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
poster:Tomatheus
thread:591969
URL: http://www.dr-bob.org/babble/20051221/msgs/592333.html