![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 8 to 32 of 32. Go back in thread:
Posted by Marty on June 29, 2008, at 11:14:41
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » Marty, posted by SLS on June 29, 2008, at 10:28:51
> MAO-A rules!
Hahaha.. what you meant is "MAO-A SUCKS!!"
just think about it... ;)> I am trying to find the abstract on Medline >that I often come across regarding moclobemide >and dopaminergic neurotransmission, but there is >a property of this drug that reduces the tone of >dopamine neurons in certain regions of the brain >(I don't recall how).
Interesting. If you find it plz Babble Post me the link !
> That's right. A selective MAO-A inhibitor >*does* increase the levels of all three of the >monoamines thought to be involved with >depression: dopamine, norepinephrine, and >serotonin. There is no need to inhibit MAO-B.Except if you want to elevate levels of some Phenethylamines which is my intent.
> I do not believe that a selective MAO-B
> inhibitor carries with it the same potency as a > MAO-A inhibitor.I dont know about the potency, but MAO-Bs compose only 30% of all MAO in the brain. So 100% MAO-B inhibition equal only about 30% the raise of dopamine than 100% MAO-A inhibition. As you know it's an oversimplisistic way of seeing things but it gives us an idea anyway.
>That said, it seems that reversibility equates
> with inferior clinical effect.Maybe, but what would I give to have my endogenous Reversible MAOI doing a better job (Tribulin/Isatin). .. that said Coffee could save my life for a couple hours. But it's arguable if it's because of its RIMA effect or Adenosine antagonistic effect. I would vote for the second as it act WAY faster.
SLS, I was wondering what you were doing in life .. you've been at the NIH as a patient or as a student/praticioner/searcher ?
Sometime I feel like going to one of those places and say "Attetion please people! I am Marty, I'm sick and I have a bunch of cool theories on which I have a lot of science to do in the next couple years. You've got 15 minutes to clear your respective labs office and exit my new research facility. Thank you!" :) ... my guess it's the only thing that would give me is the fastest "Narcissistic Personality Disorder" Dx in mankind history :P
/\/\arty
Posted by SLS on July 3, 2008, at 5:34:15
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » SLS, posted by Marty on June 29, 2008, at 11:14:41
I feel strongly that MAO-A is the main player in mood disorders.
Investigations into the gene activity that expresses MAO-A in depressed subjects has been demonstrated to be reduced. Results of genotyping have recently implicated the promoter region of the X-chromosomal MAOA gene (MAOA-uVNTR) as being underexpressed.
Moclobemide is a great example of how a selective inhibitor of MAO-A can produce a robust remission of depression, even if only transiently. I would assign the reason for the tachyphylaxis that is commonly seen with moclobemide as its being reversible.
Selegiline does not seem to be nearly as potent as Nardil or Parnate when treating severe depression, as the reported experiences on PB give an indicator to. My guess is that there is indeed some MAO-A inhibition with selegiline at the dosages necessary to treat depression. I would want to research that a bit before calling this a fact. The risk of tyramine reaction increases with dosage. Investigators warn of this when discussing hypertensive crisis, such that it is recommended to not ingest tyramine at any dosage above the minimum of 6mg/24hr. This would be an indicator that selegiline inhibits MAO-A in the gut.
I wouldn't be afraid of MAO-A inhibitors. Just be afraid of moclobemide. It can elicit intense depressive reactions in some people that I don't believe is due to MAO inhibition. I remember reading that it can deplete dopamine, but I don't remember how.
"Conclusions: STS [selegiline transdermal], an monoamine oxidase inhibitor antidepressant that potentiates the three major monoamine neurotransmitters (serotonin, norepinephrine, and dopamine)"
- Scott
**********************************************1: Psychopharmacol Bull. 2007;40(3):15-28.Links
Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials.
Robinson DS, Gilmor ML, Yang Y, Moonsammy G, Azzaro AJ, Oren DA, Campbell BJ.Worldwide Drug Development, Burlington, VT.
Objective: Selegiline transdermal system (STS) is efficacious for the treatment of major depressive disorder (MDD). This meta-analysis explores treatment effects of STS for individual symptoms of MDD derived from line-item analyses of the 28-item Hamilton Rating Scale for Depression (HAM-D28) and the Montgomery-Asberg Depression Rating Scale (MADRS). Methods: Change in score from baseline to end of treatment for each item of the HAM-D28 and MADRS was assessed using a multilevel model for meta-analysis of continuous outcome data from all five short-term, randomized, placebo-controlled efficacy trials conducted during preapproval clinical development of STS for MDD. Utilizing a random-effects model with trial effects fixed and adjusting for baseline scores, confidence intervals (95%) were computed for treatment differences between STS and placebo. Results: STS exhibited significant treatment effects on core depression symptoms (HAM-D Bech-6 items: depressed mood, guilt, work and activities, retardation, psychic anxiety, general somatic symptoms), reverse vegetative symptoms (oversleeping, overeating), motoric retardation, suicide, and genital symptoms (libido). Significant STS treatment effects were also noted for each MADRS item except for reduced sleep and appetite. The most prominent MADRS effects were improvement in sadness, lassitude, and poor concentration. Conclusions: STS, an monoamine oxidase inhibitor antidepressant that potentiates the three major monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), has beneficial therapeutic effects for a spectrum of individual symptoms rated by the HAM-D28 and MADRS. Analyses of specific symptoms assessed by depression rating scales can offer guidance to clinicians in individualizing drug therapy based on presenting symptoms.
