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Dr. Bob is Robert Hsiung, MD,
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Posted by floatingbridge on February 22, 2010, at 1:20:59
In reply to Re: where the idea comes from + a small link » floatingbridge, posted by conundrum on February 6, 2010, at 17:44:14
Well, it could be. Though unlike the woman studied, I was given a cns for my depression. And I guess I am having all three boosted. Nothing worked until a stim was on board.
pristiq
xanax
dexwe are considering a lithium adjunct
and fyi, I am on a lower dose of xanax now than before stim addition. go figure.
I've been asking for an maoi trial--one doc suggested the patch (Emsam--yeah, I know--don't all yell at once....)
(I really wouldn't mind some solid information about long term amp usage. My doc acts like it's not a big deal....)
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Posted by conundrum on February 22, 2010, at 1:21:00
In reply to Re: Dopamine not the magic answer folks, posted by bulldog2 on February 6, 2010, at 11:46:20
I thought ritalin was mostly a reuptake inhibitor not a substrate that releases DA. Just a shorter acting reuptake inhibitor.
Posted by conundrum on February 22, 2010, at 1:21:00
In reply to Re: where the idea comes from + a small link » conundrum, posted by floatingbridge on February 6, 2010, at 17:51:24
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1448202/
Many people say that stimulants are mostly DA enhancing but if you look at that study you can see they increase NE a bit more than DA. I wonder what would happen if NE was antagonized? BTW many people attribute NE to the physical effects of stimulants, like increased heart rate, but I think that is too simplistic.
I'm glad that no matter what it is, these drugs are helping you.
Posted by conundrum on February 22, 2010, at 1:21:00
In reply to Re: where the idea comes from + a small link » floatingbridge, posted by conundrum on February 6, 2010, at 18:24:16
sorry I meant to say "amphetamines" not stimulants. Obviously they dont' all increase NE more. Ritalin doesn't and MDMA doesn't.
Posted by bulldog2 on February 22, 2010, at 1:21:00
In reply to Re: Did you actually read the studies you posted?? » bulldog2, posted by linkadge on February 6, 2010, at 17:22:20
> A quote from THE VERY FIRST STUDY YOU POSTED:
>
> "In laboratory tests with mice, researchers found prolonged exposure to dopamine through this pathway inactivated a regulatory protein in the brain known as Akt and caused the mice to behave like they were depressed in response to stress."
>
> This is my point. I'm not even going to read the others cause I'm assuming you havn't either.
>
> LinkadgeOf course I read all the studies. It is not valid to cherry pick when the study actually backs up the dopamine theory.
The reality is I use what works for me and that is what is my study. We all have to figure out what works for us as individuals.
Many of us are dopamine responders and that is a fact for us even if you believe it is not true.
You always complain how horrible the current drugs are yet you deny that dopamine may be a player in depression.
You were also very rude to Floatingbridge. That is a reality for her and her doctor's conclusion. You owe her an apoligy for your response.
I'm not saying that dopamine is all that has to be tweeked. I know you despise ssirs. We are saying that drugs that lower dopamine or do not raise it may be missing a piece of the puzzle. Obviously since dopamine is a neurotransmitter in our brains it must have a function. If we tinker with se and ne why is dopamine off limits. ? Even sjw by some accounts raises dopamine.
Read And Enjoy from "The Good Drug Guide"
THE DOPAMINE CONNECTION
What's missing, crucially, is the therapeutic enrichment of hedonic tone via a combination of mu opioid pathway enhancement and prolonged stimulation of meso(cortico-)limbic dopamine function.This is really much more fun than it sounds. Yet the socially responsible use of reward pathway enhancements/remedial therapies is a technical, bioethical and medico-legal minefield. Complications aside, the currently available experimental evidence has persuaded many - but not all - investigators that the mesolimbic dopamine system serves as the final common pathway for pleasure in the brain. Enhanced responsiveness of post-synaptic dopamine D2/D3 receptors is vital to long-term emotional well-being. Insofar as they work, all "serotonergic" and "noradrenergic" mood-brighteners eventually act on the mesolimbic dopamine pathway, albeit in differing degrees and with varying delay. Even SSRIs depend on sensitization of the mesolimbic dopamine D2 receptors for their (modest) mood-lifting effect. New anti-Parkinsonian agents, notably the neuroprotective dopamine D3 receptor subtype selective pramipexole (Mirapex), ropinirole (Requip), and cabergoline (Dostinex) owe their potential role as fast-acting pro-sexual antidepressants to their dopaminergic action. Likewise, the possible mood-brightening effect of low doses of the dopamine receptor antagonist amisulpride (Solian), more commonly considered an antipsychotic agent, is explicable because amisulpride preferentially blocks the presynaptic dopamine D2/D3 autoreceptors; dopaminergic transmission is thereby enhanced.
