen times that happens and you see them crash and burn it's easy to get a little cynical. That's when I know it's time to step back from this work for a while. 

 

The individual variations are interesting, I agree. I think there are large scale trends that are pretty consistent: when people are started on these drugs in childhood or youth while the brain is still forming, when people are on them for a long time like say 5 years or longer and especially after decades, and when people have a history of past going on and off and on and off various doses of various drugs, that's when it's going to be trickier to taper and they really need to go slow and be prepared for the process taking years and maybe not getting all the way off everything. (That's another thing that's hard--it's a process of realization and acceptance and you can't really push that, but you know where it's going to end up.)

 

Anyway, glad you're doing that work.

 

 

Hi Rhiannon,

Sorry, I completely missed your reply! Yes I totally agree with your point about people coming in, in bad way and then ignoring the advice. This might sound negative, but we have to remove some of them as they really upset the members who are following the advice and still suffering withdrawal symptoms. I don't like doing it but, some people just do not want to listen and as you say, think they are the exception. Unlike this forum, Fb doesn't allow us to isolate threads, so everyone can see their comments as plain as day. Like you we are all volunteers and have to support the majority who want to taper safely. The numbers just keep growing and we turn down about 40% of new member requests! (i.e. people who are starting the drug, not tapering etc, who we just can't support).

Cheers

Caspur