Jump to content
dcrmt

Why taper? Paper demonstrates importance of gradual change in plasma concentration

Recommended Posts

dcrmt   
dcrmt

Hi, I thought I'd share this as it's quite relevant, not 100% sure if this is the right subforum, will post in both this and research.

 

PDF of American Journal of Psychiatry article or

Summary and excerpts from study in the Journals forum of survivingantidepressants

 

The pretty pictures are from page 4 onwards in the PDF. (Admin note: Pretty pictures here.  See this post for graph of "perfect" 10% taper of previous dose with 4 week holds)

 

 

What these fellows did here, was attempt to measure serotonin transporter occupancy at various doses for 5 different drugs. (Zoloft, celexa  paxil, effxor and Prozac, not in that order). They fit curves for both the oral doses and blood concentrations.

 

Long story short for anyone who doesn't know, SSRI’s ‘work’ by binding to the serotonin transporter protein (SERT) and stopping it doing it’s normal thing (reuptake of post-synaptic serotonin), resulting in serotonin hanging around for longer.

 

Now a couple of interesting things:

-at minimum therapeutic doses in every case, there was about 80% SERT occupancy. That shocked me personally. Even the minimum doses are locking down 80% of your brains reuptake ‘capacity’. Higher doses do more but it’s obviously not linear – they actually have plotted curves, and they’re quite a good fit statistically, particularly for the blood concentrations. Really good in fact. 

Point here though is that there’s a long way between 0% at no drug and 80% at the minimum dose.

 

-the curves man, look at the curves. This gives a fairly good indication of why some people find tapering necessary. You NEED a percentage taper just to get a linear decrease in SERT occupancy. Linear decreases in dose will actually hit you with exponentially increasing drops in SERT occupancy, particularly drops between the minimum therapeutic dose and 0

 

Basically, this paper provides a real basis for percentage reductions in dose when discontinuing SSRI’s.

I realize I'm kinda preaching to the converted and telling people what they already know, but it seems there may actually be a real reason why some people find it necessary to do these percentage tapers to get off SSRI's.

 

 

Caveat: I have no idea what the relationship between SERT occupancy and post synaptic serotonin is, it’s probably not linear since if it was higher doses would have basically no effect, but this is nevertheless very interesting to look at.

They were only looking at one part of the brain but pointed out it correlated strongly to elsewhere.

 

Moderator notes

 

To search for whether there is a study for your medication, google the generic name of the drug with these other two search terms: 5HTT occupancy

 

If you find a paper, please post the both the name of the medication and a link to the paper.

 

2016-July-01, Cymbalta (duloxetine)

MMarie found this paper on dose and 5HTT occupancy. The site,  academia.edu, requires login: http://www.academia....orter_occupancy

 

 

Link to screen shot of dose-occupancy and dose-plasma concentration curves

 

 

2016-November-12, Anafranil (clomipramine) and Luvox (fluvoxamine)

 

 

Link to study on occupancy vs. dose 

Link to chart of occupancy-dose relationship

 

Edited by ChessieCat
add Anafranil and Luvox study

Share this post


Link to post
Share on other sites
Rhiannon   
Rhiannon

Wow. That's amazing to actually see charted. No wonder, as I have said "it seems like there's a big difference between even a small amount and zero." That's because it's exponential so it's practically a straight vertical line when you get close to zero.  Just looking at the citalopram chart, I'm on 1 mg (10 is the "minimum therapeutic dose") and it looks like that's still about 20% occupancy!

 

And I bet it's the same way with the other drugs that seem to have the same exponential effect experientially. HA. We're not crazy. 

 

I am so going to print these charts out to show any doctor who gives me any crap about tapering slowly at low doses.

 

Thank you for finding and posting this!

Share this post


Link to post
Share on other sites
dcrmt   
dcrmt

Wow. That's amazing to actually see charted. No wonder, as I have said "it seems like there's a big difference between even a small amount and zero." That's because it's exponential so it's practically a straight vertical line when you get close to zero.  Just looking at the citalopram chart, I'm on 1 mg (10 is the "minimum therapeutic dose") and it looks like that's still about 20% occupancy!

