Posted by desolationrower on April 6, 2011, at 16:35:59
In reply to For serious 5ht2C-antagonism, LOW doses are needed, posted by Brainbeard on April 6, 2011, at 2:26:19
> > not sure which of the two drugs. But you need a highish dose of prozac/fluoxetine for the 5ht2c to be significant.
>
> The very opposite is true in this case! You need a low dose of Prozac for the 5ht2C-antagonism to be significant.
>
> This is why: 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). On top of that, 5ht2C-antagonism and SRI are opposing mechanisms. At normal and higher doses of Prozac, the 5ht2C-antagonism is lost since it is flushed away by all the serotonin that begins to agonize 5ht2c-receptors (as well as all other serotonin subtype receptors). This is borne out by the fact that Prozac, in high doses, can be used as an agent against bulimia since it suppresses - which is an effect of 5ht2C-agonism.
>
> For reference/evidence, see http://www.pnas.org/content/94/5/2036.full.pdf. I've written about this before in this post: http://www.dr-bob.org/babble/neuro/20091104/msgs/931609.html
>hm, i guess it is plausible to have a nonlinear quasi cubic function effect between the two. i think this is generally true, not something unique about fluoxetine. its why polypharmacy with selective drugs is a good idea. I'm not convinced about the 'only need a little antagonism for a significant effect'.
the average binding is 1-2 orders of magnitude greater for teh transports than the 5ht2c receptor, so i think they are being optimistic, and you are being optimistic in interpreting that study. I couldn't find any citing studying confirming your posited function.
also, antagonists aren't the same as inverse agonists. afaik, fluoxetine is an antagonist, which means it has the same effect at a 5ht2c receptor that [null] binding to it would. So don't think in terms of (percent of 5ht2c occupied by 5ht)/(percent of 5ht2c occupied by fluoxetine); think of (percent of 5ht2c occupied by 5ht)/(total). also, the part of the study that shows significant effect of a small amount of fluoxetine at 5ht2c is on cloned oocytes, not actually in a brain.
there is a problem in that higher doses will marginally increase reuptake pump blockage, doing little to increase 5ht levels, but greatly increasing the number of fluoxetine molecules which can block 5ht from 5ht receptors. i don't see anything in the linked study that shows different. It is not true that very high sri gives you super 5ht which could displace the antagonist, though you do get higher levels than lower dose.
reuptake pumps are not like on/off switches, but they do have a sigmoid curve (flattening off from reduced effect and increasing action on autoreceptors). I think it a matter of the grainyness of the data (same reason you can't get one AD to show efficacy advantage over another) that it looks like reuptake inhibitors are all or nothing: it is based on clinical eg HAM-D data.
in this case, the addition of agomelatine is going to act as another competitor for the 5ht2c, resulting in less fluoxetine there, and more fluoxetine elsewhere. If you want 5ht2c antagonism, the agomelatine is much cleaner. targeting a slip in the function of fluoxetine is going to be tricky if possible at all. which is why choosing are more selective drug is better. and the OP has the option of a 5ht2c antagonist in agomelatine.
-d/r
Better living through chemistry, socialism, and big phallic rockets (with a side of roquette)
poster:desolationrower
thread:982000
URL: http://www.dr-bob.org/babble/20110406/msgs/982099.html