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Posted by Marty on July 3, 2008, at 15:14:48
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » Marty, posted by SLS on July 3, 2008, at 5:34:15
> I feel strongly that MAO-A is the main player in mood disorders.
If you mean that inhibiting MAO-A helps more people in depression, then I agree. But I don't think MAO-A or MAO-B is part of the causation in most people and in most mood disorders. That said I'M 100% SURE some people (a VERY SMALL % of ALL the people complaining about depression issues) has some poor MAO in terms of Quality in some and in terms of Quantity in others. And even some mixes : too much MAO (quantity) because of poor quality of MAO (quality). Now that begins to be fun to figure out what it means and for which system it does. Everything goes.
> Investigations into the gene activity that expresses MAO-A in depressed subjects has been demonstrated to be reduced. Results of genotyping have recently implicated the promoter region of the X-chromosomal MAOA gene (MAOA-uVNTR) as being underexpressed.If you means PARTS of the code is underexpressed then I see the point. BUT if it means the WHOLE code that would mean LESS MAO-A which doesn't support your idea that most depressed people benefit mostly from MAO-A inhibition. I found genetic medical literature to be much more a bitch to read than most pure neurological/psychopharmaceutical literatures.. difficult to interpret.
> Moclobemide is a great example of how a selective inhibitor of MAO-A can produce a robust remission of depression, even if only transiently. I would assign the reason for the tachyphylaxis that is commonly seen with moclobemide as its being reversible.This conclusion don't look very scientific to me (even if I have the same gut feeling as you BTW) because there's not many RIMA to compare and so correlation is kind of difficult : "All the MAOIs works better than this loner RIMA (Moclobemide). Conclusion: RIMA sucks, MAOIs rules and the difference between the 2 being the REVERSABILITY, we propose that REVERSABILITY is the culprit and thus stinks." XD .. I sometimes wish we could publish our own amateurish paper on pubmed.
> My guess is that there is indeed some MAO-A inhibition with selegiline at the dosages necessary to treat depression. I would want to research that a bit before calling this a fact.Selegiline (Deprenyl, EMSAM) does inhibit MAO-A at higher dose while only inhibiting MAO-B at lower. And, yes, this is why the infamous Tyramine diet kicks in at higher dosage: because of the MAO-A in the gut.
The risk of tyramine reaction increases with dosage. Investigators warn of this when discussing hypertensive crisis, such that it is recommended to not ingest tyramine at any dosage above the minimum of 6mg/24hr. This would be an indicator that selegiline inhibits MAO-A in the gut.
> I wouldn't be afraid of MAO-A inhibitors. Just be afraid of moclobemide.Moclobemide has been develop in Canada and my pdoc is one of the guys who worked on it.. and he's damn proud of it. I wish I knew before I told him how it's "been the WORST of EVERY ~30 meds I tried in my life! ...." lol
/\/\arty
Posted by SLS on July 3, 2008, at 15:47:26
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity, posted by Marty on July 3, 2008, at 15:14:48
Hi Marty.
Maybe I can clear up a misunderstanding.
The allele for the more active polymorphism of MAO-A is associated with an increased risk of depression and other psychiatric disturbances.
Therapeutically, MAO-A is where it's at.
Look at this:
***********************************************
1: Int J Neuropsychopharmacol. 2008 Jun 11:1-12. [Epub ahead of print]Click here to read Links
Reduced amygdala-prefrontal coupling in major depression: association with MAOA genotype and illness severity.
Dannlowski U, Ohrmann P, Konrad C, Domschke K, Bauer J, Kugel H, Hohoff C, Schöning S, Kersting A, Baune BT, Mortensen LS, Arolt V, Zwitserlood P, Deckert J, Heindel W, Suslow T.IZKF-Research Group 4, IZKF Münster, University of Münster, Germany.
