![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 53. This is the beginning of the thread.
Posted by ed_uk on December 24, 2005, at 19:16:26
Hi all,
OK, I've just consumed (more than) a few units of alcohol so this might not be as coherent and it could have been. Anyway, I'm sure you'll let me off given the circumstances :-)
LADOSTIGIL is a *very* interesting drug. It's currently in phase II trials for Alzheimer's disease. It was created by 'blending' the molecular characteristics of rivastigmine (Exelon) with those of rasagiline (Azilect). Rivastigmine (Exelon) is a cholinesterase inhibitor which is used to treat Alzheimer's disease. Rasagiline is an MAO-B inhibitor which is used to treat Parkinson's disease. Rasagiline was recently approved in Europe. It is believed to be neuroprotective as well as offering symptomatic relief.
The result, ladostigil, is a 'brain selective' MAOI and cholinesterase inhibitor. At therapeutic doses, it inhibits both MAO-A and MAO-B in the brain. Inhibition of both forms of MAO is probably necessary to gain a 'robust' antidepressant effect. Ladostigil is particularly interesting because of its alleged 'brain selectivity'. Unlike the classical MAOIs ie. Nardil and Parnate, ladostigil has relatively little effect on the MAO enzymes in the liver and gut. As a result, the risk of a tyramine-induced hypertensive crisis should be much reduced. Although ladostigil *does* potentiate the pressor effect of tyramine, the effect it minimal and no greater than that observed with moclobemide (Manerix/Aurorix). A strict low-tyramine diet is not necessary with moclobemide.
As well as inhibiting MAO-A and MAO-B, ladostigil is a cholinesterase inhibitor (think Aricept). Cholinesterase inhibitors are used in the treatment of Alzheimer's disease to enhance cognition and memory. Unfortunately, they do at times aggravate depression. Ladostigil is not expected to aggravate depression. Even so, if ladostigil was being used 'off label' as an antidepressant, as opposed to a treatment for Alzheimer's disease, it might be necessary (in some cases) to combine it with an anticholinergic - to offset the effects of potentially excessive synaptic levels of acetylcholine. There are many anticholinergics to choose from eg. Cogentin, Artane, Akineton, Kemadrin etc.
Ed
Posted by ed_uk on December 24, 2005, at 19:27:42
In reply to A new and innovative MAOI, posted by ed_uk on December 24, 2005, at 19:16:26
What would you do?
You could try......
High-dose oral selegiline (at a dose which inhibits both MAO-A and MAO-B)
High-dose oral rasagiline (at a dose which inhibits both MAO-A and MAO-B)
Selegiline (standard dose) + moclobemide
Rasagiline (standard dose) + moclobemide
The EMSAM patch - if it ever gets approved
Moclobemide (at a high dose) in multiple divided doses eg. 300mg three times a day
Ed
Posted by linkadge on December 24, 2005, at 19:59:05
In reply to What to do if Nardil and Parnate were discontinued, posted by ed_uk on December 24, 2005, at 19:27:42
I've always wanted to try an MAO-A selective drug. Parnate make me slighly psychotic. I think I was getting to much PEA neurotransmission from parnate and exercise.
I took turmeric, at doses supposedly sufficiant to inhibit MAO-A and MAO-B significantly. Then I combined it with rosemarry, which is a fairly potenet acetylcholinsterase inhibitor.
Anyhow, adding the latter caused some really freaky effects. Kind of a panickey and depressing walk down memory lane.
I stand behind the antidepressant effects of turmeric though. Probably twice the effect on MAO-A than MAO-B.
Linkadge
Posted by ed_uk on December 24, 2005, at 20:06:13
In reply to Re: What to do if Nardil and Parnate were discontinued, posted by linkadge on December 24, 2005, at 19:59:05
Hi Link
>I've always wanted to try an MAO-A selective drug.
So why not try moclobemide?
Ed
Posted by linkadge on December 24, 2005, at 20:27:46
In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by ed_uk on December 24, 2005, at 20:06:13
I would, but doctors aren't too hot about it here in canada. I've seen about 12 different doctors and most would rather prescribe an MAOI.
They seem to contend that is just wasn't that effective.
Linkadge
Posted by ed_uk on December 24, 2005, at 20:50:02
In reply to Re: What to do if Nardil and Parnate were discontinued, posted by linkadge on December 24, 2005, at 20:27:46
Hi Link,
I bet you could get a prescription for it if you really wanted to try it :)
Ed
Posted by linkadge on December 24, 2005, at 21:26:46
In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by ed_uk on December 24, 2005, at 20:50:02
Well, it'd probably have to be from a new doctor.
I gave them all a sincere request, but they gave me the "I don't prescribe that drug, end of story" routeen. I don't have much luck. I think there must be something in my folder for which they are avoiding my requests.
I can't even get them to try a different TCA. Clomipramine was doing a number on my attention, so I wanted to try a different one, (perhaps one that was used for ADD), no luck so far.