 

And I bet it's the same way with the other drugs that seem to have the same exponential effect experientially. HA. We're not crazy. 

 

I am so going to print these charts out to show any doctor who gives me any crap about tapering slowly at low doses.

 

Thank you for finding and posting this!

 

I would keep in mind though that he relationship between SERT occupancy and levels of post-synaptic serotonin is unlike to be linear, it's possible that there's not much effect of a 20% blockade, and IMO there's probably a significant difference between 80% and 85% - after all such a change represents a 25% decrease in the remaining capacity.

The other thing is though there are other changes induced in the brain (like depletion of serotonin elsewhere in the brain) the effect of the drug on a virgin brain is probably different to that of a chronic ssri user.

 

 

But what this does show is that in that gap between 0 and the minimum therapeutic dose there's a massive change in brain chemistry and it's a bit much to be a coincidence that exponential decay, ala the percentage reductions that people have found seems to work experimentally is exactly the what you'd need to do in order to obtain linear drops in SERT occupancy.

 

SERT occupancy probably isn't the whole story, it can't be that simple, but god damn it's awfully coincidental that they fit curves like that.

Share this post


Link to post
Share on other sites
Rhiannon   
Rhiannon

 

Thanks so much, dcrmt. This is an ingenious finding.

 

Yes, you need very small decreases to keep the curve from irregular nose-diving.

Yeah, it would also tend to imply reductions could be more aggressive at higher doses, however we obviously don't know exactly what SERT occupancy implies for the actual serotonin levels so it'd be a bit of a dangerous conclusion to draw.

 

 

Right, it's tricky, I agree, there's more going on than just receptor occupancy. But I agree it's intriguing and validating that those curves match what we've found as far as anecdotal experience amassed by thousands of people.

 

The thing is that as long as you are calculating your percentage reductions on your current dose, that's an exponential curve, so you're going to be getting bigger absolute cuts at higher doses and moving "faster" anyway.

 

I've been sloppy about calculating my dose cuts based on current doses because I've been able to get away with it, but now that I'm at low doses I'm having to behave myself or I really get slammed. So at least in my case I was definitely able to be more aggressive with tapering while still at higher doses. There are a lot of anecdotal/experiential accounts of people being able to do that. 

 

Still, the key is still learning how to listen to and read your own body's signs and signals and to taper according to your own tolerance. That's the closest we can come to allowing for all the variables, I think.

Share this post


Link to post
Share on other sites
Altostrata   
Altostrata

Yeah, it would also tend to imply reductions could be more aggressive at higher doses, however we obviously don't know exactly what SERT occupancy implies for the actual serotonin levels so it'd be a bit of a dangerous conclusion to draw.

 

 

This does fit with occasional anecdotes that noticeable withdrawal symptoms kicked in part-way down. On the other hand, we have other anecdotes that people experienced severe withdrawal symptoms with an initial small reduction.

 

Clearly, sensitivity to dosage changes is individual. Consequently, we advocate a conservative 10% taper (an exponential curve, as Rhi said) to protect everyone.

Share this post


Link to post
Share on other sites
dcrmt   
dcrmt

 

Yeah, it would also tend to imply reductions could be more aggressive at higher doses, however we obviously don't know exactly what SERT occupancy implies for the actual serotonin levels so it'd be a bit of a dangerous conclusion to draw.

 

 

This does fit with occasional anecdotes that noticeable withdrawal symptoms kicked in part-way down. On the other hand, we have other anecdotes that people experienced severe withdrawal symptoms with an initial small reduction.

 

Clearly, sensitivity to dosage changes is individual. Consequently, we advocate a conservative 10% taper (an exponential curve, as Rhi said) to protect everyone.

 

Yes of course. (I think the term 'exponential decay' is what we're talking about here, but anyway).

Share this post


Link to post
Share on other sites
Altostrata   
Altostrata

Exponential decay! Thanks for the phrase.

Share this post


Link to post
Share on other sites
Addax   
Addax

This is a great article! While I've known a slow taper is of utmost importance, I now see how particularly critical it becomes at the lower doses. Per the chart, I am now poised to leap from a preverbal cliff... However, since finding this forum and the people in it, I will be CLIMBING down this fantastically steep slope slowly and with a spotter.

