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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 11 of 11. This is the beginning of the thread.
Posted by conundrum on November 26, 2009, at 10:43:21
We have been speculating that prozac is a potent 5-HT2C antagonist however according to the study below it appears to be only a moderate 5-HT2C antagonist. Low dose prozac probably won't do much but block the reuptake pumps. Subjectively, 5mgs Prozac felt similar to 5mg lexapro but maybe not as strong and taking longer to kick in with less start up side effects.
Fluoxetine's(Prozac) affinity for the serotonin transporter is Ki=1.4 nmol in vitro. Its affinity for 5-HT2C is Ki=64nmol. The smaller the number the more tightly the drug binds to the target. This means that prozac is a potent reuptake inhibitor and only a moderate 5-HT2C antagonist
Ki=64nmol isn't very strong and at low dose of fluoxetine it probably wouldn't be noticable, but at a higher dose it should kick in, but you would have significant SRI at that point. You could try to add buspar to counter fluoxetine's serotonin enhancing effects but it only works for a few hours and then the serotonin would increase again after the drugs 5-HT1a's agonist properties wear off.
For now Remeron and agomelatine seem like the best options outside APs for 5-ht2c antagonism.
Here is the study where I got the numbers.
Posted by mtdewcmu on November 26, 2009, at 23:52:21
In reply to Prozac not potent 5-HT2C antagonist, posted by conundrum on November 26, 2009, at 10:43:21
> We have been speculating that prozac is a potent 5-HT2C antagonist however according to the study below it appears to be only a moderate 5-HT2C antagonist. Low dose prozac probably won't do much but block the reuptake pumps. Subjectively, 5mgs Prozac felt similar to 5mg lexapro but maybe not as strong and taking longer to kick in with less start up side effects.
>
> Fluoxetine's(Prozac) affinity for the serotonin transporter is Ki=1.4 nmol in vitro. Its affinity for 5-HT2C is Ki=64nmol. The smaller the number the more tightly the drug binds to the target. This means that prozac is a potent reuptake inhibitor and only a moderate 5-HT2C antagonist
>
> Ki=64nmol isn't very strong and at low dose of fluoxetine it probably wouldn't be noticable, but at a higher dose it should kick in, but you would have significant SRI at that point. You could try to add buspar to counter fluoxetine's serotonin enhancing effects but it only works for a few hours and then the serotonin would increase again after the drugs 5-HT1a's agonist properties wear off.What matters most is the ratio of the two affinities. According to your numbers, Prozac is about 46 times more potent as a 5-HT reuptake blocker as it is a 5-HT2C antagonist. That suggests that at therapeutic doses, there will not be significant 5-HT2C inhibition.
Although, Prozac continues to build up in your system for about a month, so it seems to me that by the time you reach steady state you may have a large excess of Prozac in your brain.
Posted by conundrum on November 27, 2009, at 1:03:15
In reply to Re: Prozac not potent 5-HT2C antagonist, posted by mtdewcmu on November 26, 2009, at 23:52:21
Yes thats true it builds up in the body with time. I believe this explains some of the problems I have had after stopping the drug and then trying to take it again. It would take a long time to get that Norepinephrine Dopamine Disinhibiting effect from prozac and face a lot of serotonin sluggishness in the meantime.
Posted by Brainbeard on December 30, 2009, at 13:45:29
In reply to Prozac not potent 5-HT2C antagonist, posted by conundrum on November 26, 2009, at 10:43:21
The idea that Prozac (i.e. fluoxetine) would not be a potent 5HT2c-antagonist is based on a misunderstanding. The Ki values are misleading, because serotonin reuptake inhibition and 5HT2C-antagonism cannot be compared equally. Serotonin receptors have to be (nearly) saturated by a reuptake blocking molecule for SRI to reach clinical significance. 5HT2C receptors, on the other hand, only need a little antagonism to result in significant effects (boosted dopamine and noradrenaline, basically). So you can't compare the Ki values on an equal par at all.
