Why taper? SERT transporter occupancy studies show importance of gradual change in plasma concentration

[carefulprayerful]

Login is required to the website (Medscape).  I have a saved copy of the image, but it is over 40 kB so I can't attach it in this message. 

[ChessieCat]

You shouldn't post it anyway as it would be copyrighted.

[JayUT]

 

On 11/3/2017 at 8:09 AM, ZK2015 said:

Hi Krasiyan, the equation for Paroxetine will be  Occupancy% = 102*dose/(5.2+dose)

so yes at 5mg you will be at 50% occupancy, however it is really a matter of trial and error you can try different percentages till you find the one that you can tolerate and start calculating your doses based on it.

also as Gridley mentioned you can cut your pills or make liquid from them, personally I found it easier to measure doses from liquid solution.

 

This SERT Occupancy graphs makes such a difference in my understanding of why a slow taper is so important. Especially towards the end of the taper.

 

What would be the occupancy equation for Sertraline? 

 

I am giving this taper another go after being on the sidelines for 3 years. Three years ago, I had somewhat manageable withdrawal problems from 50 mg to 37.5 mg to 25 mg to 12.5 mg, but failed miserably when I CT'd at 12.5 mg. I reinstated and held at 12.5 mg for the past 3 years. It looks like 12.5 mg Sertraline is still around 55% occupancy.

 

In Nov 2018, I decided to drop from 12.5 mg to 6.25 mg. I had some withdrawal, but it appeared to be manageable. Held 6.25 mg for 2 months. Then 6.25 mg to 0 mg was a fail. 6.25 mg is still appears to be around 40% SERT occupancy. I have reinstated at 5 mg 1 week ago and waiting to stabilize.

[Sebas]

On 4/24/2014 at 10:04 PM, Mario said:

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)

 

Hi, read your history below.

What does the turtle protocol mean? I'm currently at approximately 5,6 ml paroxetine and wondering if i should stop tapering at 5,0 ml.

[ChessieCat]

1 hour ago, Sebas said:

 

Hi, read your history below.

What does the turtle protocol mean? I'm currently at approximately 5,6 ml paroxetine and wondering if i should stop tapering at 5,0 ml. 

 

I will respond in your Intro topic.

[ChessieCat]

I've added this simple explanation to Post #1 of this topic:

 

46 minutes ago, brassmonkey said:

 

Most psych drugs work by changing the levels of a specific neurotransmitter in the body. They usually increase the amount of the neurotransmitter by shutting down the receptor that absorbs it. This is called "down regulating" and a receptor that is down regulated is referred to as being "occupied".  These charts show the percentage of receptors in the body that are "occupied"  at a give dosage of the medication.  The percentage is on the left scale and the dose is across the bottom. Both charts are showing the same thing but the one on the left show the affects of the listed strength of the dose while the one on the right shows the affects of how much of the drug ends up in the blood from taking that dose.

 

If you trace a line up from the 10mg mark on the bottom of the left chaft to where it hits the curve and then over to the left it shows that at a 10mg dose 55% of the receptors in the body have been down regulated (shut off).  Do this again for 20mg and you will see that 75% of the receptors have been shut off.  As you can see the higher the dose the more receptors are shut off, but because of the curve of the line the more you take the less affect it has.

 

The curve tells us several things.  For one thing it shows that the larger the dose the less cumulative affect it has, so in reality a very high dose is not much more effective than a lower one.  But more importantly it shows that at the lower doses (10mg and below) a very small change in dose will result in a very large change in occupancy. A large decrease in occupancy means that there is a lot of healing to be done and a large increase in symptoms is most likely.  The curve also shows why it is so important to go slowly at the lower doses as a very small change in dose causes a very large change in occupancy.

 

These charts are one of the bases from which we worked out the 10% taper rule.  The curve line for a 10% taper very closely matches the curve for occupancy.  By removing the occupancy in a controlled manner we can allow the body to heal itself while the drug is still having an affect and keeping WD symptoms at a minimum. It's like playing Jenga and only removing blocks from the top of the stack.

 

 

[Lakelander82]

So if low doses have the vast majority of receptors locked down, why bother tapering at a reduction of 10percent down from 50mg of Sertraline when you could just go straight from 50mg to 12mg in one step and then conduct a 10 percent taper from 12mg to 0.00.

