![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 10 to 34 of 53. Go back in thread:
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
>
>
>
>
>
>
>
>
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.
Posted by Tomatheus on December 28, 2005, at 14:46:22
In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by ed_uk on December 28, 2005, at 13:54:06
> >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.Ed,
Thanks for the clarification. Like I said in the last post I wrote to you, I was not aware of pirlindole from the research studies that I had read, and I thank you for making me aware of the presence of pirlindole. I was just trying to restate what I was meaning to write in my *first* post because my statement in that first post accidentally ended up being erroneously wrong (I think I said that moclobemide was the only commercially available *MAOI* available anywhere in the world).
Thanks,
Tomatheus
Posted by ed_uk on December 28, 2005, at 15:23:07
In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by Tomatheus on December 28, 2005, at 14:38:54
Hi T
Thanks for the interesting post :)
>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
I agree, very much so.
I've often wondered whether p-babble has created an unrealistically negative impression of moclobemide. Most babblers who've taken moclobemide have been very treatment resistant (they have generally imported it into the US following multiple unsuccesful trials of other ADs). Moclobemide has, after all, proved to be an effective antidepressant in numerous clinical trials.
Moclobemide's official maximum dose is 600mg/day (300mg bid). Nevertheless, some sources have suggested that doses up to 1200mg/day might be necessary. Given moclobemide's reversibility and short duration of action, some patients might benefit from taking it in multiple divided doses eg. 150-300mg four times a day. Having said that, I'm sure other people can benefit from much less!
Ed
Posted by zeugma on December 28, 2005, at 16:26:16
In reply to Moclobemide vs P-babble » Tomatheus, posted by ed_uk on December 28, 2005, at 15:23:07
Moclobemide has, after all, proved to be an effective antidepressant in numerous clinical trials. >>
So has reboxetine, but I have not seen a single positive post about this AD.
How could numerous antidepressant trials be so wrong?
-z
Posted by Tomatheus on December 28, 2005, at 17:00:35
In reply to Moclobemide vs P-babble » Tomatheus, posted by ed_uk on December 28, 2005, at 15:23:07
Ed,
I think you made some valid points concerning moclobemide. As you mentioned, moclobemide has demonstrated clinical efficacy in several clinical trials. In a meta-analysis of moclobemide and brofaromine, Lotufo-Neto et al. (1999) found that moclobemide tends to be significantly more effective than placebo, about as effective as the SSRIs, and slightly less effective than the irreversible MAOIs.
And I agree that the Babblers who have taken moclobemide for depression are most likely not representative of the depressed population as a whole. Many of us here are relatively treatment resistant, so if we're more likely to be unresponsive to most drugs than most depressed patients, the same likely holds true for moclobemide. I will say that I've read that moclobemide tends to be less effective in practice than the research studies suggest. Unfortunately, I can't seem to find the source that suggested that right now, so I can't say for sure how valid that point was. I also recall reading that moclobemide was once used as a first-line treatment in New Zealand but has since dropped to second or third-line use because of its lack of efficacy. So, I think the evidence concerning moclobemide's efficacy is mixed, but I still think that the most valid sources would have to be the clinical trials, which (as you mentioned), have shown moclobemide to be relatively effective.
I also recall reading in a research study (but I can't remember which one) that some patients might benefit from doses higher than 600mg/day. And I definitely agree that the moclobemide dosing schedule likely to produce the most benefits would be the one you suggested -- dividing the dose so its taken several times a day at regular intervals. I personally tried that strategy without any success, but just because I didn't respond to moclobemide obviously doesn't mean that others won't. As I've hypothesized in other posts (see http://www.dr-bob.org/babble/20051221/msgs/591806.html if you're interested), I think that an MAOI's ability to inhibit the MAO enzymes consistently has a lot to do with the drug's efficacy. Or it's at least one important factor, IMHO. So, for some patients, it does make sense that taking moclobemide several times a day at regular intervals might be enough to do the trick.
Tomatheus
==
REFERENCE
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.
Posted by linkadge on December 28, 2005, at 18:09:31
In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by ed_uk on December 28, 2005, at 13:35:23
Interesting. I have a feeling then, that MAO inhibitors may affect the system slightly differently than mice with a genetic absence of MAO
http://www.nichd.nih.gov/autism/abstracts/holschneider.htm
http://biopsychiatry.com/mao.htmlThe above seems to suggest that genetic absence of MAO-A in mice is sufficant to markedly increase serotonin.
Linkadge
Posted by linkadge on December 28, 2005, at 18:33:24
In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by Tomatheus on December 28, 2005, at 14:38:54
The really dumb thing, is that if the drug companies want to target as many people as possable, they might almost want to try the MAO inhibitor route.
SSRI's don't routeenly or consistantly make the average person better than well. MAO's on the other hand, were discovered based on their propenisty to make normal people feel better than well.
MAO's could also be targeted towards the cigarette smokers. Parnate could probably get more people off the cigarettes than could say wellbutrin, since smoking is not purely dopaminergic. Tobacco inhibits both MAO A, and B.
I know that the drug companies have marketed the SSRI's for everything upto and including a bad hair day, mainly because they can. I don't think they have that option with MAOIs. Also a lot of people's depression is not so bad that they would have to give up on sausage.