The most informative study on the difference between the two mechanisms that I could find on the web is this: http://www.pnas.org/content/94/5/2036.full.pdf
A quote: 'So far, the therapeutic effects of fluoxetine have been attributed primarily to its inhibition of 5HT transporters. Interestingly, it has been shown that the therapeutic plasma concentration of fluoxetine is in the micromolar range, and our studies show that, at this concentration range, fluoxetine can potently inhibit the membrane current responses mediated by 5HT2C receptors. Moreover, the affinity of fluoxetine for 5HT2C receptors (Ki 5 65 nM) is close to its affinity for 5HT transporters (Ki 5 33 nM) (29), which is also well below the therapeutic plasma concentration of fluoxetine. Thus, some therapeutic effects of fluoxetine may be a consequence of blocking both 5HT transporters and 5HT2C receptors. It should be noted that the blockage of 5HT transporters and that of 5HT2C receptors would have opposing actions on serotonergic synaptic transmission. (.....) Because of the highly nonlinear dose/response relationship of 5HT2C receptors the blockage of even a small number of receptors in a cell would lead to very profound changes (.....)'.
Interestingly, the Ki value for agomelatine's binding to the 5HT2C receptor is way higher than Prozac's: it's 710nM! (http://www.medicographia.com/html/static/html/issues/article_latest.asp?page=issues/99/art_10/p_2) So you reached your conclusion that agomelatine is a better option a bit too fast. This proves my point that only a little binding to 5HT2C receptors yields a clinically significant effect.
So Prozac IS a potent 5HT2C-antagonist, and at lower doses this IS the main mechanism behind its effectiveness as an antidepressant.
Posted by mtdewcmu on December 31, 2009, at 11:36:24
In reply to Re: 'Prozac not potent (...)' - Yes it is!, posted by Brainbeard on December 30, 2009, at 13:45:29
What do you make of this statement?
"It should be noted that the blockage of 5HT transporters and that of 5HT2C receptors would have opposing actions on serotonergic synaptic transmission."
It would seem that Prozac's effects on 5-HT2C may cancel each other out.
Posted by Brainbeard on January 2, 2010, at 14:51:37
In reply to Re: 'Prozac not potent (...)' - Yes it is! » Brainbeard, posted by mtdewcmu on December 31, 2009, at 11:36:24
> What do you make of this statement?
>
> "It should be noted that the blockage of 5HT transporters and that of 5HT2C receptors would have opposing actions on serotonergic synaptic transmission."
>
> It would seem that Prozac's effects on 5-HT2C may cancel each other out.It's interesting. But time is an important factor. Normally, SRI will cause indirect agonism of all 5HT receptors including 5HT2C receptors. Indirect 5HT2C-agonism causes instant anorexia, for one thing. But when time passes by, there is a downregulation of 5HT2C receptors, so in the end indirect 5HT2C-agonism may have similar results as 5HT2C-antagonism. I suspect that this is the reason for the long-term side-effect of weight gain with SSRI's.
Anyway, because of the non-linear dose/response relationship of 5HT2C-antagonism, i.e. only a little is enough to reach significant effects, with low dose Prozac the indirect 5HT2C-agonism would probably be too weak to interfere much with the 5HT2C-antagonism.
Posted by West on March 14, 2010, at 19:34:15
In reply to Re: 'Prozac not potent (...)' - Yes it is!, posted by Brainbeard on December 30, 2009, at 13:45:29
In Pigs: agomelatine (S20098) displayed pKi values of 6.4 and 6.2 at native (porcine) and cloned, human (h)5-hydroxytryptamine (5-HT)2C receptors, respectively. It also interacted with h5-HT2B receptors (6.6), whereas it showed low affinity at native (rat)/cloned, human 5-HT2A (<5.0/5.3) and 5-HT1A (<5.0/5.2) receptors, and negligible (<5.0) affinity for other 5-HT receptors.
Posted by Franz on April 2, 2011, at 18:09:29
In reply to Re: 'Prozac not potent (...)' - Yes it is!, posted by Brainbeard on December 30, 2009, at 13:45:29
> The idea that Prozac (i.e. fluoxetine) would not be a potent 5HT2c-antagonist is based on a misunderstanding. The Ki values are misleading, because serotonin reuptake inhibition and 5HT2C-antagonism cannot be compared equally. Serotonin receptors have to be (nearly) saturated by a reuptake blocking molecule for SRI to reach clinical significance. 5HT2C receptors, on the other hand, only need a little antagonism to result in significant effects (boosted dopamine and noradrenaline, basically). So you can't compare the Ki values on an equal par at all.