The amygdala plays a pivotal role in a cortico-limbic circuitry implicated in emotion processing and regulation. In the present study, functional connectivity of the amygdala with prefrontal areas involved in emotion regulation was investigated during a facial expression processing task in a sample of 34 depressed inpatients and 31 healthy controls. All patients were genotyped for a common functional variable number tandem repeat (VNTR) polymorphism in the promoter region of the monoamine oxidase A gene (MAOA u-VNTR) which has been previously associated with major depression as well as reduced cortico-limbic connectivity in healthy subjects. In our control group, we observed tight coupling of the amygdala and dorsal prefrontal areas comprising the dorsolateral prefrontal cortex (DLPFC), dorsal parts of the anterior cingulate cortex (dACC), and lateral orbitofrontal cortex. Amygdala-prefrontal connectivity was significantly reduced in depressed patients and carriers of the higher active MAOA risk alleles (MAOA-H). Hence, depressed MAOA-H carriers showed the weakest amygdala-prefrontal coupling of the investigated subgroups. Furthermore, reduced coupling of this circuitry predicted more than 40% variance of clinical variables characterizing a longer and more severe course of disease. We conclude that genetic variation in the MAOA gene may affect the course of major depression by disrupting cortico-limbic connectivity.
***********************************************
- Scott
Posted by Marty on July 3, 2008, at 16:26:30
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity, posted by SLS on July 3, 2008, at 15:47:26
Ok thanks for the abstract. Interesting .. especially for Social Phobic.
> Therapeutically, MAO-A is where it's at.
It depends for who. Depression, which doesn't come from adverse situation in life, isn't 1 illness and so there's no 1 point-of-failure or 1 thing to target. Some scientist goes on to say that, only in the "depression" label there is at least 20 disorders hidding there! ... so to say that 1 thing or another is "where it's at", while it may be true for MANY people, cannot be an absolute truth as you already know. MAO-A inhibition was great for me the time it worked.. (Nardil, 2 months) but whatever the underlying systemic of the subtype of depression you have you're almost sure to be helped by inhibiting MAO-A :P ... I'm saying this because what I'm looking for is to target my problem the more specifically possible (so lower dose, less side-effects.. feeling more 'normal' and less drugged)
That said at this stage I've tried almost everything (accessible) except opiace (which I dont want to touch) and TCA (which I don't see the point because I'm VERY intolerant to side-effects and for me reuptake sucks) .. and so it's no more a matter of identifying what EXACTLYs going on into me but a matter to finish trying stuffs... next step for me if Tianeptine isn't enough is low-dose Selegiline....and so MAO-B.. where it's not at ;) I dare you f*ck up my placebo effect potential !!! XD loll
Can I ask you what's next for you ? what are you looking for ? available and in the pipelines ...
/\/\arty
Posted by SLS on July 3, 2008, at 16:51:34
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » SLS, posted by Marty on July 3, 2008, at 16:26:30
Hey.
Apparantly, I have no immediate need for anything else to come down the pipeline. I am responding extremely well to the following treatment regime:
Nardil 90mg
nortriptyline 150mg
Lamictal 150mg
Abilify 20mg
Deplin 7.5mg
It took many years to design this treatment. I still can't believe it is happening, but I sure do deserve it.I am finding myself spending more time thinking of things and doing things that have very little to do with studying neuroscience.
I will, of course, check in from time to time to remain apprised of the state of the clinical art. When the time comes, I would easily swap out my five drugs for a more efficient treatment. Gene therapy seems like a thing of the future.
- Scott
Posted by undopaminergic on July 4, 2008, at 7:33:29
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » Marty, posted by SLS on July 3, 2008, at 5:34:15
> I feel strongly that MAO-A is the main player in mood disorders.
>Maybe, and it is certainly true to the extent that reducing serotonin metabolism is of importance. MAO-A also deaminates noradrenaline and adrenaline, in contrast to MAO-B, but in competition with COMT.
However, both forms of MAO are responsible for dopamine metabolism, and the B form seems to be the major factor in the extracellular space in most regions of the brain - including the striatum and nucleus accumbens. To the extent that reduced breakdown of trace amines (TAs) is of importance in the antidepressive effect of MAOIs, the B form of MAO is also the major - or exclusive - factor for some of the TAs, including phenylethylamine (PEA).
Furthermore, because the complete inhibition of MAO-B is associated with very few side effects, it seems the best place to start in the quest to achieve the critical level of total MAO-inhibition required to produce a robust antidepressive response. Meanwhile, MAO-A inhibition has several adverse effects, including tyramine sensitivity and the downregulation of neurotransmitter synthesis in response to inhibition of intracellular MAO-A.
It would be desirable to also inhibit COMT, an enzyme greatly contributing to extracellular destruction of all the cathecolamines, but unfortunately, the only central COMT inhibitor, tolcapone, has turned out to be rather hepatoxic.
Regarding genes, reduced MAO-B activity has been associated with a diminished risk of Parkinson's disease, while reduced MAO-A activity is related to antisocial behaviour. In other words, reducing MAO-B activity seems more unambiguously beneficial.
