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Delayed withdrawal symptoms & "late onset" depression as a WD effect - looking for journal articles

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bubbles

Hi everyone

 

I'm trying to gather some resources - primarily journal articles or perhaps official guidelines. I am specifically after resources on two topics, but I'll make separate threads for them.

 

I have observed that many people seem to be okay for a bit after dropping meds - a bit being 2-3 months - and then there is a crash. This was my experience with my too rapid taper off Lexapro. (This isn't about me, so I'm not putting it into my personal thread. I was unable to get anyone to see it my way though. :) Absolutely no providers were prepared to entertain the possibility of a delayed withdrawal reaction. Still, it has come up so often that I feel it must exist.

 

I have been looking through the journal articles and trying to find some on my own too. So far I have found nothing that specifically documents this phenomenon. Is anyone aware of anything that I might have missed?

Cheers everyone,
Bubbles

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bubbles

I should say that that crash is probably after a too-fast taper.

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Altostrata

bubbles, this is a great question. In fact, I've tried to pursue it lately.

 

The assumption that withdrawal symptoms start immediately upon cessation appears in Schatzberg, 1997

 

You need to look at the citations for this assertion and trace it back through the years. Schatzberg, 1997 got its information from an earlier paper. Where did that paper get its information? And so forth.

 

By picking apart the trail of evidence, we might be able to show that the assumption in Schatzberg, 1997 is groundless and open up the question to new study.

 

This would be very valuable to a research project I'm working on right now (with CEPUK, Luke Montagu and Dr. James Davies), to be presented to a UK parliamentary committee.

 

If anyone wants to get involved in this, please let me know.

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bubbles

Thanks Alto. That's a great starting point. If I find anything useful for you I'll pass it on.

Cheers!

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InvisibleUnless
On 5/3/2018 at 9:19 AM, Altostrata said:

The assumption that withdrawal symptoms start immediately upon cessation appears in Schatzberg, 1997

 

You need to look at the citations for this assertion and trace it back through the years. Schatzberg, 1997 got its information from an earlier paper. Where did that paper get its information? And so forth.

 

i would be entirely unsurprised if you trace this back to someone importing it from the descriptions of other psychotropic withdrawal syndromes without doing any sort of representative trials to vet its application to antidepressant withdrawal symptomology.

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bubbles
5 hours ago, InvisibleUnless said:

i would be entirely unsurprised if you trace this back to someone importing it from the descriptions of other psychotropic withdrawal syndromes without doing any sort of representative trials to vet its application to antidepressant withdrawal symptomology.

 

That's a really good angle to take in my searching - thank you!

 

 

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Altostrata

bubbles, if you find anything about the origin of the immediate-onset theory, please let me know.

 

The citation in Schatzberg, 1997 appears to be incorrect. It is a report from the Australian government about withdrawal reactions and does not mention onset.

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bubbles

Thanks Alto. I'll keep looking. It's a slow process because I'm fitting it in among other things and this is a busy time. I'll let you know if I find anything.

 

That 1997 article - says there is "free full text" but I can't get it. :( I don't think I have enough information to find that Australian report, which might be useful, because it is clearly 20 years old.

 

 

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InvisibleUnless

the "psychiatrist.com" free full text links are to a page which requires you to enter in some personal information and credentials--you can only access the full article if you sign in.  i gather they use this information for data commercialization.  i feel like this was not always the case, but my memory may just be foggy on the notion.

 

libraries (especially school libraries or inter-library loan programs), asking your healthcare provider to snag you a copy, or writing to one or more of the authors can be tenable ways of accessing full texts.  databases like deepdyve can also provide free access to some articles in a roundabout way.

 

there are also manners in which you can allegedly infringe upon 'intellectual copyrights' in order to secure a pdf, but if you want to keep things squeaky clean then i would avoid those methods even though nobody is getting hurt and it is sometimes a legal grey area (only sometimes!).

 

i think you will probably have to end up writing to someone anyhow--someone involved with the government report, or who can at least tell you more about it.  such reports, at least in the versions offered online to the public, rarely reveal the sources of facts like the ones being incorporated in the Schatzberg article.