>
> The most informative study on the difference between the two mechanisms that I could find on the web is this: http://www.pnas.org/content/94/5/2036.full.pdf
>
> A quote: 'So far, the therapeutic effects of fluoxetine have been attributed primarily to its inhibition of 5HT transporters. Interestingly, it has been shown that the therapeutic plasma concentration of fluoxetine is in the micromolar range, and our studies show that, at this concentration range, fluoxetine can potently inhibit the membrane current responses mediated by 5HT2C receptors. Moreover, the affinity of fluoxetine for 5HT2C receptors (Ki 5 65 nM) is close to its affinity for 5HT transporters (Ki 5 33 nM) (29), which is also well below the therapeutic plasma concentration of fluoxetine. Thus, some therapeutic effects of fluoxetine may be a consequence of blocking both 5HT transporters and 5HT2C receptors. It should be noted that the blockage of 5HT transporters and that of 5HT2C receptors would have opposing actions on serotonergic synaptic transmission. (.....) Because of the highly nonlinear dose/response relationship of 5HT2C receptors the blockage of even a small number of receptors in a cell would lead to very profound changes (.....)'.
>
> Interestingly, the Ki value for agomelatine's binding to the 5HT2C receptor is way higher than Prozac's: it's 710nM! (http://www.medicographia.com/html/static/html/issues/article_latest.asp?page=issues/99/art_10/p_2) So you reached your conclusion that agomelatine is a better option a bit too fast. This proves my point that only a little binding to 5HT2C receptors yields a clinically significant effect.
>
> So Prozac IS a potent 5HT2C-antagonist, and at lower doses this IS the main mechanism behind its effectiveness as an antidepressant.What would be a low dose prozac with 5HT2C-antagonist effect?
How bad is prozac´s effect on sexual function for males?
I am considering alternatives to agomelatine.
Thanks
Posted by Brainbeard on April 3, 2011, at 5:13:22
In reply to Re: 'Prozac not potent (...)' - Yes it is!, posted by Franz on April 2, 2011, at 18:09:29
> What would be a low dose prozac with 5HT2C-antagonist effect?
5mg, 2.5mg... You could even try less.
>
> How bad is prozac´s effect on sexual function for males?
>
Very bad, usually, but that's only true at higher or more 'normal' doses, in the 20+mg range. I don't expect this side-effect on 5mg or less, but it may come into action even at 10mg.> I am considering alternatives to agomelatine.
I see.
> Thanks
Welcome.
Posted by Franz on April 3, 2011, at 8:09:29
In reply to Re: 'Prozac not potent (...)' - Yes it is!, posted by Brainbeard on April 3, 2011, at 5:13:22
> > What would be a low dose prozac with 5HT2C-antagonist effect?
>
> 5mg, 2.5mg... You could even try less.How interesting.
> >
> > How bad is prozac´s effect on sexual function for males?
> >
> Very bad, usually, but that's only true at higher or more 'normal' doses, in the 20+mg range. I don't expect this side-effect on 5mg or less, but it may come into action even at 10mg.
>Sorry, I forgot to ask about which side effects. Escitalopram 10 mg did not cause me erection problems, yes delayed eyaculation but it seems it gets better on time. Would this be a good indicatior that low dose prozac won´t be bad in this area?
Thanks
Posted by Brainbeard on April 3, 2011, at 13:52:24
In reply to Re: 'Prozac not potent (...)' - Yes it is! » Brainbeard, posted by Franz on April 3, 2011, at 8:09:29
> Sorry, I forgot to ask about which side effects. Escitalopram 10 mg did not cause me erection problems, yes delayed eyaculation but it seems it gets better on time. Would this be a good indicatior that low dose prozac won´t be bad in this area?
I was meaning the usual kind of problems, that is difficulty reaching an orgasm, less pleasurable orgasms, and possibly erection problems.
It might be an indicator, yes. You will have to try to find out. Don't forget that Prozac stays in your blood for about a month and messes with your liver enzymes, i.e. inhibits 2D6.
>
> ThanksMy pleasure.
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