 

 

[Lakelander82]

Or indeed, if you wanted to be more cautious, went from 50mg to 25mg directly and then conducted a 10percent taper from 25mg because I can’t really see a great deal of difference in the occupancy between 50mg and 25mg. Basically what I’m saying is far too much time spent tapering needlessly at the higher doses when the graphs don’t really back it up. 

[Altostrata]

It's likely that many people are taking dosages with excess capacity, i.e., they could reduce by 25% and still maintain full SERT saturation, then taper by 10% from there.

 

HOWEVER, we don't know what your individual curve looks like. It could be that a quarter of your dosage saturates your SERT receptors, or it could be that you need 90% for saturation, and a 25% reduction might throw you into acute withdrawal.

 

Admittedly -- we make this clear -- an initial 10% reduction is very cautious. But being that we only offer peer support over the Internet, we can't rescue you should you reduce by 25% and panic because you have severe symptoms. So we advise everyone to go the more cautious route of 10%, where if you do get withdrawal symptoms from tapering, they are less likely to be severe.

 

 

[nick1990]

@Altostrata, I presume that even though the SERT occupancy chart shows how rapidly things change below the 10mg range, it is only a theory that suggests that there will be an uptick in symptoms below the 10mg range and especially below 5mg?

 

I have read quite a few accounts on here of people having a relatively consistent level of WD intensity throughout their tapers. There may be times where waves are more intense but from what I’ve observed, it seems maybe that there is

alot of variability involved. 

 

Thinking back to @brassmonkey and the

description of his taper, although there were dosages throughout that he described as being a bit more of a hurdle to get past, it didn’t seem to necessarily get more intense the lower he got ? Or have I been interpreting wrong ? 

 

There are also numerous other members who have said that the lower doses have been steady and relatively smooth with a slow taper. Not noticing a worsening in their symptoms.

 

Im certainly not trying to create an argument here , more so im just interested in a discussion as to what other people’s takes are on this.

Do we actually know that the SERT occupancy has a direct correlation with how WD symptoms play out ? 

[RachelSusan]

12 hours ago, nick1990 said:

Do we actually know that the SERT occupancy has a direct correlation with how WD symptoms play out ? 

@nick1990

For me it has.  The lower I have gone the harder it has gotten.

[Gridley]

13 hours ago, nick1990 said:

 

Do we actually know that the SERT occupancy has a direct correlation with how WD symptoms play out ? 

 

Here's a discussion of the topic you might find of interest.  

 

Why taper paper: dose-occupancy curves

 

One member wrote, "The study was groundbreaking in my opinion in terms of explaining patterns as it seems to corroborate the anecdotal evidence from people here experiencing a shock when they hit the low doses and zero."

 

There are no doubt other factors that play into withdrawal (possibly explaining some members' differing experiences), but to me (no expert) this seems to be a big one.  I definitely had more difficulty once I reached the lower doses, starting around 3.5mg.

 

[Giulietta]

On 3/28/2014 at 12:20 AM, dcrmt said:

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

 

2016-July-01, Cymbalta (duloxetine) 

MMarie Found this paper on dose and 5HTT occupancy of duloxetine. Takano, 2005 A dose-finding study of duloxetine based on serotonin transporter occupancy The site,  academia.edu, requires login:

 

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

 

2019-October-24, Cymbalta (duloxetine)

Guilietta Found this paper on dose and 5HTT occupancy of duloxetine. Sho Moriguchi, MD, PhD, et al. Occupancy of Norepinephrine Transporter by Duloxetine in Human Brains Measured by Positron Emission Tomography with (S,S)-[18F]FMeNER-D2.

 

The site, Researchgate.net, requires login

 

Scroll to pages 959 and 960 of the article to see the dose-occupancy and dose-plasma concentration curves.

 

Signicance Statement excerpted from the article: "The result showed approximately 30% to 40% NET occupancies in the brain by the administration of 20 to 60mg of duloxetine."

 

[Andie]

On 2/6/2020 at 8:46 AM, Andie said:

Here is the link to what I found on Desvenlafaxine 

 

The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.

 

[getofflex]

On 8/7/2014 at 4:37 PM, btdt said:

 

 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.

Yes, I am one of those who are in significant withdrawal, and struggling to understand all of this scientific jargon.  I've been trying to read this thread for over an hour, and am still on page 1.  😕.    