Linkadge
Posted by becksA on December 25, 2005, at 10:32:49
In reply to A new and innovative MAOI, posted by ed_uk on December 24, 2005, at 19:16:26
thanks ed. always interested in reading about new drugs in the works. I may be entering the MAO area somewhat soon if the depakote doesn't do enough for my social anxiety.
Posted by Tomatheus on December 26, 2005, at 23:03:27
In reply to What to do if Nardil and Parnate were discontinued, posted by ed_uk on December 24, 2005, at 19:27:42
Ed,
I appreciate your post. If Nardil and/or Parnate were to be discontinued (in the U.S., the U.K. or elsewhere), there is little doubt in my mind that there would be both Nardil responders and Parnate responders who would have little choice but to switch to another med. I agree that the meds you listed would probably be the best options for those who are unable to obtain Nardil (or Parnate, if that is the case) from another country.
But let me make it clear that for some Nardil responders, none of options the that you listed below will be adequate substitutes. The same is probably true for Parnate responders, but I'm not sure if there's enough data in the medical literature to back up such an assertion. Those of us who have been closely following the controversy surronding the 2003 Nardil formulation switch already know that some of the patients who responded wonderfully to the "old" Nardil still have not been able to achieve a clinically significant remission with any other medication -- not even the "new" Nardil or any of the other MAOIs. Considering this, I think it's almost certain that many of those who respond to favorably to the "new" Nardil will have some of the same problems with the other MAOIs as those who were only responsive to the old formulation.
I think it's also important to point out that with the exception of moclobemide, all of the drugs you listed below are more preferential to MAO-B than they are to MAO-A, even those that inhibit both MAO enzymes at higher doses. Of course, different people respond differently to different medications, so I do think that some patients will respond favorably to the strong levels of MAO-B inhibition. But many patients -- particularly some Nardil responders -- will not. As I mentioned, all of the irreversible MAOIs that you listed below are less preferential to MAO-A than Nardil is -- even at higher doses. I don't think it's necessary at this time to summarize all of the research studies that I've read concerning such the topics of MAO-A inhibition, variants of the MAO-A gene, and the relatinship between hormone levels and MAO-A, but I will say that it is irrefutable that MAO-A levels vary considerably among the general population. For some psychiatric patients, a drug that potently inhibits MAO-A is the key to successful treatment. Unfortunately, the only commercially available MAO-inhibiting mediction in the world is moclobemide, which tends to be relatively ineffective in practice. Considering the real-world efficacy of moclobemide (or lack therof) and the research studies that have compared moclobemide to Nardil and/or Parnate, it is not uncommon or unreasonable to hypothesize that moclobemide is less effective than MAOIs such as Nardil and Parnate because moclobemide only inhibits MAO-A without inhibiting MAO-B. But based on the research material that I've read, I think it is more likely that moclobemide's pharmacological properties (possibly either moclobemide's reversibility or the inconsistency in its MAO-A inhibition) prevent it from inhibiting MAO-A potently enough to produce the benefits that are supposed to result from MAO-A inhibition. Although the efficacy of moclobemide has never been compared with that of clorgyline, an irreversible inhibitor of MAO-A, clorgyline is typically described in the scientific literature as being a highly effective antidepressant. Moclobemide has never been described in such a way (at least not in any of the research reports that I have read), even though it is no different from clorgyline in terms of being just about completely preferential to MAO-A over MAO-B. Additionally, if moclobemide inhibited MAO-A properly (or in other words, if patients received the true benefits of MAO-A inhibition from moclobemide), individuals with a genetic tendency to produce abnormally high levels of MAO-A should theoretically benefit from moclobemide. However, Müeller et al. (2002) conducted a study to determine whether depressed patients with longer alleles in the promoter region of the MAO-A gene would be more responsive to moclobemide than depressed patients with shorter alleles in the promoter region of the same gene. Molecular genetics studies have found that the longer alleles encode abnormally high levels of MAO-A production. According to the report of Müeller et al. (2002), no statistically significant associations between the allelic activity of the MAO-A gene and moclobemide responsiveness could be found. So, the point that I'm trying to make by citing all these facts is that moclobemide's lackluster efficacy is probably not due to the fact that it inhibits MAO-A without also inhibiting MAO-B; it likely has more to do with the strong possibility that moclobemide does not produce the "true" benefits of MAO-A inhibition. Why is this relevant to whether or not the options you listed below could adequately substitute for Nardil? Well, as I've said, Nardil is more preferential to MAO-A than any of the other irreversible MAOIs. Those who benefit from Nardil's effects on MAO-A probably wouldn't receive the same benefits from moclobemide's inhibition of MAO-A that they do from Nardil's inhibition of the enzyme. And it's highly unlikely that they would benefit significantly from medications such as selegiline and rasagiline, which are both a lot more preferential to MAO-B than they are to MAO-A, even at higher doses.
