dcrmt

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

61 posts in this topic

BTDT, you are so not stupid. I think it means what you think. As levels get lower, there is a much greater decrease in % of transporters affected for each little amount of drug taken away.

Share this post


Link to post
Share on other sites

I also don't think you are stupid BTDT. I think we all have to be very careful when trying to draw any finite conclusions from a study such as this.

As Alto mentioned earlier in the thread, the findings here do appear to be indicative of the reason people need to slowly taper from these drugs however I would be very careful of drawing any firm conclusions from this.

As I understand it, nobody has proven a relationship between SERT occupancy and the way a person feels furthermore there is no accurate way of measuring seratonin in a living brain ?

This study is done by measuring seratonin in the gut then extrapolating the amount they think that means is in the brain.

In addition, new research suggests that seratonin levels decrease with age so you would therefore expect people to gradually get more depressed the older they get which of course doesn't happen.

The fact is that no one really understands the full mechanics of the effects these drugs have on the human brain.

This type of research will no doubt prove one day to be a part of the jigsaw but I really believe that is all it is, just one part of the jigsaw.

Share this post


Link to post
Share on other sites

* I may be wrong, regarding how they measure SERT !

I started to read into it but lost the will to live.

Share this post


Link to post
Share on other sites

Thanks Lionboy I get trying to sort out this sort of thing can cause one to lose the will to live... 

happens to me all the time and I leave it or just forget about it naturally with my forgetful brain. 

That too happens a lot. 

I guess we are just light years behind what we thought we knew as a human race and taking drugs we have no business taking as nobody knows anything really about them  I wonder if it would make any sense to be frozen and defrosted in 3014... when they know how to fix me. If only all I loved would go with me. :) 

thanks again peace to you

Share this post


Link to post
Share on other sites

Because i have an underactive SERT gene, I was interested in how that plays in and found this in one of the citations:

 

Effects of Chronic Antidepressant Treatments on Serotonin Transporter Function, Density, and mRNA Level

http://m.jneurosci.org/content/19/23/10494.short

 

Excerpt from abstract:

 

"Based on these results, it appears that the SERT is downregulated by chronic administration of SSRIs but not other types of antidepressants; furthermore, the downregulation is not caused by decreases in SERT gene expression."

 

I hope this is not deviating too far from main topic. I believe it may be a part of why some of us who have been on these drugs for many years experience poopout and/or greater difficulty in discontinuation.

Share this post


Link to post
Share on other sites

Do you think this is the case for gaba and benzodiazepines?

 

This particular paper (which unfortunately the link doesn't work to any more) didn't cover benzos, but experientially, anecdotally, people have always found that the taper with those has to go slower as the doses get lower too. Same kind of thing where you have to cut by a percentage of the current dose not by constant increments. So presumably it's something similar going on.

Share this post


Link to post
Share on other sites

These graphs are just a brilliant thing for us in withdrawal. I was delighted to see my old buddy amitryptiline analyzed in the one study ("Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites"). I'm going to chew through that study when I have time. But as pointed out--the curves are all almost identical! Has anyone used this information to create a schedule for withdrawal that will provide even plasma level drops (or % 0f 5HTT binding)--say a 5% plasma level drop with each dosage drop? I'm going to graph that out and see what that would look like.

 

This explains a lot about the difficulties I have had with withdrawal, even though my dosages have been fairly low. I had very little issue with bouncing around between 12.5-25mg, or even 36mg at times. But trying to CT from even a low dose of 6mg. has been impossible for me. I went from 12.5 to 6mg this summer, and never apparently got stabilized--lots of issues with insomnia, stomach issues, etc...Looking at these graphs, I can clearly see why that has been so difficult!

Share this post


Link to post
Share on other sites

Other antidepressants have been similarly analyzed in other papers. The curves are all similar.

Share this post


Link to post
Share on other sites

This is absolutely fascinating. 

 

I just joined Surviving ADs and someone showed me the link to this page.  
 