[ChessieCat]

 

BrassMonkey posted this in a member's topic.  I thought it may be helpful including it here in this topic:

 

11 minutes ago, brassmonkey said:

Hi Nivsch-- Chessie sent you a link to what is called the SERT Occupancy chart.  This is the basis for the 10% every four weeks that we recommend as a starting point. By following this hyperbolic curve it is possible to remove the medication at about the same rate that the bodies receptors require to heal.  This keeps WD symptoms to a minimum during that period. If a person reduces too much or to fast there is unfinished healing that builds up in the background.  When that unfinished healing gets to be too much the person "crashes" with an outbreak of acute symptoms. This requires an extended hold period at that dose lever to allow the body to catch up.  

 

If a person goes slower than the recommended taper there is much less of a problem.  To a small extent the body can get ahead of the curve and do some healing before it is needed.  Once a taper has been established, on some cases, the body can anticipate the upcoming changes and get a head start on them. In effect becoming habituated to the idea of tapering and having some momentum in a downward direction. But it is a delicate balancing act to maintain as there are so many different factors involved in a smooth taper.

 

There are differing results for how easy a taper becomes over time. It is  split between the taper becoming easier and it becoming harder.  Because of the SERT Curve we can see that there is a bias toward it becoming harder. As you can see the lower the dose the move affect it has on the SERT loading so a small adjustment can lead to a large change. This is why we recommend people going slower and smaller changes toward the end of a taper. Frequently. if a person had fine tuned their taper, they will feel improvements the lower they go in dose.

 

[Nivsch]

My feeing goes against those occupacy curves.

 

1. Every time I reduce my dose of cymbalta (today in 50.8) by 1% I feel well the reduce after 2-4 days.

The cymbalta occupacy graph says: "Mast be from something else. you changed only 0.05% in serotonin occupaccy".

(screenshot added).

and 0.05% is 1/2000! 

Mutliply by 0.85 (assuming this is the max occupacy) and get 1700.

 

Are you really going to tell me I have to feel this - medium in difficulty - simptom 1700 more times before I fully recover?

 

This graph must be significantly wrong in my case.

 

2. In the past when I tried to reduce venlafaxine from 187.5mg to 150mg I felt very significant anxiety and had to updose back.

The venlafaxine occupacy graph: "you did nothing".

 

How can we explain that?

 

In one side this upsetting when you reduce so little and feel significant change.

But in the other side its also good news, because it says you are NOT in the saturation zone and the reduction holds in it a significant amount of healing points 😮

 

Note that only next week I will know for sure if the reductions in cymbalta cause these feeling and not other things.

 

 

 

[Altostrata]

After a dose reduction, decline of the drug in your bloodstream is gradual. Because of Cymbalta's half-life, you are feeling the dose reduction when the change fully registers in your bloodstream. For most antidepressants, this takes about 4 days.

 

Your experience matches the expected dose-response curve.

[Nivsch]

12 hours ago, Altostrata said:

After a dose reduction, decline of the drug in your bloodstream is gradual. Because of Cymbalta's half-life, you are feeling the dose reduction when the change fully registers in your bloodstream. For most antidepressants, this takes about 4 days.

 

Your experience matches the expected dose-response curve.

 

So the problem here is (probably) cymbalta's short half-life which makes significant symptoms regardless of the occupacy graph?

 

Which means my body doesn't have time to smoothly-adjust no matter how small is the reduction (because of the 12h half life), which makes the gap to always be felt?

[ChessieCat]

One of the former moderators was taking Cymbalta and created some graphs.  Check these posts out:

 

https://www.survivingantidepressants.org/topic/11950-☼-scallywag-cymbalta-skipping-doses-didnt-work-time-to-taper/?do=findComment&comment=228513

 

https://www.survivingantidepressants.org/topic/11950-☼-scallywag-cymbalta-skipping-doses-didnt-work-time-to-taper/?do=findComment&comment=229036

 

[Nivsch]

@ChessieCat

Thanks. It drops so fast. no wonder.

I start to think there is no future to keep tapering this absurd pill.

 

I will give it one more try next week, if it keep be the same i will try 0.5% (~one bead) every 3 days and if IT also won't be good i will do a switch. 0.5% every 4-5 days will be too slow and I dont want to be in 30mg only in october 2021... there is also a limit to how SLOW I can tolerate (not only to how fast)

 

[Altostrata]

5 hours ago, Nivsch said:

 

So the problem here is (probably) cymbalta's short half-life which makes significant symptoms regardless of the occupacy graph?

 

Which means my body doesn't have time to smoothly-adjust no matter how small is the reduction (because of the 12h half life), which makes the gap to always be felt?