>
> Moclobemide is a great example of how a selective inhibitor of MAO-A can produce a robust remission of depression, even if only transiently.
>On the other hand, at least some people report subtype selective doses of selegiline to be more antidepressive than subtype selective doses of moclobemide. (Of the two, I've only tried selegiline, and I found its antidepressive effect to be transient.)
> Selegiline does not seem to be nearly as potent as Nardil or Parnate when treating severe depression, as the reported experiences on PB give an indicator to.
>That is probably dose-dependent. Few people seem to use more than modest doses of selegiline - such as the 12 mg patch. Meanwhile, doses of 100 mg or even more of Nardil and Parnate are not uncommon.
> My guess is that there is indeed some MAO-A inhibition with selegiline at the dosages necessary to treat depression.
>Although small doses may be sufficient in rare cases, I think your guess is correct.
> Investigators warn of this when discussing hypertensive crisis, such that it is recommended to not ingest tyramine at any dosage above the minimum of 6mg/24hr. This would be an indicator that selegiline inhibits MAO-A in the gut.
>It appears that the 12 mg patch may sufficiently inhibit MAO-A in the gut to create a risk of tyramine related hypertensive crisis, but only in some people. In some trials of the 12 mg patch there were no dietary restrictions observed, but no hypertensive complications were reported. However, in tyramine sensitivity tests, a few of of those treated with the 12 mg patch, were found to be sufficiently senstitive to be at risk.
Posted by SLS on July 4, 2008, at 8:18:55
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity, posted by undopaminergic on July 4, 2008, at 7:33:29
Excellent post!
> > I feel strongly that MAO-A is the main player in mood disorders.
> >
>
> Maybe, and it is certainly true to the extent that reducing serotonin metabolism is of importance. MAO-A also deaminates noradrenaline and adrenaline,> in contrast to MAO-B, but in competition with COMT.
COMT is of minor consequence. The intrasynaptic levels of this enzyme are rather small. It would only lead to more background noise were it to be inhibited.
> However, both forms of MAO are responsible for dopamine metabolism,Yes.
> and the B form seems to be the major factor in the extracellular space in most regions of the brain - including the striatum and nucleus accumbens.
> Furthermore, because the complete inhibition of MAO-B is associated with very few side effects, it seems the best place to start in the quest to achieve the critical level of total MAO-inhibition required to produce a robust antidepressive response. Meanwhile, MAO-A inhibition has several adverse effects, including tyramine sensitivity and the downregulation of neurotransmitter synthesis in response to inhibition of intracellular MAO-
Clorgyline, a *specific* inhibitor of MAO-A, is a potent antidepressant. It probably is more potent than any other MAOI. It is certainly more potent than selegiline. I know for fact that the NIMH department of clinical pharmacology used clorgyline in those people resistant to Nardil and Parnate treatment. No, I have to disagree with you as to the critical role that MAO-A inhibition plays in producing an antidepressant effect. I took clorgyline 15mg myself for several months. It was the only drug that could break through my wall of treatment resistance. I responded well to it, but eventually I reached a plateau that was not acceptable. The NIMH protocol did not allow for additional antidepressants to be used. I think I would have done well with the addition of desipramine or nortriptyline, but my doctor refused to take a risk with a drug that was not approved for marketing. I know I keep saying this, but the NIMH called clorgyline their "ace in the hole". At the time it became no longer available, people who were previously treatment refractory had been in remission for over ten years.
Sometimes you have to look at things clinically rather than theoretically. If it were necessary to understand the mechanism of action of a drug before administering it, no antidepressants would be available.
I feel that selegiline is generally a dud. There are people who respond well to it, but not that many. I followed the development of selegiline from as early as 1983. It was never impressive as an antidepressant in the oral form. Transdermal administration seems to be more effective, but it is no "big gun".
Again, moclobemide can make people feel GEAT, but not without continued dosage escalation. I attribute the MAOI reversibility of this drug to this tachyphylaxis phenomenon and as the cause of this clinical dead end.
- Scott
Posted by Marty on July 4, 2008, at 9:23:07
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » undopaminergic, posted by SLS on July 4, 2008, at 8:18:55
Hi SLS, Hi Undopaminergic (nice nickname btw)
SLS.. Do you think every depression has the same etiology in the brain ? Depression isn't a DISEASE but a DISORDER which one day will be split in many other diseases and in many other disorders BASED ON THEIR DIFFERENT ETIOLOGIES. As I assumme you already know and understand that, I wonder why you're insisting on the importance of ONE mechanism of action or drug target ... is that because your into a 'treatment resistant' psychopharmaceutical logic ? .. that may explain why your talking about the H-BOMB of AD mechanisms. I'm more into finding something more specific to my specific etiology because I CAN... a luxery many people here doesn't have saddly. I'm not TR but I'm very much side-effect intolerant and that's why I'm in the 'trial circus' ...