The full story is inevitably complex. Dopamine agonists and reuptake inhibitors are often inadequate long-term mood-brighteners by themselves. The mesolimbic dopamine system mediates reward-signalling, incentive salience and a sense of urgency and significance, not the essence of pure bliss. Dopamine isn't itself the magic pleasure-chemical, though its functional role in conjunction with glutamate and mu opioid agonists in regulating medium spiny neurons of the rostromedial shell of the nucleus accumbens is critical. Researchers into affective disorders can prematurely become over-attached to one particular neurotransmitter system, its receptor sub-types and their signal-transduction cascades. Traditionally, serotonin and noradrenaline have attracted the fiercest rival partisans in antidepressant research. "Dopaminergic" (and opioid) agents, by contrast, are suspect. They are politically incorrect since they are potentially "abusable". Moreover it can be argued that the research and development of safe and sustainable Ecstasy-like empathogens and sociabilisers is at least as morally urgent as the license of safe and sustainable euphoriants. At any rate, enhanced mesolimbic dopamine release, exclusively or otherwise, enriches the intensity of experience; increases pleasure and libido, and potentially boosts cognitive performance. Even better, whereas some dopaminergics are potentially toxic, some dopamine-enhancing agents may have neuroprotective properties as well.
So what are the other contemporary options for chemical life-enhancement?
METHYLPHENIDATE (RITALIN); MINAPRINE (CANTOR); NOMIFENSINE (MERITAL)
A SSRI can be combined ("augmented" sounds more soothing to the official medical ear) with a dopaminergic such as methylphenidate. As Ritalin, methylphenidate is prolifically dispensed to American schoolchildren for different purposes altogether. It is sometimes abused as an instrument of social control. In spite of its structural relationship to amphetamine, methylphenidate resembles in many ways a more benign version of cocaine, yet with a much longer half-life. Methylphenidate blocks the reuptake of, but doesn't significantly release, the catecholamines noradrenaline and dopamine. If it is taken in sustained-release form or combined with an SSRI, all of which have anti-obsessive-compulsive properties too, then the likelihood of dose-escalation is minimised. In Europe and North America, students sometimes take Ritalin to gain a competitive edge in exams. However, its long-term effect on the developing brain is poorly understood.Chewing coca leaves with a dash of powdered lime is a nutritious and energising way to sustain healthy mood. Unfortunately, it's illicit and not very good for one's teeth.
A more cautious but still interesting option might be minaprine (Cantor). Minaprine blocks the reuptake of both dopamine and serotonin. It is also in some degree cholinomimetic. Thus it may exhibit both mood-brightening and nootropic properties. Much more research is needed. Unfortunately, minaprine is now obtainable only as a "research chemical".
Merital (nomifensine) showed great promise as a pleasantly stimulating dopaminergic that also potently inhibits the reuptake of noradrenaline and - to a much lesser extent - serotonin. It was marketed by its manufacturers Hoechst with the slogan "vive la difference!" Merital was withdrawn from licensed use after the discovery of its rare side-effect of precipitating a serious blood-disorder. For retarded melancholics, however, it was typically a very effective and well-tolerated mood-brightener with minimal side-effects. The risk/reward ratio of its carefully-monitored use may have been misjudged. Nomifensine is now obtainable only as a research chemical too.
And than there is amineptine that the US effectively had banned.
Dopamine is no diiferent than any of the other ads. For some depressed people raising serotonin may not be correct and the same may be true for norepinephrine.
