![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 22 of 22. This is the beginning of the thread.
Posted by OldSchool on February 20, 2002, at 9:35:39
Its scandalous that RIMA MAOIs such as Moclobemide are not available in the USA. These drugs have uses in treatment resistant depression and unlike the older irreversible MAOIs they have a good side effect profile. No MAOI diet is required to use them.
Moclobemide, while not as potent as the irreversible MAOIs like Parnate/Nardil/Marplan, it certainly has advantages over the SSRIs. For once, it works on dopamine. While it is mostly selective for MAO-A, you do get small amounts of MAO-B with Moclobemide, which can be useful in treatment resistant depression.
I just dont understand why RIMA MAOIs are not available here...these drugs are available EVERYWHERE else...every single industrialised country in the world has RIMAs.
I found this article on RIMAs...its pretty good.
http://www.mhsource.com/pt/p960623.html
The Canadian Experience with RIMAs
by Russell T. Joffe, M.D.
Psychiatric Times June 1996 Vol. XIII Issue 6
--------------------------------------------------------------------------------
(At press time, Psychiatric Times learned of letters to the editor published in the May 11 issue of Lancet [some months after the following article was written]. The letters have to do with recent findings of serious adverse effects associated with the use of moclobemide, and readers are directed to pages 1329-1330 of Lancet, Vol. 347, No. 9011-Ed.)
In the last six years, several new classes of antidepressants have been introduced into Canada. Among these are the reversible inhibitors of monoamine oxidase (RIMAs), with moclobemide the first drug in this class.The various classes of the new generation of antidepressants, with their comparable efficacy and superior tolerability and safety, clearly have many advantages over the first-generation tricyclic antidepressants and monoamine oxidase inhibitors. Consequently, in Canada these new-generation antidepressant classes, particularly the selective serotonin reuptake inhibitors (SSRIs), have gained increased acceptance as first-line treatments of major depression. In fact, when moclobemide was introduced into Canada in about 1992, the SSRIs, particularly fluoxetine (Prozac), had become established as the most commonly prescribed antidepressants for major depressive disorder.
Moclobemide is a unique antidepressant with distinctive pharmacological features. It is a reversible and selective inhibitor of the enzyme monoamine oxidase A. This enzyme is the subtype of monoamine oxidase, which is responsible for the degradation of serotonin and norepinephrine as well as dopamine, which is also metabolized by monoamine oxidase type B (Nair and coworkers).
Moclobemide has limited effect on monoamine oxidase B and is a very weak reuptake inhibitor of both serotonin and norepinephrine. The properties of reversibility and selectivity of monoamine oxidase A inhibition that are characteristic of moclobemide have important pharmacological and clinical implications. In particular, they have a significant impact on the tyramine pressor effect of the compound. Specifically, the degree of reversibility of a monoamine oxidase inhibitor affects both the potency and the duration of the tyramine pressor effect. The degree of reversibility refers to how "tightly" the drug bonds to the monoamine oxidase. First-generation monoamine oxidase inhibitors bind tightly and are not readily displaced. In contrast, moclobemide is more easily displaced by dietary tyramine, allowing it to be metabolized, thereby avoiding accumulation of this pressor substance.
Tyramine sensitivity is raised by a factor of 10 to 30 by all irreversible monoamine oxidase A inhibitors. However moclobemide, because of its reversibility, is less likely to raise tyramine sensitivity than irreversible monoamine oxidase A inhibitors by a factor of 3 in usual doses and by a factor of approximately 7 to 10 at the highest therapeutic doses (Zimmer).
The clinical consequence of this pharmalogical property is that no dietary restrictions are required when moclobemide is used. Consequently, patients are much more willing to take this drug, compliance is improved and the risk of a "cheese reaction" is substantially reduced. This greater ease of administration removes a major barrier to the use of drugs of the monoamine oxidase inhibitor class. In addition, moclobemide is a relatively safe drug in overdose. Due to its lack of cardiotoxicity, post-marketing surveillance reveals that there are no cases of death reported with moclobemide overdose. Once again, this distinguishes moclobemide from the first-generation monoamine oxidase inhibitors (Hilton and colleagues).
Moclobemide's Efficacy
Moclobemide, in various controlled trials, has been shown to have superior efficacy to placebo and to have comparable efficacy to the tricyclic antidepressants (Angst and colleagues 1995), the first generation of monoamine oxidase inhibitors (Larsen and coworkers; Heinze and coworkers) as well as the selective serotonin reuptake inhibitors such as fluvoxamine (Luvox) (Bougerol and colleagues) and fluoxetine (Williams and coworkers). Despite this clear demonstration of the efficacy of this compound-borne out by our own clinical experience in Canada-this drug rapidly developed the reputation for being less effective than other antidepressants. This was supported by a report from the Danish University Antidepressant Group, which demonstrated chlorimipramine (clomipramine [Anafranil]) to have superior efficacy to moclobemide in a controlled trial. In addition to being regarded as a weaker antidepressant, it was also suggested that moclobemide be reserved for the milder or atypical forms of depression and that in more severe or so-called endogenous cases of the disorder that other antidepressants were preferable to moclobemide.
I believe this reputation of moclobemide as a weaker antidepressant than others is undeserved and is not supported by either research data or clinical experience. In fact, the data suggest the contrary. In three different meta-analyses performed by Angst and collaborators (1993) the efficacy of moclobemide is documented across a range of subtypes and degrees of severity of major depressive disorder. Moclobemide is equally effective in mild, moderate and severe depression. Moclobemide is no more or less effective in depression marked by psychomotor retardation or agitation nor in major depression with atypical features. The notion that moclobemide may be a weaker antidepressant appears to be an artifact of the dosage used in particular studies.
The studies which conclude that moclobemide is a weak antidepressant generally use doses lower than 400 mg per day. Studies in which moclobemide is used in doses in excess of 400 mg per day consistently demonstrate efficacy superior to placebo and comparable to other antidepressants. In doses below 400 mg per day, moclobemide efficacy is much more equivocal. The literature (Angst and Stabl) and our own clinical experience suggest that a minimum of 450 mg per day and usually 600 mg per day is required for optimal antidepressant response. Moclobemide is approved for use in Canada in the dose range of 300 to 600 mg per day. It has been suggested that lower doses in the range of 300 mg per day may be sufficient for milder depression whereas higher doses in the range of 600 mg per day are more effective for severe depression. This recommendation is not supported by the data.