 

This is not a problem, it's the way your body reacts to the drug. You maybe a fast metabollzer. You might try a slightly smaller reduction.

 

The occupancy graphs have nothing to do with the half-life of any of the drugs.

[Altostrata]

18 minutes ago, data17 said:

A receptor occupancy curve is not the same thing as a dose- response curve.

 

That is correct. If you look at Nivsch's symptom pattern, it matches the decay in dose-response after decrease.

 

Aronson, J. K., & Ferner, R. E. (2016). The law of mass action and the pharmacological concentration–effect curve: Resolving the paradox of apparently non‐dose‐related adverse drug reactions. British Journal of Clinical Pharmacology, 81(1), 56–61. https://doi.org/10.1111/bcp.12706

 

As discussed somewhere above, the SERT occupancy data is only a very rough indicator of overall adaptation of the organism to the action of a drug. (Personally, I consider it to be a metaphor.)

 

Hyman, S. E., & Nestler, E. J. (1996). Initiation and adaptation: A paradigm for understanding psychotropic drug action. American Journal of Psychiatry, 153(2), 151–162. https://doi.org/10.1176/ajp.153.2.151

[Nivsch]

3 hours ago, Altostrata said:

 

As discussed somewhere above, the SERT occupancy data is only a very rough indicator of overall adaptation of the organism to the action of a drug. (Personally, I consider it to be a metaphor.)

 

Hyman, S. E., & Nestler, E. J. (1996). Initiation and adaptation: A paradigm for understanding psychotropic drug action. American Journal of Psychiatry, 153(2), 151–162. https://doi.org/10.1176/ajp.153.2.151

 

What this means is that although the occupacy graph slope is significant only in the first 10-20 mg, still because there are many other factors like cellular changes, genes etc which makes the real pictures much more complicated, it is still possible that reduction from 50mg to 40mg and the reduction from 20 to 10 can still be equally significant in the amount of healing they give (regardless of what the graph says)?

[Nivsch]

4 hours ago, Altostrata said:

The occupancy graphs have nothing to do with the half-life of any of the drugs.

 

Yes I just thought that how can it be that a reduction of only 0.05% in occupacy will be felt at all? Because its so little. So maybe its strenghten the assumption that the occupacy graph is just a very tiny part of the picture.

 

If the occupacy graph was a good indicator, I would suppose to barely feel or feel only weakly a reduction of 0.05% (1/2000) no matter how fast my metabolism, no?

[Altostrata]

4 hours ago, Nivsch said:

If the occupacy graph was a good indicator, I would suppose to barely feel or feel only weakly a reduction of 0.05% (1/2000) no matter how fast my metabolism, no?

 

Probably.

[DataGuy]

Escitalopram vs Citalopram serotonin transporter occupancy available in this study, for those who are interested: https://link.springer.com/article/10.1007/s00213-006-0486-0

 

"In vivo imaging of serotonin transporter occupancy by means of SPECT and ADAM in healthy subjects administered different doses of escitalopram or citalopram

 

Background: Escitalopram is a dual serotonin reuptake inhibitor (SSRI) approved for the treatment of depression and anxiety disorders. It is the S-enantiomer of citalopram, and is responsible for the serotonin reuptake activity, and thus for its pharmacological effects. Previous studies pointed out that clinically efficacious doses of other SSRIs produce an occupancy of the serotonin reuptake transporter (SERT) of about 80% or more. The novel radioligand [123I]ADAM and single photon emission computer tomography (SPECT) were used to measure midbrain SERT occupancies for different doses of escitalopram and citalopram."

 

Note this diagram is only after a single dosage. Daily dosages would result in greater occupancy of the SERT.

 

[Superwoman]

On 10/28/2017 at 6:13 PM, ZK2015 said:

fter going through the paper I found that the percentage for Prozac occupancy follows the following equation:

 

Occupancy% = 86*dose/(1.94+dose)

Does anyone know what the equation for Effexor xr (Venlafaxine xr), percentage occupancy is?  

[Colonial]

From the "Amusing article from a psychiatrist" on page one of this thread:

 

"higher doses aren't more, they are different.(2)"

 

Which is why new symptoms can occur at any point in a taper.

 

 

[JanCarol]

On 4/10/2021 at 10:04 PM, Go2zero said:

 

Bases on calculations the SERT is about 53% at a dose of 3,2mg. These drugs are extremely powerful at low doses. If you look carefully at the graph on page 4, you can also see that the SERT is close to 50% at a dose of 3,2%.

