Posted by JohnX2 on November 17, 2001, at 16:06:03
In reply to Re: new bupropion mode of action abstract- CAM,SLS,JG » JohnX2, posted by Cam W. on November 17, 2001, at 11:51:48
Hi Cam,Thanks a lot for your feedback. I hope you'll
take the chance to read this to help me
figure out what to do next about my situation.I've been trying to understand why my body
can't "lock-on" to anti-depressants succesfully,
and how "poop-out" and tension headaches may occur.I tried nearly every anti-depressant and I got
a solid response from 3: Zoloft,Wellbutrin, and
St. John's wort. My pre and post-responses
to all the meds were somewhat similar.I believe that I have PTSD, and this is a very
difficult to treat depression. Generally in
PTSD their can be a dysfunctional feedback
mechanism associated with the locus coerulus.
The binding and affinity states (high/low) for
the alpha-2 feedback receptors become dysfunctional.
Also the "balance" between pre and post synaptic
adrenorecptors can make a sustainable anti-depressant
response elusive. So I'm trying to find *anyway*
to treat this problem that makes sense.So I have been trying to figure out if and what
is the common demonitator between my response to
Zoloft and Wellbutrin. Until now I could not
explain Wellbutrin. I think it is boiling
down to poor interaction between the LC and its
target junctions like the raphe sertononergic
projections. So how do I treat this?My theory behind my emotional numbing and tension
headache comes from a paper entitiled "Buspar as
an anti-dote for SSRI incuced bruxism". It explains
many cases of Zoloft doing to others what happens
to me. In particular it says that Zoloft can
inhibit dopaminergic firing out of the VTA, and
there is a reciprocal relationship between
activation of 5ht-1a and 5ht-2 receptors stemming
from the cell bodies of the raphe nuclei. The
5ht-2 receptor activation inbits dopamine firing
in the mesocortical tract and the 5ht-1a induces
firing. This projects into the prefrontal cortex
among other areas, and the prefrontal cortex
has dopamine neurons with no autoreceptors (they
control the facial muscles/masseter). The prefrontal
dopamine neuron firing are dependant on the firing from
the dopamine body at the ventral tegemental area
(where the 1st 5ht-2a,5ht-1a interaction occurs)
and a similar junction at the prefrontal cortex
itself. The suggestion was that Zoloft is dampening
this pathway via heavy activation of the 5ht-2
receptors.So here was my response to Zoloft when it
worked:- pre response (a) - > a bit of emotional numbing,
insomnia,more energy.- post response (b) - > a short lived depression
lift *which also accompanies a relief of pain
in the face*. Also hypomania.- post response (c) - > an abrupt switch into
*severe* emotional numbing and massive pain
in my jaw and head.The timing between (b) and (c) was a wildcard.
On St. John's Wort and Wellbutrin the only
really noticeable difference was less emotional
numbing at the start of the anti-depressant.
But the switch from (b) to (c) was very repeatable
across many trials. Now I have a permanent tension
headache and even ingesting a little Wellbutrin
or St. John's wort will generally put me straght
to (c). This permanent headache started 3 weeks
after taking a lot of flax/fish oil. Before that
the headache would go away if I stopped the
offensive med. I don't know if this is relevant.- addition of anti-convulsants besides lamictal
of been of little benefit.- So I have found that Serzone complete alleviates
my pain. Serzone is an alpha-1 antagonist and
5ht-2a antagonist, so it would have a dampening
effect on the raphe nucleus. Zyprexa helps
too but to a lesser degress (and with less
cognitive decline). I punted serzone because
it made me extrordinarily drowsy.- Klonopin alleviates my pain, probably via
GabaA receptors tonically buffering the
serotonin projections (and probably other
modes too).- Adderall supposedly inhibits LC firing and also firing
out of the VTA.When it works it releived my
facial pain. Although it inhibits the VTA firing,
its pro-dopaminergic effect at the PFC increases
dopamine at that sight (I have verified this).
But, I *quickly* grow tolerant to Adderall after 3 days.- No other anti-depressant worked well.
So I could never quite explain why wellbutrin
would contribute to this tension headache/numbing
state unless it also had an interaction with
the raphe serotonergic neurons, which I always
secretly expected may be true. This article was
the 1st to verify that it may be the case.Now, I have challenged Wellbutrin with Zyprexa.