Even though it may seem that I'm trying to pick apart your post as much as possible, I am sincere when I say that I found your post very helpful -- and no, not just as something to pick apart. As I've said in some of my other posts, Nardil users in the U.S. (and also Parnate users in the U.K.) need to start developing contingency plans to either order their meds from another country or find another medication capable of producing comparable benefits. Some Nardil users might just succeed in finding another medication capable of producing a clinically significant response. But based on the limited amount of research that I've done (and I do mean limited!), I can say that there is already a significant amount of evidence pointing to the likelihood that a lot of Nardil responders will never be able to achieve remission on any of the other medications that are currently available. I intend to do a lot more research on this matter, and I suspect that I will eventually find enough evidence to fully support the idea that for far too many patients, there is absolutely no substitute for Nardil. I'm not suggesting at all that you were trying to send a message to everybody here that the options that you listed below are guaranteed to be adequate replacements for Nardil and/or Parnate. I know that you just wanted to make us aware of some potentially beneficial possibilities. But if anybody gets the idea from reading your post that a vast majority of Nardil responders will be able to find effective alternatives, then they better think again. There is plenty of evidence out there to indicate otherwise, and I will do everything in my power to make sure that the evidence speaks for itself if Pfizer tries to discontinue Nardil based on the rationale that there are plenty of other alternatives available.
Tomatheus
==
REFERENCE
Müeller, D. J., Schulze, T. G., Macciardi, F., Ohlraun, S., Gross, M. M., & Scherk, H. (2002). Moclobemide response in depressed patients: Association study with a functional polymorphism in the monoamine oxidase A promoter. Pharmacopsychiatry, 35, 157-58.
==
> What would you do?
>
> You could try......
>
> High-dose oral selegiline (at a dose which inhibits both MAO-A and MAO-B)
>
> High-dose oral rasagiline (at a dose which inhibits both MAO-A and MAO-B)
>
> Selegiline (standard dose) + moclobemide
>
> Rasagiline (standard dose) + moclobemide
>
> The EMSAM patch - if it ever gets approved
>
> Moclobemide (at a high dose) in multiple divided doses eg. 300mg three times a day
>
> Ed
Posted by ed_uk on December 27, 2005, at 12:11:34
In reply to Re: What to do if Nardil and Parnate were discontinued » ed_uk, posted by Tomatheus on December 26, 2005, at 23:03:27
Hi Tom
>But let me make it clear that for some Nardil responders, none of options the that you listed below will be adequate substitutes.
I agree. I was just making a few suggestions.
>Unfortunately, the only commercially available MAO-inhibiting mediction in the world is moclobemide
I think pirlindole is still available in Russia (as Pyrazidol) and Portugal (as Implementor). Pirlindole seems to have been studied mainly in Russia.
>it is not uncommon or unreasonable to hypothesize that moclobemide is less effective than MAOIs such as Nardil and Parnate because moclobemide only inhibits MAO-A without inhibiting MAO-B
I think it's highly likely. See.......
The author examined the acute anxiolytic effects of monoamine oxidase inhibitors on freezing behavior, a putative index of anxiety, induced by conditioned fear stress. The selective serotonin1A receptor agonist inhibited freezing dose dependently. The irreversible, non-selective monoamine oxidase inhibitors tranylcypromine (3 and 15 mg/kg) and phenelzine (30 and 80 mg/kg) reduced freezing significantly. Clorgyline (10 mg/kg, irreversible selective monoamine oxidase A inhibitor), Ro 41-1049 (30 mg/kg, reversible selective monoamine oxidase A inhibitor), selegiline (3 mg/kg, irreversible selective monoamine oxidase B inhibitor) and lazabemide (10 mg/kg, reversible selective monoamine oxidase B inhibitor) had no effect on freezing behavior. However, combined administration of clorgyline (10 mg/kg) and selegiline (3 mg/kg) reduced freezing significantly, as well as combined administration of clorgyline (10 mg/kg) and lazabemide (10 mg/kg), Ro 41-1049 (30 mg/kg) and selegiline (3 mg/kg), or Ro 41-1049 (30 mg/kg) and lazabemide (10 mg/kg). These effects of monoamine oxidase inhibitors on freezing were not due to non-specific motor effects.
These results suggest that acute inhibition of both monoamine oxidase A and B reduces anxiety or fear, while inhibition of monoamine oxidase A or B alone fails to reduce anxiety or fear. In vivo microdialysis studies showed that the irreversible monoamine oxidase A inhibitor clorgyline and the irreversible monoamine oxidase B inhibitor selegiline induced a mild increase and no increase in extracellular serotonin, respectively. Interestingly, the combined treatment with clorgyline and selegiline resulted in much larger increases in extracellular serotonin in the medial prefrontal cortex than did either monoamine oxidase inhibitor alone. Our previous studies have indicated that facilitation of 5-HT neurotransmission decreases conditioned freezing, i.e., anxiety or fear. The results of these in vivo microdialysis studies may account for the results of this study that the simultaneous blockade of both monoamine oxidase A and B reduced conditioned freezing, whereas blockade of either monoamine oxidase alone failed.