 

The SERT at each dosage can be calculated with the formula shown on page 4 (under the graph).

 

Here is a chart of several dosages of Prozac, showing the SERT (calculated with the formula mentioned above).

 

 

 

% of 1 pill(20 mg)	Dosage in mg Prozac	% blockage serotonin receptor (SERT)
100	20	78
50	10	72
25	5	62
12,5	2,5	48
10	2	44
7,5	1,5	37
5	1	29
4	0,8	25
3	0,6	20
2	0,4	14,5
1,5	0,3	11
1	0,2	8
0,5	0,1	4
0,25	0,05	2
0,1	0,02	0,9
0,05	0,01	0,5

 

[manymoretodays]

  

On 5/24/2021 at 6:35 AM, Go2zero said:

 

 

The formula to calculate the SERT for Prozac is: (86xdose in mg)/(1,94+dose in mg).

I do not have the exact formula for calculating the SERT for escitalopram/Lexapro. But I do know that the SERT graph curves do not differ that much from Prozac.

 

If you want to use the Prozac formula to calculate the SERT for escitalopram you should multiply the escitalopram dose by 2, since 10mg escitalopram is comparable with 20 mg Prozac. So the formula would be then (86 x dose in mgx2)/(1,94 + dose in mgx2).

 

 

Please know that these calculations are not exact. Everybody reacts different in SERT to specific dosages. But this formula is giving an average.

 

More important is that it calculates and shows clearly how extremely high the SERT still is at very low dosages. Many of us think that they can stop after they went 90% down in dosage. Not knowing that the SERT may around 30% (whereas the SERT was around 75% at the full dose of 100%)

 

This thread says a lot about this subject: Please read everything to get a good understanding. However the SERT occupancy graphs say nearly everything at one glance, if you really understand them.

https://www.survivingantidepressants.org/topic/6036-why-taper-sert-transporter-occupancy-studies-show-importance-of-gradual-change-in-plasma-concentration/

 

 

More interesting information about this subject:

 

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.161.5.826

 

 

More of Go2zero's explanation on calculating sert occupancy's.

[Cheeky]

On 7/18/2021 at 10:30 PM, manymoretodays said:

  

 

More of Go2zero's explanation on calculating sert occupancy's.

Hi @Go2zero would it be a pain if I asked you what it would be for Seroquel, I’m currently taking 16mg and would really appreciate your help. 

[Go2zero]

6 hours ago, Cheeky said:

Hi @Go2zero would it be a pain if I asked you what it would be for Seroquel, I’m currently taking 16mg and would really appreciate your help. 

 

I would love to help you there. But Seroquel (quetiapine) is something completely different than an SSRI. Seroquel is an antipsychotic drug and works completely different than antidepressants.

I have hardly any knowledge from it. Maybe @brassmonkey can help you. Not sure if he knows more.

 

I have no formula to calculate the blockage percentages. Not even sure if it exists. For lots meds these calculations or graphs are not available....

[Cheeky]

Just now, Go2zero said:

 

I would love to help you there. But Seroquel (quetiapine) is something completely different than an SSRI. Seroquel is an antipsychotic drug and works completely different than antidepressants.

I have hardly any knowledge from it. Maybe @brassmonkey can help you. Not sure if he knows more.

 

I have no formula to calculate the blockage percentages. Not even sure if it exists. For lots meds these calculations or graphs are not available....

Okay not a problem would you know Paxil, that is the other one I’m tapering off, currently at 20mg . There is no rush I understand your really busy helping people. Thankyou 

[Go2zero]

Yes, Paxil I do have. See underneath.   Please understand that SERT levels give very interesting information. But there is much more to it.... For example, the SERT levels of Paxil and Prozac are pretty much the same. But tapering Paxil is much more difficult. Half life is also a very important factor. But there are more factors that determine whether tapering is easier or more difficult. 

And it can differ per person as well....

 

 

% of 1 pill(20 mg)	Dosage in mg Paxil / Paroxetine/ Seroxat	% blockage serotonin receptor (SERT)
100	20	78
50	10	72
25	5	62
12,5	2,5	48
10	2	44
7,5	1,5	37
5	1	29
4	0,8	25
3	0,6	20
2	0,4	14,5
1,5	0,3	11
1	0,2	8

[Cheeky]

Thanks so much, I appreciate it.