New study reveals the epigenetic effects of Citalopram

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nasibi
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New study reveals the epigenetic effects of Citalopram

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The first study of its kind. Finally a step in the right direction.

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

Riya R. Kanherkar, Bruk Getachew, [...], and Antonei B. Csoka

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."

"postmarketing clinical trials documented adverse effects mostly in terms of sexual dysfunction including anorgasmia, erectile dysfunction, genital anesthesia, and diminished libido in almost 75% of treated patients [6, 10–12]. Interestingly, these side effects appear to endure after treatment in some cases [13, 14], which is hard to explain using a standard pharmacological model.

"A plausible cause of these persistent side effects is changes to the epigenome [1–3].
The epigenome of a cell is a unique, dynamic entity consisting of distinct DNA methylation patterns across gene enhancers, promoters, and bodies along with histone modifications that do not involve any changes to the actual DNA sequence...
Epigenetic changes resulting from environmental effects such as traumatic life events can rewire neural circuits and alter neurotransmitter and endocrine systems resulting in stress-related psychiatric disorders such as major depression or posttraumatic stress disorder [15]. Based on this evidence, it can be posited that potential unknown mechanisms of action of SSRIs, as well as side effects, could be through epigenetic modification of genes [1, 2, 15]."

"Finally, top physiological systems affected by citalopram identified by IPA included nervous system development diseases and function with 24 genes involved in neurotransmission (p value = 1.25E − 02), 23 genes related to outgrowth of neurites (p value = 1.59E − 02), 9 genes related to excitatory postsynaptic potential (p value = 1.48E − 02), 6 genes related to quantity of synapse (p value = 1.21E − 02), and 3 genes related to loss of dendritic spines (p value = 1.42E − 02). Additionally, 47 genes related to morphology of the nervous system (p value = 1.95E − 02), 35 genes related to development of the central nervous system (p value = 1.45E − 02), 21 genes related to sensation (p value = 3.67E − 03), 11 genes related to development of the cerebral cortex (p value = 1.20E − 02), 8 genes related to abnormal morphology of the hippocampus (p value = 1.72E − 02), 7 genes related to abnormal morphology of the synapse (p value = 2.96E − 03), and 3 genes related to development of the hypothalamus (p value = 1.50E − 03) were identified (Supplement 8). These results, in particular, were interesting because of the known mechanism of citalopram action on the nervous system-based serotonin transporter, along with unknown targets affected by epigenetic mechanisms, that can be further delineated in the future."

Among the genes downregulated (turned off) are also those related to the neuroendocrine system. Like Gnrh, LH, FSH, the dopa pathway, Oxytocin etc.

"We have previously outlined a potential mechanism for understanding the direct and indirect effects of environmental factors, including pharmaceutical drugs [1, 15] on the epigenome. Here, we attempted to confirm the hypothesis that pharmacological agents can cause permanent changes via epigenetic reprogramming. The results show that our first test drug, citalopram, can cause genome-wide DNA methylation alterations as revealed by significant differential methylation in hundreds of genes, as well as predicted impact on signaling pathways and/or physiological systems"

"One potential limitation with this pilot study is that HEK-293 cells have not been shown to express high levels of the serotonin transporter, SERT, nor been shown to synthesize high amounts of serotonin in the extracellular medium, compared to neurons. Hence, in this case, we argue that the effects of citalopram seen on DNA methylation in these cells are more likely to be 5HT-independent. HEK-293 cells are known to abundantly express a diverse repertoire of receptors such as β2-adrenergic, muscarinic acetylcholine, sphingosine-1-phosphate, P2Y1 and P2Y2, corticotropin-releasing factor type 1, and somatostatin- and thyrotropin-releasing hormone receptors, and citalopram has been shown to interact strongly with some of these receptors, in the concentration range used in this study, so it may well be eliciting epigenetic effects through these pathways. Moreover, the data is consistent with our initial hypothesis that the epigenetic effects of chemicals could be both direct (acting directly on DNA or DNA-modifying enzymes) and indirect (acting through receptors or signaling pathways) [1, 15], in which case a direct effect on SERT is not necessary to induce epigenetic changes. It is also possible that in the presence of 5-HT and SERT, we may see different epigenetic effects of citalopram from those observed in the HEK-293 cells. In any case, we intend to repeat this experiment using primary human neurons as the target cells, rather than a proliferating cell line, in order to gain greater insights into potential in vivo effects."