...........................................................................................................................
It is my belief that the co-administration of moclobemide with a low dose of rasagiline (eg. 1mg/day) might produce a substantial anxiolytic/antidepressant effect in some patients. As is the case with traditional MAOIs, a low tyramine diet would be necessary.
>is typically described in the scientific literature as being a highly effective antidepressant
The scientific literature has a tendency to describe most drugs as 'potent' ;-)
>moclobemide does not produce the "true" benefits of MAO-A inhibition
Perhaps. It's short elimination half life may be relevant. It might work better in multiple divided doses eg. 300mg three times a day.
>So, the point that I'm trying to make by citing all these facts is that moclobemide's lackluster efficacy is probably not due to the fact that it inhibits MAO-A without also inhibiting MAO-B; it likely has more to do with the strong possibility that moclobemide does not produce the "true" benefits of MAO-A inhibition.
Potent inhibition of MAO-A alone seems to produce only small rises in extracellular serotonin. The anxiolytic efficacy of clorgyline is likely to be weak. Inhibition of both forms of MAO may be necessary to produce a substantial effect. The anxiolytic/antidepressant efficacy of phenelzine (Nardil) is likely to be closely linked to its strong serotonergic properties. Of course, Nardil has other pharmacological actions which may also play a role. Moclobemide alone appears to be (only) weakly serotonergic.
>it's highly unlikely that they would benefit significantly from medications such as selegiline and rasagiline
Perhaps not alone, but in combination with moclobemide such medications may be useful.
> But if anybody gets the idea from reading your post that a vast majority of Nardil responders will be able to find effective alternatives, then they better think again.
Ouch, that hurt.
Regards
Ed
Posted by ed_uk on December 27, 2005, at 12:12:12
In reply to Re: What to do if Nardil and Parnate were discontinued » ed_uk, posted by Tomatheus on December 26, 2005, at 23:03:27
Hi
So what do you think of ladostigil?
Ed
Posted by mystery road on December 27, 2005, at 18:31:50
In reply to Re: What to do if Nardil and Parnate were discontinued, posted by linkadge on December 24, 2005, at 19:59:05
> I've always wanted to try an MAO-A selective drug. Parnate make me slighly psychotic. I think I was getting to much PEA neurotransmission from parnate and exercise.
>
> I took turmeric, at doses supposedly sufficiant to inhibit MAO-A and MAO-B significantly. Then I combined it with rosemarry, which is a fairly potenet acetylcholinsterase inhibitor.
>
> Anyhow, adding the latter caused some really freaky effects. Kind of a panickey and depressing walk down memory lane.
>
> I stand behind the antidepressant effects of turmeric though. Probably twice the effect on MAO-A than MAO-B.
>
>
> Linkadge
Hi Linkadge..Could you write more about your turmeric experiences?..Has it worked for you?..At what doses?
MR
>
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>
>
>
>
>
>
Posted by Tomatheus on December 27, 2005, at 21:02:56
In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by ed_uk on December 27, 2005, at 12:11:34
Ed,
See below for my responses to parts of your post.
> >But let me make it clear that for some Nardil responders, none of options the that you listed below will be adequate substitutes.
> I agree. I was just making a few suggestions.
I know. I wasn't trying to suggest that you were guaranteeing that your suggestions would be effective substitutes for all Nardil and/or Parnate responders. As unconscionable as it would be for Pfizer, for example, to discontinue Nardil, there is a real possibility that this might happen. If it does indeed happen, those without the means to order Nardil from outside the United States are going need to resort to trying to find a medication or med combo that's the "next best thing" to Nardil. Based on the limited amount of research I've done, I do think that the "next best thing" will hardly be a sufficient option for many Nardil responders. But nevertheless, Nardil users are going to need to know what their options are if Pfizer ends up doing the unthinkable. And so it's great that you're decided to suggest some alternatives. I do think that the options you recommended are the best alternatives to consider in the absence of Nardil and/or Parnate, and I'm truly glad that you made the suggestions that you did. I just think that for many patients, there will be no substitute for Nardil, and I wanted to make it clear that the availability of meds that *might* be decent alternatives for some Nardil responders can in no way be used to justify discontinuing the medication -- just in case anybody gets that idea. I think that there is definitely some evidence to suggest that some Nardil users will not achieve clinically significant remission with any other medication, and I intend to continue my hunt for more evidence for my own personal reasons.
But anyway, I think we're on the same wavelength on this issue. I just wanted to explain that I did find your suggestions helpful, but I was concerned that others might make the false assumption that Nardil and Parnate responders should have no problem finding another medication (or med combo) that effectively treats their psychiatric condition.
