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

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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 by Altostrata
Journals format

Started on Prozac and Xanax in 1992 for PTSD after an assault. One drug led to more, the usual story. Got sicker and sicker, but believed I needed the drugs for my "underlying disease". Long story...lost everything. Life savings, home, physical and mental health, relationships, friendships, ability to work, everything. Amitryptiline, Prozac, bupropion, buspirone, flurazepam, diazepam, alprazolam, Paxil, citalopram, lamotrigine, gabapentin...probably more I've forgotten. 

Started multidrug taper in Feb 2010.  Doing a very slow microtaper, down to low doses now and feeling SO much better, getting my old personality and my brain back! Able to work full time, have a full social life, and cope with stress better than ever. Not perfect, but much better. After 23 lost years. Big Pharma has a lot to answer for. And "medicine for profit" is just not a great idea.

 

Feb 15 2010:  300 mg Neurontin  200 Lamictal   10 Celexa      0.65 Xanax   and 5 mg Ambien 

Feb 10 2014:   62 Lamictal    1.1 Celexa         0.135 Xanax    1.8 Valium

Feb 10 2015:   50 Lamictal      0.875 Celexa    0.11 Xanax      1.5 Valium

Feb 15 2016:   47.5 Lamictal   0.75 Celexa      0.0875 Xanax    1.42 Valium    

2/12/20             12                       0.045               0.007                   1 

 

I'm not a doctor. Any advice I give is just my civilian opinion.

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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? 


1999:  Paroxetine (20mg). Age 16. 2007-2008: Fluoxetine (Prozac) for 1.5 years (age 25) Citalopram 20mg 2002-2005, 2009: Escitalopram (20mg), 2 weeks, (age 26) (adverse manic reaction)/*Valium 5mg/Temazepam 10mg 2010: Mirtazipine (Remeron)( do not remember dosage) 2010, 5 months.                     

2010-2017: Citalopram (20mg) (age 27 to 34) 2016: i.1st Sept- 31st Oct Citalopram 10mg , ii.1st November 2017-30th November 2017, Citalopram 5mg iii.1st December 2017- 4th February 2018, Citalopram 0mg, iv.5th February 2018- March 2018 Citalopram 5mg (10mg every other day) 28th February- tried titration of 5mg ( some adverse effects)

2018: 1st March 2018- 1st June Citalopram 10 mg (tablet form) /started titration 8mg , then 7 mg.2018: June 15th- 10th July Citalopram 10 mg pill every other day 2018: 10th July - 13th Sept Citalopram- 0mg  (CBD oil first month of 0mg, passiflora on and off) 2018 13th Sept Citalopram  2mg ,  approx 16th Sept 4mg , approx 25th Sept 6mg held.  2019: 11 Feb 19: 7mg (instant bad rxn) 12 Feb 19 6mg held 1 May 19 5.4mg held 5 Oct 19 5.36mg 22 Oct 19 5.29mg 30 Oct 19 5.23mg 4/NOV/19 5.18mg 12 Nov 19 5.08mg 20 Nov 19 4.77mg

(Herbal/Supplements since 1st September: Omega Fish Oil 1200mg, 663mg of EPA- 2 tablets a day, magnesium and magnesium bath salts)

I did not die, and yet I lost life’s breath
- Dante

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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


2011 - started Venlafaxine (again) at 75mg Raised to 150 mg at some point - unsure of dates. Reduced back down to 75 mg. Doctor advised this would be a lifetime, maintenance dose

2017 - Side effects now intolerable. started taper from June 15th - 5% dose reduction steps (two 12 hourly doses).

2017 - October 20th - took last does of Venlafaxine - 4 mg. Debilitating symptoms followed.

2017/18 - diazepam - 8mg/day for 1 month - 7 week taper Feb 2018

2017/18 - duloxetine - max 90mg - now stopped

2018 - Feb 25mg quetiapine, increased to 50mg.

2018 - March/April - increased venlafaxine slowly (10mg steps) to 75 mg/day. Recovery from withdrawal followed.

2018 - July 13 - stopped quetiapine after 2 month taper. Late July - had to reinstate quetiapine due to intolerable withdrawal. Now tapering from 25mg

2019 - June - stopped quetiapine after 10 month taper. Mild insomnia only symptom.

2020 - sept  - venlafaxine 17.1 mg.

 

Taper history details

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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.  


1994  Venlafaxine XR 300mg, 2003 tapered, 2004 off briefly back to 37.5 then 75mg, held, June 2019 up to  150mg, Aug.12 tapered down to 112.5mgs, Oct. 21, 2019 96mg;  Dec. 8, 2019  90mg, Jan. 8 2020 81mg, Feb. 4, 75mg;

2003/2004? Diazepam 10mg/bedtime

2013 Lyrica 300mg to 25mg; April 6, 2020 17mg; April 28, <5mg; May 7, 2020 Lyrica 0 mg!

2013 Tramadol 50mg tablets, 200mg/day divided

2005? Trazodone 50mg bedtime, Feb. 12, 2020 40mg, March 7, 25mg; Oct 1 20mg

2009? Zolpidem 5mg at bedtime. Nov. 9, 2019 Zolpidem 0 mg! 

1990? Omeprazole 20mg in morning.

2010? Levothyroxine 75mcg morning

2011? Liothyronine 5mcg morning

1999? Buspirone 30mg twice a day  August 2019 15mg once a day,  Oct.21, 2019 2.5mg evening  Oct. 25, 2019 Buspirone 0 mg!