https://www.ncbi.nlm.nih.gov/pmc/articl ... po=3.60825

There are alot of other interesting points in this study. May be others could chime in on that.
Last edited by nasibi on Sun Oct 21, 2018 6:25 am, edited 3 times in total.
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anacleta
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Re: New study reveals the epigenetic effects of Citalopram

Unread post by anacleta »

It seems very relevant!
I see that it is public since July! I look for new things every day but this is new to me
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anacleta
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Re: New study reveals the epigenetic effects of Citalopram

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3.2.1. Reproductive and Sexual Function
The OXT gene, producing oxytocin, is downregulated by citalopram. Since oxytocin plays a significant role in parturition and milk ejection and is also implicated in cognition, tolerance, adaptation, and complex sexual and maternal behavior, its downregulation by SSRIs may be one of the underlying causes of sexual dysfunction seen in many cases [12, 19].


Who knows if women with PSSD have higher risks of pregnancy failure and childbirth?
I feel an extra condemnation on me :(
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Re: New study reveals the epigenetic effects of Citalopram

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So it's a complex damage...
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Re: New study reveals the epigenetic effects of Citalopram

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HEK 293 cells were supposedly derived from a human adrenal gland and has characteristics similar to neurons. Definitely a very interesting study. Makes the case stronger for epigenetic mechanisms being the cause of PSSD.
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Re: New study reveals the epigenetic effects of Citalopram

Unread post by TalkingAnt »

Another interesting point - the gut microbiome can modify your epigenome. This could explain why some PSSD people improve when their gut microbiome improves.

Gut bacteria can produce short chain fatty acids. Valproate is a SCFA, although I dont think it is produced by bacteria. Some SCFA produced by gut bacteria, like butyrate, are HDAC inhibitors.

So maybe what has happened to us is:

1. Gut microbiome is already screwed up from poor diet, lifestyle, antibiotics, other factors
2. Gut microbiome thus lacks proper epigenome-regulating bacteria
3. Take SSRI, which causes epigenetic modifications, thus PSSD
4. Lack of proper gut bacteria fails to reverse epigenetic modifications. Healthy gut people may not get PSSD because of this.

So the solution could be to restore gut bacteria such as to promote healthy epigenetic regulation. Or alternatively, directly regulate the epigenome with exogenous substances.

Good article on this:

http://clinical-epigenetics.imedpub.com ... ?aid=18979
Last edited by TalkingAnt on Sun Oct 21, 2018 3:04 pm, edited 1 time in total.
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nasibi
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Re: New study reveals the epigenetic effects of Citalopram

Unread post by nasibi »

Gut microbiome is BS. The epigentic modifications done by SSRIs is mainly DNA hypermethylation, which in turn attracts HDAC. You are right about SCFA acting as HDAC inhibitors. I have suggested Keto deit (ß-hydroxyButyrate) or Valproate for that purpose in my previous posts.

But HDAC inhibitors alone won't solve the problem, because of the persisting upstream problem of DNA hypermethylation. I think the only way would be to trial pharmaceutical DNA hypomethylating agents like Decitabine. If the first cycle shows no improvement, further cycles can be augmented with Keto deit or Valproate for HDAC inhibition.
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Re: New study reveals the epigenetic effects of Citalopram

Unread post by Snake »

Question for all those science freaks here... Basing on this research, are those DNA-something changes reversible or should we start worrying more?
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nasibi
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Re: New study reveals the epigenetic effects of Citalopram

Unread post by nasibi »

Snake wrote:Question for all those science freaks here... Basing on this research, are those DNA-something changes reversible or should we start worrying more?
They are reversible with drugs like Decitabine.
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Trazohell
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Re: New study reveals the epigenetic effects of Citalopram

Unread post by Trazohell »

nasibi wrote:
Snake wrote:Question for all those science freaks here... Basing on this research, are those DNA-something changes reversible or should we start worrying more?
They are reversible with drugs like Decitabine.
What is with Valporate? It can reverse epigentic changes too I thought?
Steven that had always PSSD from Trazodone cured with it and Ella One, you think I will try these first?
June 2015 - April 2016 Fluoxetine
April 2016 - March 2017 Fluvoxamine
December 2017 9 days Trazodone
After Trazodone PSSD: loss of libido & spontaneous/night/morning erections, prostate/pelvic pain, genital numbness, lower sperm count, Anhedonia
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