Share this post


Link to post
Share on other sites
dcrmt   
dcrmt

Bumping this thread so it doesn't exponentially decay onto page 2... :-)

 

I think it's really important! I'm going to print out the chart on page 4 and take it to my next medical appointment.

 

It's certainly very interesting. However I do want to emphasize that what is happening in the synapse is probably more complex. People need to keep in mind that what's being measured there isn't the 'final' effect of the drug, but the extent to which the serotonin transporters have been locked down - that then consequently affects the amount of serotonin in the synapses.

 

I'm not expert, but I would expect that at the higher doses (ie above the min therapeutic dose) the relationship between the 'duration' or 'amount' of serotonin in the synapses and the SERT occupancy is probably somewhat proportional to 1/(1-'occupancy%'), which would make the relationship with dose something vaguely approaching linear. 

It probably does matter how long you've been on the drug since there's some evidence (rat studies) that production of serotonin get's throttled and there are enzymes at work as well (ie: monamine oxidase).

 

Obviously the resemblance between those curves and the tapering technique that's been arrived at experimentally is utterly uncanny and probably isn't a coincidence but still, I want to caution that the article isn't the whole story. I did point it out to David Healy as well when I noticed it though.

Share this post


Link to post
Share on other sites
dcrmt   
dcrmt

 

 

Thanks so much, dcrmt. This is an ingenious finding.

 

Yes, you need very small decreases to keep the curve from irregular nose-diving.

Yeah, it would also tend to imply reductions could be more aggressive at higher doses, however we obviously don't know exactly what SERT occupancy implies for the actual serotonin levels so it'd be a bit of a dangerous conclusion to draw.

 

Grace E Jackson says the drug leaves the brain much more slowly than it does the blood stream... 

in one of her books please read them with your decent brain :)

 

How did you find this btw...

I think I seen it before but am not sure where.

 

 

I found it accidentally googling SERT or serotonin transporter saturation.

 

I was interested in finding out to what extent these drugs locked down the serotonin transporter. I found the abstract on pubmed or somesuch site, then happened to google the paper's name and found the pdf freely available.

I never expected that someone had actually done quantitative research like this, to the point of measuring the occupancy of different drugs at varying doses like this, I didn't even know it was possible.

 

It's 10 years old but it seems nobody investigating SSRI withdrawal had noticed it, it's clearly relevant - especially insofar as explaining why some people, particularly it seems for paxil can only tolerate small drops in dose.

 

Personally though I don't think tapering has much relevance for protracted withdrawal symptoms, maybe a bit but I've run into quite a few people who've suffered them regardless of having tapered

I absolutely understand the necessity for people who go haywire at small dose reductions, and the fact that the 5% or 10% method came up completely independently through trial and error yet near perfectly matches the curves in that paper can't be a coincidence.

Share this post


Link to post
Share on other sites
Altostrata   
Altostrata

Here are examples of the fit curves:

 

04_meyer_occupancy_fig1_small-1.png

 

I am thinking this explains why some people do fine until they hit a certain point -- the dosage they're taking is excessive and pushes them to the right on the X axis. They have quite a ways to go to work off the excess before a decrease will cause a noticeable deficit -- the oh-oh point.

Share this post


Link to post
Share on other sites
dcrmt   
dcrmt

Yeah it can definitely explain a few things. I'd really love to see some kind of modeling as to what exactly is meant to be happening in the synapses, I mean it shouldn't be completely impossible to do - but I don't really know where to look as far as finding if anyone's done anything, I stumbled on this completely by accident.

 

 

Here are examples of the fit curves:

attachicon.gif04_meyer_occupancy_fig1_small-1.png

I am thinking this explains why some people do fine until they hit a certain point -- the dosage they're taking is excessive and pushes them to the right on the X axis. They have quite a ways to go to work off the excess before a decrease will cause a noticeable deficit -- the oh-oh point.

Share this post


Link to post
Share on other sites
dcrmt   
dcrmt

Prozac as an extremely long half life compared to other SSRI/SNRI's (several days)

 

Effexor has an extremely short half life compared to SSRI's (like 11 hours I think). Cymbalta is similarly short.