I was wondering if you could help me understand the SERT occupancy concept -- or more specifically, the idea that 
I think that is exactly what is going on with me, and I would love to understand it.
 
The study talks about "minimum therapeutic doses," but I am on only 1.2 mg (!!!) of Paxil and still having extreme difficulty with each tiny dose decrease. I hardly think that 1.2 mg can be considered a therapeutic dose. 
 
So  Altostrata, from your clear explanation, I think what was true for me is that at 60 mg Paxil, 50 mg., 40 mg., 30 mg, no problems with tapering: this was past the saturation point for my receptors, and I wasn't yet hitting my uh-oh point. For me "uh-oh" started at 20, and has been difficult since. 
 
"-at minimum therapeutic doses in every case, there was about 80% SERT occupancy. Even the minimum doses are locking down 80% of your brains reuptake ‘capacity’."
Point here though is that there’s a long way between 0% at no drug and 80% at the minimum dose."
 
Looking at the chart for Paxil/paroxetine, where I am (1.2 mg) there is still 40% SERT occupancy. Well, hello!!!! No *wonder* this has been so difficult. And I can't believe my doctor told me I could "probably just stop" Paxil when I got to 5 mg. !!!!!!
 
What does 40% SERT capacity mean, exactly? That 40% of my neurons are still having serotonin reuptake inhibited by Paxil? 
 
Thanks!!

Share this post


Link to post
Share on other sites

"Therapeutic doses" means the dosages found in clinical studies to reduce symptoms of "depression." These tend to be the tablet dosages available, e.g. 10mg, 20mg, 30mg Paxil.
 
(Whether the dosages actually do reduce symptoms of "depression" has produced a huge volume of literature critical of psychiatric drug development.)
 
Although you'll see many references to "therapeutic doses" in journal articles, they are a hypothetical construct, the drug companies' best guesses at what will "work" for the largest number of people. In fact, these are very strong drugs and probably commonly dosed too high, resulting in excess SERT occupancy.
 
These drugs are psychoactives. Some people feel an effect at very low dosages. SERT occupancy is only one factor in causing the neurological changes leading to these effects.
 
If you have been on a drug such as Paxil for a long time, it has caused changes in your nervous system far beyond SERT occupancy. It has changed the inter-relationship of all your hormonal systems, the functioning of your digestive system, your sleep pattern, etc. When you get down to a low dose, which may mean partial SERT occupancy, the rest of your body has to adjust. It is this adjustment that causes withdrawal symptoms.
 
In addition, paroxetine in particular is a very difficult drug to quit, perhaps the worst of all the antidepressants. This is probably because of its effects beyond SERT. For example, it is the SSRI that is the most anti-cholinergic, directly affecting an entire autonomic system.

 

See “It’s Anticholinergic” – What Does That Mean? http://pro.psychcentral.com/its-anticholinergic-what-does-that-mean/002836.html#

 

In medical school pharmacology courses, many of us were taught about cholinergic effects with the mnemonic “SLUD”: Salivation, Lacrimation, Urination, Defecation. I suggest augmenting this with a “C” standing for “Cognition.” If ACh facilitates SLUDC, drugs that are anticholinergic – for example, the tricyclics, Paxil (paroxetine), Cogentin (benztropine), Artane (trihexyphenydil), and Benadryl (diphenhydramine) – are “Anti-SLUD-C.” This means that they cause dry mouth, dry eyes (and blurry vision), urinary retention, constipation, and confusion.

 

Share this post


Link to post
Share on other sites

.. As levels get lower, there is a much greater decrease in % of transporters affected for each little amount of drug taken away.

What exactly does this mean please?  What are "transporters" in simple language?

Share this post


Link to post
Share on other sites

Well, this is how I understand it: there are little transporters that carry serotonin back to their starting place after they carry a message across the space between neurons. Basically they are sent off and bind to the neuroreceptor, stimulating it. Then they are carried back by binding to the transporter (called SERT...serotonin reuptake transporter, I can't remember what E is) and riding back.

