![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 8 of 8. This is the beginning of the thread.
Posted by SLS on February 23, 2001, at 14:55:02
How does Wellbutrin (bupropion) work?
- Scott
Posted by Cam W. on February 23, 2001, at 15:53:21
In reply to How does Wellbutrin work ?, posted by SLS on February 23, 2001, at 14:55:02
Scott - In all sincerity, I don't know. I haven't seen any articles addressing the WB mechanism of action.
Somehow it recouples the HPA axis, but at a link that hasn't been found, yet (ie indirectly). Perhaps it has something to do with the regulation of glucocorticoid receptors or perhaps altering the expression of CRH or ACTH somehow. I really don't have a clue, but I'll bet it has little to do with the proposed reuptake mechanisms.
I found that it worked for my endogenous, possibly genetically or environmentally (ie developmental) induced depression, but it did not seem to work at all for this most recent exogenous (reactive or stress-induced) depression.
Sorry pal, can't help ya - Cam
> How does Wellbutrin (bupropion) work?
>
>
> - Scott
Posted by Sunnely on February 23, 2001, at 22:07:02
In reply to How does Wellbutrin work ?, posted by SLS on February 23, 2001, at 14:55:02
Stephen M. Stahl, MD (Essential Psychopharmacology, 2000, 2nd ed., Cambridge University Press, Cambridge, UK) explains it this way:
"Bupropion is the prototypical agent of the norepinephrine and dopamine reuptake inhibitors. For many years, its mechanism of action was unclear. Bupropion itself has weak reuptake properties for dopamine, and weaker yet reuptake properties for norepinephrine. The action of the drug on norepinephrine and dopamine neurotransmission, however, has always appeared to be more powerful than these properties could explain, which has led to proposals that bupropion acts rather vaguely as an adrenergic modulator of some type. Bupropion is metabolized to an active metabolite, which is not only a more powerful norepinephrine reuptake blocker than bupropion itself but is also concentrated in the brain. In some ways, therefore, bupropion is more of a pro-drug (i.e., precursor) than a drug itself. That is, it gives rise to the "real" drug, namely its hydroxylated active metabolite (hydroxybupropion), and it is this metabolite that is the actual mediator of antidepressant efficacy via norepinephrine and dopamine reuptake blockade."
===============================================
> How does Wellbutrin (bupropion) work?
>
>
> - Scott
Posted by JohnX on March 2, 2001, at 3:50:03
In reply to Re: How does Wellbutrin work ? » SLS, posted by Sunnely on February 23, 2001, at 22:07:02
> Stephen M. Stahl, MD (Essential Psychopharmacology, 2000, 2nd ed., Cambridge University Press, Cambridge, UK) explains it this way:
>
> "Bupropion is the prototypical agent of the norepinephrine and dopamine reuptake inhibitors. For many years, its mechanism of action was unclear. Bupropion itself has weak reuptake properties for dopamine, and weaker yet reuptake properties for norepinephrine. The action of the drug on norepinephrine and dopamine neurotransmission, however, has always appeared to be more powerful than these properties could explain, which has led to proposals that bupropion acts rather vaguely as an adrenergic modulator of some type. Bupropion is metabolized to an active metabolite, which is not only a more powerful norepinephrine reuptake blocker than bupropion itself but is also concentrated in the brain. In some ways, therefore, bupropion is more of a pro-drug (i.e., precursor) than a drug itself. That is, it gives rise to the "real" drug, namely its hydroxylated active metabolite (hydroxybupropion), and it is this metabolite that is the actual mediator of antidepressant efficacy via norepinephrine and dopamine reuptake blockade."
>
> ===============================================
>
> > How does Wellbutrin (bupropion) work?
> >
> >
> > - ScottScott,
I read an article which debated the mechanism of action of Wellbutrin based off of experimental data. The conclusion was that the metabolite hydroxy-bupropion (as Stahl indicates) does most of the work via norepinephrine re-uptake. In the animal models at therapeutic doses, the dopamine reuptake was insignificant. However, they did hypothesize that an unknown genomic mechanism was responsible for increasing the sensitivity of dopamine receptors in the nucleus accumbens.