If MAOI's were not as "dangerous", the drug companies could probably do the same with the MAOI's that they did with the SSRI's.
I would argue that the only reason the SSRI's are so widely distributed is reated to their presumed safety. I think that even the notion that MAOI's "only help a small subset of depressed people", is just a drug company attempt to direct us towards the newer SSRI drugs. How do we know that they only help a small subset of the depressed population? They've only been given to a small subset of depressed people. Maybe if they were used first line, remission rates would be higher.
For all the placebo's I have ingested over the years, parnate was really the only "active drug".
I won't likely get another shot at an MAOI. No doctor wants to take the "risk"
Linkadge
Posted by linkadge on December 28, 2005, at 18:47:20
In reply to Re: Moclobemide vs P-babble » ed_uk, posted by zeugma on December 28, 2005, at 16:26:16
I agree that the preception of a drug can dramatically affect its use. How many people are on a particular drug these days because their doctor told them it worked better?
There are a lot of unsubstantiated opinions out there that frame the way doctors approach drugs.
How do you get people on drugs? The more people who simply try the drug, the more people who will continue taking it. As long as a drug is better than nothing, and widely distributed, it could become sucessfull.
I think that moclobemide is probably not prescribed that much, because it just seems like the "odd one out", with all of the SSRI's about.
Prozac has a name for itself.
Linkadge
Posted by Tomatheus on December 28, 2005, at 21:14:16
In reply to Re: What to do if Nardil and Parnate were discontinued, posted by linkadge on December 28, 2005, at 18:33:24
Linkadge,
My responses are below...
> MAO's could also be targeted towards the cigarette smokers. Parnate could probably get more people off the cigarettes than could say wellbutrin, since smoking is not purely dopaminergic. Tobacco inhibits both MAO A, and B.That might not be such a bad idea. The only problem I see with it is that some smokers might not be willing to give up the forbidden tyramine-containing foods if they're not willing to give up smoking.
> If MAOI's were not as "dangerous", the drug companies could probably do the same with the MAOI's that they did with the SSRI's.
I think you're absolutely right.
> I would argue that the only reason the SSRI's are so widely distributed is reated to their presumed safety. I think that even the notion that MAOI's "only help a small subset of depressed people", is just a drug company attempt to direct us towards the newer SSRI drugs. How do we know that they only help a small subset of the depressed population? They've only been given to a small subset of depressed people. Maybe if they were used first line, remission rates would be higher.
It looks like I wrote my statement regarding the drug companies' lack of interest in helping a small subset of depressed people without thinking of the context I was putting it in. I do think that the drug companies are more interested in making drugs that they can market to large numbers of people than they are in making drugs that would likely only be prescribed to a relatively small number of depressed individuals. And I think you're absolutely correct in stating that MAOIs would help more people if more doctors were to prescribe them.
With respect to the idea that MAOIs only help a small subset of depressed patients, I would actually argue (or perhaps I should say "speculate") that most, if not all, antidepressants only help relatively small percentages of patients -- at least when factors such as the placebo effect and the lack of long-term studies are taken into account. As critics of psychiatry often argue, it's difficult to determine whether or not any given antidepressant actually "helps" depressed patients based on clinical trials that only last four to six weeks. I know that I'm just speculating here, but my guess is that all antidepressants would actually turn out to be effective in less than 50 percent of those with endogenous depressive disorders if an "effective" drug were to be defined as one that produces a clinically significant response in a patient over an extended period of time.
So, I'm not really trying to say that the MAOIs only help a small number of depressives in comparison to the SSRIs. I haven't personaly come across any reserch studies that have directly compared an MAOI with an SSRI, but I would be surprised if such a study hasn't been done. Based on the limited amount of research material that I've read, it seems that the MAOIs would be at least comparable to the SSRIs in terms of their efficacy. After all, judging from meta-analysis data that moclobemide tends to be about equally as effective as the SSRIs but less effective than the irreversible MAOIs (Lotufo-Neto et al., 1999), it would seem that MAOIs might actually be more effective than the SSRIs. So, even though I think that the notion of the MAOIs only being effective in a small subset of depressed patients is somewhat problematic (mostly because a "small subset" can mean a minority as small as 1 percent or something more like 30 percent), I think the bigger problem is the tendency of the drug companies to create the impression that SSRIs are highly effective.
> For all the placebo's I have ingested over the years, parnate was really the only "active drug".
> I won't likely get another shot at an MAOI. No doctor wants to take the "risk"I'm sorry to hear that. :(
Tomatheus
==
REFERENCE
Lotufo-Neto, F., Trivedi, M. Thase, M. E. (1999). Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology, 20, 226-47.
Posted by linkadge on December 29, 2005, at 10:31:45
In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by Tomatheus on December 28, 2005, at 21:14:16
No I know what you are saying.
Not so much based on what you said.
I remember reading about the definition of an MAO inhibitor on a SSRI website (can't recall which one). Basically it tried to give the idea that they were old fashoned drugs, and that the newer SSRI's were safer and more effective.
Linkadge
Go forward in thread:
Psycho-Babble Medication | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.