After trying about ~30 meds + ~25 so called supplements can you guess what's helping me the most for the depression part ? CHROMIUM PICOLINATE and EVENING PRIMROSE ......... NOW, can you see why I would consider almost ANYTHING as beeing possibly helpful ? MAO-B inhibition seems to help way more poeple than CHROMIUM don't you think ? :P
Btw, I'm very happy for you about the success of your newest cocktail ! Congrat!/\/\arty
Posted by Marty on July 4, 2008, at 9:44:24
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » undopaminergic, posted by SLS on July 4, 2008, at 8:18:55
Hi,> It would be desirable to also inhibit COMT, an enzyme greatly contributing to extracellular destruction of all the cathecolamines, but unfortunately, the only central COMT inhibitor, tolcapone, has turned out to be rather hepatoxic.
What about Entacapone (Comtan) ?
>Regarding genes, reduced MAO-B activity has been associated with a diminished risk of Parkinson's disease, while reduced MAO-A activity is related to antisocial behaviour.
Interesting then that Nardil is the best med for Social Phobic: They have about 6x more chances of developing Parkinson's disease AND social avoidance, from a certain point of view, could be considered as being the opposite of antisocial behaviour (agressivity/confrontational).
>To the extent that reduced breakdown of trace amines (TAs) is of importance in the antidepressive effect of MAOIs, the B form of MAO is also the major - or exclusive - factor for some of the TAs, including phenylethylamine (PEA).That's why I'm interested in trying low dose Selegeline. I think my mood is very sensitive PEA.. dark chococate lift my mood in a way that nothing else does, except Tianeptine. Espcially with dark chocolate with coffee chunks into it.. then it seems like I could use that as an AD on its own! interestingly coffee is a reversible MAO inhibitor .. Less MAO-B + More PEA seems like a good enough AD effect for me.
What are you on Undopaminergic ?
/\/\arty
Posted by SLS on July 4, 2008, at 11:44:13
In reply to --) SLS, posted by Marty on July 4, 2008, at 9:23:07
> SLS.. Do you think every depression has the same etiology in the brain
No.
> ? Depression isn't a DISEASE but a DISORDER
How do you define these two words? What is the difference between them?
> which one day will be split in many other diseases and in many other disorders BASED ON THEIR DIFFERENT ETIOLOGIES.
That has been the goal of neuroscience for decades.
> I wonder why you're insisting on the importance of ONE mechanism of action or drug target
I go with what works. I pinpoint MAO-A, not because I am describing a particular etiology, but, rather, to characterize the properties of effective drugs.
Our diminutive theories don't compare with the sophistication and volume of work being done in the field by professional scientists and investigative clinicians - and these people don't presume to understand a damned thing.
> Btw, I'm very happy for you about the success of your newest cocktail ! Congrat!
Thanks.
:-)
- Scott
Posted by Marty on July 4, 2008, at 13:26:29
In reply to Re: --) SLS, posted by SLS on July 4, 2008, at 11:44:13
> > ? Depression isn't a DISEASE but a DISORDER
>
> How do you define these two words? What is the difference between them?In the case of psychiatric/brain related pathologies, DISEASE would be the one where we understand the etiology of a cluster of symptoms or AT LEAST we know(can proove) that there is a biological causation that is physical (versus psychogenic/psychological) ... DISORDER refer to a cluster of symptoms that we group and label in order to more effectively treat them .. the day we both get a DISEASE diagnostic rather than a DISORDER one is a day I'm looking forward to .. I'm about 30 and so I expect to see this before I die. (finger crossed for the genetic therapy..)
BTW -> I know that EVERYTHING I JUST SAID (like most things I already told you) YOU ALREADY KNEW SINCE DECADES. .. I don't underestimate you. Quite the opposite (not overestimate, just estimate)
> > which one day will be split in many other diseases and in many other disorders BASED ON THEIR DIFFERENT ETIOLOGIES.> That has been the goal of neuroscience for decades.
Of course. I'm just pointing to the fact that IT WILL happen .. and until it does we're stuck with trying a truck load of different molecule quasi-randomly ..
> I wonder why you're insisting on the importance of ONE mechanism of action or drug target
> Our diminutive theories don't compare with the sophistication and volume of work being done in the field by professional scientists and investigative clinicians - and these people don't presume to understand a damned thing.Only a fool could think otherwise.. but.. wait a min ........ :|
;) /\/\arty
Posted by undopaminergic on July 4, 2008, at 13:36:27
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » undopaminergic, posted by SLS on July 4, 2008, at 8:18:55
>
> Clorgyline, a *specific* inhibitor of MAO-A, is a potent antidepressant.
>Clorgyline, similarly to selgiline, is subtype selective in low doses.