How well the animal models correlate to people
is a good topic of debate.-JohnX
Posted by SLS on March 2, 2001, at 8:58:31
In reply to Re: How does Wellbutrin work ?, posted by JohnX on March 2, 2001, at 3:50:03
> I read an article which debated the mechanism of action of Wellbutrin based off of experimental data. The conclusion was that the metabolite hydroxy-bupropion (as Stahl indicates) does most of the work via norepinephrine re-uptake. In the animal models at therapeutic doses, the dopamine reuptake was insignificant. However, they did hypothesize that an unknown genomic mechanism was responsible for increasing the sensitivity of dopamine receptors in the nucleus accumbens.
Dear JohnX,Thank you. This seems very reasonable.
The involvement of NEergic activity has been suspected by many for a long time, but the mechanism remained elusive. Who would have thought to be smart enough to test active metabolites? ;-)
The nucleus accumbens think is very exciting.
> How well the animal models correlate to people
> is a good topic of debate.It depends on the glue.
(Stupid, I know, but I smiled, and that's all that counts).
:-)
- Scott
Posted by JohnX on March 9, 2001, at 2:33:56
In reply to Re: How does Wellbutrin work ? » JohnX, posted by SLS on March 2, 2001, at 8:58:31
>
> > I read an article which debated the mechanism of action of Wellbutrin based off of experimental data. The conclusion was that the metabolite hydroxy-bupropion (as Stahl indicates) does most of the work via norepinephrine re-uptake. In the animal models at therapeutic doses, the dopamine reuptake was insignificant. However, they did hypothesize that an unknown genomic mechanism was responsible for increasing the sensitivity of dopamine receptors in the nucleus accumbens.
>
>
> Dear JohnX,
>
> Thank you. This seems very reasonable.
>
> The involvement of NEergic activity has been suspected by many for a long time, but the mechanism remained elusive. Who would have thought to be smart enough to test active metabolites? ;-)
>
> The nucleus accumbens think is very exciting.
>
> > How well the animal models correlate to people
> > is a good topic of debate.
>
> It depends on the glue.
>
> (Stupid, I know, but I smiled, and that's all that counts).
>
> :-)
>
>
> - Scottsome other notes:
A lot of the action occured in the locus coereleus
(spelled right?) part of the brain where NE turnover was slowed down substantially.Their was a decrease in tryrosine-hydroxylase immunreactivity (the limiting step in dopamine and NE production).
Down-regulation of beta-adrenoreceptors was not
noted at therapeutic doses.I'm guessing that the genomic decrease in tyrosine-hydroxylase sensitizes the dopamine post receptors since the dopamine reuptake is minimal to counteract this. But the norepinephrine reuptake probably counteracts the effect in the norepinephrine neurons which would explain the lack of beta-adrenoreceptor down-regulation.
I still think there is some splainin to do!
-john
Posted by terra miller on March 9, 2001, at 10:47:52
In reply to Re: How does Wellbutrin work ? » SLS, posted by JohnX on March 9, 2001, at 2:33:56
so, according to all that i just read in this thread, i see nothing to do with serotonin. am i correct?
i remember reading elsewhere here that wellbutrin very weakly effects serotonin. correct?
is this why wellbutrin often is taken along with SSRI's/similar acting meds?
everything is starting to add up, if i've got it right, that is. (do i?)
terra.
Posted by JohnX on March 9, 2001, at 17:53:08
In reply to Re: How does Wellbutrin work ?, posted by terra miller on March 9, 2001, at 10:47:52
> so, according to all that i just read in this thread, i see nothing to do with serotonin. am i correct?
>
> i remember reading elsewhere here that wellbutrin very weakly effects serotonin. correct?
>
> is this why wellbutrin often is taken along with SSRI's/similar acting meds?
>
> everything is starting to add up, if i've got it right, that is. (do i?)
>
> terra.Terra,
You got it.
The action on serotonin is extrememly weak (negligible).
Most anti-depressants have some measurable amount
of action on many different types of receptors like serotonin,norepinephrine,dopamine,acetylcholine,gaba,glumtamate,etc.
But they usually are *very* targeted at a particular type or group of receptors, so the action on the other receptors is negligible.
The older tricylclic anti-depressants were less selective and had stronger action on cholinergic and muscanaric receptors etc, which lead to side effects and no additional tharapeutic action.-john
This is the end of the thread.
Psycho-Babble Medication | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.