Our clinical experience has been to use doses between 450 and 900 mg per day and, in rare cases, to even exceed this upper dose range and use doses up to 1200 mg per day. At doses above 600 mg per day, side effects, particularly those resulting from psychomotor stimulation, may increase in frequency. However, moclobemide still has a very favorable side effect profile when compared to other new-generation antidepressants such as the SSRIs and of course the tricyclics as well as the first-generation MAOIs.
Considering Side Effects
Gastrointestinal symptoms, headache and dizziness are commonly reported with moclobemide (Hilton and others), but generally the side-effect burden is very favorable with moclobemide even when compared with other new-generation antidepressants. In particular, moclobemide may be less likely to cause sexual dysfunction, a side effect commonly reported with other classes of new-generation antidepressants.
As previously noted, moclobemide can be used without any dietary restrictions, considerably increasing ease of use. Furthermore, drug interactions are less common with moclobemide than with the first-generation monoamine oxidase inhibitors. Use of moclobemide with sympathomimetic agents is not necessarily contraindicated, although there may still be a serious drug interaction with synthetic narcotics such as meperidine (Demerol) (Nair and others). One of the great advantages of moclobemide over the older MAOIs is its greater flexibility in use with the other classes of antidepressants. The first-generation MAOIs have to be used with caution with the tricyclics and are absolutely contraindicated with the SSRIs. In contrast, moclobemide can even be added to tricyclics (Korn and colleagues). Furthermore, the combination of moclobemide and SSRIs has been shown to be effective and well-tolerated in selected cases of refractory depression (Joffe and coworkers), although these data are preliminary and do not suggest that this combination is safe for general use. Furthermore, the current package insert guidelines for the drug in Canada specify that moclobemide should not be used in combination with selective serotonin reuptake inhibitors.
(Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide -clomipramine overdoses have been reported however. See Neuvonen PJ, et al. Lancet. 1993;342[8884]:1419-Ed.)
The major problem with moclobemide is that it was introduced into Canada several years after the selective serotonin reuptake inhibitors became available. The SSRIs rapidly established themselves as first-line treatment for depression because of their comparable efficacy and greater tolerability and safety as compared to first-generation antidepressants. The role of moclobemide relative to these newer antidepressants has not been clarified. Although a strong case can be made for its use as a first-line treatment, it is my impression that it has generally not been used as such. This is more likely a consequence of its having been introduced into the market after the SSRIs had become well-established and gained widespread acceptance rather than because of any of its clinical features. Although moclobemide has comparable efficacy and tolerability to SSRIs in controlled trials (Bougerol and coworkers; Williams and others), these studies do not assist in deciding the relative advantages or disadvantages of moclobemide over other new-generation antidepressants in a particular patient or clinical situation.
Further studies are necessary to clarify the role of different classes of antidepressants as first-line treatments for major depressive disorder and its subtypes. It is important to note, also, that moclobemide is not a direct substitute for the first-generation MAOIs such as phenelzine (Nardil) or tranylcypromine (Parnate). In controlled studies moclobemide has been shown to have comparable efficacy to the first-generation monoamine oxidase inhibitors (Larsen and colleagues; Heinze and colleagues). Furthermore, it is free of dietary precautions and therefore can be used with greater ease and safety by both psychiatrists and family physicians. However, in individual patients, moclobemide is not necessarily a successful substitute for one of the first-generation MAOIs. It has been our experience that if phenelzine or tranylcypromine is substituted with moclobemide, relapse of depressive symptoms may occur. Furthermore, in such patients, when the original MAOI is reintroduced after discontinuation of moclobemide, remission of symptoms occurs.
In summary, moclobemide is the first drug of a new class of antidepressants. It is effective across a broad range of depressive symptoms and is well-tolerated. Drug interactions are not a major problem with moclobemide and the lack of dietary restriction makes for ease of administration. Its place among the antidepressant options currently available requires further clarification.
Dr. Joffe is professor and chair of the department of psychiatry at McMaster University, Hamilton, Ont. He is also psychiatrist-and-chief at Hamilton Psychiatric Hospital, one of the affiliated psychiatric teaching hospitals of McMaster University.Old School
Posted by fachad on February 20, 2002, at 10:33:02
In reply to Why isnt Moclobemide available in the USA?, posted by OldSchool on February 20, 2002, at 9:35:39
That's a very easy question to answer. I actually got the chance to pose that question "off the record" to someone from Roche (the company that makes Moclobemide)a few years ago.
It's all about the $$.
The drug companies look at the cost to bring a product to market, which in the US is very high due to red tape surrounding the FDA requirements.
Then they look at the potential market share that could be captured by that drug, and the revenue it would bring in.
Basically, the idea is that the US psych drug market place is already saturated with ADs, and the return on investment would not be quick enough to justify spending the money to make Moclobemide available in the US.
We should never forget that the whole psyco-pharmaceutical industry is a for-profit business, and that their objectives are focused on profitabiltiy and high dividends to stockholders, not on our well being or response to their products.
Sorry to sound so cynical, but it's the way things are in the real world.
Posted by IsoM on February 20, 2002, at 11:31:14
In reply to Re: Why isnt Moclobemide available in the USA? » OldSchool, posted by fachad on February 20, 2002, at 10:33:02
Posted by jay on February 22, 2002, at 2:46:58
In reply to Why isnt Moclobemide available in the USA?, posted by OldSchool on February 20, 2002, at 9:35:39
Moclobemide, which I have taken here in Canada, just doesn't seem to cut it as an a.d. In honesty, all's it really felt like was that I had taken a strong cup of coffee when I took it. In the monograph, it also states that Moclobemide should be used with caution in those who are in "aggitated/aggressive" states.I couldn't stand it for long, but that doesn't mean it doesn't work. Mind you, it seems to be a very unpopular drug here. My p.doc even jokingly refered to it as St. John's Wort x20. It doesn't seem to have the more calming and easing effects of other a.ds.
Just IMHO..
Jay
> Its scandalous that RIMA MAOIs such as Moclobemide are not available in the USA. These drugs have uses in treatment resistant depression and unlike the older irreversible MAOIs they have a good side effect profile. No MAOI diet is required to use them.