I.e. I take a dose of Wellbutrin that normally
would trigger instand headache and I find that
Zyprexa antagonizes this, but not enough to
continue with the Wellbutrin.So it just seems to me that if there is poor
balance (noradrenergic tone) resulting from
chronic stress and a break down in these
cross-talk between the LC and other brain areas,
then getting a "sustainable" response on anything
would be near impossible unless the medication
regimen improved the "tone".In the literature, it describes clonodine as
a potential anti-dote as it is a partial agonist
at the alpha-2 autoreceptors and a slight antagonist
at the postsynaptic autoreceptors. Supposedly
this can help to "re-link" the functioning of
the noradrenaline paths. Another idea was Tenex,
an alpha-2 agonist. There are also theries about
crf antagonists, etc and implications in the HPA
axis as you cited.But how do I treat my current condition? I see
respite in solutions that:- antagonize alpha-1 adrenoreceptors
- agonize alpha-2 receptors.
- 5ht-2a antagonists
- 5ht-1a agonists
- dopaminergics.and finally:
- nmda receptor antagonism. i.e set up a referee
at the heart of the matter.Currently lamictal is the only med that I tolerate
that lifted major depression but leaves me
dysthymic. If I bump my lamictal dose past 225
mg, it kicks me into state (c). Strange!.So earlier I was thinking that given what I learned
about the SSRI induced bruxism and the tolerance/
sensitization path of amphetamine that a medication
that is a "referee" and stabilizes that VTA dopamine
firing may stabilize the whole system. The nmda
antagonist looked interesting. Another approach
would be to balance adrenergic meds like clonodine
or guanfacine , and I thought maybe an alpha-1
antagonist may be usefull.Anyways, these noradrenergic conections do not
feed back properly, and I'm wondering if I have
push them so much that the receptors are chronically
up or down regulated and taking an anti-depressnat
besides the meds with my proposed modes of action
would be futile.What do you think about what to do?
I would "love" to be able to get a Wellbutrin
response, and am very curious if adjunctive
adrenergic meds (stuff the turns the dials on
the alpha-1,2 receptors) and/or the nmda antagonist
may allow this to happen.Please help me with some insight, as I am
really at a standstill on relieving the
dysthymia. Originally I came across this memantine
idea thinking that if it could prevent Adderall
poop-out, then I would throw in the towel and
take a stim forever (as long as it is non-addictive/
safe). But it seems that such intervention by
an nmda-antgonist like memantine might "reset"
these other interactions and act as a referee.
According to the literature a very slight or
no decrease is seen from the VTA firing for WB
and Zoloft, but I'm thinking my brain is lopsided
and the medications potently reduce the firing
in some manner.
Until now, I never could come up with a plausible
explanation for the WB thing. But now that I learn
that it increases the serotonin conductance it
seems to fall in the same routine as Zoloft
potentially.thanks for any insight
-john
> John - It has ben widely known (ie. since Wellbutrin™ - bupropion - was relased) that the blockade of the reuptake of norepinephrine (NE) and dopamine (DA) could not be the mechanism of action of bupropion. The dose required to to effectively block the NE and DA reuptake mechanisms would have to be higher than 600mg/day. Since most people respond to dose of 300mg/day, scientists have been looking at the larger picture of bupropion mechansm of action.
>
> Where and when was the study that you quoted published. I'd like to look over the article a little closer.
>
> Also, reciprocal regulation of the locus ceruleus and raphe nuclei by serotonin (5-HT) and NE repspectively, has been also be known for a number of years. The same has been shown for the regulation of the VTA (ventral tegmental area - structure involving primary DA output).
>
> Be careful interpreting your response to medications in terms of these circuits, though. Alterations in your undividual circuitry may account for some of the effects that you have noticed, but the body's conpensatory mechanisms (involving upregulation and downregulation of various neurotransmitter concentrations and their respective receptors and their receptor subtypes; involvement of endocrine, and other overlapping systems; changes in the gene expression of neuroactive enzymes and proteins, resulting from changes in second messenger signaling; etc.) , try to return the body to it's existing homeostatic state.
>
> In simpler terms, there will be different short term and long term effects, potentially wide spread throughout the brain circuitry, in response to medications. While other serotonergic neurotransmission may not be affected increases in the concentration of NE, what other systems and brain structutres are affected by this increase in concentration? Then, how do these systems and structures affect the the components of the HPA axis (concentrations of CRH, ACTH, glucocorticoid receptors, cortisol levels), the interconnected and overlapping sex hormone system, etc.?
>
> We have a lot of these pieces; now researchers should focus on putting it back together. I thank you for your insight into bupropion's mechanism of action and I think that you are on the right track to discovering where your personal "miswiring" is occuring, but don't forget the compensatory mechanisms, and the "collateral effects" in other brain areas and systems, resulting from increasing or decreasing any single neurotransmitter.
>
> Thanks again for the insight. - Cam
poster:JohnX2
thread:84499
URL: http://www.dr-bob.org/babble/20011113/msgs/84520.html