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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.


Started on Prozac and Xanax in 1992 for PTSD after an assault. One drug led to more, the usual story. Got sicker and sicker, but believed I needed the drugs for my "underlying disease". Long story...lost everything. Life savings, home, physical and mental health, relationships, friendships, ability to work, everything. Amitryptiline, Prozac, bupropion, buspirone, flurazepam, diazepam, alprazolam, Paxil, citalopram, lamotrigine, gabapentin...probably more I've forgotten. 

Started multidrug taper in Feb 2010.  Doing a very slow microtaper, down to low doses now and feeling SO much better, getting my old personality and my brain back! Able to work full time, have a full social life, and cope with stress better than ever. Not perfect, but much better. After 23 lost years. Big Pharma has a lot to answer for. And "medicine for profit" is just not a great idea.

 

Feb 15 2010:  300 mg Neurontin  200 Lamictal   10 Celexa      0.65 Xanax   and 5 mg Ambien 

Feb 10 2014:   62 Lamictal    1.1 Celexa         0.135 Xanax    1.8 Valium

Feb 10 2015:   50 Lamictal      0.875 Celexa    0.11 Xanax      1.5 Valium

Feb 15 2016:   47.5 Lamictal   0.75 Celexa      0.0875 Xanax    1.42 Valium    

2/12/20             12                       0.045               0.007                   1 

 

I'm not a doctor. Any advice I give is just my civilian opinion.

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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.

 

 


Started on Prozac and Xanax in 1992 for PTSD after an assault. One drug led to more, the usual story. Got sicker and sicker, but believed I needed the drugs for my "underlying disease". Long story...lost everything. Life savings, home, physical and mental health, relationships, friendships, ability to work, everything. Amitryptiline, Prozac, bupropion, buspirone, flurazepam, diazepam, alprazolam, Paxil, citalopram, lamotrigine, gabapentin...probably more I've forgotten. 

Started multidrug taper in Feb 2010.  Doing a very slow microtaper, down to low doses now and feeling SO much better, getting my old personality and my brain back! Able to work full time, have a full social life, and cope with stress better than ever. Not perfect, but much better. After 23 lost years. Big Pharma has a lot to answer for. And "medicine for profit" is just not a great idea.

 

Feb 15 2010:  300 mg Neurontin  200 Lamictal   10 Celexa      0.65 Xanax   and 5 mg Ambien 

Feb 10 2014:   62 Lamictal    1.1 Celexa         0.135 Xanax    1.8 Valium

Feb 10 2015:   50 Lamictal      0.875 Celexa    0.11 Xanax      1.5 Valium

Feb 15 2016:   47.5 Lamictal   0.75 Celexa      0.0875 Xanax    1.42 Valium    

2/12/20             12                       0.045               0.007                   1 

 

I'm not a doctor. Any advice I give is just my civilian opinion.

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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.


Started on Prozac and Xanax in 1992 for PTSD after an assault. One drug led to more, the usual story. Got sicker and sicker, but believed I needed the drugs for my "underlying disease". Long story...lost everything. Life savings, home, physical and mental health, relationships, friendships, ability to work, everything. Amitryptiline, Prozac, bupropion, buspirone, flurazepam, diazepam, alprazolam, Paxil, citalopram, lamotrigine, gabapentin...probably more I've forgotten. 

Started multidrug taper in Feb 2010.  Doing a very slow microtaper, down to low doses now and feeling SO much better, getting my old personality and my brain back! Able to work full time, have a full social life, and cope with stress better than ever. Not perfect, but much better. After 23 lost years. Big Pharma has a lot to answer for. And "medicine for profit" is just not a great idea.

 

Feb 15 2010:  300 mg Neurontin  200 Lamictal   10 Celexa      0.65 Xanax   and 5 mg Ambien 

Feb 10 2014:   62 Lamictal    1.1 Celexa         0.135 Xanax    1.8 Valium

Feb 10 2015:   50 Lamictal      0.875 Celexa    0.11 Xanax      1.5 Valium

Feb 15 2016:   47.5 Lamictal   0.75 Celexa      0.0875 Xanax    1.42 Valium    

2/12/20             12                       0.045               0.007                   1 

 

I'm not a doctor. Any advice I give is just my civilian opinion.

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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


2011 - started Venlafaxine (again) at 75mg Raised to 150 mg at some point - unsure of dates. Reduced back down to 75 mg. Doctor advised this would be a lifetime, maintenance dose

2017 - Side effects now intolerable. started taper from June 15th - 5% dose reduction steps (two 12 hourly doses).

2017 - October 20th - took last does of Venlafaxine - 4 mg. Debilitating symptoms followed.

2017/18 - diazepam - 8mg/day for 1 month - 7 week taper Feb 2018

2017/18 - duloxetine - max 90mg - now stopped

2018 - Feb 25mg quetiapine, increased to 50mg.

2018 - March/April - increased venlafaxine slowly (10mg steps) to 75 mg/day. Recovery from withdrawal followed.

2018 - July 13 - stopped quetiapine after 2 month taper. Late July - had to reinstate quetiapine due to intolerable withdrawal. Now tapering from 25mg

2019 - June - stopped quetiapine after 10 month taper. Mild insomnia only symptom.

2020 - sept  - venlafaxine 17.1 mg.

 

Taper history details

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