![[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 JohnX2 on November 17, 2001, at 9:36:17
This is quite technical, but for those who are
interested:There was a new article in psychopharmocology
on Wellbutrin's mode of action.Basically came to some of the same conclusions as
another article I read, but also came up with 1 more
piece of data which I always thought would be true:
Bupropion increases serotonin conductance!I thought this may be true and I don't have the
whole article, but the abstract points out that
bupropion increases NA levels in the locus coerulus
and inhibits firing. This was antagonized by
idazoxan (alpha-2 antagonist).
At the higher doses the mean firing rate of serotonin
neurons (I'm assuming in the dorsal raphe) was
increased by 100%. The dopamine firing pattern in the
VTA was not affected. In the other articles I read
on bupropion and zoloft, the vta firing pattern was
very moderately dampened. I have a theory that in
some of us (i.e. me), the vta firing pattern
is severely dampened. Leading to bruxism or tension headaches and emotional
numbing. I also theorize that an nmda antagonist
i.e. memantine may stabilize the vta firing and
provide a sustained anti-depressant effect.Also, this would indicate the an 5ht-2a antagonist and/or
an alpha-1 antagonist would antagonize the bupropion
induced increased in serotonin conductance, which
I believe Zyprexa is doing for me since I can tolerate
a low dose of buprion while on zyprexa.The increased serotonin firing in the dorsal raphe
likely comes from alpha-1 adrenoreceptors located
on the raphe somotodendric cell bodies. At these sights
noradrenaline (diffused from the locus coerulus) increases
the firing of serotonin. This is explained in Stephen
Stah'l Essential Psychopharmacology book when he
looks at Remeron. I would also suspect therfore that
there could be interactions at the serotonin nerve
endings that have alpha-2 heteroreceptors that brake
5ht release. Here any extra noradrenaline would brake
the release of serotonin. Hmm, more conductance but
less serotonin released. Interesting battle.Anyways, confirms my feeling regarding interactions
between the locus coerulus and the raphe projections.Most other NE reuptake blockers leave unaltered the
serotonin conductance. The abstract theorizes that
Wellbutrin therefore is more of a NE release inhancer
than a reuptake inhibitor (why?). My one failed trial
on WB I was also taking buspar, I think the buspar
action would work the opposite of what WB wanted to
do since buspar is an alpha-2 antagonist, etc. Hmmm.original investigation: Modification of norepinephrine and serotonin, but not
dopamine, neuron firing by sustained bupropion treatmentJianming Dong, Pierre Blier
Department of Psychiatry and Neuroscience, McKnight Brain Institute, University of Florida, P.O. Box 100256, Gainesville, FL 32610, USA
Phone: +1-352-392-3681 Fax: +1-352-392-2579Received: 12 June 2000 / Accepted: 20 November 2000 / Published online: 14 March 2001
Abstract. Rationale: Bupropion is widely used in the treatment of depression and as an anti-craving medication for the cessation of tobacco
smoking. Because it is a very weak inhibitor of norepinephrine (NE) and dopamine (DA) reuptake, its mechanisms of action remain to be
elucidated. Methods: Bupropion was administered subcutaneously via osmotic minipumps over 2 days to determine its effects on the
spontaneous firing activity of NE, serotonin (5-HT), and DA neurons in the brain of anaesthetised male Sprague-Dawley rats. This treatment
was used in order to obtain levels of the parent compound and its putatively active metabolites that would more adequately reflect the clinical
condition than utilizing acute injections. Results: When given by minipump for 2 days, bupropion produced a dose-dependent attenuation of
the mean spontaneous firing NE neurons (7.5 mg/kg per day: 15%; 15 mg/kg per day: 61%; 30 mg/kg per day: 80%) which was reversed by
the < alpha >2-adrenoceptor antagonist idazoxan. At the highest regimen, the mean firing rate of 5-HT neurons was 100% higher than in control
rats, but unaffected in NE-lesioned rats. In contrast, DA neurons in the ventral tegmental area displayed a normal firing rate during the latter
bupropion treatment. Conclusions: Sustained bupropion administration decreased the firing rate of NE neurons due to an increased
activation of their inhibitory somatodendritic < alpha >2-adrenoceptors. This effect of the bupropion treatment would be attributable mainly to
an enhancement of NE release and not to reuptake inhibition. This contention is based essentially on the observation that NE reuptake
blockers leave unaltered the firing rate of 5-HT neurons, whereas bupropion enhanced it via a NE-dependent mechanism. The present study
did not put into evidence any DA activity of bupropion at the level of the cell body of mesolimbic/cortical DA neurons at a regimen exerting
profound alterations of the firing activity of NE and 5-HT neurons.Keywords. Antidepressant · Locus coeruleus · Dorsal raphe · Ventral tegmental area · < alpha >2-Adrenoceptors and autoreceptors
Posted by Cam W. on November 17, 2001, at 11:51:48
In reply to new bupropion mode of action abstract- CAM,SLS,JG, posted by JohnX2 on November 17, 2001, at 9:36:17
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
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
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
Posted by Mitch on November 18, 2001, at 0:33:44
In reply to new bupropion mode of action abstract- CAM,SLS,JG, posted by JohnX2 on November 17, 2001, at 9:36:17
>
> This is quite technical, but for those who are
> interested:
>
> There was a new article in psychopharmocology
> on Wellbutrin's mode of action.
