Posted by JohnX2 on November 17, 2001, at 16:10:10
In reply to Re: new bupropion mode of action abstract- CAM,SLS,JG » Cam W., posted by JohnX2 on November 17, 2001, at 16:06:03
Ps I forgot to mention that I have non-texbook
symptoms of bipolar II and some add. The
psychiatrist find it strange that my hypomania
is generally short lived. They are also
perplexed in general as to how to treat me
so I do my own research to try to come up with
*some* plausible explanation and treatment
course. And I think the dysfunctional supersesitive
up/down regulation of the noradrenergic
receptors could explain this phenomina.-john
>
> 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/84521.html