 

Zoloft, Paxil, Citalopram ect range from 23-36 hours. That's why missing a dose of effexor matters but prozac not so much, since the prozac takes several days even for the amount in your system to fall significantly, let alone work it's way out, whereas after a day most of the effexor in your system is already gone.

 

Is prozac just as bad as these others, i.e. effexor?  I thought it really did not work the same way.  I never had brain zaps or much of any withdrawal symptoms while on prozac if I missed one or two doses as I did on effexor so I thought it was not the same type of drug.  

 

I don't understand a lot of the technical info above except for that it is scaring me when I think of tapering down from the 1/2 tab of 225mg I am taking now.  Since it is a tablet I have just cut the 225 mg in half but was thinking of just now cutting the 1/2 in half but am rethinking that since it seems that tapering at lower doses can be extremely tricky.  

Share this post


Link to post
Share on other sites
Altostrata   
Altostrata

We do have people who feel a missed dose of Prozac, despite the long half-life. They may be extraordinarily sensitive or at a dose just right of the the oh-oh point.

Share this post


Link to post
Share on other sites
btdt   
btdt

I am sure the reality inside the brain is more complex this is a clue a puzzle piece... 

I can't eager to see the entire puzzle put together and for the truth of it all to be known.

Share this post


Link to post
Share on other sites
Rhiannon   
Rhiannon

We do have people who feel a missed dose of Prozac, despite the long half-life. They may be extraordinarily sensitive or at a dose just right of the the oh-oh point.

 

I've found that when I get down to the lower doses I do better splitting my daily dose and taking some more often. Might be that oh-oh point or it might have to do with metabolizing the drug faster at lower doses, not sure, but it seems like that approach has helped some other people who are tapering too--that is, even though they're taking a drug with a longer half-life which supposedly only needs to be taken once a day, they do better if they divide it up and take two or three doses.

 

I like the "uhoh point". Have stumbled over a few of those.

 

And I agree that this demonstrates a possible reason why people often can make bigger drops at high doses. As you can see on the graph, after a point the receptor occupancy levels off even as doses increase, and so many people are on such high doses, well above the maximum amount that's going to have any receptor-occupancy effect.  Unfortunately receptor occupancy isn't the only effect these drugs have, they also seem to have all kinds of hormonal effects, effects on cortisol levels, histamines, etc. plus stuff that hasn't been measured, so those high doses can cause a lot of problems.

Share this post


Link to post
Share on other sites
Altostrata   
Altostrata

Exactly. Many people are taking dosages in excess of saturation. They have some room before receptor occupancy drops.

I expect it's impossible to predict how far to the right you are in the saturation zone. The distribution of dots indicates some individual variation; my guess is there's also individual sensitivity to dosage changes. Receptor occupancy isn't the whole story, but this is a good way to visualize how to move down the curve safely.

(For those mystified as to how to read the curves, from left to right, they show what happens as you increase the dose. If you look at them from right to left, you can see what happens as you decrease the dose.)

 

I've reversed the graphs here, to illustrate (the numbers in the scale at the bottom are backwards because the image is reversed):

 

04_meyer_occupancy_fig1_rev.png

 

This is indeed a key paper for our argument about gradual tapering. Thank you very much for sharing this, dcrmt. I see some potentially interesting papers in the citations if you care to delve deeper, but this paper seems to be a good summary -- and the charts are priceless.

Share this post


Link to post
Share on other sites
Mario   
Mario

nice article !

the shapes of the curves also support the idea that the reduction speed should be reduced at lower dosages of SSRI,

like it is suggested in the turtle protocol (http://ssrigr.altervista.org)

Share this post


Link to post
Share on other sites
Altostrata   
Altostrata

Correct, but you don't know when you're leaving your own personal saturation zone.

Share this post


Link to post
Share on other sites
btdt   
btdt

Correct, but you don't know when you're leaving your own personal saturation zone.

Extremely important point. 

Cannot be emphasized enough. 