>
> Basically came to some of the same conclusions as
> another article I read, but also came up with 1 more
> piece of data which I always thought would be true:
> Bupropion increases serotonin conductance!
>John, et al,
I can't explain why I feel so much better, since I have added on a low dose of bupropion. I seem to have improved sleep architecture like I had on Adderall without feeling panicky. I don't seem to have the *avoidance* I used to have. I really seem to be getting a paradoxical *anxiolytic* response to this med. I also have needed less Klonopin-I only took 1/4 of a .5mg tab all day today! I should be getting very sluggish and melancholic now (SAD symptoms-late fall/early winter), but it isn't happening. The best way to sum this up is like taking a pstim with little anxiety. I notice some improvement with attention-but nowhere as marked as with a pstim. But, there is no *degradation* of cognitive function that I normally experience at this time of year.
Go figure,Mitch
Posted by JohnX2 on November 18, 2001, at 13:33:53
In reply to Re: new bupropion mode of action abstract- CAM,SLS,JG » JohnX2, posted by Mitch on November 18, 2001, at 0:33:44
Hey this is great news.I also get a *substantial*
anxiolytic response from Wellbutrin.
Supposedly it is effective
for peripheral neuropathy from a report
I recently read too.I really wish I could find
a way to make wellbutrin work. The only
other med that really cured my dysthymia was
Adderall and it had its problems. WB is a
good med if one can get it to work.I believe the anxiolytic action comes
from its action in the locus coerulus area
of the brain (the noradrenaline flight/fight)
area. It increase norepinephrine, but slows
down the firing which is usually anxiolytic.
A lot of people get edjy on Wellbutrin, so that
must be from some other interaction in the head,
because slowing the LC almost always
translates to less anxiety. Amphetamine
slows the LC too and some people actually feel
more calm on amphetamine than off amphetamine.regards,
john
> >
> > This is quite technical, but for those who are
> > interested:
> >
> > There was a new article in psychopharmocology
> > on Wellbutrin's mode of action.
> >
> > Basically came to some of the same conclusions as
> > another article I read, but also came up with 1 more
> > piece of data which I always thought would be true:
> > Bupropion increases serotonin conductance!
> >
>
> John, et al,
>
> I can't explain why I feel so much better, since I have added on a low dose of bupropion. I seem to have improved sleep architecture like I had on Adderall without feeling panicky. I don't seem to have the *avoidance* I used to have. I really seem to be getting a paradoxical *anxiolytic* response to this med. I also have needed less Klonopin-I only took 1/4 of a .5mg tab all day today! I should be getting very sluggish and melancholic now (SAD symptoms-late fall/early winter), but it isn't happening. The best way to sum this up is like taking a pstim with little anxiety. I notice some improvement with attention-but nowhere as marked as with a pstim. But, there is no *degradation* of cognitive function that I normally experience at this time of year.
> Go figure,
>
> Mitch
Posted by Mitch on November 18, 2001, at 17:35:00
In reply to Re: new bupropion mode of action abstract- CAM,SLS,JG » Mitch, posted by JohnX2 on November 18, 2001, at 13:33:53
John,
I also have noticed a significant reduction in the need to "keep moving" (my restlessness/akathisia). I also feel less "pressured" to get everything done all at once. I feel actually somewhat emotionally "neutral", and relaxed. I don't have fifty things all going at once. The dystonia (tight throat muscles) from the tiny bit of Zoloft I take seems to be less and I am not grinding my teeth as much. I even was focused enough to SIT STILL for two hours and set up my own mood chart on a spreadsheet.
That is too bad you can't seem to get the WB to "work" for you. Maybe the nortriptyline you have been thinking about could kick-start it. I would take it at bedtime to start off, though. It is somewhat sedative (although I took it in the daytime, too in divided doses).Mitch
>
> Hey this is great news.
>
> I also get a *substantial*
> anxiolytic response from Wellbutrin.
> Supposedly it is effective
> for peripheral neuropathy from a report
> I recently read too.
>
> I really wish I could find
> a way to make wellbutrin work. The only
> other med that really cured my dysthymia was
> Adderall and it had its problems. WB is a
> good med if one can get it to work.
>
> I believe the anxiolytic action comes
> from its action in the locus coerulus area
> of the brain (the noradrenaline flight/fight)
> area. It increase norepinephrine, but slows
> down the firing which is usually anxiolytic.
> A lot of people get edjy on Wellbutrin, so that
> must be from some other interaction in the head,
> because slowing the LC almost always
> translates to less anxiety. Amphetamine
> slows the LC too and some people actually feel
> more calm on amphetamine than off amphetamine.
>
> regards,
> john
>
>
> > >
> > > This is quite technical, but for those who are
> > > interested:
> > >
> > > There was a new article in psychopharmocology
> > > on Wellbutrin's mode of action.