>
> Moclobemide, while not as potent as the irreversible MAOIs like Parnate/Nardil/Marplan, it certainly has advantages over the SSRIs. For once, it works on dopamine. While it is mostly selective for MAO-A, you do get small amounts of MAO-B with Moclobemide, which can be useful in treatment resistant depression.
>
> I just dont understand why RIMA MAOIs are not available here...these drugs are available EVERYWHERE else...every single industrialised country in the world has RIMAs.
>
> I found this article on RIMAs...its pretty good.
>
> http://www.mhsource.com/pt/p960623.html
>
> The Canadian Experience with RIMAs
> by Russell T. Joffe, M.D.
> Psychiatric Times June 1996 Vol. XIII Issue 6
>
>
> --------------------------------------------------------------------------------
> (At press time, Psychiatric Times learned of letters to the editor published in the May 11 issue of Lancet [some months after the following article was written]. The letters have to do with recent findings of serious adverse effects associated with the use of moclobemide, and readers are directed to pages 1329-1330 of Lancet, Vol. 347, No. 9011-Ed.)
> In the last six years, several new classes of antidepressants have been introduced into Canada. Among these are the reversible inhibitors of monoamine oxidase (RIMAs), with moclobemide the first drug in this class.
>
> The various classes of the new generation of antidepressants, with their comparable efficacy and superior tolerability and safety, clearly have many advantages over the first-generation tricyclic antidepressants and monoamine oxidase inhibitors. Consequently, in Canada these new-generation antidepressant classes, particularly the selective serotonin reuptake inhibitors (SSRIs), have gained increased acceptance as first-line treatments of major depression. In fact, when moclobemide was introduced into Canada in about 1992, the SSRIs, particularly fluoxetine (Prozac), had become established as the most commonly prescribed antidepressants for major depressive disorder.
>
> Moclobemide is a unique antidepressant with distinctive pharmacological features. It is a reversible and selective inhibitor of the enzyme monoamine oxidase A. This enzyme is the subtype of monoamine oxidase, which is responsible for the degradation of serotonin and norepinephrine as well as dopamine, which is also metabolized by monoamine oxidase type B (Nair and coworkers).
>
> Moclobemide has limited effect on monoamine oxidase B and is a very weak reuptake inhibitor of both serotonin and norepinephrine. The properties of reversibility and selectivity of monoamine oxidase A inhibition that are characteristic of moclobemide have important pharmacological and clinical implications. In particular, they have a significant impact on the tyramine pressor effect of the compound. Specifically, the degree of reversibility of a monoamine oxidase inhibitor affects both the potency and the duration of the tyramine pressor effect. The degree of reversibility refers to how "tightly" the drug bonds to the monoamine oxidase. First-generation monoamine oxidase inhibitors bind tightly and are not readily displaced. In contrast, moclobemide is more easily displaced by dietary tyramine, allowing it to be metabolized, thereby avoiding accumulation of this pressor substance.
>
> Tyramine sensitivity is raised by a factor of 10 to 30 by all irreversible monoamine oxidase A inhibitors. However moclobemide, because of its reversibility, is less likely to raise tyramine sensitivity than irreversible monoamine oxidase A inhibitors by a factor of 3 in usual doses and by a factor of approximately 7 to 10 at the highest therapeutic doses (Zimmer).
>
> The clinical consequence of this pharmalogical property is that no dietary restrictions are required when moclobemide is used. Consequently, patients are much more willing to take this drug, compliance is improved and the risk of a "cheese reaction" is substantially reduced. This greater ease of administration removes a major barrier to the use of drugs of the monoamine oxidase inhibitor class. In addition, moclobemide is a relatively safe drug in overdose. Due to its lack of cardiotoxicity, post-marketing surveillance reveals that there are no cases of death reported with moclobemide overdose. Once again, this distinguishes moclobemide from the first-generation monoamine oxidase inhibitors (Hilton and colleagues).
>
> Moclobemide's Efficacy
>
> Moclobemide, in various controlled trials, has been shown to have superior efficacy to placebo and to have comparable efficacy to the tricyclic antidepressants (Angst and colleagues 1995), the first generation of monoamine oxidase inhibitors (Larsen and coworkers; Heinze and coworkers) as well as the selective serotonin reuptake inhibitors such as fluvoxamine (Luvox) (Bougerol and colleagues) and fluoxetine (Williams and coworkers). Despite this clear demonstration of the efficacy of this compound-borne out by our own clinical experience in Canada-this drug rapidly developed the reputation for being less effective than other antidepressants. This was supported by a report from the Danish University Antidepressant Group, which demonstrated chlorimipramine (clomipramine [Anafranil]) to have superior efficacy to moclobemide in a controlled trial. In addition to being regarded as a weaker antidepressant, it was also suggested that moclobemide be reserved for the milder or atypical forms of depression and that in more severe or so-called endogenous cases of the disorder that other antidepressants were preferable to moclobemide.
>
> I believe this reputation of moclobemide as a weaker antidepressant than others is undeserved and is not supported by either research data or clinical experience. In fact, the data suggest the contrary. In three different meta-analyses performed by Angst and collaborators (1993) the efficacy of moclobemide is documented across a range of subtypes and degrees of severity of major depressive disorder. Moclobemide is equally effective in mild, moderate and severe depression. Moclobemide is no more or less effective in depression marked by psychomotor retardation or agitation nor in major depression with atypical features. The notion that moclobemide may be a weaker antidepressant appears to be an artifact of the dosage used in particular studies.
>
> The studies which conclude that moclobemide is a weak antidepressant generally use doses lower than 400 mg per day. Studies in which moclobemide is used in doses in excess of 400 mg per day consistently demonstrate efficacy superior to placebo and comparable to other antidepressants. In doses below 400 mg per day, moclobemide efficacy is much more equivocal. The literature (Angst and Stabl) and our own clinical experience suggest that a minimum of 450 mg per day and usually 600 mg per day is required for optimal antidepressant response. Moclobemide is approved for use in Canada in the dose range of 300 to 600 mg per day. It has been suggested that lower doses in the range of 300 mg per day may be sufficient for milder depression whereas higher doses in the range of 600 mg per day are more effective for severe depression. This recommendation is not supported by the data.