 

If a person is on more than one drug the importance multiplies I think. Bad enough if both drugs are ssri or ssri and snri... but throw in a benzo... and other drugs as many are on... this tilt a whirl effect throws the curve importance ... and maybe how relative it is... and maybe the curve itself wonky...

 

It is still important as a piece of the puzzle but when you take a look at the reality of some who have been poly drugged as some of us have the light dims the complexity skyrockets.

 

I want more research and knowledge.. I know we all do.

peace

Share this post


Link to post
Share on other sites
Rhiannon   
Rhiannon

Is prozac just as bad as these others, i.e. effexor?  I thought it really did not work the same way.  I never had brain zaps or much of any withdrawal symptoms while on prozac if I missed one or two doses as I did on effexor so I thought it was not the same type of drug.  

 

I don't understand a lot of the technical info above except for that it is scaring me when I think of tapering down from the 1/2 tab of 225mg I am taking now.  Since it is a tablet I have just cut the 225 mg in half but was thinking of just now cutting the 1/2 in half but am rethinking that since it seems that tapering at lower doses can be extremely tricky.  

 

One of the charts is for Prozac (labeled "fluoxetine".)

 

It follows the same pattern as the rest of them.

 

As dcrmt explained, the reason you might not feel that immediate withdrawal is because it stays in your system for a few days. But the relationship between the dosage that you're taking and how much it's changing the chemistry at your synapses (which is what the charts show) is the same as with the other ones.

Share this post


Link to post
Share on other sites
Rhiannon   
Rhiannon

Correct, but you don't know when you're leaving your own personal saturation zone.

 

Yep, we're all different, and as btdt points out, it's extra complex with multiple meds in the picture. Also, I suspect, with more complex histories of previous usage and previous CTs and what have you. Which is why once again the expert has to be your own body and we have to learn to listen to ours.

 

Still like Alto says, these charts are priceless, not least because you can show them to your doctor when she says "oh just 1 mg, you should be able to jump right off that."  And when we say taper following an exponential decay pattern (percentage of your current dose not of your initial dose), now we can point to a nice picture demonstrating why that works. 

 

I am totally taking copies of these with me to my next doctor appointment and having her stick them in my chart.

Share this post


Link to post
Share on other sites
dcrmt   
dcrmt

It's not really the same deal as antipsychotics though, for the SSRI's what's being measured is the occupancy of the serotonin transporter, not serotonin receptors.

SSRI binds to SERT, resulting in increased synaptic serotonin and the serotonin itself then goes and interacts with receptors.

Share this post


Link to post
Share on other sites
dcrmt   
dcrmt

Yeah but the SERT occupation is not the final effect of the drug.

Without knowing the relationship between SERT occupation and serotonin in the synapse, and then on top of that serotonin in the synapse and activation of the various 5-HT receptors you cannot say for sure that the 'topping out' actually is topping out.

 

I had severe personality severely on 20mg of escitalopram and completely lost my mind on 30 and 40mg. That can't really be accounted for by it acting as an antihistamine (which is the next bucket to be filled, though the affinity is pretty sh*tty), it really has to be due it it's primary mode of action.

 

Thus what I wrote about on the other post - given saturation of the remaining transporters with serotonin the effect on the duration and/or quantity of synaptic serotonin  could be something like 1/(1-occupancy)

Those 'minor' increases in occupancy could still translate to significant increases in synaptic serotonin.

 

Celexa has significantly stronger affinity for H1 than lexapro (other stereoisomer) I think, and lexapro isn't charted. As far as I'm aware Lexapro is the most 'selective' SSRI so I'd kind of expect that at higher doses it'd build up that much more 'unbound' drug, pushing on the equilibrium with SERT.
It definitely has the lowest affinity for other monoamine transporters - I just wonder if the (qualitatively high it seems) proportion of people I've run into with long term effects from escitalopram could be due to this.
If you happen to metabolize it particularly poorly or something, end up with high blood doses:

-with something like sertraline it quickly starts hitting the dopamine transporter, similar deal though not as clear cut for most other SSRI's

-for escitalopram, it can push the equilibrium that much further towards total saturation of SERT.

I don't know how to do the maths unfortunately, but it seems plausible.

 

 

It's really not comparing like with like with the Antipsychotics in terms of final effects.