 

Selective Serotonin Reuptake Inhibitors (SSRI's) are the class of antidepressants that bind to those transporters so they can't carry serotonin and more serotonin therefore stays in the space between neurons. I think...it's late at night :). The lower the dose, the greater percent of transporters are blocked with each bit of medicine. As they get unblocked, there is less serotonin in the space and it is harder for those serotonin messages to get through to the receptors which have become less sensitive because they have been so flooded with serotonin when more transporters are blocked. This probably is a very inadequate and possibly inaccurate explanation...what questions do you have now? The bottom line is it is completely normal for tapering to get harder at the end.

Share this post


Link to post
Share on other sites

Thanks for your description, however  am still confused!  Transporters sound like buses going to and fro taking serotonin but get hijacked or something...

 

Not to worry, I perfectly understand your last sentence that the lower we go the harder it is and I constantly need to to remember that!  It is still very interesting how all these things work - and don't work when they aren't in their "right order" and just shows we shouldn't play around with our brain with drugs.

Share this post


Link to post
Share on other sites

If you have been on a drug such as Paxil for a long time, it has caused changes in your nervous system far beyond SERT occupancy. It has changed the inter-relationship of all your hormonal systems, the functioning of your digestive system, your sleep pattern, etc. When you get down to a low dose, which may mean partial SERT occupancy, the rest of your body has to adjust. It is this adjustment that causes withdrawal symptoms.

 

In addition, paroxetine in particular is a very difficult drug to quit, perhaps the worst of all the antidepressants. This is probably because of its effects beyond SERT. For example, it is the SSRI that is the most anti-cholinergic, directly affecting an entire autonomic system.

 

See “It’s Anticholinergic” – What Does That Mean? http://pro.psychcent...an/002836.html#

 

 

 

What Alto posted here is good and helps with understanding, thanks

Edited by JanCarol
fixed quotes

Share this post


Link to post
Share on other sites

I've just found a post in someone's topic by Brassmonkey which contained this explanation:

 

"These drugs work by making physical changes to the nerve endings referred to as "down regulating".  In general the first 5mg affect about 60% of a persons nerve ending while 10mgs affect about 80% .  Increase the dose to 20mg and only 85% are affected. So a lot of changes happen with the first 5mgs."

 

I hope that helps to explain it.

Share this post


Link to post
Share on other sites

The fact that it affects the nerve endings helps explain a lot of things.  What I have had in the past and am experiencing worse now, is an itchy, prickling sensation which drives me crazy.  It is like someone touching me with stinging nettles in one place, then  in another place, and so on and I figured this had to be nerve ending sensations.

Share this post


Link to post
Share on other sites

I tabulated some of the data from one of the graphs. I took the first sertraline graph and came up with this. It's incomplete - I didn't plot it all. :) This is VERY rough - I enlarged the graph on my screen and held up envelopes to the screen to try to work it out. To do that I'd print it out large and do some careful measuring. I started at 75mg because I was on that dose for the longest time. :) The next point is 50mg, just because. :)

 

75mg     85%

50mg     82%

45mg     80%

40mg     78%

35mg     77%

30mg     75%

25mg     70%

20mg     67%

15mg     60%

10mg     54%

5mg       36%

0mg       0%

 

Specifically - look at what happens at about the 12.5mg mark, which is half of a 25mg tablet (being the lowest dose available in the US, I think?) - it's going to be a bit under 60% - let's call it 57%.

 

I'd think that there wouldn't be many people on less than, say, 25mg or 12.5mg (being half a 25mg tablet) so I imagine that would be the smallest dose for which they'd really have data. So the curve must be extrapolated and calculated? I wonder what is really happening down at the small end of things.

 

Anyway, just musing. It certainly does suggest that the drop from 5mg to 0mg might be more problematic than the drop from 75mg to 50mg. 