It would seem to the most casual of observers that dopamine has to become part of the puzzle of creating a better ad. Why is ritalin part of your cocktail or at least was. It blocks reuptake of both ne and da.
I want more from my drug than being lifted out of depression and being a zombie than cannot feel pleaure because my med has depressed dopamine.
I don't understand how you can challenge people whose doctors with the patient symtoms present a picture of dopamine defeciency. Their clinical symtoms present that diagnosis. Your argument is studies that show how raising dopamine causes problems. Nobody is challening the fact that if dopamine is to high it can create problems.
The drug exctasy causes a massive release of serotonin. That causes people to feel touchy and feely and very sociable. Of course after the trip is over there can be massive depression. So you single out dopamine.
I can't really argue this with you anymore. Those of us who are dopamine responders understand the truth. For some of us this is our reality. Our minds are complex and we need a precise interactions of neurotransmitters. If one is titrated incorrectly the result will be bad.
Now if blocking dopamine for certain mental illness produces a good result does it not make sense that some may need a boost?
Posted by conundrum on February 22, 2010, at 1:21:00
In reply to Re: where the idea comes from + a small link » floatingbridge, posted by conundrum on February 6, 2010, at 18:24:16
This article shows that NE is needed for reward. Drugs and chocolate increase NE and if you block any the rats in the study don't know that they prefer it or dislike lithium.
http://www.pnas.org/content/104/12/5181.full
Posted by linkadge on February 22, 2010, at 1:21:01
In reply to Re: where the idea comes from...one view » floatingbridge, posted by conundrum on February 6, 2010, at 17:35:12
>My psychiatrist said that about 80 percent of >patients respond to SSRIs and then a portion of >those need NE boosted, and a smaller portion of >those need dopamine. In his experience if >someone needs dopamine he does a test with >ritalin and says they should feel something.
Thats not really a definitive test though as ritalin is not selective to dopamine. It has strong effect on NE too and its metabolite is primarily a NRI with 5-ht1a agonist activity. This could augment antidepressants in a manner like buspar.
Linkadge
Posted by linkadge on February 22, 2010, at 1:21:01
In reply to Re: where the idea comes from...one view » linkadge, posted by floatingbridge on February 6, 2010, at 17:44:44
I'm not shouting. If my ideas are too loud for you, skip my posts.
Linkadge
Posted by emmanuel98 on February 22, 2010, at 1:21:01
In reply to To make it more complicated., posted by conundrum on February 6, 2010, at 18:38:14
MAOIs raise norepinephrine, serotonin and dopamine. Also melatonin. And they seem to work better than selective inhibitors. At least for me.
Posted by floatingbridge on February 22, 2010, at 1:21:01
In reply to Re: where the idea comes from + a small link » floatingbridge, posted by conundrum on February 6, 2010, at 18:24:16
Thanks Conundrum--! Interesting. Muscled through it best I could. Good question, I think, regarding NET antagonist. Hmmm.
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Posted by linkadge on February 22, 2010, at 1:21:02
In reply to Re: Did you actually read the studies you posted?? » linkadge, posted by bulldog2 on February 6, 2010, at 18:34:38
>Of course I read all the studies. It is not >valid to cherry pick when the study actually >backs up the dopamine theory.
You obviously have no idea what that first study is suggesting. The *whole* idea behind the first study is that increasing dopamine levels in mice leads to depresive like behaviors. If you are unable to realize that I think you need to read it again. This is not cherry picking - it is the *entire* point of that first study.
>Many of us are dopamine responders and that is a >fact for us even if you believe it is not true.
What does a "dopamine responder" mean? You can call yourself whatever you want. Provide me with logical, conclusive evidence that your depression responds to dopamine. As I have said, response to a stimulant does not mean you are low on dopamine.
>You always complain how horrible the current >drugs are yet you deny that dopamine may be a >player in depression.
I am just going in circles here. I did not say that dopamine is absolutely not involved in depression, I just said we have no proof that dopamine is low in depression. Response to a stimulant is not proof that your dopamine levels are low. Sorry - try again.