 

and even if you bedrock at 'expert opinion', that doesnt really tell us how that opinion came about.  prescribing experiences?  unpublished trials?  talking with other doctors?  it is a rabbithole, for sure.  if youd like to delegate anything to me, i can put some of my time into digging around, just let me know what would be most helpful.  i cannot guarantee enduring contributions, but i would like to help in what ways i can.

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bubbles

Thanks InvisibleUnless

 

I've come up to a busy time at work and school, so I've had to park this bit of research, but I still want to follow it up. I didn't know about deepdyve, so I'll follow that up.


I will get back to it, but I have to prioritize some other stuff first.

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Barbarannamated

This is what happened to me in a sloppy taper of Pristiq in 2010-11 (if I recall correctly).  I was waiting for brain zaps like I had when I was late with a dose of Effexor, but they never happened, so I marched on.  I recall that I actually felt energized and, judging by the screen name and crazy heading I came up with, perhaps a bit hypomanic..?  In retrospect, I was very disconnected, dissociated...weird. There was also someone i know stalking me online, which was 100% factual, but added to the weirdness. 

 

I don't know when I crashed, but I think it was roughly 3 months out and I've never fully recovered.  There are several drugs involved, but this was specifically after Pristiq *taper*.  I even ended up hospitalized for bradycardia. 

 

If I can help in any way, I certainly will.  I have far too much free time and have to be careful about what I focus on.  Social media (Facebook) is not my friend. 

 

I was mildly fatigued and a bit "blah" (not depressed) when I was given Zoloft samples by an MD friend long ago.  I have no basis of comparison for this withdrawal state.  

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bubbles

@Barbarannamated I often wonder whimsy made me choose Bubbles as my name here. I am not the Bubbles type! Bubbles seem optimistic so that's probably it.

 

Unfortunately, I think it is going to be a long project, trawling through papers and following citations back to their papers and so on. It may also be that I have to accept papers calling it relapse without explanation. Perhaps comparing relapse rates for unmedicated people, people with wd and people staying on. I think Robert Whitaker has looked at that. 

 

Stuart Shipko mentions it, but I think he is talking observationally about his clients, not research. Still, perhaps it is worth contacting him to ask.

 

Also, Robert Whitaker talks about worsening chronicity with them, which might have to do with WD but I don't think that's considered - I think he's looking more at population level data about being on disability etc. I don't have his book, I should see if I can get it through my library.

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Henosis

I’ve also been baffled by this and always searching for new information. Some of the newer Fava papers mention “late onset” or “delayed onset”, but I’ve never seen anything concrete.

 

Shipko and others think it’s a tardive reaction, but I have always been skeptical after experiencing it. When I stopped Paxil, the months leading up to full-blown withdrawal were uneventful and I didn’t experience any change in anxiety or OCD symptoms. I would have assumed I would have at least returned to a baseline, pre-SSRI state during this period. It seemed like the drug was still active in my brain during this time.

I did find an interesting paper examining Celexa washout. They only had six people, but it showed an approx. 3x longer half-life in the brain than blood plasma. Obviously that doesn’t explain a multi-month delay, but perhaps with some people with genetic variations / long duration of use, this actually gets extended to weeks or months.  Food for thought anyways, I am not a neurobiologist.

 

 

 

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bubbles

It is an interesting thought.

 

A related idea is the thought that the drug might be stored in our fat for a while. I have read something by Healy, I think, suggesting this, and that it might soften the withdrawal for a bit. If that is the case, I imagine it could have the effect of a delayed withdrawal. That is - it might give you effectively an extra long "half life" so you did discontinue it in March, but you've still got a bit in your system until June or July and then it's all gone.  However, I think Healy's just hypothesizing, not that he has anything concrete. Or, frankly, how you even measure that! Or the mechanism by which it might come out of our fat etc.

 

I think it is only a hypothesis, but I wonder if it might have some merit. I have a vague idea I've seen an issue somewhere that babies might still have somewhat increased risks if mom discontinued the drug even some time before the pregnancy. I'm not sure where I saw this, or how the timing worked out - ie, if it was up to a year, or if the taper was rapid etc etc. Still, it stuck in my mind and when I recently read Healy's thoughts it made me think. Worth following that up, come to think of it.