Share this post


Link to post
Share on other sites

I beleive this article and the the incredible graphs within it, explecitly depict what ADs do at various doses. IMO reading this article should become the standard of care and a mandatory part of informed consent for health care providers and their patients when taking, tapering or considering taking ADs. 

 

Prior to reading this article I was totally unaware of the the exponential fashion in which these drugs work at doses which are much, much lower than those which are typically prescribed.

 

Please do not do this, but this is in fact what happened to me. I was taking 40mg Cymbalta/day for four years.  One day I decided to cut my dose in half and take only 20mg Cymbalta/day; this was without any taper whatsoever.  I never experienced any wd symptoms at all. 

 

Six years later, I thought that could simply do this again (same dosage right :blink: ) so I "cold turkey" stopped the 20mg Cymbalta/day, just as I had done in the past, but this time I crashed and burned BAD! :o : 10/10 severe: insomnia, anxiety, restlessness/akathesia, Tinnitus.    

 

So, slow and low is good.

Share this post


Link to post
Share on other sites

Our esteemed scallywag has made a chart showing what skipping doses does to your blood level of Cymbalta, for example:
 

I'm seeing a fair amount of discussion with newcomers about skipping doses.  I've created a spreadsheet that shows the % concentration decay, comparing daily dose, alternate day dosing and skipping 2 days. This chart is for Cymbalta (duloxetine) or a drug that has a 12-hour half-life.
 
The chart is in a spreadsheet (.xlsx).  I'm going to refine it, maybe showing every 12 hours instead of every 24 and setting it up so that any half-life can be "inputted." Then I'll attach it to another post.
 
The blue line is taking daily doses; green is every other day dosing; red is every 2 days.

 

scallywag_skipping_doses.jpg
 
http://www.mediafire.com/view/ni0hmq4si6qatlq/scallywag_skipping_doses.jpg

Edited by Altostrata
updated link

Share this post


Link to post
Share on other sites

For some reason, Alto's link isn't showing.  It's in my attachments:  Click for chart

 

Share this post


Link to post
Share on other sites

I found this explanation by NZ in a post to Otter:  Regarding the SERT diagram

 

 

 


....
 
Regarding the SERT diagram.
Here's my take on it.
The SERT study (and its diagrams) is not about tapering per se. However it does provide a validation for the tapering regimen that is recommended on this site. And what people have found to provide the best chance of getting of these drugs and staying off.
10% of the previous dose per month tracks according to a decreasing geometric progression and provides a very close approximation to the SERT graphs. (a kind of  logrithmic curve only we are travelling in reverse direction) Which is what the mid section of these graphs follow.
Recall: Abrupt changes in serotonin levels is what can trigger suicidal and homicidal ideations.
So we do not want to taper in a manner that triggers abrupt changes in serotonin levels.
 
Note: The graph does not follow an arithmetic progression ie a straight line trajectory.
Hence inferring the safest way to taper and the way to follow the graphs is to make each drop smaller than the previous drop. (Done by making each successive dose a % of the previous dose, each successive drop will be smaller)
This has proven the best way to get off the drugs. It allows the brain time to adjust to a smaller dose and remain stable.
 
Note also how critical it is at lower doses ...the serotonin occupancy is very dose sensitive at lower levels ie at lower dose levels small changes have big effects unlike at large doses there is not so much of a change. Perhaps because there is an over-saturation of the drug.
This is why many people can get from 60 to 20 say without too much trouble but struggle to go lower after that.
 
Similarly you appear to have gotten from 200 to 100 okay (emphasis on 'appear to' as wdl symptoms can be delayed and we dont know what may be currently in the pipeline) but sooner or later if you don't slow down you will crash heavily.
In other words the lower you go the slower you must go. Following a straight line trajectory may eventually cause you to fall off a cliff.
 
Online support groups such as this have found that 10% of previous dose (not the original dose)  is the best way to taper and minimize withdrawal symptoms. Some may be able to go faster some have to go even slower.
 