>
> Our clinical experience has been to use doses between 450 and 900 mg per day and, in rare cases, to even exceed this upper dose range and use doses up to 1200 mg per day. At doses above 600 mg per day, side effects, particularly those resulting from psychomotor stimulation, may increase in frequency. However, moclobemide still has a very favorable side effect profile when compared to other new-generation antidepressants such as the SSRIs and of course the tricyclics as well as the first-generation MAOIs.
>
> Considering Side Effects
>
> Gastrointestinal symptoms, headache and dizziness are commonly reported with moclobemide (Hilton and others), but generally the side-effect burden is very favorable with moclobemide even when compared with other new-generation antidepressants. In particular, moclobemide may be less likely to cause sexual dysfunction, a side effect commonly reported with other classes of new-generation antidepressants.
>
> As previously noted, moclobemide can be used without any dietary restrictions, considerably increasing ease of use. Furthermore, drug interactions are less common with moclobemide than with the first-generation monoamine oxidase inhibitors. Use of moclobemide with sympathomimetic agents is not necessarily contraindicated, although there may still be a serious drug interaction with synthetic narcotics such as meperidine (Demerol) (Nair and others). One of the great advantages of moclobemide over the older MAOIs is its greater flexibility in use with the other classes of antidepressants. The first-generation MAOIs have to be used with caution with the tricyclics and are absolutely contraindicated with the SSRIs. In contrast, moclobemide can even be added to tricyclics (Korn and colleagues). Furthermore, the combination of moclobemide and SSRIs has been shown to be effective and well-tolerated in selected cases of refractory depression (Joffe and coworkers), although these data are preliminary and do not suggest that this combination is safe for general use. Furthermore, the current package insert guidelines for the drug in Canada specify that moclobemide should not be used in combination with selective serotonin reuptake inhibitors.
>
> (Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide -clomipramine overdoses have been reported however. See Neuvonen PJ, et al. Lancet. 1993;342[8884]:1419-Ed.)
>
> The major problem with moclobemide is that it was introduced into Canada several years after the selective serotonin reuptake inhibitors became available. The SSRIs rapidly established themselves as first-line treatment for depression because of their comparable efficacy and greater tolerability and safety as compared to first-generation antidepressants. The role of moclobemide relative to these newer antidepressants has not been clarified. Although a strong case can be made for its use as a first-line treatment, it is my impression that it has generally not been used as such. This is more likely a consequence of its having been introduced into the market after the SSRIs had become well-established and gained widespread acceptance rather than because of any of its clinical features. Although moclobemide has comparable efficacy and tolerability to SSRIs in controlled trials (Bougerol and coworkers; Williams and others), these studies do not assist in deciding the relative advantages or disadvantages of moclobemide over other new-generation antidepressants in a particular patient or clinical situation.
>
> Further studies are necessary to clarify the role of different classes of antidepressants as first-line treatments for major depressive disorder and its subtypes. It is important to note, also, that moclobemide is not a direct substitute for the first-generation MAOIs such as phenelzine (Nardil) or tranylcypromine (Parnate). In controlled studies moclobemide has been shown to have comparable efficacy to the first-generation monoamine oxidase inhibitors (Larsen and colleagues; Heinze and colleagues). Furthermore, it is free of dietary precautions and therefore can be used with greater ease and safety by both psychiatrists and family physicians. However, in individual patients, moclobemide is not necessarily a successful substitute for one of the first-generation MAOIs. It has been our experience that if phenelzine or tranylcypromine is substituted with moclobemide, relapse of depressive symptoms may occur. Furthermore, in such patients, when the original MAOI is reintroduced after discontinuation of moclobemide, remission of symptoms occurs.
>
> In summary, moclobemide is the first drug of a new class of antidepressants. It is effective across a broad range of depressive symptoms and is well-tolerated. Drug interactions are not a major problem with moclobemide and the lack of dietary restriction makes for ease of administration. Its place among the antidepressant options currently available requires further clarification.
>
>
> Dr. Joffe is professor and chair of the department of psychiatry at McMaster University, Hamilton, Ont. He is also psychiatrist-and-chief at Hamilton Psychiatric Hospital, one of the affiliated psychiatric teaching hospitals of McMaster University.
>
> Old School
Posted by Elizabeth on February 23, 2002, at 19:42:37
In reply to Re: Why isnt Moclobemide available in the USA? » OldSchool, posted by jay on February 22, 2002, at 2:46:58
> Moclobemide, which I have taken here in Canada, just doesn't seem to cut it as an a.d.
This is consistent with most of what I've heard: it seems that (in actual practice, as opposed to clinical trials -- for whatever reason, the results of trials don't always bear out in real life) moclobemide is a decent first-line antidepressant, but it isn't that great for depressives who've failed to respond to many other treatments (that is, the treatment-resistant). Its mechanism of reversible (competitive) binding to the MAO-A isoenzyme doesn't compare favorably with the irreversible inhibition of both MAO-A and MAO-B in terms of efficacy, although it does have the advantage that the moclobemide can be displaced by tyramine so that food-drug interactions are unlikely.
Moclobemide also has its own side effects -- agitation, headache seems to be very common -- and many patients do have a hard time tolerating it. I also think its tolerability is questionable: sometimes it's comparable to the SSRIs, but it's quite a bit more likely to cause potentially dangerous side effects (as opposed to simply unpleasant ones) than the SSRIs are. This makes a big difference.
It might well be that the reported lack of efficacy of moclobemide results from insufficient doses (I think the same may be true of Buspar), but if this is true, then tolerability at effective doses would likely be worse than has been reported. Agitation -- quite common with moclobemide -- is a serious side effect in depressed people, since agitated depression is often associated with suicidality. There are of course other side effects, but agitation is very common, and the other side effects are unpleasant but not dangerous. The lack of sexual side effects is a plus, but moclobemide is hardly unique in this regard.
I think that if you want to take a dopaminergic AD without dietary restrictions, low-dose (5-10 mg) selegiline would be a better choice. (I'm not convinced that there's any way to predict what neurotransmitter needs to be targeted in the treatment of any individual with depression.)
As to the reason why moclobemide wasn't marketed in the USA: Roche decided it wasn't worth it because the market here was already flooded, of course.