I might get in contact with Healy and ask if he has anything more on the topic.

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Bee5

Hi bubbles,

I am fascinated with this topic. I have experienced the akathisia/terror/suicidal ideation combination symptom three times in my life. I want to share these events with you in the hope that they might provide some leads for you to follow:

  1. Cold turkey off escitalopram when I found out I was pregnant. Pregnancy was fine (people speak of the phenomenon of the 'protective effects of pregnancy'), got a bit of anxiety toward the end of pregnancy. Full-on akathisia-terror-suicidal ideation within 6 days of baby's birth.
  2. Benzo cessation withdrawal following polypharmacy for postnatal depression. Full-on akathisia-terror-suicidal ideation within a period of days, not weeks or months. 
  3. Tapered off paroxetine, over 6 months (too fast), was "fine" except for some brain zaps. Four months after cessation, full-on akathisia-terror-suicidal ideation.

From the above three events, I have some ENTIRELY ANECDOTAL theories, which might help you with which directions to pursue in your research:

  • I have not encountered any overweight moms that got postpartum anxiety/depression. Therefore, I wonder if increased body fat percentage has some protective effects?
  • The akathisia I experienced was the same 9 months after cessation of escitalopram, few days after cessation of benzos, and 4 months after cessation of paxil, so it seems to me that the akathisia is a CNS regulation effect, rather than specific to certain receptors, since benzo/SSRI receptor modulation is different (to my knowledge)
  • I have read that brain zaps are linked to central temperature regulation (this is why some people get brain zaps when they have fever as a result of illness).
  • I hypothesise that SSRIs 'fill up' some storage system in the brain, which takes months to 'drain' and I think this is why people get protracted withdrawal.

Please keep us posted on this thread if you find anything related to why withdrawal is protracted/delayed.

 

Thank you for helping us find answers.

 

Regards,

Bee

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marconyc

Is it possible that the delayed onset of withdrawal is related to the effect of SSRIs on neurogenesis? If these drugs work in large part through promoting neurogenesis, that might help explain the delayed onset of effect and the delayed onset of withdrawal. I imagine that neurogenesis would take longer to increase and decrease than, say, the effect on reuptake.

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bubbles

Hi @Bee5 and @marconyc

 

Bee5, I certainly thought I was fat after my babies (gosh, I wish I could be as "fat" now, lol) but wasn't. I did know an overweight mom who had PPD though, and she was the only person I knew who was medicated for it back then (20 years ago they weren't handed out like candy quite as much).


I experienced the feeling of wellbeing from pregnancy. I've read a journal article that said that it didn't exist, or at least not in the case of antidepressant withdrawal, so I wonder if the WD can be too much (at least sometimes) for the wellbeing to cope with. If that makes sense... There is so much (hormonally) going on during a pregnancy and after the birth.

 

I have described the feeling of the delayed reaction as "the brain having enough of a store of whatever, and then running out", which is much the same as what you're saying. I do think the incidence of delayed WD is massively understated. I've seen a bunch of youtube videos where people "successfully" get off them over a few weeks, then a few months later they've "relapsed" and are back on meds. This was the case with one of the gentlemen who have "invented" the tapering strips - he used them (and presumably avoided the zaps/acute stage) but then ended up depressed and back on them again. He interpreted it - as I think most people do - as their next episode. Maybe it is. My own experience, according to the likes of Glenmullen, was more likely relapse than withdrawal. But it is so common that there must be more to it than that.

 

Marconyc, there just hasn't been any research into any of this, so I don't think anyone could comment. It would be something worth considering though - maybe in light of the next sentence. "Contrary to a widely held belief in psychiatry, studies that purport to show that antidepressants promote neurogenesis are flawed because they all use a method that cannot, by itself, distinguish between neurogenesis and neuronal death. In fact, antidepressants cause neuronal damage and mature neurons to revert to an immature state, both of which may explain why antidepressants also cause neurons to undergo apoptosis (programmed death)" - from this link:

 

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peng

In my 2-year taper of effexor ending this summer with a crash, and back on 100mg XR today, I was certainly feeling good until below 60-70mg.