My long pontification can be summed up in one sentence:
Alto: We show the receptor occupancy curve in reverse to suggest you have to come off the drugs slowly to match the curve and avoid causing a precipitous slide towards the end.
Edited by Altostrata
added quote

Share this post


Link to post
Share on other sites

Posted (edited)

Looking at the graphs of receptor occupancy.... I would almost try to plot the receptor occupancy to work out dosage reductions. 

 

For example, looking at the Citalopram graph, if it was decided that a safe drop in receptor occupancy was 5% per dose change  (I'm sorry, I can't stick the picture in because I'm not that techy) then the dosages look as follows

 

80% occupancy      20mg dose         

75%                        12.5mg           37.5% drop in dosage

70%                        9mg               28% drop in dosage

65%                        7mg               22% drop in dosage

60%                        6mg               14 % drop in dosage

55%                       5mg               etc....

50%                       4mg

 

From that point it becomes hard to interpret because of the resolution of the image and the scale of the graph, so I can't really calculate the lower numbers.

 

 

I'm not putting this out there to try and change the recommendations, stick with 10%, slow and steady wins the race. It may however explain why I didn't feel any withdrawals when I dropped my escitalopram from 10mg to 5mg in one go, but lost the plot completely when I stopped taking the medication at 1.25mg (extrapolating from the citalopram graph I estimate the occupancy dropping from 80% to about 70% with the first drop, but from 40% to nothing with the second, my system could handle the 10% drop, but not 40% in one hit - and my extrapolations are based on the escitalopram being twice the strength of citalopram for ease of interpretation, i.e. 10mg Escitalopram +20mg of citalopram).

 

If there were to be some more research into receptor occupancy I think it would be very interesting. 

 

Additional link 

http://link.springer.com/article/10.1007/s00213-006-0666-y?view=classic

looking at this abstract, it seems as though Escitalopram has more than double the binding ability of citalopram - at a 10mg dose, escitalopram had an 81% occupancy, while 20mg of citalopram was only 64%.

Also interesting was that the plasma levels of the s-enantiomer were the same, suggesting that the r-enantiomer (the other half of the chemical which is in citalopram but NOT in escitalopram) has some level of inhibitory effect over the active part of the drug. Very interesting

Edited by KtKat

Share this post


Link to post
Share on other sites

I disagree that the exponential relation between drug dose and receptor occupancy at low drug levels is the real reason for a slow taper, at least not in many long-term users. That is because the number of receptors is not fixed, but changes slowly over time.

 

I am tapering an antipsychotic that blocks dopamine receptors and over time (decades) I have had to gradually increase the dose, reflecting an increase in dopamine receptors, to get the same effect. In other people, the drug may have become less effective at the same dose. Similarly to SERT graphs, the clinically effective doses of antipsychotics blocks 60-80% of receptors, so lies on the plateau part of the dose vs occupancy curve.

 

Suppose I am taking a dose that is just above the exponential part of the occupancy curve. If I then cut the dose, the withdrawal is due to two things - there is reduced receptor occupancy due to going onto the exponential part of the curve, but also I have a supersensitive system due to the extra receptors and this is what creates the long-lasting effects, because receptor numbers change quite slowly.

 

However, if I hold for a few weeks or months, the number of receptors decreases and once again 60-80% are blocked - even though I am now at a lower drug dose - so the reduction in dose has not put me permanently onto the exponential part of the occupancy curve, I have gone back to the plateau part. Next time I cut, the same thing happens - acute withdrawal, receptors decrease, but overall I remain at 60-80% receptor occupancy.

 

I still agree with small cuts, but it is because of the slow rate of change of receptor numbers, not because of exponential changes in receptor occupancy.

 

Eventually the dose will be so low, that I decide to jump. But by that time, the hope is that the receptor numbers will be normal and so I won't be dealing with a supersensitive system.

 

(Of course this isn't the whole story, changes may take place at different rates in different parts of the brain, there are other physical changes, learned changes and collateral life damage from decades on drugs) 

 

 

 

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