> > >
> > > Basically came to some of the same conclusions as
> > > another article I read, but also came up with 1 more
> > > piece of data which I always thought would be true:
> > > Bupropion increases serotonin conductance!
> > >
> >
> > John, et al,
> >
> > I can't explain why I feel so much better, since I have added on a low dose of bupropion. I seem to have improved sleep architecture like I had on Adderall without feeling panicky. I don't seem to have the *avoidance* I used to have. I really seem to be getting a paradoxical *anxiolytic* response to this med. I also have needed less Klonopin-I only took 1/4 of a .5mg tab all day today! I should be getting very sluggish and melancholic now (SAD symptoms-late fall/early winter), but it isn't happening. The best way to sum this up is like taking a pstim with little anxiety. I notice some improvement with attention-but nowhere as marked as with a pstim. But, there is no *degradation* of cognitive function that I normally experience at this time of year.
> > Go figure,
> >
> > Mitch
Posted by JohnX2 on November 18, 2001, at 17:51:57
In reply to Re: new bupropion mode of action abstract- CAM,SLS,JG » JohnX2, posted by Mitch on November 18, 2001, at 17:35:00
Hi Mitch,Your experience is somewhat consistent with mine.
I can only sit down at best like 30 min out of 60
doingw ork because I can't sit still. Fortunately I
can get a shit load done in those 30 mins.
Sometimes its so bad I have to leave my building and drive my
car. For some reason "movement" calms me down.
I also feel compelled to get up and talk to
people. My doctor thinks this is more of a
mixed state in bipolar, but it seems more add to
me. Drinking a lot of caffeine helps me to stay
focused too. At one point before I entered the
world of psychiatry I was drinking 15+ diet cokes
a day and driving my car like 30k miles a year.
I would chase this at night with alcohol just
to calm me down. Eventually after many medication
failures I landed on a combo of Adderall + Klonopin.
I thought it was funny that basically all this
psychiatry did after 1 year was elevate
me from caffeine+alcohol to amphetamine+sedative. ;)I was fine on Adderall + Klonopin, but grew
tolerant to Klonopin and Adderall then made
me manic. I have a problem with wellbutrin when
I hit the therapeutic dose it kicks in , makes
me manic, and then peters out. But I can take
a sub-therapeutic dose to help calm my nerves,
stabilize my mood, and help with concentration.Glad to here that things are going well. I
wish you continued success.regards,
john> John,
>
> I also have noticed a significant reduction in the need to "keep moving" (my restlessness/akathisia). I also feel less "pressured" to get everything done all at once. I feel actually somewhat emotionally "neutral", and relaxed. I don't have fifty things all going at once. The dystonia (tight throat muscles) from the tiny bit of Zoloft I take seems to be less and I am not grinding my teeth as much. I even was focused enough to SIT STILL for two hours and set up my own mood chart on a spreadsheet.
> That is too bad you can't seem to get the WB to "work" for you. Maybe the nortriptyline you have been thinking about could kick-start it. I would take it at bedtime to start off, though. It is somewhat sedative (although I took it in the daytime, too in divided doses).
>
> Mitch
>
> >
> > Hey this is great news.
> >
> > I also get a *substantial*
> > anxiolytic response from Wellbutrin.
> > Supposedly it is effective
> > for peripheral neuropathy from a report
> > I recently read too.
> >
> > I really wish I could find
> > a way to make wellbutrin work. The only
> > other med that really cured my dysthymia was
> > Adderall and it had its problems. WB is a
> > good med if one can get it to work.
> >
> > I believe the anxiolytic action comes
> > from its action in the locus coerulus area
> > of the brain (the noradrenaline flight/fight)
> > area. It increase norepinephrine, but slows
> > down the firing which is usually anxiolytic.
> > A lot of people get edjy on Wellbutrin, so that
> > must be from some other interaction in the head,
> > because slowing the LC almost always
> > translates to less anxiety. Amphetamine
> > slows the LC too and some people actually feel
> > more calm on amphetamine than off amphetamine.
> >
> > regards,
> > john
> >
> >
> > > >
> > > > This is quite technical, but for those who are
> > > > interested:
> > > >
> > > > There was a new article in psychopharmocology
> > > > on Wellbutrin's mode of action.
> > > >
> > > > Basically came to some of the same conclusions as
> > > > another article I read, but also came up with 1 more
> > > > piece of data which I always thought would be true:
> > > > Bupropion increases serotonin conductance!
> > > >
> > >
> > > John, et al,
> > >
> > > I can't explain why I feel so much better, since I have added on a low dose of bupropion. I seem to have improved sleep architecture like I had on Adderall without feeling panicky. I don't seem to have the *avoidance* I used to have. I really seem to be getting a paradoxical *anxiolytic* response to this med. I also have needed less Klonopin-I only took 1/4 of a .5mg tab all day today! I should be getting very sluggish and melancholic now (SAD symptoms-late fall/early winter), but it isn't happening. The best way to sum this up is like taking a pstim with little anxiety. I notice some improvement with attention-but nowhere as marked as with a pstim. But, there is no *degradation* of cognitive function that I normally experience at this time of year.
> > > Go figure,
> > >
> > > Mitch
This is the end of the thread.
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