Personally, I haven't heard any success stories from people with TRD who tried moclobemide. But if you really want to see how moclobemide works for you, you can arrange to get it from Canada. I don't know the exact procedure, but I do know that it's 100% legal. Ask your pdoc about it if you're interested; he ought to be able to figure out what to do, if he agrees that moclobemide would be a good thing for you to try.
-elizabeth
Posted by JohnX2 on February 23, 2002, at 23:20:40
In reply to Why isnt Moclobemide available in the USA?, posted by OldSchool on February 20, 2002, at 9:35:39
I talked to a nurse at Roche Pharmaceuticals
to inquire about obtaining moclobemide and asked
why it wasn't made available in the US. She seemed
to indicate that it purely was for marketing reasons.
It seemed to be more because of the stigma associated
with MAO inhibitors and the tyramine effect depite the RIMA
mode of action in Manerix. The huge cost to get get moclobemide
approved and marketed in the US and given the current market conditions
and misconceptions regarding the dangers of such medications
did not warrant a good invest from a risk/reward stand point.
Sad.-John
> Its scandalous that RIMA MAOIs such as Moclobemide are not available in the USA. These drugs have uses in treatment resistant depression and unlike the older irreversible MAOIs they have a good side effect profile. No MAOI diet is required to use them.
>
> Moclobemide, while not as potent as the irreversible MAOIs like Parnate/Nardil/Marplan, it certainly has advantages over the SSRIs. For once, it works on dopamine. While it is mostly selective for MAO-A, you do get small amounts of MAO-B with Moclobemide, which can be useful in treatment resistant depression.
>
> I just dont understand why RIMA MAOIs are not available here...these drugs are available EVERYWHERE else...every single industrialised country in the world has RIMAs.
>
> I found this article on RIMAs...its pretty good.
>
> http://www.mhsource.com/pt/p960623.html
>
> The Canadian Experience with RIMAs
> by Russell T. Joffe, M.D.
> Psychiatric Times June 1996 Vol. XIII Issue 6
>
>
> --------------------------------------------------------------------------------
> (At press time, Psychiatric Times learned of letters to the editor published in the May 11 issue of Lancet [some months after the following article was written]. The letters have to do with recent findings of serious adverse effects associated with the use of moclobemide, and readers are directed to pages 1329-1330 of Lancet, Vol. 347, No. 9011-Ed.)
> In the last six years, several new classes of antidepressants have been introduced into Canada. Among these are the reversible inhibitors of monoamine oxidase (RIMAs), with moclobemide the first drug in this class.
>
> The various classes of the new generation of antidepressants, with their comparable efficacy and superior tolerability and safety, clearly have many advantages over the first-generation tricyclic antidepressants and monoamine oxidase inhibitors. Consequently, in Canada these new-generation antidepressant classes, particularly the selective serotonin reuptake inhibitors (SSRIs), have gained increased acceptance as first-line treatments of major depression. In fact, when moclobemide was introduced into Canada in about 1992, the SSRIs, particularly fluoxetine (Prozac), had become established as the most commonly prescribed antidepressants for major depressive disorder.
>
> Moclobemide is a unique antidepressant with distinctive pharmacological features. It is a reversible and selective inhibitor of the enzyme monoamine oxidase A. This enzyme is the subtype of monoamine oxidase, which is responsible for the degradation of serotonin and norepinephrine as well as dopamine, which is also metabolized by monoamine oxidase type B (Nair and coworkers).
>
> Moclobemide has limited effect on monoamine oxidase B and is a very weak reuptake inhibitor of both serotonin and norepinephrine. The properties of reversibility and selectivity of monoamine oxidase A inhibition that are characteristic of moclobemide have important pharmacological and clinical implications. In particular, they have a significant impact on the tyramine pressor effect of the compound. Specifically, the degree of reversibility of a monoamine oxidase inhibitor affects both the potency and the duration of the tyramine pressor effect. The degree of reversibility refers to how "tightly" the drug bonds to the monoamine oxidase. First-generation monoamine oxidase inhibitors bind tightly and are not readily displaced. In contrast, moclobemide is more easily displaced by dietary tyramine, allowing it to be metabolized, thereby avoiding accumulation of this pressor substance.
>
> Tyramine sensitivity is raised by a factor of 10 to 30 by all irreversible monoamine oxidase A inhibitors. However moclobemide, because of its reversibility, is less likely to raise tyramine sensitivity than irreversible monoamine oxidase A inhibitors by a factor of 3 in usual doses and by a factor of approximately 7 to 10 at the highest therapeutic doses (Zimmer).
>
> The clinical consequence of this pharmalogical property is that no dietary restrictions are required when moclobemide is used. Consequently, patients are much more willing to take this drug, compliance is improved and the risk of a "cheese reaction" is substantially reduced. This greater ease of administration removes a major barrier to the use of drugs of the monoamine oxidase inhibitor class. In addition, moclobemide is a relatively safe drug in overdose. Due to its lack of cardiotoxicity, post-marketing surveillance reveals that there are no cases of death reported with moclobemide overdose. Once again, this distinguishes moclobemide from the first-generation monoamine oxidase inhibitors (Hilton and colleagues).
>
> Moclobemide's Efficacy
>
> Moclobemide, in various controlled trials, has been shown to have superior efficacy to placebo and to have comparable efficacy to the tricyclic antidepressants (Angst and colleagues 1995), the first generation of monoamine oxidase inhibitors (Larsen and coworkers; Heinze and coworkers) as well as the selective serotonin reuptake inhibitors such as fluvoxamine (Luvox) (Bougerol and colleagues) and fluoxetine (Williams and coworkers). Despite this clear demonstration of the efficacy of this compound-borne out by our own clinical experience in Canada-this drug rapidly developed the reputation for being less effective than other antidepressants. This was supported by a report from the Danish University Antidepressant Group, which demonstrated chlorimipramine (clomipramine [Anafranil]) to have superior efficacy to moclobemide in a controlled trial. In addition to being regarded as a weaker antidepressant, it was also suggested that moclobemide be reserved for the milder or atypical forms of depression and that in more severe or so-called endogenous cases of the disorder that other antidepressants were preferable to moclobemide.
