Posted by djmmm on February 24, 2009, at 6:52:36
Monoamine oxidase inhibitors
All text ©Dr Ken Gillman MRC Psych
http://www.psychotropical.com/maois_full.shtmlThe old monoamine oxidase inhibitors, tranylcypromine and phenelzine, undoubtedly justify retaining a greater place in our treatment armamentarium than they now occupy. As a scientist I recognise the potentially misleading nature of anecdotal evidence. Nevertheless, many patients may be heartened to hear this brief story of the man who, after 20 years treatment with just about every drug in the book from a big city teaching hospital, came to retire (early) to our neck of the woods (Greetings from Tropical North Queensland!), and consulted me. He had been given every b----y SSRI in the book, but had never had MAOIs, easy descision, so I put him on tranylcypromine. At his third visit, six weeks after starting treatment, he stormed into my room looking very animated and banged his fist on my desk very emphatically. Being confident of what he was about to say, I leaned back in my chair and smiled. Some, who have had similar experiences, will be able to guess what he said next: why didnt some bastard put me on this 30 years ago. He found the diet to be no problem, and had less side effects than on any other drug (see (1))(I would not relate that anecdote were it not for the fact that similar scenarios have been played out in my consulting room on many occasions.
Unfamiliarity and ignorance leads to apprehension concerning MAOIs; this is a major factor influencing their low usage. It is doubtless the case that withdrawal of all advertising and promotion about them, contrasted with the immense sums spent on new drugs, exacerbates the disparity.
Psychiatry does not have a good track record in science and the scientific method, especially in relation to pharmacology. The state of many psychiatrists' general knowledge about serotonin syndrome and MAOIs exemplifies that. It is sad and unscientific that one sees frequent references, even in specialist texts, about MAOIs being 'dangerous' drugs. The brainwashing activities of the advertising spin doctors have been so successful that many doctors now believe that there is no debate or argument about the notion that the new drugs are better and safer than all old drugs.
An approximation of the risk to benefit ratio of NSAIDs compared with MAOIs will place things in perspective. This is especially topical and pertinent in view of the recently recognised association between SSRIs and GI bleeding. NSAIDs are mostly used for arthritis which rarely has a fatal outcome. In major depression there is a 10-15% life-time risk of suicide as well as a greatly increased standardised mortality ratio (SMR). Consider the number of deaths from GI bleeds associated with NSAIDs (the figure is 1,200 deaths every year in the United Kingdom (2), not to mention cases of Stevens-Johnson syndrome/toxic epidermal necrolysis (3). Most doctors will have seen quite a few cases. Compare that to the rarity of cerebral bleeds from MAOIs. Most doctors will never ever see, or even hear of, a single case in their entire career. Deaths from MAOI induced hypertension are very rare. It is hard to find many reported in the last 50 years. A search of the whole Pubmed data base returns 67 hits for the keywords fatal + monoamine oxidase inhibitor. Many of these relate to serotonin toxicity, older reports to hepatic toxicity, but not one single report of intra-cranial bleeding. Another possible perspective is to note that fatal cerebral bleeds are documented as a result of the increase in arterial blood pressure secondary to weight lifting (4), which can elevate BP to 480 mm Hg. So, although exact figures for cerebral bleeds are imprecise this comparison puts the matter into perspective. It is abundantly clear that to regard MAOIs as dangerous is not just an over-reaction but also an egregious example of the unscientific and ill informed opinions not uncommon in the psychiatric fraternity.
Monoamine oxidase inhibitors are, for a significant proportion of patients, the most effective but least used drugs in the therapeutic armamentarium of psychiatrists. Despite substantive evidence of their superior effectiveness for various groups of patients (1) research shows that many specialists never use monoamine oxidase inhibitors. The more one contemplates that finding the more regrettable and inappropriate it appears.
Many clinicians are finding that the new MAOI (or 'RIMA'), moclobemide, is not an effective antidepressant; this view is substantiated by some clinical trials which constitute evidence that moclobemide is no more effective than placebo. In my opinion it is totally ineffective, I gave up using it years, no decades, ago. The minimal effect it has on neurotransmitters is detailed in my recent review (5).
Knowing how, and for what, to use monoamine oxidase inhibitors continues to be important for all doctors.
Most patients experience less day to day side effects with tranylcypromine (especially lack of sexual side effects or weight gain) than with either the TCAs or the SSRIs, or other new drugs.
Although monoamine oxidase inhibitors are usually lumpted together in discussions there are many important differences between tranylcypromine and phenelzine. Tranylcypromine is so superior in relation to side effects that, in my opinion, it is difficult to justify the use of phenelzine, in most clinical situations, unless tranylcypromine has been tried first.