 

What we actually experience is the activation, downregulation, ect of serotonin receptors but what's being measured here is two steps removed from that.

Funny that I'm playing down the significance of the paper a little I guess but it is a very big deal that the SSRI's are binding to the transporters, not the receptors. Everything they do really comes down to the serotonin they cause to accumulate in the synapses and some individual differences in effects probably come down to that, even diet a bit. I mean you can potentially cause serotonin syndrome if you take 5-htp supplements with SSRI's and even a tryptophan rich diet probably has a significant effect on what happens in your brain if you're on SSRI's - it's enough to be dangerous on MAOI's afterall.

 

The curves are strikingly similar. More about the atypicals here, with charts http://thelastpsychiatrist.com/2007/08/arent_two_antipsychotics_bette.html

Here's more about Celexa and Effexor, with charts from the study you found, dcrmt http://thelastpsychiatrist.com/2007/07/no_not_effexor_too_the_most_im.html

Share this post


Link to post
Share on other sites
btdt   
btdt

I think we should consider how the drug changes or damages the liver ...the affect this has on metabolism.

There is much more to this than meets the eye a puzzle piece when it presents itself can cause as many

or more questions than it answers I feel somebody some where has these answers all of them...

I also sadly think they work for pharma. 

Share this post


Link to post
Share on other sites
Altostrata   
Altostrata

btdt, this is a serious discussion. Quoting swaths of thelastpsychiatrist.com derails the conversation. I have hidden your posts as off-topic.

 

dcrmt, you are correct, Meyers, 2004 addresses only serotonergic effects. These drugs are not nearly as "targeted" as claimed and it might well be that overage per SERT affects other systems.

 

Certainly the existence of serotonin syndrome demonstrates there are effects beyond "topping out" per SERT.

 

We need to keep in mind that not only do these drugs affect multiple neurotransmitters, they trigger unknown reactions among other hormonal systems, and they may block their own metabolism or other drugs. Serotonergic action does not completely explain effects considered "beneficial" or adverse.

 

The action of MAOIs is different, they knock out an enzyme that would aid in conversion of serotonin (and other neutransmitters) to other hormones -- the natural cycle. That's how they raise the level of serotonin in the synapses.

 

To me, the similarity of the curves is valuable to visualize what happens when you decrease dosage. The pharmacological action depicted is not as important.

 

Wikipedia http://en.wikipedia.org/wiki/Escitalopram

(under Pharmacology) has a good explanation of why escilatopram is stronger, milligram for milligram, than citalopram (or other SSRIs, for that matter)

Share this post


Link to post
Share on other sites
Rhiannon   
Rhiannon

dcrmt, I hear and understand what you're saying, but I actually think it's more complicated than that. Biochemistry is incredibly complicated, and nowhere more complicated than in the nervous system. Every chemical reaction affects a cascade of reactions downstream, in complex feedback loops. Nothing is isolated. There are no separate compartments in the chemistry of the body.

 

It's tempting to try to simplify it and say "serotonin in the synapses does this thing, transporters do this thing, receptors do this thing" as if it were mechanical and predictable and those were all separate parts, but it's not. It is incredibly more complex than that. And that's just talking about synapses. You've got glial cells interacting with everything else, all of it reacting and responding in nanoseconds (literally), causing more reactions to happen elsewhere, causing cascades and loops which then feed back in multiple places. There is no neurotransmitter that acts in isolation. They all affect each other.

 

And although scientists talk about this stuff as if they understand it (well actually the REAL neuroscientists don't, mostly it's the psychiatrists, who are apparently not reading much neuroscience)--we understand probably less than 1% of what's actually going on. The state of the science is not very advanced, relative to what there is to learn.

 

We are conditioned to think using mechanical or computer analogies about this stuff, but that is simply not how it works. There are no separate compartments. Everything affects everything.

 

So the take-away point about these charts for me and probably for Alto as well, isn't really what piece is doing what. It's not really the effect of the drug--we find that the effects of the drugs themselves are highly variable in different individuals, even more so once they have some history of taking psych drugs of any kind, and that makes sense given the complexity involved.

