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
poster:OldSchool
thread:94769
URL: http://www.dr-bob.org/babble/20020215/msgs/94769.html