>
> I believe this reputation of moclobemide as a weaker antidepressant than others is undeserved and is not supported by either research data or clinical experience. In fact, the data suggest the contrary. In three different meta-analyses performed by Angst and collaborators (1993) the efficacy of moclobemide is documented across a range of subtypes and degrees of severity of major depressive disorder. Moclobemide is equally effective in mild, moderate and severe depression. Moclobemide is no more or less effective in depression marked by psychomotor retardation or agitation nor in major depression with atypical features. The notion that moclobemide may be a weaker antidepressant appears to be an artifact of the dosage used in particular studies.
>
> The studies which conclude that moclobemide is a weak antidepressant generally use doses lower than 400 mg per day. Studies in which moclobemide is used in doses in excess of 400 mg per day consistently demonstrate efficacy superior to placebo and comparable to other antidepressants. In doses below 400 mg per day, moclobemide efficacy is much more equivocal. The literature (Angst and Stabl) and our own clinical experience suggest that a minimum of 450 mg per day and usually 600 mg per day is required for optimal antidepressant response. Moclobemide is approved for use in Canada in the dose range of 300 to 600 mg per day. It has been suggested that lower doses in the range of 300 mg per day may be sufficient for milder depression whereas higher doses in the range of 600 mg per day are more effective for severe depression. This recommendation is not supported by the data.
>
> Our clinical experience has been to use doses between 450 and 900 mg per day and, in rare cases, to even exceed this upper dose range and use doses up to 1200 mg per day. At doses above 600 mg per day, side effects, particularly those resulting from psychomotor stimulation, may increase in frequency. However, moclobemide still has a very favorable side effect profile when compared to other new-generation antidepressants such as the SSRIs and of course the tricyclics as well as the first-generation MAOIs.
>
> Considering Side Effects
>
> Gastrointestinal symptoms, headache and dizziness are commonly reported with moclobemide (Hilton and others), but generally the side-effect burden is very favorable with moclobemide even when compared with other new-generation antidepressants. In particular, moclobemide may be less likely to cause sexual dysfunction, a side effect commonly reported with other classes of new-generation antidepressants.
>
> As previously noted, moclobemide can be used without any dietary restrictions, considerably increasing ease of use. Furthermore, drug interactions are less common with moclobemide than with the first-generation monoamine oxidase inhibitors. Use of moclobemide with sympathomimetic agents is not necessarily contraindicated, although there may still be a serious drug interaction with synthetic narcotics such as meperidine (Demerol) (Nair and others). One of the great advantages of moclobemide over the older MAOIs is its greater flexibility in use with the other classes of antidepressants. The first-generation MAOIs have to be used with caution with the tricyclics and are absolutely contraindicated with the SSRIs. In contrast, moclobemide can even be added to tricyclics (Korn and colleagues). Furthermore, the combination of moclobemide and SSRIs has been shown to be effective and well-tolerated in selected cases of refractory depression (Joffe and coworkers), although these data are preliminary and do not suggest that this combination is safe for general use. Furthermore, the current package insert guidelines for the drug in Canada specify that moclobemide should not be used in combination with selective serotonin reuptake inhibitors.
>
> (Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide -clomipramine overdoses have been reported however. See Neuvonen PJ, et al. Lancet. 1993;342[8884]:1419-Ed.)
>
> The major problem with moclobemide is that it was introduced into Canada several years after the selective serotonin reuptake inhibitors became available. The SSRIs rapidly established themselves as first-line treatment for depression because of their comparable efficacy and greater tolerability and safety as compared to first-generation antidepressants. The role of moclobemide relative to these newer antidepressants has not been clarified. Although a strong case can be made for its use as a first-line treatment, it is my impression that it has generally not been used as such. This is more likely a consequence of its having been introduced into the market after the SSRIs had become well-established and gained widespread acceptance rather than because of any of its clinical features. Although moclobemide has comparable efficacy and tolerability to SSRIs in controlled trials (Bougerol and coworkers; Williams and others), these studies do not assist in deciding the relative advantages or disadvantages of moclobemide over other new-generation antidepressants in a particular patient or clinical situation.
>
> Further studies are necessary to clarify the role of different classes of antidepressants as first-line treatments for major depressive disorder and its subtypes. It is important to note, also, that moclobemide is not a direct substitute for the first-generation MAOIs such as phenelzine (Nardil) or tranylcypromine (Parnate). In controlled studies moclobemide has been shown to have comparable efficacy to the first-generation monoamine oxidase inhibitors (Larsen and colleagues; Heinze and colleagues). Furthermore, it is free of dietary precautions and therefore can be used with greater ease and safety by both psychiatrists and family physicians. However, in individual patients, moclobemide is not necessarily a successful substitute for one of the first-generation MAOIs. It has been our experience that if phenelzine or tranylcypromine is substituted with moclobemide, relapse of depressive symptoms may occur. Furthermore, in such patients, when the original MAOI is reintroduced after discontinuation of moclobemide, remission of symptoms occurs.
>
> In summary, moclobemide is the first drug of a new class of antidepressants. It is effective across a broad range of depressive symptoms and is well-tolerated. Drug interactions are not a major problem with moclobemide and the lack of dietary restriction makes for ease of administration. Its place among the antidepressant options currently available requires further clarification.
>
>
> Dr. Joffe is professor and chair of the department of psychiatry at McMaster University, Hamilton, Ont. He is also psychiatrist-and-chief at Hamilton Psychiatric Hospital, one of the affiliated psychiatric teaching hospitals of McMaster University.
>
> Old School
Posted by Lorraine on February 24, 2002, at 11:04:03
In reply to Re: Why isnt Moclobemide available in the USA? » OldSchool, posted by JohnX2 on February 23, 2002, at 23:20:40
I think Moclobemide works based on my experience. I just had the same problems with heightened anxiety that I get on many meds. I am thinking of going back to Moclobemide with more anxiety tools in my pocket (Klonopin). I just got a US prescription for it and ordered it from a Canadian pharmacy via fax.
Lorraine
Posted by Ray on February 25, 2002, at 0:27:02
In reply to Re: Why isnt Moclobemide available in the USA? » OldSchool, posted by JohnX2 on February 23, 2002, at 23:20:40
The North American studies of moclobomide for Social Phobia showed no statistical benefit. Brofaromine did show moderate benefit though, but that one looks gone for good.
For depression, I'm not sure how well moclobomide works. I tried it and I did not experience any adverse effects except prosexual (yes!), and also I was a bit sweaty and nervous. Trial was too short for only a week and dose normally goes real high for SP whereas I was medium. But at side effect profile seemed consistent with what I read. ie; slightly prosexual, slight anxiety and/or insomnia.