 

The exciting take-away of these charts is that they make it so brilliantly, visually clear that the effects--whatever they may end up being--increase and decrease in an exponential fashion. We had observed this anecdotally, but to have the data and a visual graph is just absolutely brilliant and priceless. It makes it so much easier for people to understand why they must taper following an exponential/logarithmic curve rather than just a linear decrease. And we can show these charts to our doctors when they say "you're just taking 2 mg, that's such a low dose you can just stop." 

 

I'm thrilled to have this tool. I cannot thank you enough for bringing it here.

Share this post


Link to post
Share on other sites
Rhiannon   
Rhiannon

yeah like Alto said while I was typing that, only in SO many fewer words. Thanks Alto. 

 

Let me add: my rant is actually directed not just at this thread, but at everyone who says "oh it's the D2 blockers" "oh it's this piece" "oh it's that piece"... saying not "well, maybe, it's a guess, a little bit of it could maybe work this way" but "this. is. how. it. works."

 

NO. We don't know that. We don't understand it well enough yet to say things like that with any authority. Our knowledge is teeeeeeny. It's not that simple, we aren't there yet, we don't have good models, we don't have any models, these are all speculative hypotheses which will undoubtedly inevitably be proven incorrect or drastically and tragically incomplete eventually. (That much we do know from experience.)

 

This stuff is not only not proven, we don't even know enough to make good guesses, and we need to keep that in mind while we play with it and learn more. And NOT play with human lives and minds based on our extremely imperfect knowledge and our definitely-incomplete ideas.

 

That is the same kind of hubris that has gotten our planet into the shape it's in today.  The same hubris that has gotten most of us who are here on this forum where we are today.

 

We humans are not as smart as we think we are. Not even close. 

Share this post


Link to post
Share on other sites
lionboy   
lionboy

I think this paper makes really interesting reading and there are also some very astute comments from the various contributors on here.

My fundamental problem with the graphs is that if we consider them as demonstrating the importance of a % taper at the lower end of the dose scale then we would also have to conclude that (in the case of the citalopram graph I looked at) they demonstrate large drops at the higher end of the dose range should be fine. The curve shows SERT as almost identical at 40mg and 60mg of citalopram.

If SERT was the sole / main reason we experience problems in dose reduction then the graph would indicate that a drop in dose from 60mg to 40mg would be barely noticeable.

Of course in reality it would most likely cause carnage.

Share this post


Link to post
Share on other sites
Meimeiquest   
Meimeiquest

Have you read Alto's theory of withdrawal symptoms , it's in a pinned section of tapering. There is not only the issue of receptors, but a specific part of the brain going into hyper-drive, sensing that things are changing. Why do some people do that? I don't know. Before I became totally sensitized at the end of my Wellbutrin taper, I could drop a lot off the top. Partly, it depends on someone's liver processing capacities. Someone who is a slow metabolizer will have a different blood level at a given dose than a rapid metabolizer. The other drugs that are having an impact matter as well. What screams at me from this graph is that most people are taking much, much higher dosages than they actually need. All the more to make side effects with.

Share this post


Link to post
Share on other sites
lionboy   
lionboy

He there.

I have read the 'why taper by 10%' piece by alto.

I certainly understand the problems we face in withdrawal and I completely accept the need to taper.

I agree in principle with everything alto says re the 10% taper just not sure the reason that is true is revealed in this paper / graph.

I am not sure that this paper / graph shows the full picture (as others have mentioned).

I started of my journey by reducing from 50mg to 40mg and had quite bad withdrawal. To my mind this graph, if considered as showing the full effect of the medication, would suggest that drop to be easy. Incidentally I had my best success last year, dropping from 25mg to 11mg in 5 months in 1mg increments.

I certainly take your point on the doses people take.

Knowing what I know now I would think 10mg is ample for most people. I was on 80mg at one point !

Professor Healy refers to ssri's as grossly overpowered for purpose like a high power sports car in a small village.

