Pharmacology - Why Effexor (Venlafaxine) has different effects at different dosage levels

[lulz]

This is the followup of an article about why antipsychotics don't work the way people expect them to - http://www.drugs-forum.com/forum/sho...d.php?p=295920

Let's review the idea of sequential binding. A drug with affinity for multiple receptors doesn't bind to all of them simultaneously, but rather sequentially, like an aging polygamist, starting with the system for which it has the greatest affinity. Eventually, this maxes out, and it goes and adds the receptor system for which it has the second greatest affinity.

Once it has maxed out a receptor system, pushing the dose doesn't get you any more of that effect (or side effects.) You don't get less, but you don't get any more. You know what else is like that, sort of? Chlamydia.

Let's look at an SSRI, Celexa. That first S stands for selective (serotonin reuptake inhibitor.) Allof it's clinical effect is coming from one single receptor system; this rum fountain has only one level-- and it's not that deep. By about 20mg, you've gotten as much serotonin effect as you are going to ever get.



Certainly, by 40mg, you're all done. Do you expect the clinical difference from 10mg to 20mg to be significant? Maybe. How about 20mg to 40mg? Not so much. 40mg to 60mg? You woke me up for this? Don't touch me.

In other words, there's only one level in Celexa's rum fountain, and it's pretty much filled by 40mg. Pushing it to 60mg ("Now, with 50% more citalopram!") gets you a whole 3% more serotonin transporter binding. Which is embarrassing. I said don't touch me. Do it again and I'm calling an adult.


So what about Effexor, the serotonin/norepinephrine reuptake inhibitor, invented at Wyeth Labs by Kirsten Dunst, aka Vitamin C?





From the American Journal of Psychiatry study:

la, la, la , la , la, la ,la ,la ,la ,la
la ,la ,la,la, la,la
yeah, yeah, yeah,
la, la, la, la, la, la, [repeat x 36]
we will still be friends forever [sic]

Which is exactly the point. You don't get both S and N at all doses, it is, again, sequential: level 1 is S, maxed out by 75mg; and level 2 is N. Guess when level 2 (N) really kicks in? 150mg.

So anything after 150mg is really two systems at once, with the N increasing from there. 300mg is the same amount of S as 150mg, but the N is more.
Would you expect 75mg Effexor to be generally more efficacious than 40mg Celexa? No, because they are both doing the same thing: blocking about 80% of serotonin transporters. But what about after 150mg, when you have S and N?





From An Inconvenient Truth, 2006



This is why Effexor studies only show superior efficacy at doses above 150mg-- because at 150mg, you start adding N on top of your already maxed out S. It's not adding more of the same drug, it is like adding a second drug. It's not more Effexor; it's taking a maxed out SSRI, and adding a NRI. It's like being with Princess Leia, but then adding Princess Ardala. And if you understood that joke, you should put down Yars' Revenge and kill yourself.

Let me be clear: I'm not saying Effexor is or is not better than an SSRI. I am saying that

1. it would be impossible for it to be better then SSRIs, across a population, at less than 150mg.
2. if it is going to be better, it would be better after 150mg, and only because you are adding a second system.
3. If you are a doctor who "went all the way" up to 75mg Effexor for depression (or 300mg Seroquel for psychosis, etc, etc) and then stopped it because "it wasn't helping at all" then you should probably punch yourself in the testicles/uterus, you have missed the point. How one responds at 75mg IS NOT AT ALL PREDICTIVE of what might happen at 150 or more (or, for Seroquel and psychosis, 500mg or more) again, and for the last time, because higher doses aren't more, they are different.(2)

You can see this most clearly if you look at an MRI:




which is self-explanatory.(3)


What you may want to ask is this: why haven't you heard this stuff before? You think I discovered all this, in my basement lab, the one I use to create Jessica Simpson clones? I'm the Ponce de Leon of psychiatry?(4) Why the accepted delusion that a drug is the same, regardless of dose? Perhaps its because this is new? Only new drugs that are this way? The old ones-- Thorazine, Elavil, Pamelor, Remeron, Wellbutrin-- all blunt instruments, single receptor system drugs?
Why do we think that an inanimate object has a fixed identity, when even a person doesn't?