For such a well tolerated antidepressant I would think it would generally be far more popular everywhere everywhere it is available than it is, and that it would be in USA also; if it were highly effective for various types of depression. But I don't know. Just my thoughts...
Ray
> I talked to a nurse at Roche Pharmaceuticals
> to inquire about obtaining moclobemide and asked
> why it wasn't made available in the US. She seemed
> to indicate that it purely was for marketing reasons.
> It seemed to be more because of the stigma associated
> with MAO inhibitors and the tyramine effect depite the RIMA
> mode of action in Manerix. The huge cost to get get moclobemide
> approved and marketed in the US and given the current market conditions
> and misconceptions regarding the dangers of such medications
> did not warrant a good invest from a risk/reward stand point.
> Sad.
>
> -John
>
Posted by JohnX2 on February 25, 2002, at 0:38:10
In reply to Re: Why isnt Moclobemide available in the USA? » JohnX2, posted by Ray on February 25, 2002, at 0:27:02
I just seem to get the impression that the medicine
had the words MAO in it and thats about all that mattered.
Wasn't worth the money to market and educate the public
that MAO did not equate to evil much less the regular
marketing challenges.Even today doctors are stupid, I told 2 doctors that
I took moclobemide , a reversible mao inhibitor, and they
both freaked out and said that they were aweful medicines.
There still is a black cloud hanging out there over those
few tyramine deaths. Doctors think about insurance. Its
the game you know.-John
> The North American studies of moclobomide for Social Phobia showed no statistical benefit. Brofaromine did show moderate benefit though, but that one looks gone for good.
>
> For depression, I'm not sure how well moclobomide works. I tried it and I did not experience any adverse effects except prosexual (yes!), and also I was a bit sweaty and nervous. Trial was too short for only a week and dose normally goes real high for SP whereas I was medium. But at side effect profile seemed consistent with what I read. ie; slightly prosexual, slight anxiety and/or insomnia.
>
> For such a well tolerated antidepressant I would think it would generally be far more popular everywhere everywhere it is available than it is, and that it would be in USA also; if it were highly effective for various types of depression. But I don't know. Just my thoughts...
>
> Ray
>
>
>
> > I talked to a nurse at Roche Pharmaceuticals
> > to inquire about obtaining moclobemide and asked
> > why it wasn't made available in the US. She seemed
> > to indicate that it purely was for marketing reasons.
> > It seemed to be more because of the stigma associated
> > with MAO inhibitors and the tyramine effect depite the RIMA
> > mode of action in Manerix. The huge cost to get get moclobemide
> > approved and marketed in the US and given the current market conditions
> > and misconceptions regarding the dangers of such medications
> > did not warrant a good invest from a risk/reward stand point.
> > Sad.
> >
> > -John
> >
Posted by Elizabeth on February 27, 2002, at 0:58:04
In reply to Re: Moclobemide Efficacy, posted by Lorraine on February 24, 2002, at 11:04:03
Hi Lorraine.
That's great that moclobemide helped you. What was your experience on it, more specifically? I don't hear about too many moclobemide success stories. I'd like to hear in more detail how it helped.
Moclobemide seems like a "hit or miss" drug, you know? Works like a dartboard?
Trying moclobemide again with Klonopin seems like a good idea. Good luck and keep us informed!
-elizabeth
Posted by Lorraine on February 27, 2002, at 10:02:54
In reply to Re: Moclobemide Efficacy » Lorraine, posted by Elizabeth on February 27, 2002, at 0:58:04
Moclobemide worked very quickly--within 4 days I was up and running. It is activating like Parnate. Sleep was very difficult, but then I wasn't taking sleep meds at the time. I had energy, motivation, mood support, no sexual or weight gain side effects. It was just the aggitation and anxiety that drove me nuts. I keep trying to find the balance with it and Neurontin, but Neurontin just wasn't a heavy duty enough anxiolytic to do the job. I have anxiety without the Moclobemide as well but Moclobemide exacerbated it significantly, though not as bad a Wellbutrin, which had me crawling out of my skin. I felt "normal" on the Moclobemide, not dummied down or anything like that. It was easy to get legally with a prescription from the US. I really liked it. But you know me, I am very wierd with meds.
Lorraine
Posted by Lia Mason on February 28, 2002, at 23:42:31
In reply to Re: Moclobemide Efficacy » Elizabeth, posted by Lorraine on February 27, 2002, at 10:02:54
Just my 2 cents...
I did not do well on moclobemide. In all fairness, I was pretty low and depending on a drug to pull me out, not just maintain me. I gave it a good long try, but had to go back to Prozac and its crummy side effects. i found moclobemide very "clean" of side effects, just not effective. But gosh knows everybody's different.
Posted by Lorraine on March 1, 2002, at 10:33:27
In reply to Re: Moclobemide Efficacy, posted by Lia Mason on February 28, 2002, at 23:42:31
Moclobemide shouldn't need a good long trial. I felt it the first day and fully by four days. The good news is that if it doesn't work for you, you don't have to invest months to find out. What dose were you on?
Lorraine
Posted by Lia Mason on March 1, 2002, at 14:42:53
In reply to Re: Moclobemide Efficacy, posted by Lorraine on March 1, 2002, at 10:33:27
I went back into my records. It was a long time ago (1994). It seems I went up to 750 before I stopped.
Posted by Lorraine on March 1, 2002, at 18:31:12
In reply to Re: Moclobemide Efficacy, posted by Lia Mason on March 1, 2002, at 14:42:53
Posted by shelliR on March 3, 2002, at 0:15:43
In reply to Re: Pretty amazing! Def. not drug for you! (nm) » Lia Mason, posted by Lorraine on March 1, 2002, at 18:31:12
Posted by Lorraine on March 4, 2002, at 21:16:53
In reply to Re: What's going on with provigil? (nm) » Lorraine, posted by shelliR on March 3, 2002, at 0:15:43
Shelli:
The Provigil is good. I think it is a good drug because a) it increases motivation, b) it keeps me awake and alert without the high stimulation of ritalin and adderal, c) it has an easy on/easy off aspect--I definately hated coming down from adderall or ritalin, d) it is mildly prosexual, e) it is mildly anti-depressant. Bad news is AGGITATION and ANXIETY. But not as bad as the others and not as bad as selegiline or moclobemide. All the things that work for me cause this. Or maybe I just get aggitated easily and have an anxiety disorder (this I definately do). Anyway, between the Klonopin .75 at night and the neurontin, that was under control pretty much, but why not mess with a good thing? So I am trying to go off the Klonopin (I think I have a nose thing with it--right now have a pretty bad case of sinusitus) (plus hair loss?)(and dysorgasmia--slight) and use buspar instead. Will that work? Haven't a clue, but it sure would be elegant if it did.