>Read And Enjoy from "The Good Drug Guide"
>THE DOPAMINE CONNECTION
>What's missing, crucially, is the therapeutic >enrichment of hedonic tone via a combination of >mu opioid pathway enhancement and prolonged >stimulation of meso(cortico-)limbic dopamine >function.The cover page to the "Good drug guide" is *not a scientific journal*. It is an opinion piece - basing its ideas on theories about the involvement of dopamine in depression. This is not evidence. Sorry try again.
Linkadge
Posted by Metafunj on February 22, 2010, at 1:21:02
In reply to Re: where the idea comes from...one view, posted by linkadge on February 6, 2010, at 19:48:34
Also short acting atoms have a different effect from ones requiring down regulation.
Posted by floatingbridge on February 22, 2010, at 1:21:02
In reply to Re: where the idea comes from...one view » floatingbridge, posted by linkadge on February 6, 2010, at 19:50:41
> I'm not shouting. If my ideas are too loud for you, skip my posts.
>
> LinkadgeHey Link, glad you clarified that for me. The capitalized WFT in your post are what threw me.
Ideas are fine w/ me-- I feel no need to skip your posts. As a babble participant, I'm aware that avoiding posts is always an option.
No harm, no foul?
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Posted by floatingbridge on February 22, 2010, at 1:21:02
In reply to To make it more complicated., posted by conundrum on February 6, 2010, at 18:38:14
Thanks--another informative link. Interesting, the release of NE in reaction to both positive and negative stimulation. How easy it is to mess somebody up, or one's self up, with that two way system. Coming from the view of stress-induced illness that is. Humans are a complex web.
Their must be some sort of electrical
term for the double work of NE
(But the poor mice...!)Thanks for complicating the thread!
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Posted by Mikez on February 22, 2010, at 1:21:03
In reply to Re: To make it more complicated. » conundrum, posted by floatingbridge on February 6, 2010, at 23:29:33
Linkadge , when you say if one responds to stimulants they are not necessarily a dopamine responder is that because stimulants work on other transmitters (ie Nora) as you said earlier? Just wanting to confirm because it helps me rule out certain drugs in my 'dopamine' trial. I want a drug that has minimal or no effect on nora compared to dopa. What do you think about L-dopa as a trial? The other one I can think of is low dose seligiline
Posted by conundrum on February 22, 2010, at 1:21:03
In reply to Re: To make it more complicated. .. linkadge, posted by Mikez on February 7, 2010, at 10:48:23
Mirapex is the only pure DA drug I can think of. Its an agonist. I guess segeline as well as a patch form because it only inhibits MAO-B. Orally you will get MAO-A and serotonin/norepinephrine as well. L-Dopa can cause damage in the long run. I don't think a low dose of amulsipride would really hit much else than dopamine either.
Posted by Mikez on February 22, 2010, at 1:21:03
In reply to Re: To make it more complicated. .. linkadge » Mikez, posted by conundrum on February 7, 2010, at 11:05:30
Thanks conundrum, unfortunately we dont get the selegiline patch here in Aus. I thought that a low dose, say 5mg orally would still be selective just for MAOI-B? Why is this not the case? Also why is l-dopa harmful long term? Thanks again.
Posted by floatingbridge on February 22, 2010, at 1:21:03
In reply to Re: To make it more complicated. .. linkadge » Mikez, posted by conundrum on February 7, 2010, at 11:05:30
Conundrum, this suggests you see some link one of my docs saw by suggesting emsam. Thanks again-- your knowledge sharing is much appreciated. (No real question here.)
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(Good luck to you Mikez!)
Posted by conundrum on February 22, 2010, at 1:21:04
In reply to Re: To make it more complicated. .. linkadge, posted by Mikez on February 7, 2010, at 11:44:55
Sorry for scaring you, after doing more reading L-Dopa seems to be safe. As for Segeline I just know that the oral adds some MAO-A inhibition. I don't know the dose that does this. I think it will still increase dopamine more though.