> >Unfortunately, the only commercially available MAO-inhibiting mediction in the world is moclobemide
>
> I think pirlindole is still available in Russia (as Pyrazidol) and Portugal (as Implementor). Pirlindole seems to have been studied mainly in Russia.Oops. I clearly wasn't thinking right when I wrote that statement ("Unfortunately, the only commercially available MAO-inhibiting mediction in the world is moclobemide"). What I wanted to say was that moclobemide is the only commercially available medication available anywhere in the world that is highly preferential to MAO-A over MAO-B. But based on your response, it actually seems that you somehow understood what I was meaning to say, which I am thankful for.
I have never come across any information concerning the availability of pirlindole in any of the MAOI review articles I've read, but then again, most of the research articles I've read are at least a few years old, so maybe the information I have is dated. Either that or I overlooked something, which is possible.
But anyway, thanks for the info on pirlindole. Of course, moclobemide is still the only medication available in most Western countries that is highly preferential to MAO-A over MAO-B. And it's not even available in the United States. So, even though most Americans should have the means to obtain moclobemide from an overseas pharmacy, there are a few who won't be able to afford it. And of course, Pfizer will never be able to seriously suggest taking moclobemide (either as monotherapy or in combination with a drug that's preferential in its inhibition of MAO-B) as an alternative to Nardil unless the FDA approves moclobemide. In terms of the Nardil alternatives that Pfizer can legally suggest, all of them are more preferential to MAO-B than Nardil is, which would be a problem for the subset of Nardil responders who receive their primary benefits from the drug's inhibition of MAO-A.
> >it is not uncommon or unreasonable to hypothesize that moclobemide is less effective than MAOIs such as Nardil and Parnate because moclobemide only inhibits MAO-A without inhibiting MAO-B
>
> I think it's highly likely.
>
>...
>
>
> It is my belief that the co-administration of moclobemide with a low dose of rasagiline (eg. 1mg/day) might produce a substantial anxiolytic/antidepressant effect in some patients.I think there's a good chance that your belief may be correct. I wasn't meaning to suggest that the suggestions you made won't work for anybody. This is just my opinion, of course, but yeah, I do think that selegiline+moclobemide and rasagiline+moclobemide would likely be effective combos for some patients.
And I do think that for some patients, the therapeutic benefits of inhibiting both MAO-A and MAO-B are definitely more pronounced than the benefits of solely inhibiting MAO-A. The abstract that you provided clearly suggests that the combined inhibition of MAO-A and MAO-B is more effective at reducing anxiety or fear (as measured in terms of "freezing behavior") than the inhibition of either just MAO-A or just MAO-B.
So for some patients, the difference in efficacy between moclobemide and Nardil (and moclobemide and Parnate) may partially be due to the fact that moclobemide only inhibits MAO-A, while Nardil and Parnate inhibit both MAO-A and MAO-B. As I said, I do think that is a reasonable hypothesis, and I see now that there is some evidence to support it. At the same time, I do think that there is some evidence to suggest that moclobemide's inhibition of MAO-A is not equipotent to Nardil's inhibition of MAO-A. So, I do think that the difference in efficacy between moclobemide and Nardil (as well as moclobemide and Parnate) is at least partially due the strong possibility that moclobemide does not produce the "true" benefits of sustained MAO-A inhibition.
> >is typically described in the scientific literature as being a highly effective antidepressant
>
> The scientific literature has a tendency to describe most drugs as 'potent' ;-)True, but I don't think I've ever come across a reseach article that has described moclobemide as "potent." I can't say with 100 percent certainty that clorgyline is more potent than moclobemide because the two drugs have never been compared in any published studies (at least not in any that I'm aware of), but everything I've read suggests that it's a strong possibility.
> > But if anybody gets the idea from reading your post that a vast majority of Nardil responders will be able to find effective alternatives, then they better think again.
>
> Ouch, that hurt.Sorry, I didn't mean to be hurtful, but I don't think that there's enough evidence to suggest that a "vast majority" of Nardil responders will be able to find another medication or med combo that provides clinically significant relief from the symptoms of their psychiatric illnesses. I think this is especially true in the United States, where (from a legal standpoint), moclobemide is not available. Although the number of patients who have reported being responsive to the "old" Pfizer Nardil but not the "new" Pfizer Nardil (or any other medicatinon or med combo) is not incredibly huge, I wouldn't say that these patients represent a small minority, either (especially considering that there are probably a significant number of "new" Nardil non-responders who never realized that their problem with Nardil was due to the change in their medication's formulation). In light of the fact that there are still some "old" Nardil responders who have not been able to achieve a clinically significant remission with another medication, it is likely that many of those who have been responsive to both the "old" Nardil and the "new" Nardil will also not be able to find an effective substitute for Nardil.
Tomatheus
Posted by linkadge on December 27, 2005, at 21:32:18
In reply to Re: What to do if Nardil and Parnate were discontinued » ed_uk, posted by Tomatheus on December 26, 2005, at 23:03:27
But moclobemides lack of efficacy may be more due to the fact that it inhibits the MAO-A enzyme reversably, as opposed to nardil and parnate.