MAOIs are of average toxicity in over-dose (6,7).
Differences in side effects between phenelzine and tranylcypromine
Phenelzine is a hydrazine derivative, and tranylcypromine is a non-hydrazine. Hydrazines inactivate vitamin B6 causing deficiency and are also liver toxic which is why most of them were withdrawn from the market.
Phenelzine may be metabolised by acetylation which shows great genetic variation. The possible implication (research is still equivocal) of this is the dose may have to be greatly varied between patients depending on their genetic acetylater status. The data established for the structurally similar drug, isoniazid, is probably a model, particularly for their shared properties of neuropathy and hepatotoxicity (8-12).
A further difference and potential complication is that phenelzine has non-linear pharmacokinetics because it both blocks, and is metabolised by, monoamine oxidase (13-15).
Isoniazid is an inhibitor both CYP2C19 and CYP3A isoforms, this is the likely mechanism by which it slows the elimination of e.g. phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators may be at increased risk for adverse drug interactions, as the degree of inhibition is concentration dependent (16).
Phenelzine also potentiates hypoglycaemia due to a direct influence on gluconeogenesis, related to its hydrazine structure (17-19). Tranylcypromine does not appear to have an adverse effect on diabetes and does not affect gluconeogenesis.
Phenelzine raises brain GABA levels (14), tranylcypromine does not (? related to weight gain).
phenelzine:- marked weight gain, oedema and sedation B6 deficiency are common, tranylcypromine:- No weight gain, both sedation and oedema much less frequent.
The evidence concerning overall side effects indicates that tranylcypromine has sufficient advantages over phenelzine to conclude that it is usually appropriate to save phenelzine as the second choice.
There is evidence that MAOIs are the treatment of choice for some particular types of depression and they can also be effective for panic attacks and migraine.
Note that selegiline, used for Parkinson's, is similar to tranylcypromine, i.e. it is an irreversible MAOI, albeit somewhat selective for the MAO-B sub-type, at least if used in doses not more than 15 mg. It therefore has much the same interaction risks. Although it is selective for MAO-B in low doses, it is still an irreversible MAOI. This means that once it has bound to MAO the enzyme is permanently inactivated and new MAO must be synthesised before activity is restored. This may take up to 40 (forty) days, especially in the elderly (20). If selectivity for MAO-B has been lost then the risk of interactions with serotonin reuptake inhibitors will be similar to tranylcypromine, but an MAOI diet is not required.
In view of the substantial evidence that MAOIs improve Parkinson's disease, hypertension and dementia (and epilepsy) it really is surprising that more psychiatrists do not at least give them a trial in more patients, especially elderly depressives who, not infrequently, tolerate MAOIs better than they do SSRIs or TCAs.
Combinations of different antidepressantsCombinations of different antidepressants are either implicitly or explicitly proscribed by specialist colleges in both Australia and the UK e.g. (21) . The general view, at present, seems to be that there is insufficient evidence such combinations are more effective. Not all experience accords with that, selected combinations may be efficacious. There are some serious risks and pitfalls if you do not have an extensive understanding of psychopharmacology. In view of the prevailing opinion, and the toxicity of some TCA/MAOI combinations, it is wise to avoid initiating such regimes in general practice, and most ordinary psychiatrists have insufficient experience, they should remain in the exclusive domain of experienced psychopharmacologists. Remember, it is quite possible to enter the area of significant mortality risk if you combine different types of antidepressants.
Combinations of MAOIs and TCAs may occasionally be used in specialist practice; but not all specialists have sufficient knowledge or experience to do this safely; it is uncertain how much is to be gained from the technique. The main danger is serotonin syndrome which can be fatal. This is likely to be caused by:-- MAOIs (including RIMAs such as moclobemide) when they are combined with 'SSRIs', or any TCA which is also a serotonin reuptake inhibitor (SRI) i.e. clomipramine and imipramine. Dual action drugs are also dangerous viz. venlafaxine, sibutramine or milnacipran (see other serotonin toxicity notes for details). TCAs that are essentially only noradrenaline reuptake inhibitors, which is in fact most of them-- see (5) are quite safe when combined with MAOIs. So adding a small dose of amitriptyline, nortriptyline or doxepin to improve sleep (via H1 blockade, and perhaps 5-HT2A/C blockade) in a patient on MAOIs is most unlikely to cause any major side effect problems and does not give rise to any risk of serotonin syndrome.