There was a definite lag of several weeks in depression/anxiety flashes/extreme fatigue/loss of appetite returning.  

The same thing happened in 2006 when I tapered rapidly to zero without the knowledge we have today with, e.g, SA.

I was doing outside work in frosty weather in February 2006 for part of that time.  Possibly a bit manic?  A few days later I found myself weeping during - of all things - a tv documentary about a hero of mine, Quincy Jones.  Stuff about his early youth, IIRC.

Next day or so I found myself at my GP's who implied that if I had stopped the reduction at, say, 75mg, "we wouldn't be having this conversation now".

 

As for the 2016/2018 taper from 225mg. I find myself wondering if I was as conscientious as I think I was in carrying it out.

It is easy to press on with dose reductions when you are feeling "not too bad"?

Thus, essentially, tapering too fast.

Saw the same GP as 12 years ago (who is senior man with knowledge and experience that I respect)and from my excel spread sheet of dosage/mood, confirmed that I seem to be at my best at 150mg dose - one of the threshholds at which effexor can work best.  (Curse it.)

 

 

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Bee5

Allow me to use the analogy of the brain being a sponge. Considering the fact that something causes the sponge to fill up, and then a few months after cessation the sponge becomes empty, how were we functioning before the first "fill"? Or did life events drain the sponge initially?

And if we look at the stories on this site, it seems impossible to come off these meds because once the sponge is empty, horrific symptoms ensue, and most people end up reinstating (except those fortunate enough to have a support structure/system that allows them to become housebound).

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bubbles

Hi @Bee5

 

The way I think it happens - when the brain is unmedicated, it makes the right amount of chemicals. When we take meds, it seems that the brain reduces its output of the chemicals to compensate for all of the extra chemicals coming from the brain. The brain/sponge - after an initial stage - reduces output so that the "correct" amount of chemical is floating around. We remove the meds and the brain can't go back to normal quite fast enough, so the filling is too slow. The emptying continues as usual but this is going to


I'm confident that it does eventually go back to normal, or I wouldn't be tapering, but I have no idea how long it might take to return to normal.

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Bee5

I am holding thumbs for both us of to be able to come off the meds eventually. I am just astounded that there isn't more research going into the topic of protracted WD, and on finding 'markers' to understand what is happening chemically.

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peng
2 hours ago, Bee5 said:

Or did life events drain the sponge initially?

 

Yes.  For myself, I have come to the view that childhood/youth trauma/PTSD did do that.

One can read of the brain being altered/remapped during early life by such occurrences.

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Bee5

Thanks for the insight @peng. I would certainly be interested in finding answers for how/why external experiences (university and family stress in my case) can change/affect neurotransmitter production and/or receptor modulation.

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Colonial
On 9/11/2018 at 3:14 AM, Bee5 said:

And if we look at the stories on this site, it seems impossible to come off these meds because once the sponge is empty, horrific symptoms ensue, and most people end up reinstating (except those fortunate enough to have a support structure/system that allows them to become housebound).

 

If I had not already been qualified as disabled with nothing else to do all day but lay in bed and be physically ill, I never would have gotten as far as I have in WD..

The physical side effects have been crippling as well as the increased anxiety, and there's no possible way I could have done anything other than be "homebound" for most of the past 4 years.

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UnfoldingSky

Wondering how the research into delayed withdrawal went?

 

 

 

 

 

 

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UnfoldingSky
On 5/2/2018 at 9:09 PM, bubbles said:

Hi everyone

 

I'm trying to gather some resources - primarily journal articles or perhaps official guidelines. I am specifically after resources on two topics, but I'll make separate threads for them.

 

I have observed that many people seem to be okay for a bit after dropping meds - a bit being 2-3 months - and then there is a crash.
Bubbles

 

In case it's still relevant I may have the answer but on re-reading this I realized I'm not sure what you meant by dropping meds do you mean the withdrawal is delayed AFTER totally stopping them, or while in the midst of tapering withdrawal starts to catch up with the person?

