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SSRIs do mess with nor-epinephrine and dopamine uptake....


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After reading the charts on this guy's website http://www.preskorn.com/books/ssri_s3.html , it is obvious that there are SSRIs that aren't so selective in their reuptake of serotonin. A handful of us could guess the particular SSRIs that mess with nor-epinephrine and dopamine re-uptake to an extent........ anyone? My initial guess would've been Zoloft and Prozac....ding ding ding!

According to Preskorn's charts based off of a few studies (whether or not the studies are totally legit I don't know.....right now I'm too benzoed to figure to look for legitamacy, but since the guy based a book off of these studies I'd think they'd be legit, plus he seems to be legit throughout the states and Europe)...

Okay, according to his charts..... for dopamine uptake, Zoloft was more pronounced in keeping the dopamine within the synapse than any of the TCAs and SSRIs as it avg. 140 (the lower avg the more it keeps the dopamine within the synapse for usage), followed by Paxil at around 2300, and Prozac being more prounced than any other TCAs and SSRIs at around 3500, Luvox and Celexa avg. in two studies at around 25,000. Though for the TCAs DA uptake isn't a labeled function, but the study at least does give an idea of how dopamine is affected by SSRIs and TCAs.... The TCAs were in the range of 8,000 to 11,000.

Now for nor-epinephrine.....the TCAs are pretty much serotonin and nor-epinephrine inhibitors, now how do some of the SSRIs compare with the TCAs in this respect?

Paxil in 3 trials averaged a 45, Zoloft averaged 183, Prozac avg. 198, Luvox at around 460, and Celexa avg. a whoppin 4,000 (the higher the more nor-epinephrine escapes back into the neuron without being blocked, the lower thus represents the more nor-epinephrine is blocked from re-uptake and kept in the synapse for use).........the TCAs: Elavil: avg. 17.3, Tofranil: avg. 13, and Norpramin avg. 0.70........................

This at the very least explains to me anyways, why Zoloft, Prozac, and Paxil are so much more activating than Celexa/Lexapro, and Luvox....

For Serotonin re-uptake here were the following averages: Paxil at .48, Zoloft at 1.48, Celexa at 2.25, Luvox at 3.4, and Prozac at a stunning 62. The TCA Anafranil was at 1.8, but with a 17 on the NE charts....which with someone with a pre-disposed anger/rage issue this could elevate it to an extent if that individual is already taking a CNS stim of some kind.....

If anything, these stats show how any particular SSRI may react when taking along with a med that is already acting on the nor-epinephrine and dopamine productions and re-uptake of both neuros. Such as someone with an OCD/GAD issue taking Lexapro with Adderall, instead of Zoloft or Prozac with Adderall (just one of a few CNS stims).

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Um. Those numbers are absolutely meaningless unless you explain what they mean and how they relate to each other. They are not always linear. I'm slowly getting my brain back. I'll try and post more later.

I suggest people try and read the preskorn piece themselves rather than going by this interpretation.

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I find this quite interesting, and yet I have NO desire to wade thru this amount of arcane data.

I had not seen any comparative values for the different drugs, though I suppose they have existed in the pharmacology community.

What is exciting to me is the idea that out of such research could come easy to use pocket references for psychiatriast to use. Combine that with say, a patient DNA analysis for drug sensitivity, which are starting to become available to the public, and we might start to take psych medications from a hit or miss art, to a true science.

a.m.

p.s. Dr. Preskorn works for a great university. Go JayHawks!

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jonathanupr,

Thanks for posting that link; I haven't thought about this in a while. Another good read in this regard might be another article that Preskorn wrote that specifically considers whether Zoloft could be clinically considered a dopamine reuptake inhibtor. He points out that what matters is not the absolute binding numbers, rather the ratio between them.

With Zoloft, he points out that standard dosing leads typically to 80% inhibition at the serotonin (5-HT) re-uptake pump. Zoloft is 250 times more selective for 5-HT than dopamine (DA), which means that with standard dosing binding at the DA uptake pump would be minimal.

Based on the numbers in the article jonathanupr linked to, we'd expect the following in term of reuptake inhibition (RI):

Celexa, 40 mg; 60% 5-HT RI => 0.32 - 1.05% DA RI

Prozac, 20 mg; 80% 5-HT RI => 0.11 - 2.44% DA RI

Luvox, 150 mg; 70% 5-HT RI => 0.01 - 0.02% DA RI

Paxil , 20 mg; 80% 5-HT RI => 0.00 - 0.03% DA RI

Zoloft, 50 mg; 80% 5-HT RI => 0.32 - 1.05% DA RI

So, yeah, Zoloft and Prozac have the greatest dopamine re-uptake properties. With 200 mg of Zoloft, the maximal DA reuptake would be about 4% and with 100 mg of Prozac, that would be about 12.5%. The last number, achieved with a mega-dose of the drug, is still pretty low and one wonders if it is clinically relevant. Especially given the super saturation of the serotonin receptors.

In terms of norepinephrine (NE) uptake, there would be a similar range of values. Except for Prozac, where the numbers on potency are wildly discordant. At a 20 mg dose, NE RI varies from 1.47 - 81.6%. Actually there's another study that indicates Prozac as having an effect on extra cellular NE almost as great as the effect on 5-HT.

That study does conclude a substantial increase in DA for Prozac (and Cymbalta). But a third paper seems to indicate that the basis for this might be beyond the simple reuptake systems. More important might the direct binding properties of these drugs on various receptors. E.g. Prozac has a pretty strong affinity for the 5-HT2C receptors, which can relase dopamine (and norepinephrine, I think) in certain parts of the brain. So, I think even more from this perspective, you could think of Prozac as being a pretty "dirty" SSRI, having substantial effects on NE and DA.

But as you can see, the mechanisms with Prozac are more complicated than the simple (and often clinically insignificant) reuptake properties for NE/DA. There might also be similar indirect effects of the other SSRIs, but I haven't really come across them.

In any case, I think the rational polypharmacology that you describe is still a ways off. And in the mean time we're still, unfortunately, left with clinicians' experience and trial and error.

Good luck,

cache-monkey

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Could these effects on dopamine and norepinephrine be why they cause hypo/mania in bipolars? Or is it the way it acts on serotonin? Or don't they know?

I'm wondering why AAPs seem to be mostly OK (although some can cause mania) for treatment of BD when SSRIs are frowned upon even though they both act on serotonin.

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good post cache monkey........... precisely one of the main reasons I posted the info was to get people "of the know" to come out of the woodwork with the info that I was looking for. Preskhorn's studies are a bit aged, but there is definitely some interest for people with certain co-morbid issues for lining the SSRIs up in the order of the ones that may provoke and promote more DA and NE re-uptake than would the other SSRIs.

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I've been trying to examine the effects of 'S'SRIs on NE and DA, and it looks like much of it is downstream effect from the drug hitting the 5HT receptors, and has less to do with direct reuptake inhibition of DA and NE.

This might be part of the basis for my research project (finding out how to augment the initial potentiation as well as the treatment longevity of SSRIs).

I would give y'all a more thorough explanation with citations, but I'm afraid y'all wouldn't understand my nerdbabble. Actually, I'm afraid I won't understand what I just wrote.

Now if you don't mind, I've got to get back to the 2 foot high stack of journal articles sitting on my living room table.

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I would give y'all a more thorough explanation with citations, but I'm afraid y'all wouldn't understand my nerdbabble. Actually, I'm afraid I won't understand what I just wrote.
I say: give it a crack if you have time, herrfous!

~cache-monkey

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