Reversible and Selective MAOIs in Combination with (S)SRIs: Risk of Serotonin Toxicity

Moclobemide

Summary

Therapeutic doses of Moclobemide combined with any (S)SRI carries a significant risk of potentially fatal serotonin toxicity. This is especially so when multiple pharmaco-kinetic interactions via CYP-450 come into play.

Introduction

Moclobemide definitely confers a risk of severe and fatal serotonin toxicity if combined with (S)SRIs although the history and evidence relating to its interactions is clouded with misleading information, some of it put out by the drug company. This is now largely past history because few people use this drug any more: there seems to be widespread appreciation of the view I promoted decades ago which is that moclobemide is ineffective as an anti-depressant drug. Indeed, I have stated on more than one occasion that those of my colleagues who thought it was an effective antidepressant neither understood depression nor how to treat it. Ridiculous as that might seem more psychiatrists fit into that category than one might imagine. History has proved me to be correct because there is no other reason not to use moclobemide other than it’s ineffectiveness, because it has no significant side effects.

I will re-post my original detailed analysis about moclobemide & ST separately at some later date, the original section in the serotonin toxicity document posted years ago needs tidying up and re-referencing and because it is of ‘historical’ interest to some researchers.

Suffice it to say that even at therapeutic doses, and most definitely following overdoses, one can get quite severe serotonin toxicity reactions and deaths have occurred. I summed it up more than ten years ago in this brief comment (1), see below.

This update and addition to this commentary (March 2015) has been prompted by a discussion that was brought to my attention recently from an Internet site. It may be educative to pick a few themes from this thread to illustrate the perspicacity of the old adage ‘a little knowledge is a dangerous thing’.

http://www.socialanxietysupport.com/forum/f30/moclobemide-ssri-combination-1367249/

An opening comment is ‘This forum is interesting with the amount of information & knowledgeable people here.’ However, remember what Shaw said (2) ‘Beware of false knowledge; it is more dangerous than ignorance.’ The problem for many readers of such forums is the difficulty of distinguishing between real and false knowledge.

From the thread: ‘My personal experience with this was very positive with 20mg Fluoxetine and 150mg Moclobemide. Fluoxetine increases blood levels of Moclobemide so low doses can be used, even though the studies use dosages up to 600mg.’

I will not beat about the bush. The doctor supervising this treatment (if there is one) is putting himself in significant danger of a) being successfully sued by the family, should the patient be unfortunate enough to die, or worse, suffer severe permanent morbidity, b) as well as being in danger of being struck off the medical register.

I am prepared to wager a considerable sum that most psychiatrists would not be able to give an accurate précis of the data I am about to summarise here. This combination of Fluoxetine/Moclobemide is a perfect storm looming on the horizon.

First, there is no doubt that a therapeutic level of any SRI combined with a high therapeutic level, or small overdose, of moclobemide is capable of inducing fatal serotonin toxicity.

Second, moclobemide levels are increased by inhibition of CYP450 2C19 and Moclobemide itself inhibits P450 2D6 (3-8), this can elevate levels to an extent comparable to the levels expected with a small overdose (9).

It is therefore inevitable that in some individuals small changes of blood levels, or dose, of a drug that inhibits P450 could elevate blood levels enough to precipitate ST in someone who previously appeared well and without problems on their previous dosage. These references to cases of ST (10-14) all involved ‘therapeutic’ doses, all are pre 1998. I have not even bothered to retrieve further examples after 1998! Published examples are only the tip of the iceberg, this and personal experience (journal refereeing, medico-legal cases and discussions with colleagues who are toxicologists) indicate that quite a lot of people have been killed by such combinations.

This highlights the importance of understanding that the milligram dose ingested does not always equate consistently and predictably to the concentration of the drug at its site of action. There are many intervening variables which mean that although the same dose is being ingested the concentration of the drug at its site of action can vary by as much as tenfold or even more. There are many doctors who fail to appreciate this and/or forget it, never mind non-medical people searching the Internet. Such people are like innocent children walking through a minefield.

The scenario is an example of what I said above which is ‘a little knowledge is a dangerous thing’ and unfortunately this doctor and his patient are in the category of those who have insufficient knowledge.

Fluoxetine is the worst possible choice for an SSRI to combine with moclobemide (fluvoxamine comes a close second) because it is a potent inhibitor of several cytochrome P-450 enzymes including 2C19, which is responsible for metabolizing moclobemide. In such situations potently inhibiting these enzymes can increase blood levels of drug to the equivalent of those in persons who have taken a small overdose (and thus produce a risk of severe ST). The situation may be further complicated by other drugs in the patient’s regime which affect blood levels of either fluoxetine or moclobemide, because in this particular instance not only will fluoxetine inhibit moclobemide metabolism but also moclobemide will inhibit the metabolism of fluoxetine making it a two-way street. So any other drug which raises blood levels of either fluoxetine or moclobemide (of which there are plenty) can potentially start the snowball rolling.