Share this post


Link to post
Share on other sites
Meimeiquest   
Meimeiquest

I don't think it shows 10%, it shows that if it is hard to rebuild receptors, one needs slow. Which is entirely individual, but 10% is a good perspective. Most importantly, the steep slope at the bottom points towards lowering the percentage at the end, when doctors think it is ridiculous or "homeopathic." I think the main thing is to know oneself, an ability mostly gained by making mistakes :)

Share this post


Link to post
Share on other sites
Altostrata   
Altostrata

lionboy and meimei, thank you for your comments.

 

lionboy, you are correct. We do often see people being able to taper by large amounts at first, then running into more difficulty. One might surmise they were oversaturated dosage-wise.

 

Most likely, the saturation point varies from individual to individual (the graphs are averages of scatterplots showing individual variability). One person may be oversaturated at 40mg while another does not reach saturation until 60mg.

 

The graphs do not match a 10% decrease, what they show is that exponential decay in tapering is closer to the descending curve (the amount of decrease gets continually smaller). We are only approximating the curve with a 10% decrease.

 

As meimei says, accommodation to decreased dosage is multi-factorial. But the curves do support the rationale for slow tapering.

Share this post


Link to post
Share on other sites
btdt   
btdt

dcrmt, I hear and understand what you're saying, but I actually think it's more complicated than that. Biochemistry is incredibly complicated, and nowhere more complicated than in the nervous system. Every chemical reaction affects a cascade of reactions downstream, in complex feedback loops. Nothing is isolated. There are no separate compartments in the chemistry of the body.

 

It's tempting to try to simplify it and say "serotonin in the synapses does this thing, transporters do this thing, receptors do this thing" as if it were mechanical and predictable and those were all separate parts, but it's not. It is incredibly more complex than that. And that's just talking about synapses. You've got glial cells interacting with everything else, all of it reacting and responding in nanoseconds (literally), causing more reactions to happen elsewhere, causing cascades and loops which then feed back in multiple places. There is no neurotransmitter that acts in isolation. They all affect each other.

 

And although scientists talk about this stuff as if they understand it (well actually the REAL neuroscientists don't, mostly it's the psychiatrists, who are apparently not reading much neuroscience)--we understand probably less than 1% of what's actually going on. The state of the science is not very advanced, relative to what there is to learn.

 

We are conditioned to think using mechanical or computer analogies about this stuff, but that is simply not how it works. There are no separate compartments. Everything affects everything.

 

So the take-away point about these charts for me and probably for Alto as well, isn't really what piece is doing what. It's not really the effect of the drug--we find that the effects of the drugs themselves are highly variable in different individuals, even more so once they have some history of taking psych drugs of any kind, and that makes sense given the complexity involved.

 

The exciting take-away of these charts is that they make it so brilliantly, visually clear that the effects--whatever they may end up being--increase and decrease in an exponential fashion. We had observed this anecdotally, but to have the data and a visual graph is just absolutely brilliant and priceless. It makes it so much easier for people to understand why they must taper following an exponential/logarithmic curve rather than just a linear decrease. And we can show these charts to our doctors when they say "you're just taking 2 mg, that's such a low dose you can just stop." 

 

I'm thrilled to have this tool. I cannot thank you enough for bringing it here.

"We had observed this anecdotally, but to have the data and a visual graph is just absolutely brilliant and priceless. It makes it so much easier for people to understand why they must taper following an exponential/logarithmic curve rather than just a linear decrease. "

 

Could you say this is simpler terms.  

I left this thread long ago today I find it extremely confusing exponential/logarithmic curve... really what is that?

And I did try to look it up...

http://www.sosmath.com/algebra/logs/log4/log42/log42.html

Still it does not translate into anything understandable to my brain. 

 

And Alto this

 exponential decay in tapering is closer to the descending curve

Maybe I am just flat out stupid I don't know but I don't get what your trying to say. 

I thought the graphs showed the amount the body/brain could use had a limit beyond that limit it was a waste of the drug and who knows that the excess does to the body.  

And that tapering is easy at the start because the drug was in excess anyway which was off the graph... so effects were not felt till tapering reached the graph where affects were felt. 

I do worry that maybe others here especially new folks in hard withdrawal will have trouble with this jargon... I could be stupid often think I am.

Share this post


Link to post
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now

×

Important Information

By using this site, you agree to our Terms of Use.