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Re: wellbutrin

Posted by Cam W. on May 14, 2000, at 0:50:42

In reply to Re: wellbutrin, posted by Andre Allard on May 13, 2000, at 14:20:47


Samantha - Wellbutrin is working wonders on my depression. I have had failures on both Zoloft and Paxil (actually with the Zoloft, I may have not given it time to work, but I didn't like the side effects). I had reached 60mg of Paxil daily over 6 months without improvement (and a possible worsening).

As for Wellbutrin's mechanism of action (MOA), I am almost sure it has little to do with norepinephrine or dopamine reuptake, as is the common theory. Even the manufacturer admits that the blockade of norepinephrine reuptake and dopamine reuptake occurs at much higher doses than are taken for depression. These effects really are not significant until a person is taking 600mg daily (increased risk of seizure at this level - >4%)

Possible mechanism of action of Wellbutrin (•caution - for HPA axis purists only•):

Modulation (or smoothing out the flow) of norepinephrine through the locus ceruleus (contains about 50% of the body's norepinephrine fibers), makes the norepinephrine signaling less erratic. This may improve norepinephrine flow through the body and may downregulate ß-adrenergic receptors, leading to decreased CRH gene expression. Less CRH release (from the hypothalamus) which causes less ACTH release (from the pituitary) which leads to a downregulation of ACTH receptors (and improves the blunted adrenal response to ACTH; but actually decreases ACTH activity), thus leading to decreased cortisol release from the adrenals. This decrease in cortisol release may allow the downregulation of the glucocrticoid receptors in the hypothalamus and pituitary and restore the feedback mechanism that turns off cortisol release from the adrenals. This may restore the functioning of the HPA axis (body's main stress response system), thus ameliorating the symptoms of depression.

I believe the above to be an intriguing theory.

Or - All antidepressants (all classes) seem to have action at the body's corticosteroid receptors in the hypothalamus and pituitary. Most downregulate glucocorticoid receptors (citalopram downregulates mineralocorticoid receptors - extended theory upon request). Does this kickstart the cascade I mentioned above? (Kinda a chicken/egg thing). This would explain why antidepressants that don't act on norepinephrine (eg SSRIs) work.

I am going to go out on a limb here and hypothesize that the reason SSRIs (eg fluoxetine, paroxetine) work for some people, NRIs (eg reboxetine, desipramine) and mixed SNRI TCAs (eg amitriptyline, nortriptyline) work for other people, is that some have a breakdown of the HPA axis that requires serotonin to resolve depression (responders to SSRIs) or a breakdown requires norepinephrine to resolve depression (responders to NRIs). This may also be why many European psychiatrists believe that the TCAs are still the best pharmaceutical antidepressants we have, because they have both SRI and NRI activity. It's just that the TCAs' effects on muscarinic/cholinergic and œ-adrenergic receptors cause too many side effects (some of them life threatening or at least interfering with daily functioning).

Wellbutrin has worked for me (on 2 occations) where SSRIs haven't and I do not believe that it is placebo effect.

Geez, I gotta stop this thinking out loud - Cam


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poster:Cam W. thread:33345
URL: http://www.dr-bob.org/babble/20000508/msgs/33406.html