The chess-like complexity of this situation is yet further magnified by the fact that fluoxetine inhibits its own metabolism and has an unusually long elimination half-life of up to 10 days, thus blood levels can unexpectedly elevate via various mechanisms. All of which justifies my opinion that fluoxetine should have been taken of the market years ago and that doctors who still use it are pharmacological ignorami of an inexcusable sort (see my editorial ‘Drug interactions and fluoxetine: a commentary from a clinician’s perspective (15)). A double dose taken by mistake and various other circumstances might easily lead to a fluoxetine or moclobemide level that unexpectedly becomes considerably higher than usual.

So the ‘personal experience’ mentioned above of one individual (probably over a short period of time) is unhelpful and seriously misleading for the general ‘unscientific’ reader. One hardly needs to point that we are not going to hear the opinions of people who have taken such combinations and died.

It is also stated:

‘You will find multiple papers endorsing this combination, the mainstream view is its dangerous, which is misinformed.’

Leaving aside the hubris of this contributor and the ultracrepidarian tenor of the statement, I trust readers with a more sophisticated understanding of scientific research and literature will appreciate that this is a dangerous and unhelpful statement. It is incorrect. There are only a very small number of published reports of poorly controlled non-blinded ‘studies’ (16-19) involving only small numbers of patients which claimed, naïvely and overoptimistically, that this treatment was helpful and safe. In Hawley’s larger study many of the side effects encountered were rated as ‘severe’ (20) which influenced them to cease further investigation. See below for detailed references which I have discussed in detail elsewhere.

Another commentator hit the nail on the head when he pointed out that these papers were published 20 years ago and have never subsequently been followed up. A cautious enquirer would want to know why these researchers failed to capitalise on this ‘successful’ breakthrough that would have enhanced their reputations and careers. In most instances I can inform readers from first-hand knowledge that this was because the doctors concerned encountered serious problems which they did not report but which discouraged their efforts and because ethical committees (rightly) vetoed further efforts.

Since those reports I have corresponded with all of the relevant researchers one or two of whom failed to respond to, or declined to answer, enquiries about outcome and difficulties, others revealed they had encountered difficulties. Indeed, only a few months ago I again corresponded with Dr Prof Udo Bonnet in Germany whose paper concerning this was widely cited (21) and commented on at the time by me (1). My comment concluded:

“The above data indicates clearly that moclobemide/SRI combinations represent a predictably risky strategy and constitute a balancing act, between efficacy and fatality, of such delicacy as to be unattainable in clinical practice. Moclobemide, if combined with any SRI, produces a significant risk of severe ST and also the possibility of fatalities even with ‘therapeutic’ doses. There is no substantive evidence of significant therapeutic benefit. The current medico-legal climate in most western countries means that an informed Doctor, or ethics committee, would be courageous to sanction any such trials except in very special circumstances.”

In Nov 2014 I asked Prof Bonnet if he had any further views or experience in this field. He did reply and reported that he has not used that treatment since writing that article in 2004. He states he only ever treated half a dozen patients in this way, encountered problems, and confirms that the treatment is officially contraindicated in the German guidelines.

I know of no research centre, reputable or otherwise, that has done work with this combination in the last 15 years.

Next,this thread also states:

He [Gillman] states the same conclusion, this should only be done in low doses. If you go beyond 20mg Fluoxetine for example, you increase the chance of SS quite drastically.

Wrong. This discussion may possibly have life or death consequences for people making decisions as a result of what they have read. This correspondent seems to read the source material carelessly and seriously misrepresents my position. I have never made the statement attributed to me above.

It is not possible to state that some such combination might not be useful, it might be, but it is clear that most of the practitioners who have dabbled in this area do not know enough about pharmaco-kinetics, pharmaco-dynamics or serotonin toxicity to experiment safely. I suspect a lot of ethics committees have agreed with that.

Last, I note one particular curious comment about avoiding this combination in patients who are suicidal. Patients who are potentially going to become suicidal would be the only candidates for this sort of treatment because serious endogenous (drug-responsive) depression, for which such combinations would be the only conceivable indication, may lead periodically to worsening which will possibly entail suicidal thoughts and intent. That fact makes the argument illogical, especially because suicidal thoughts and intent are difficult both to ascertain and to predict.

Caveat lector. Enough said.

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