>
> It probably is more potent than any other MAOI. It is certainly more potent than selegiline. I know for fact that the NIMH department of clinical pharmacology used clorgyline in those people resistant to Nardil and Parnate treatment. No, I have to disagree with you as to the critical role that MAO-A inhibition plays in producing an antidepressant effect. I took clorgyline 15mg myself for several months. It was the only drug that could break through my wall of treatment resistance. I responded well to it, but eventually I reached a plateau that was not acceptable. The NIMH protocol did not allow for additional antidepressants to be used. I think I would have done well with the addition of desipramine or nortriptyline, but my doctor refused to take a risk with a drug that was not approved for marketing. I know I keep saying this, but the NIMH called clorgyline their "ace in the hole". At the time it became no longer available, people who were previously treatment refractory had been in remission for over ten years.
>If clorgyline has superior antidepressant efficacy relative to other MAO inhibitors at doses that produce equivalent MAO inhibition, that suggests the existence of additional pharmacological properties of clorgyline.
> Sometimes you have to look at things clinically rather than theoretically. If it were necessary to understand the mechanism of action of a drug before administering it, no antidepressants would be available.
>Indeed, considering the incomplete knowledge of the nervous system, a complete understanding of the mechanisms of action of any drug is not feasible.
> I feel that selegiline is generally a dud. There are people who respond well to it, but not that many. I followed the development of selegiline from as early as 1983. It was never impressive as an antidepressant in the oral form. Transdermal administration seems to be more effective, but it is no "big gun".
>Oral administration of selegiline is somewhat unreliable, considering its variable and extensive first-pass metabolism. Transdermal administration addresses that issue. As I suggested in my previous post, it is likely that the doses of selegiline typically used are more than inadequate in many cases, and although this problem seems to be more common with selegiline, it's by no means unique to it, but has plagued not only clinical use but also research with all the MAOIs - for example, the MAOIs have often erroneously been concluded to be less effective in comparison with TCAs because insufficicent doses were used.
Posted by Marty on July 4, 2008, at 13:41:46
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity, posted by undopaminergic on July 4, 2008, at 13:36:27
> If clorgyline has superior antidepressant efficacy relative to other MAO inhibitors at doses that produce equivalent MAO inhibition, that suggests the existence of additional pharmacological properties of clorgyline.Every MAOI has some preferences has to where they inhibe more or less. Talking about 'location' in the brain. So depending of "where and how much" the effect can be quite different from a MAOI and another one.
/\/\arty
Posted by undopaminergic on July 4, 2008, at 13:56:47
In reply to --) Undopaminergic, posted by Marty on July 4, 2008, at 9:44:24
>
> Hi,
>Hi
> > It would be desirable to also inhibit COMT, an enzyme greatly contributing to extracellular destruction of all the cathecolamines, but unfortunately, the only central COMT inhibitor, tolcapone, has turned out to be rather hepatoxic.
>
> What about Entacapone (Comtan) ?
>It's not hepatoxic, but it doesn't cross the blood-brain-barrier.
>
> What are you on Undopaminergic ?
>For the depression, the most significant symptoms of which are anhedonia and lack of motivation (but my mood is OK), I mainly use methylphenidate and buprenorphine, usually augmented with sulpiride, and sometimes with rasagiline (formerly selegiline). I'm also taking guanfacine, pramiracetam (or aniracetam) and huperzine A for improving cognition and/or ADD symptoms. The next planned experiment is beta2-adrenergic agonists (e.g. Ventoline), probably in combination with L-dopa and other neurotransmitter precursors.
Posted by Sigismund on July 4, 2008, at 15:12:39
In reply to Re: --) Undopaminergic, posted by undopaminergic on July 4, 2008, at 13:56:47
>usually augmented with sulpiride, and sometimes with rasagiline (formerly selegiline).
How does rasagaline differ for you from selegeline?
Posted by SLS on July 4, 2008, at 15:45:34
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity, posted by undopaminergic on July 4, 2008, at 13:36:27
> Clorgyline, similarly to selgiline, is subtype selective in low doses.
I am not aware of a loss of selectivity at any dose. It is not like selegiline in this regard. It is specific (not selective) to MAO-A. I would not yet presume additional mechanisms of action contributing to its antidepressant efficacy. Clorgyline is the most reliable probe specific to MAO-A and is the standard of reference by which MAO-A is assayed.
- Scott
Posted by undopaminergic on July 6, 2008, at 2:34:12
In reply to Re: --) Undopaminergic » undopaminergic, posted by Sigismund on July 4, 2008, at 15:12:39
> >usually augmented with sulpiride, and sometimes with rasagiline (formerly selegiline).
>
> How does rasagaline differ for you from selegeline?
>It may be too early to conclude anything, considering how much less experience I have from rasagiline in comparison to selegiline. However, my preliminary impression is that rasagiline has less effect. I haven't noticed any definite effects at all from it. This may suggest that selegiline's metabolites significantly contribute to its pharmacological profile.