Combinations of MAOIs and TCAs got a bad name in the sixties because imipramine was used. It occasionally proved to have enough activity as an serotonin reuptake inhibitor to cause serotonin toxicity (serotonin syndrome). Such reactions were not then understood. Serotonin toxicity reactions were sometimes wrongly interpreted as hypertensive reactions. Many current pharmacological texts still get all this wrong by mixing up serotonin syndrome and tyramine induced hypertension. The irony is that mixing a TCA (one which is not also an SRI) with an MAOI makes it safer! This is because the cheese reaction (potentially catastrophic hypertension) requires that the provoking dietary component (the amino acid tyramine) must first enter the pre-synaptic nerve, from whence it displaces noradrenaline which then mediates the hypertension. Tyramine is actively moved into the pre-synaptic nerve by the very same reuptake mechanism that is blocked by TCAs, which are NRIs.
MAOIs and blood pressureI am sure a survey of psychiatrists would reveal that most think that MAOIs raise the blood pressure. MAOIs are effective hypo-tensive agents. A substantial proportion of hyper-tensive patients who take MAOIs for their depression are able to cease some, or even all, of blood pressure treatments they were previously taking. How and why the oft quoted admonition not to use MAOIs in patients with hypertension arose is utterly opaque to me. The usual pattern of BP change with MAOIs (see figure below) is for a postural drop to occur when the dose is raised to a therapeutic level. Partial or complete acclimatisation to this drop develops over one to three weeks. Regular monitoring of the sitting and standing BP (this is best done immediately on standing, and again after one minute) allows the dose to be adjusted without problematic hypo-tension developing. A significant but not incapacitating degree of hypo-tension indicates that the minimum therapeutic dose has been achieved.
Figure 1
Orthostatic blood pressure changes on MAOI
(This figure is missing at present!)
Standing 1, done immediately on rising from sitting, standing 2 done after 1 minute. Data is illustrative modal values taken from authors computer data base of patient values. Baseline: before treatment, standing BP is slightly higher than sitting (normal response). Day 4, small initial drop with rapid recovery to baseline level; day 7, some recovery but not to baseline and 2nd standing is higher than the 1st; day 11, second standing value lower than first; day 18, degree of postural drop lessening; days 21-28, equilibrium with 2nd standing BP below baseline. If the pattern at day 7 and 11 is like the day 4 pattern then the dose is probably insufficient.
In a small percentage of cases (<5%) one sees brief spontaneous hyper-tension; this usually occurs after the second dose of the day, especially when higher doses are being used. It is very rarely high enough to constitute a significant problem.
I have treated at least one thousand patients with tranylcypromine, but relatively few with phenelzine (probably less than fifty). A vast majority obtain optimal benefit from tranylcypromine in the dose range of 30-50 mg per day, usually given morning and around noon, although taking the second dose later is not always the problem it is usually said to be (re sleep). It should be remembered that at the plasma half-life of tranylcypromine is very short (22), a couple of hours or so, but that this does not have the same implication as it would with other drugs. This is because it forms a an irreversible complex with the enzyme MAO monoamine oxidase, which is permanently taken out of action. Function is only restored by a synthesis of new enzyme for the genetic code. This occurs at the rate of about 5-10 per cent per day. It seems that around 80-90 per cent inhibition is sufficient to produce the clinical effect. Thus, you do not have to be a rocket scientist to realise that it should be possible to miss out tranylcypromine for two or three days without loss of effect. I am disappointed that no one has ever tested this obvious hypothesis in a clinical trial. It would of course tell us something about the mode of action of these drugs, and support or refute, the notion that it works because of inhibition of monoamine oxidase.
One perfectly splendid paper by the neurologists at Toulouse, where I lectured once, did this experiment with the closely related drug selegiline that they were using to treat Parkinsons. It demonstrated what would be expected, that twice-weekly dosing was just as effective at blocking MAO. doses of 5 or 10 mg daily, and of 10 mg given twice weekly, induced a complete inhibition of platelet MAO-B activity (96.0-99.5%) (23) . If only someone could repeat this with tranylcypromine.
'Directly' acting sympathomimetics that are 'safe' are:- adrenaline and noradrenaline. So local anaesthetics with adrenaline are not likely to cause severe hyper-tension. If there is concern in a dental situation and one has to advise a dentist who may be uncertain, either of the facts or of your authority, then the option of using a non-sympathomimetic vaso-constrictor like felypressin is available. Remember that advice about analgesics (eg avoid pethidine etc.) may also be needed (24,25).
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taken from: http://www.psychotropical.com/maois_full.shtml
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