Nardil and parnate, also have some secondary properties which may boost their antidepressant efficacy.
Nardil affects gaba, and parnate actually does some weird things with monoamine transporters (it acutally poseses some serotonin uptake inhibition)
Cause, I think we have some irreversable inhibitors of MAO-A, that are more effective than moclobemide.
Linkadge
Posted by linkadge on December 27, 2005, at 21:39:09
In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by ed_uk on December 27, 2005, at 12:11:34
>The author examined the acute anxiolytic effects >of monoamine oxidase inhibitors on freezing >behavior, a putative index of anxiety, induced >by conditioned fear stress
I remember this study. I would actually like to see more studies done on other selective inhibitors of MAO-A. It seems kind of strange to me that the addition of a MAO-B inhibitor would increase serotonergic neurotransmission since generally MAO-B inhibitors only effect PEA levels. Some strange synergy I guess.
I'm not saying the study isn't right, I'd just like to see other MAO-A selective drugs tested. I have a feeling that not all MAO-A inhibitors would fail as antipanic agents.
Linkadge
Posted by Tomatheus on December 28, 2005, at 0:44:10
In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by ed_uk on December 27, 2005, at 12:12:12
> So what do you think of ladostigil?
It definitely sounds like ladostigil has a lot of potential, particularly because of its "brain selectivity." The drug companies are obviously not interested in developing any more MAOIs that carry a significant risk of potentiating a tyramine-induced hypertensive crisis, so it's possible that ladostigil might end up becoming a highly desirable medication. I do think that its efficacy will need to be established first, though. In my opinion, if ladostigil is capable of inhibiting both MAO-A and MAO-B in a manner that is consistent over time, there is a good chance that it will turn out to be one of the more effective MAOIs on the market. Of course, there are other factors that could influence the drug's efficacy. But no matter what factors contribute to ladostigil's efficacy (or lack thereof, if that turns out to be the case), it's obviously important from our perspective as patients that the drug is reasonably effective. I also think that ladostigil's potential as an antidepressant might be hampered by the fact that it functions as both an MAOI and a cholinesterase inhibitor, depending on the potency of the drug's cholinesterase inhibition. Personally, I wouldn't have a problem with combining ladostigil with an anticholinergic, as long as the ladostigil provided me with a clinically significant remission. Other patients, however, might find the addition of an anticholinergic to be too much of a hassle, especially if their response to ladostigil is less than robust.
Tomatheus
Posted by Tomatheus on December 28, 2005, at 1:02:23
In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by linkadge on December 27, 2005, at 21:32:18
Linkadge,
See below for my responses to sections of your post...
> But moclobemides lack of efficacy may be more due to the fact that it inhibits the MAO-A enzyme reversably, as opposed to nardil and parnate.
I agree. As I mentioned in my post, I suspect that moclobemide's lackluster efficacy is likely at least partially due to its reversibility and/or the lack of consistency in its MAO-A inhibition.
> Nardil and parnate, also have some secondary properties which may boost their antidepressant efficacy.
>
> Nardil affects gaba, and parnate actually does some weird things with monoamine transporters (it acutally poseses some serotonin uptake inhibition)True.
> Cause, I think we have some irreversable inhibitors of MAO-A, that are more effective than moclobemide.
I think you're right. Clorgyline, an irreversible inhibitor of MAO-A used exclusively for research purposes, has never been compared directly against moclobemide -- or at least it hasn't been done to my knowledge. But based on the limited body of information available on clorgyline, there is little doubt in my mind that it would end up being more effective than moclobemide, even though both drugs basically do the same thing on paper. I think it's unfortunate that no irreversible inhibitors of MAO-A were ever pursued because I think there's a good chance that some patients might have ended up becoming uniquely responsivee to them. At one point, Eli Lilly was apparently testing an irreversible MAO-A inhibitor called "Lilly 51641," but it is my understanding that the irreversible MAO-A inhibitors were never introduced because of their capacity to potentiate a hypertensive crisis. Thus, this subclass of MAOIs was not seen as a significant advance over drugs such as Nardil and Parnate.
Tomatheus
Posted by ed_uk on December 28, 2005, at 1:31:10
In reply to Re: What to do if Nardil and Parnate were discontinued, posted by Tomatheus on December 27, 2005, at 21:02:56
Dear Tom
>Sorry, I didn't mean to be hurtful, but I don't think that there's enough evidence to suggest that a "vast majority" of Nardil responders will be able to find another medication or med combo that provides clinically significant relief from the symptoms of their psychiatric illnesses.