Posted by undopaminergic on July 6, 2008, at 2:47:33
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity, posted by SLS on July 4, 2008, at 15:45:34
> > Clorgyline, similarly to selgiline, is subtype selective in low doses.
>
> I am not aware of a loss of selectivity at any dose. It is not like selegiline in this regard. It is specific (not selective) to MAO-A.
>My impression is definitely that clorgyline affects MAO-B - insignificantly at low doses, but very much so at higher doses. I don't have any references at this time, but I know they exist.
To my knowledge, no perfectly specific MAO-inhibitors exist, although selegiline, rasagiline and clorgyline all have sufficient subtype-preference in order to be useful as research tools for clarifying the roles of the different types of MAO. As you suggest:
> Clorgyline is the most reliable probe specific to MAO-A and is the standard of reference by which MAO-A is assayed.
>
>
> - Scott
Posted by SLS on July 6, 2008, at 5:15:18
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity, posted by undopaminergic on July 6, 2008, at 2:47:33
It might be worth your looking into if it is important enough to you. I have. Clorgyline is a specific inhibitor of MAO-A. Just enter "clorgyline" and "specific" as keywords when performing a Medline search.
Just because clorgyline and selegiline are propargyl MAOIs doesn't guarantee any similarity in biological activity at all. Look at amineptine and tianeptine, for example. Tianeptine is a sister drug to amineptine, yet does not directly affect dopamine uptake at all.
You might have to relegate yourself to the uncomfortable position of having to trust me on this one. Inhibition of MAO-A is of greater therapeutic effect than is inhibition of MAO-B in treating depression. In fact, inhibiting MAO-B might be counterproductive. Clorgyline is a much more effective antidepressant than selegiline, especially when selegiline dosages are kept low enough to remain selective for MAO-B.
To the degree that one would want to assign the contribution of MAO inhibition to one subtype being more effective in treating depression, MAO-A has consistently shown itself to be more important.
- Scott> > > Clorgyline, similarly to selgiline, is subtype selective in low doses.
> >
> > I am not aware of a loss of selectivity at any dose. It is not like selegiline in this regard. It is specific (not selective) to MAO-A.
> >
>
> My impression is definitely that clorgyline affects MAO-B - insignificantly at low doses, but very much so at higher doses. I don't have any references at this time, but I know they exist.
>
> To my knowledge, no perfectly specific MAO-inhibitors exist, although selegiline, rasagiline and clorgyline all have sufficient subtype-preference in order to be useful as research tools for clarifying the roles of the different types of MAO. As you suggest:
>
> > Clorgyline is the most reliable probe specific to MAO-A and is the standard of reference by which MAO-A is assayed.
Posted by undopaminergic on July 6, 2008, at 13:12:44
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » undopaminergic, posted by SLS on July 6, 2008, at 5:15:18
> It might be worth your looking into if it is important enough to you. I have. Clorgyline is a specific inhibitor of MAO-A. Just enter "clorgyline" and "specific" as keywords when performing a Medline search.
>Unfortunately, you seem to be reading too much significance into the word "specific". In reality, clorgyline doesn't have perfect specificity, but rather a significant - and practically useful - preference for MAO-A over MAO-B. However, at higher doses, it binds to other targets as well, including at least MAO-B in a manner that inhibits its activity. There are few, if any, drugs that are perfectly specific for anything.
"rats were treated for 21 days with either deprenyl (0.25 mg/kg), TVP-1012 [0.05 mg/kg], an irreversible inhibitor of MAO-B that is not metabolized to amphetamines, clorgyline (0.2 mg/kg)"
"Chronic treatment with the MAO-B inhibitors reduced striatal MAO-B activity by 90%, with 15% (TVP-1012) or 40% (deprenyl) inhibition of MAO-A. Clorgyline inhibited MAO-A by 95%, with 30% inhibition of MAO-B."
(from http://www.ncbi.nlm.nih.gov/pubmed/8858937 )> Just because clorgyline and selegiline are propargyl MAOIs doesn't guarantee any similarity in biological activity at all.
>OK, but incidentally, I think the fact that both bind irreversibly to MAO enzymes already qualifies as substantial similarity in biological activity. I'm not denying that the similarity coexists with significant differences between the two compounds.
> Look at amineptine and tianeptine, for example. Tianeptine is a sister drug to amineptine, yet does not directly affect dopamine uptake at all.
>I suspect that it does affect dopamine uptake at high doses, but that's another story.
> You might have to relegate yourself to the uncomfortable position of having to trust me on this one. Inhibition of MAO-A is of greater therapeutic effect than is inhibition of MAO-B in treating depression. In fact, inhibiting MAO-B might be counterproductive.
