Posted by SLS on February 9, 2003, at 9:53:29
In reply to Re: another question on gepirone, posted by noa on February 9, 2003, at 7:03:47
Hi Noa.
In re: duloxetine (Cymbalta)
Duloxetine is a dual-action antidepressant being developed by Eli Lilly (makers of Prozac and Strattera). In this case "dual-action" refers to the ability of duloxetine to inhibit the uptake of both norepinephrine and serotonin. It is similar to Effexor in this regard. However, duloxetine is thought to be better balanced, inhibiting each to roughly the same extent. With Effexor, its action on serotonin is at least 10 times stronger than of norepinephrine. I don't recall the ratio for duloxetine, but I am pretty sure it is no greater than 3 times more potent at serotonin as norepinephrine. If the results of the investigations into the effectiveness of duloxetine can be trusted, it appears to be a particularly potent antidepressant. It demonstrates a robust ability to mitigate the somatic features (pain symptoms) of depression as well as those mental. The onset of antidepressant effect is reported to be quicker with duloxetine than the SSRIs (similar to Effexor), and at least one study found duloxetine significantly more effective than Paxil. An analysis of over 2000 subjects given Effexor demonstrates that, not only does it produce improvements in a larger number of people, but it also tends to bring people closer to full remission. I hope duloxetine does the same. It is hoped that it becomes available within the next few months. It is pending final FDA approval, having already been issued an "approvable letter."
In re: gepirone (Ariza)Gepirone is a serotonergic drug being developed by Organon. It is tentatively scheduled to be approved in 2004 as an extended-release preparation. Gepirone binds tightly to the serotonin receptor, 5-HT1a, without affecting dopamine D2 receptors. JRBecker explained this very well.
http://www.dr-bob.org/babble/20030208/msgs/140184.html
Gepirone is a full agonist of the 5-HT1a presynaptic autoreceptor. The stimulation of these receptors actually reduces the synthesis and release of serotonin, reducing neuronal activity. It also binds to postsynaptic 5-HT1a receptors, an action that tends to increase neuronal activity. Although bound to a receptor, it does not necessarily stimulate it. It is thus called a "partial agonist" at this site. Not only do 5-HT1a receptors exist on serotonergic neurons, they are also found on dopaminergic neurons. The stimulation of these receptors can increase the release of dopamine from these neurons.
* partial agonist: a drug with lower intrinsic activity than a full agonist, producing a lower maximum effect.
So, what is the net effect of gepirone on serotoninergic activity? I'm not sure. It appears to me that it might act as a sort of a synaptic stabilizer, moderating serotonergic tone to prevent hyperexcitability of neurons. There are several other sites along the neuron that 5-HT1a receptors are located. They appear on the axon (the "transmission cable") and the soma (cell body containing the nucleus and control machinery). I'm pretty sure that these receptors act as autoreceptors to regulate and decrease serotonergic activity. This is probably the mechanism by which it is reported by some that pindolol accelerates the antidepressant response to SSRIs (although not increasing the percentage of people who respond). Pindolol is probably acting as a temporary dampener of neuronal excitability until postsynaptic receptors are downregulated. That's my guess, anyway. I guess I should study this stuff more closely. I don't find myself with the energy nor motivation to research things so much anymore. I'd rather be married with children.
Oh well...
- Scott
poster:SLS
thread:139984
URL: http://www.dr-bob.org/babble/20030208/msgs/140278.html