Posted by linkadge on February 22, 2010, at 1:21:06
In reply to Re: To make it more complicated. .. linkadge, posted by Mikez on February 7, 2010, at 10:48:23
>Linkadge , when you say if one responds to >stimulants they are not necessarily a dopamine >responder is that because stimulants work on >other transmitters (ie Nora) as you said >earlier?
l-dopa is an option, but I'm not exactly sure if it works like tyrosine (ie a precursor to norepinephrine as well). Selegeline is preferential to MAO-B. Contrary to popular believe MAO-B does not readily metabolize dopamine. MAO-A inhibitors have a much stronger effect on dopamine metabolism than MAO-B inhibitors. MAO-B preferentially demeniates phenylethylamine or PEA. The issue is complicated as selegiline is metabolized into (meth?)amphetamine. PEA and amphtetamine have similar actions.
Dopamine agonist are selective to certain dopamine receptors. Some (such as mirapex) have activity at 5-ht1a 5-ht2b and other receptors - thus they are not selective to dopamine receptors. Furthermore because they affect certain dopamine receptors more than others, their effect would not mimic an overall increase or decrease in dopamine. Also mirapex appears to have an ability to increase BDNF (seeminly independant of its dopamine agonist activity). This may be responsible for its antidepressant effect, and not the dopamine agonist effect.
Another issue is that the dopamine transporter has the ability to reabsorb serotonin as well. When SSRI's are adminstered, the dopamine transporter appears to reabsorb more serotonin than usual. So, perhaps augmentation of an SSRI with a DAT inhibitor actually exerts its effect by preventing DAT from eating serotonin.
This is an alternate explaination for why SSRI's poop out. Perhaps instead of squelching dopamine, the drugs poop out because the dopamine transporter starts to reuptake the extra serotonin and so the theraputic serotonin enhancing effect is lost.
So to answer your question, I don't know. Its so friggen complex and thats the point I am trying to make. Neurotransmitters do not exist in a vaccum. You cannot alter one without altering them all. Response to a drug does not mean anything more than response to a drug.Linkadge
Posted by linkadge on February 22, 2010, at 1:21:06
In reply to Re: To make it more complicated. .. linkadge » Mikez, posted by conundrum on February 7, 2010, at 13:52:09
I don't think the jury is out on whether or not l-dopa is safe. In some studies it appears to damage dopaminergic neurons with long term administration.
Linkadge
Posted by conundrum on February 22, 2010, at 1:21:07
In reply to Re: To make it more complicated. .. linkadge, posted by linkadge on February 7, 2010, at 18:22:36
True, I've been reading about people being pushed off of Effexor onto Pristiq and not responding well to it. It works on the same neurotransmitters and should be the same ratios etc, but some people respond to one drug over the other despite the similarity.
Posted by West on February 22, 2010, at 1:38:35
In reply to Re: correct link » West, posted by conundrum on February 6, 2010, at 6:50:40
>> I'm curious if it increases norepinephrine how it decreases constipation. Maybe it blocks some other adrenergic receptors as well.
That didn't occur to me. a-antagonists decrease NE release and inhibit the NE system as a whole/decreasing sympathetic tone/lowering blood pressure and create a (relative) state of hypotension. It would be interesting to what the clinical effect of a combined catecholaminergic/anticatecholaminergic drug would be. i would have thought that antagonzing a-receptors would produce undesirable effects in depression, but who knows? Guanfacine, an a-2 antagonist, has both diarrhea and constipation as listed side-effects.
>>i see holeUnfortunately Savella isn't FDA approved for the treatement of depression in the U.S. It is only approved for fibro/cfs. I guess U of O want their creation approved for depression.
Ken Gilman, of psycotropical, among others seems to see 1:1, NE:5-HT, as the hold grail. i personally find that a bit much. I agree that NE plays a crucial role though.
Posted by conundrum on February 22, 2010, at 1:38:36
In reply to Re: correct link, posted by West on February 6, 2010, at 8:25:53
Well thats a scientific mind for you I guess. Not much real understanding of depression as if everyone will fit that ratio.
Posted by Phillipa on February 22, 2010, at 20:14:40
In reply to Re: correct link » West, posted by conundrum on February 22, 2010, at 1:38:36
Seriously I know it's old but Kramer's Listening to Prozac explains neurotransmitters in simple terms and the book starts with dancing TB patients on a med no longer available. But shows the transition to where we are now med wise. Phillipa
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Dr. Bob is Robert Hsiung, MD,
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