It's the same old day by day. I was out of town last weekend and have been sick physically and sort of grouchy. I had my naturalpathic doctor test me for a bunch of viruses and come out positive for them (based on growing them in a petri dish PCR)--HHV6, Ebstein Barr, Cytlomega--all variations of herpes I believe. We have all been exposed to these at one point or another, but in my case, they are active viruses. Also, a test of my natural killer cells showed that although I have enough of them they are not functioning properly. Hence? Hence, what. I don't know. Hence, my immune system sucks b/c I have depression or hence my depression looks a lot like chronic fatigue. Either way, they are just symptom clusters, not actual diseases--or you might say they are diseases of unknown etiology. And, better, yet, noone has a clue how to solve the puzzle for either of these things really.
That said, and acknowledging that I am in a really crappy mood (sinusitus and all), the Provigil seems like it might do the thing for me if I can get the dosage and anti-anxiety stuff together. (No reason to think I can't.)
I am so pleased to hear that you are stable and are on the path to finding the right doctor. Good for you. You are one tough cookie in terms of sticking it out through some hard times. I admire you for that.
Lorraine
Posted by shelliR on March 5, 2002, at 23:01:40
In reply to Re: What's going on with provigil? » shelliR, posted by Lorraine on March 4, 2002, at 21:16:53
Posted by Zo on March 6, 2002, at 0:18:16
In reply to Re: What's going on with provigil? » shelliR, posted by Lorraine on March 4, 2002, at 21:16:53
Somebody is treating active HHV-6. . .the theory being that those of us with CFS feel/are sick when the virus is active. . .like it isn't supposed to be, I guess it's supposed to just lie there dormant, har har.
Have you heard anything about this?
Zo
Posted by BarbaraCat on March 7, 2002, at 19:59:23
In reply to Re: What's going on with provigil? » shelliR, posted by Lorraine on March 4, 2002, at 21:16:53
Lorraine,
Was very interested in your post about HHV-6 since I'm reading The Virus Within about the discovery of HHV-6 and it's implication to aids, chronic fatigue, on and on. I have fibromyalgia and/or chronic fatigue along with (because of?) depression and have felt for a long time that so many of these strange etiologies are virus related. Please keep me posted as to what you find out as far as treatment. I'm not expecting much other than the usual immune support regimen, but your naturopath may have something unique to offer. I didn't know there was a test for all these critters. Hope you're feeling a tad better now. - Barbara
Posted by Lorraine on March 7, 2002, at 20:38:01
In reply to HHV-6 » Lorraine, posted by BarbaraCat on March 7, 2002, at 19:59:23
I think my naturalpathic doctors approach is to look for heavy metals. She herself has chronic fatique and the thing that helped her most was chelation. (I do believe that this is an honest person and not a quack.) I have had 2 tests for heavy metals (hair and cellular), both negative, but when I asked her if we could rule out heavy metals, she said you can never rule them out. She would like to due a heavy metal challenge test with me, but she believes that I am way too weak for that now. So she is working on the immune system with vitamins and MGN3 (which enhances natural killer cell activity). I am also taking alpha lipaic (?) acid which helps detoxify gently. I am thinking that I should think about detoxifying as a long term project and assemble the more gentle supplements for this and perhaps just take them over a one or two year period.
Also I guess gingovocular (something likee that--I mean really who has a brain anymore?) works for HHV6, but it is liver toxic and can only be given intervenously and must be given for the rest of your life. They have recently come out with it in pill form. So I am going to ask her about that. Plus some of the other herpes viruses respond to valtrex. So maybe that would be in order.
Anyway, I will keep you posted. It looks like boosting the immune system is the order of the day (colostrum as well).
Let me know if you hear of anything. I think it is so interesting how they keep saying these herpes viruses (which they all are--HHV6, Epstein Barr and cytameglo virus) are just a nuisance. They can pass the blood brain barrier (at least HSV 1 can) and I just suspect that they are more involved in this stuff than we acknowledge. For instance, they know that people with HSV2 herpes have a higher degree of depression, but they chalk it up to the knowledge of the fact that they have HSV2. Nonsense. It is just a correlational analysis--no causal connection is proven. Let's turn it on it's head and say the HSV2 cuases the depression--what then. HHV6 is implicated with MS and MS is associated with depression as well. Herpes viruses are also associated with chronic fatigue. Same with fibromylagia. All of these conditions are "diseases of unknown etiology"--they are clusters of symptoms (except for MS, which can be diagnosed physically).
We know next to nothing about the brain, viruses, or depression. It's pretty pathetic. Just spouting off I guess.
Keep me posted on your journey as well.
Lorraine
Posted by BarbaraCat on March 8, 2002, at 0:03:33
In reply to Re: HHV-6 » BarbaraCat, posted by Lorraine on March 7, 2002, at 20:38:01
Well, I have been on the detox regimen as well and have been following the work of Paul Cheney, MD who has been on the frontier of CFIDS research. He's been using Immunocal and ImmuneProRx, which are denatured whey protein isolates that work to raise the glutathione levels. The whole glutathione concept is very intriging. Here's a link to one of the talks
www.nutritionadvisor.com/cheneymd.html
I've been using both (very expensive stuff) and I think they're helping. Of course, I've been stuffing myself with every nutritional hocus pocus, started lithium, doing everything I can to feel better, so I can't isolate which one thing is contributing - probably everything together.I'm also concerned with mercury amalgams in tooth filling. Been working at getting all mine replaced. I haven't heard of the products you mentioned, especially MGN2, and will do a search on them. Also, is HSV2 good ol' genital herpes? Funny thing about that since that's another of my woes and always felt it was a major player in my health and depression concerns, but nobody seems to be making the connection. Stay in touch. - Barbara
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