--------
1. From the Celexa package insert: (warning: PDF-- clear your schedule)


2. Punching yourself in the testicles/uterus is not likely to help you learn this, it is more for my benefit.
3. It's technically an fMRI, bt the point is the same.
4. Ponce de Leon did not actually discover psychiatry, but he was the first to make it available to the masses.

http://thelastpsychiatrist.com/2007/...e_most_im.html

Reputation Comments on this post:

	excellent post, comprehnsive and easy to understand.
	woah great post/find! ! more of this kind please
	Not only informative, but hysterical.

[Broshious]

Do you have any information on the dopamine reuptake inhibition effects of Effexor at, I think 300mg+?

[lulz]

The dopamine reuptake seems to be quite weak, which is why you don't hear much specific information about it. I think the dosage levels required to have a significant effect would be too high to be useful.



^ that's the reason right there (sorry about the poor quality of the image). It shows the binding affinities that the effexor molecule has for the reuptake proteins for serotonin (1), norephinephrine (2), and dopamine (3). As you can see, the gap between binding affinities for serotonin and norepinephrine are fairly close together, but the gap between norepinephrine and dopamine is much greater.

Reputation Comments on this post:

Thanks for the info

[godzcamera]

Hey thanks for this information swim was wondeirng why his dr wanted to increase his dose from 100mg of effexor to 150mg of effexor. if you have the time what exactly is the purpose of the NRI what will it do for swim. swim is very new at learning about SSRI's and what they actually do in the brain but hopefully swim will find more information the farther swim search for it in the forums. or if you have the time an can dirrect swim into some easy to understand information that would be great too!

[lulz]

I hate to state the obvious, but neuropharmacologists don't seem to have a fantastic understanding of how one single neurotransmitter affects the brain as a whole.

The reason why your doctor might want to increase the dosage for effexor is best illustrated in this thread:

http://www.drugs-forum.com/forum/showthread.php?t=36427

It's about antipsychotic medications, but the principle is the same.

Affinity is like magnetism. At 100 mg the magnetism of the effexor may only be working on serotonin. But like the illustrations in the previous link illustrate, once one neurotransmitter is being stimulated to the maximum, it'll only then move on to the next neurotransmitter.

The tone of these articles is totally facetious, but the facts are accurate. Different doses of effexor (or similarly cymbalta) will have different effects depending on how high the dosage is. These drugs don't work like simple single-neurotransmitter drugs like Prozac, they work on different pathways of the brain depending on how high the dose is.

If you think you need help, and single-neurotransmitter drugs like Prozac aren't cutting it, then it makes sense to go along with a doctors suggestion to increase the dosage of an SNRI like effexor or cymbalta.

The only things to watch out for mainly are: side effects, and mania. But you're in good hands on this forum, if you post feedback you'll get some good advice on how it's working for you (assuming you're not a latent manic depressive).

[0utrider]

awesome post.
yet, what about the efficiency of Venlaxafine as such?
What SWIM doesnt understand is that, altough the exact same neurotransmitters (or magnets as SWIY put it in a comprehensive way) are satisfied by either SSRIs or Venlafaxine or whatever else works on Serotonine, how come that the effects are different? Does it matter what shape my hammer has, if the point is just to hit the nail ? Obviously, the short half-time of venlaxafine is one reason for its strong withdrawal; however, not only withdrawal-wise but also effect and side-effect wise venlafaxine seems to be for some a great thing while for others quite terrible. while this is true for most ADs SWIM has the impression the, at least on internet reviews, more people are complaining about Venlafaxines strong side effects than about other SSRIs, even in doses that are below the noradrenaline threshold.

also SWIM'd like to know if the noradrenaline is the reason for the manic potential of it ?