 

 

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UnfoldingSky
On 6/19/2018 at 2:31 AM, bubbles said:

It is an interesting thought.

 

A related idea is the thought that the drug might be stored in our fat for a while.

 

I could be wrong as my memory is terrible but I think that Dr. Grace Jackson (who wrote Drug-Induced Dementia) talks about this, there is probably a link on this site somewhere about it...not sure if it can be accessed anymore or not though.

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bubbles
On 6/3/2019 at 3:31 PM, UnfoldingSky said:

 

In case it's still relevant I may have the answer but on re-reading this I realized I'm not sure what you meant by dropping meds do you mean the withdrawal is delayed AFTER totally stopping them, or while in the midst of tapering withdrawal starts to catch up with the person?

 

Both really, and I suspect that the difference between the two may be speed of taper and/or 'pushing through' too much. I see a lot of people - myself included - who tapered too fast and got through feeling reasonably unscathed, and then a few months later crash and burn.

 

I think Moncrieff did something about extended WD, but I'm not sure if it talked about delayed onset, though I can't put my hand on the paper now to check. I don't think she talked about mechanisms either.

 

 

Quote

Wondering how the research into delayed withdrawal went?

 

It didn't get much further than that, sadly.  If it exists, I couldn't find the research about it, and couldn't find evidence that it is being investigated. I suspect that we (patients who've experienced it) are the only ones who even believe it exists - certainly my experience was that my health advisers did not believe there was any WD involved, that it was my underlying broken-ness reasserting itself and proof positive that I needed drugs for life. I feel that my current taper is proving them wrong. :)

 

 

 

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Bee5

@bubbles if you make it off, you will be a beacon for me. I still have SO far to go, and I curse the fact that when I crashed, my pdoc immediately put me on high doses instead of the minimum dose to end the withdrawal symptoms. I am tackling quetiapine first, because goodness knows how it decimates pretty much every system in your body. I am hoping to finish the quetiapine taper in about 8 months from now. Then I will be tackling Paxil, to get my sex life back. 

I will keep looking for late-onset withdrawal; I am very active on Twitter so I'd like to think that I am quite up to date with the psych literature.

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UnfoldingSky
On 6/5/2019 at 8:21 PM, bubbles said:

 

Both really, and I suspect that the difference between the two may be speed of taper and/or 'pushing through' too much. I see a lot of people - myself included - who tapered too fast and got through feeling reasonably unscathed, and then a few months later crash and burn.

 

I think Moncrieff did something about extended WD, but I'm not sure if it talked about delayed onset, though I can't put my hand on the paper now to check. I don't think she talked about mechanisms either.

 

 

 

It didn't get much further than that, sadly.  If it exists, I couldn't find the research about it, and couldn't find evidence that it is being investigated. I suspect that we (patients who've experienced it) are the only ones who even believe it exists - certainly my experience was that my health advisers did not believe there was any WD involved, that it was my underlying broken-ness reasserting itself and proof positive that I needed drugs for life. I feel that my current taper is proving them wrong. :)

 

 

 

 

I agree that speed of taper may have something to do with it.  And good to hear your taper is proving them wrong! :)

 

I have one of Moncrieff's books and I just checked in it to see if delayed withdrawal was mentioned.  So far no direct mention however, she does touch on a study (using rats), where it was said that after removing Imipramine there was a "relapse of depression" forty days later.

 

Now given that this is rats we are talking about, it could be that was actually withdrawal--since they can't report their withdrawal symptoms...not sure how they'd be able to tell it was 'depression' (unless the rats got something like akathisia or other movement disorder thereby indicating it's definitely withdrawal.) 

 

(The study was written by D'Aquila, Panin, and Serra 2004 in case you want to try to track it down.)

 

Also, Alto had said to trace backwards to see where the immediate onset idea came from...well I read that and wondered if I could find where it started and I think I have.