I do agree. I never suggested that that would be the case :(
Kind regards
Ed
Posted by gardenergirl on December 28, 2005, at 4:10:01
In reply to Linkadge..Tumeric as MAO inhibitor?, posted by mystery road on December 27, 2005, at 18:31:50
Sorry to interrupt,
I redirected posts related to turmeric to the Alternatives board.Here is a link:
http://www.dr-bob.org/babble/alter/20051208/msgs/592689.htmlgg
Posted by linkadge on December 28, 2005, at 11:03:31
In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by Tomatheus on December 28, 2005, at 1:02:23
Its funny. They probably don't see new MAOI's as advances over Nardil/Parnate, but yet they're willing to release SSRI after SSRI.
Where I do think that mixed MAO-A/B inhibitors have the advantage over MAO-A inhibitors is in the subset of people who gain a significant antidepressnat effect from increased PEA neurotransmission.
Some doctors have detected low PEA neurotransmission in certain subsets of depression. Depression that is accompanied by low energy, cravings, poor attention and other features.
These people are not going to get major help from SSRI, SNRI's, and probably never will.
Linkadge
Posted by ed_uk on December 28, 2005, at 13:35:23
In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by linkadge on December 28, 2005, at 11:03:31
Hi Link
AFAIK........In the absense of MAO-A, serotonin is metabolised by MAO-B. As shown in the study I posted above, clorgyline only mildly increased serotonin levels wheareas Nardil greatly increased serotonin levels. This could be an important reason why moclobemide's efficacy may be less than that of Nardil.
Regards
Ed
Posted by ed_uk on December 28, 2005, at 13:39:05
In reply to Re: What to do if Nardil and Parnate were discontinued, posted by Tomatheus on December 27, 2005, at 21:02:56
Hi T
>I wanted to make it clear that the availability of meds that *might* be decent alternatives for some Nardil responders can in no way be used to justify discontinuing the medication.......
That's an important point. Many psychiatrists would no doubt argue than MAOIs are no longer necessary in an era of SNRIs etc. We both know that that's not true!!!
Ed
Posted by ed_uk on December 28, 2005, at 13:54:06
In reply to Re: What to do if Nardil and Parnate were discontinued, posted by Tomatheus on December 27, 2005, at 21:02:56
Hi T
>What I wanted to say was that moclobemide is the only commercially available medication available anywhere in the world that is highly preferential to MAO-A over MAO-B.
Like moclobemide, pirlindole is considered to be a RIMA.
Regards
Ed
Posted by ed_uk on December 28, 2005, at 14:01:55
In reply to Re: What to do if Nardil and Parnate were discontinued, posted by Tomatheus on December 27, 2005, at 21:02:56
Hi Tom
Pirlindole has been researched mainly in Russia. Pirlindole is not a new drug by any means. Numerous psychiatric drugs invented in Russia, France, Japan, Hungary etc have only been marketed in their 'home country'.
Ed
Posted by Tomatheus on December 28, 2005, at 14:38:54
In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by linkadge on December 28, 2005, at 11:03:31
Linkadge,
See below for my responses...
> Its funny. They probably don't see new MAOI's as advances over Nardil/Parnate, but yet they're willing to release SSRI after SSRI.
Yeah, in terms of introducing medications that might actually produce clinically significant benefits in treatment-resistant patients, it really doesn't make sense why more MAOIs haven't been pursued. However, you know as well as I know (or probably better) that the drug companies are more interested in making meds that will maximize their profits than those that could potentially help a relatively small group of treatment-resistant patients. I'm not saying at all that these small groups of patients are insignificant, but the drug companies obviously don't stand to make as much money off of meds that that are targeted toward a subgroup of depressed patients as they do from so-called "blockbuster" meds that they can market to all patients with depressive disorders, patients with other psychiatric conditions, and patients who just feel "down" for a short period of time as a result of circumstances in the lives. And of course, if the drug companies can claim that a particular class of drugs is safe -- and if they have the power to discredit anyone who dares to suggest otherwise -- they can succeed at at getting people with a wide range of depressive symptoms (including those that can be directly attributed to "depressing" life circumstances) to request these drugs from their doctors. Because the capacity of the irreversible MAOIs (including the selective MAO-A inhibitors clorgyline and Lilly 51641) to potentiate hypertensive crises has been well-known for decades, it would be impossible for the drug companies to market them as "safe." This of course would translate into a low profit potential from such medications.
I should also probably clarify that Lilly 51641 is actually not a "new" MAOI, but a medication that Lilly began pursuing in the mid-1960s. Lilly 51641 was studied experimentally until the late 1970s, but I have not been able to find any information to indicate to what extent (and for how long) Lilly was actually trying to pursue the drug for commercial use. But considering that Lilly is a commercial drug company, it would make sense that they were trying to pursue it at one point. It seems likely that that Lilly decided against pursuing it as a commercial drug because of its ability (like that of clorgyline) to potentiate hypertensive crises. According to Lotufo-Neto et al. (1999), "Clorgyline is an irreversible enzyme inhibitor, and has some liability to cause hypertensive crises in the face of high substrate concentrations, despite its selectivity (Laux et al., 1995, as cited in Lotufo-Neto et al.). Thus, clorgyline was not considered to represent much of an advance over the nonselective MAOIs and was not vigorously pursued."