>That's possible, but more counterproductive side effects are known for MAO-A inhibition than for MAO-B inhibition. Unfortunately, you are probably right in that considerable MAO-A inhibition is required. It might even be sufficient, but if that's the case, this isn't about dopamine or any of the three major monoamine neurotransmitter, but possibly about a trace amine or other substance potentiated by MAO-A inhibition, or about adaptive changes that occur within the cell and has some antidepressant effect in the long term. One proposal for the antidepressant trace substance is acetylserotonin, the melatonin precursor.
Posted by SLS on July 6, 2008, at 13:56:46
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity, posted by undopaminergic on July 6, 2008, at 13:12:44
Just a quickie:
http://biopsychiatry.com/clorgvparg.htm
I bet the results of the study you cited were in error. Clorgyline does not inhibit MAO-B at any dosage. Again, this is a significant finding when it comes to assessing therapeutic effect.
- Scott.
Posted by Marty on July 6, 2008, at 22:16:54
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity, posted by SLS on July 6, 2008, at 13:56:46
Hi Scott,
> Just a quickie:
>
> http://biopsychiatry.com/clorgvparg.htm
>
> I bet the results of the study you cited were >in error. Clorgyline does not inhibit MAO-B at >any dosage. Again, this is a significant finding >when it comes to assessing therapeutic effect.I wonder what we are arguing about at this stage... as I'm sure we all agree that MAO-A inhibition helps more people than MAO-B inhibition BUT sometimes MAO-B inhibition works for some for which MAO-A inhibition didn't help much or enough.
Your quickie isn't helping your point much since it validate to some extent what Undopaminergic is telling you: quote "clorgyline, a preferential inhibitor of monoamine oxidase (MAO) type A"
PREFERENTIAL .. which means that it ALSO like EVERY OTHER MAOIs inhibit, to some level the untargeted isoform, MAO-B when dosage is sufficient. I wouldn't be surprised if there's no inhibitor -100%- specific to one isoform or the other. To my knowledge we don't have many very highly specific/selective molecule at this time. Even the most selective SSRIs somehow flirt with other things at some dosage. And how are we suppose to be PERFECTLY specific to one MAO isoform when they seems to share (yes I know, to some -very- small degree except dopamine and cie which they both equally *likes* ) all of the same substrates... ie: MAO-B does have some very small affinity for Serotonin even if MAO-A prefers it greatly. ... at higher dosage it seems impossible to NOT effect both isoform to some level.. specially in the case of a specific MAO-A inhibitor since MAO-B is only 30% of brains MAOs.
That said I feel WAY out of my league as to how scientist can be 100% specific to one isoform.. there is surely more differences betweens the two that there preferencial specificity for some substrates and maybe those other difference are "targetable" ... what do I know :)Anyway, why would we want a perfectly specific MAO-A or MAO-B inhibitor ? I'm sure we can live with an inhibition level of MAO-A 90%+ and MAO-B 30%- ... and MAO-A 10%- and MAO-B 90%+ .. I dont see the need to be more selective than that. Am I missing something ?
Hope your doing well,
/\/\arty
Posted by SLS on July 7, 2008, at 4:16:41
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » SLS, posted by Marty on July 6, 2008, at 22:16:54
I will suggest to you what I suggested to Undopaminergic. If you are truly interested in knowing whether or not clorgyline is specific to MAO-A, do your own research. Look at more than one citation. You have not done so.
Yes, why is this important enough for YOU to argue about?
It seems to me that the dosages people arrive at when taking Emsam are above the lowest dose form. At this point, I am entertaining the notion that most people are responding to MAO-A inhibition. People responding to the low-dose oral form of selegiline as an adjunct might be benefiting more from its metabolites than from MAO-B inhibition. Again, though, most people using selegiline as monotherapy for depression generally take 10mg or more, which is beyond the threshold of selectivity.
By the way, I didn't need a lecture on the use of the two words "preferential" and "specific". I'm sure some authors will use the term "preferential" because they simply don't know any better. Also, if you would like to use logic of diction, "preferential" can designate a 100% bias. However, "specific" means no less than 100%. Right?
You might want to read my posts along this thread again. I grow weary of repeating myself.
- Scott
Posted by SLS on July 9, 2008, at 4:26:02
In reply to Re: +++ MAO-A or B ? Gerovital (procaine) selectivity » Marty, posted by SLS on July 7, 2008, at 4:16:41
More...
http://www.rxlist.com/cgi/generic/emsam_cp.htm
"Pharmacodynamics
Selegiline (the drug substance of EMSAM) is an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. MAO exists as two isoenzymes, referred to as MAO-A and MAO-B. Selegiline has a greater affinity for MAO-B, compared to MAO-A. However, at antidepressant doses, selegiline inhibits both isoenzymes (see below)."
- Scott
This is the end of the thread.
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