 

Apparently the first antidepressant withdrawal syndrome from ADs on record was from Imipramine, and I believe that was documented starting in the late fifties. (I got this off wikipedia though under "antidepressant discontinuation syndrome" so it being wiki and everything maybe this is not where it starts...but I'll assume for the time being it does start there.)

 

Very likely then (if wiki is accurate) AD immediate onset might be traced all the way back there.  Although SSRIs are a different class of drugs (Imipramine is a tricyclic) I would guess that probably if they established immediate onset as typical for tricyclics that idea would influence subsequent ideas about SSRI withdrawal.

 

This paper has a number of references of documentation of early cases of Imipramine withdrawal, one of them they note documented withdrawal in a number of people happening in a few days of stopping.  The paper they are referencing is from 1961. 

 

Here's the link for the first paper:

 

https://journals.sagepub.com/doi/pdf/10.1177/070674376601101S27

 

And this is a bit off topic but worthy of mention too, they say that in one of the papers they noticed that the immediate onset withdrawal from Imipramine went away without treatment after a few days.  So this may also be evidence for the idea that they had a preconceived notion of how long SSRI withdrawal should last, and this very old Imipramine data has managed to influence how they view SSRI withdrawal now.  What they were looking at also may be evidence of "windows and waves" since it's doubtful they took the time to track people for many years after they stopped...it's possible that those with withdrawal who were never treated (ie never had the drug reinstated) later had other episodes of withdrawal, ie waves, that no one wrote anything about.

 

---------------------------------------------------------

 

And in researching this subject I found this recent publication, which suggests that (if they reviewed the literature) there really won't be much of anything supporting the idea that delayed withdrawal exists (as well as long term withdrawal):

 

Recognising and managing antidepressant discontinuation symptoms

by Peter M. Haddad and Ian M. Anderson

 

https://www.cambridge.org/core/journals/advances-in-psychiatric-treatment/article/recognising-and-managing-antidepressant-discontinuation-symptoms/7ECB0DBFF550A7E46CEBAA3BBDF484E5

 

The paper talks about every class of ADs causing withdrawal and also says this:

 

"All these syndromes, even isolated discontinuation symptoms, share three common features that facilitate diagnosis; abrupt onset within days of stopping the antidepressant, a short duration when untreated and rapid resolution when the antidepressant is reinstated.

 

So here we have not only the abrupt onset idea which is only some people's experience, but, we also have the wrong notion that withdrawal always clears up in a short period without treatment. 

 

 

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Cocopuffz17

Have you done any research into gut health?(The big thing for me on the nutrition level is that a majority of your body’s serotonin is produced in the gut) I was unable to come of paroxetine, 4-5 times I tried. I changed my diet and I am almost 5 months off. I did eat crappy and withdrawals came back hard recently but went back to 100% compliant and they have retreated. I still have the brain fog and a tough time prioritizing things in my brain. But I’ve read so many success stories that it gets better. 

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bubbles
On 7/9/2019 at 9:48 AM, Cocopuffz17 said:

Have you done any research into gut health?(The big thing for me on the nutrition level is that a majority of your body’s serotonin is produced in the gut) I was unable to come of paroxetine, 4-5 times I tried. I changed my diet and I am almost 5 months off. I did eat crappy and withdrawals came back hard recently but went back to 100% compliant and they have retreated. I still have the brain fog and a tough time prioritizing things in my brain. But I’ve read so many success stories that it gets better. 

 

No, though I've thought for many years that the low fat diet that my dietitian put me on many years ago when I thought I was fat (I wasn't) was a contributing factor. It reduced my meat intake so my iron was low. I was probably deficient in fat-soluble vitamins as well, given that the low fat diet was, well, low fat!

 

I'm now eating enough meat to get adequate iron levels  without having to take supplements, which has improved my overall health significantly. Eating adequate meat must have increased my B12 as well. I'm not scared of fat any more and that change alone seems to have helped my mood. I have lost a bit of weight without trying very much so I'm now hopeful I can actually lose weight without having to starve. Doc thinks I'm "cured" of my depression (long story, not worth getting into here). There are other factors - my thyroid is better treated, I get more sleep etc etc, but I think my improved diet has helped a lot.

 

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