> Where I do think that mixed MAO-A/B inhibitors have the advantage over MAO-A inhibitors is in the subset of people who gain a significant antidepressnat effect from increased PEA neurotransmission.
>
> Some doctors have detected low PEA neurotransmission in certain subsets of depression. Depression that is accompanied by low energy, cravings, poor attention and other features.I think you could be right.
I also think that there is a subgroup of individuals who stands to benefit from the selective inhibition of MAO-A. Studies that have measured MAO-A levels in cultured skin fibroblasts and placentas have found that levels of the enzyme vary "over 50-fold" among control individuals (Hotamisligil & Breakfield, 1991). Furthermore, variants of the MAO-A gene that encode for abnormally high levels of the enzyme have shown statistically significant associations with major depression and sleep disturbance in males (Du et al., 2004); depressed suicide in males (Du et al, 2002); major depression in females (Schulze et al., 2000); panic disorder in females (Deckert et al, 1999); anxiety disorders, agoraphobia, and specific phobias in females (Samochowiec et al., 2004), and ADHD in children (Domschke et al., 2005; Jiang et al., 2001). In my opinion, it seems possible that in some individuals, the genetic tendency to produce abnormally high levels of MAO-A could be just one of multiple genetic abnormalities that contributes to their illness. And the relationship between the abnormally high MAO-A levels and the ways in which the associated psychiatric illnesses manifest themselves does seem to be different in males than it is in females. This could be because the MAO-A gene is located on the X chromosome, because of estrogen's ability to influence MAO-A activity MAO-A activity (Chakravorty et al., 1997), or possibly both. But it seems clear that there are some individuals whose psychiatric symptoms are at least partially mediated by genetically determined high levels of MAO-A. Furthermore, MAO-A activity has been reported to rise significantly with aging (Hotamisligil et al., 1991), indicating that the selective inhibition of MAO-A may be beneficial in treating geriatric depression. So, between the genetic tendencies to produce abnormally high levels of MAO-A and the potential that hormonal differences could also influence MAO-A levels, there is little doubt in my mind that there are some individuals (note: I'm not saying *all* individuals) who would benefit from a potent selective inhibitor of MAO-A.
> These people are not going to get major help from SSRI, SNRI's, and probably never will.
I agree.
Tomatheus
==
PRIMARY SOURCE REFERENCES
Chakravorty, S. G., & Halbreich, U. (1997). The influence of estrogen on monoamine oxidase activity. Psychopharmacology Bulletin, 33, 229-33.
Deckert, J., Catalano, M., Syagailo, Y. V., Bosi, M., Okladnova, O., Di Bella, D., et al. (1999). Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Human Molecular Genetics, 8, 621-24
Domschke, K., Sheehan, K., Lowe, N., Kirley, A., Mullins, C., O'Sullivan, R., et al. (2005). Association analysis of the monoamine oxidse A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: Preferential transmission of the MAO-A 941G allele to affected children. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), 134B, 110-14.
Du, L., Bakish, D. Ravindran, A., & Hrdina, P. D. (2004). MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males. NeuroReport, 15, 2097-2101.
Du, L. Faludi, G., Palkovits, M. Sotonyi, P., Bakish, D., & Hrdina, P. D. (2002). High activity-related allele of MAO-A gene associated with depressed suicide in males. NeuroReport, 13, 1195-1198.
Hotamisligil, G. S., & Breakfield, X. O. (1991). Human monoamine oxidase A gene determines levels of enzyme activity. American Journal of Human Genetics, 49, 383-92.
Lotufo-Neto, F., Trivedi, M., & Thase, M. E. (1999). Meta-analysis of the reversible inhibitors of monoamine oxidse type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology, 20, 226-47.
Samochowiec, J. Hajduk, A. Samochowiec, A., Horodnicki, J., Stepien, G., Grzywacz, A., et al. (2004). Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Research, 128, 21-26.
Jiang, S. Xin, R., Lin, S. Qian, Y., Tang, G., Wang, D., et al. (2001). Linkage studies between attention-deficit hyperactivity disorder and the monoamine oxidase genes. American Journal of Medical Genetics (Neuropsychiatric Genetics), 105, 783-88.
Schulze, T. G., Müller, D. J., Krauss, H., Scherk, H., Ohlraun, S., Syagailo, Y. V., et al. (2000). Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder. American Journal of Medical Genetics (Neuropsychiatric Genetics), 96, 801-03.
SECONDARY SOURCE REFERENCE
As cited in Lotufo-Neto et al. (1999): Laux, G., Volz, H. P., & Möller, H. J. (1995). Newer and older monoamine oxidase inhibitors. A comparative profile. CNS Drugs, 3 (Suppl 2), 145-58.
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