PsychoTropicalResearch, serotonin and serotonin syndrome research.
Serotonin toxicity, serotonin syndrome
Moclobemide in combination with (S)SRIs: risk of serotonin toxicity
Introduction
This essay considers how the pharmaceutical company Roche have represented their drug moclobemide and how this has influenced the perception of doctors, and their ability to understand the limitations and risks associated with moclobemide. This is now largely a lesson in history, because moclobemide is now used so little, presumably because of general recognition of its weak effects, that it may soon fade into obscurity. However, although it is safe by itself, even after large over-doses (it seems that it is very rare for it to cause significant problems), it does contribute to deaths if it is mixed with selective serotonin reuptake inhibitors (SSRIs) or MDMA, ecstasy (3,4-methylenedioxymethamphetamine). In my opinion it is educative to understand how medical training and pharmaceutical companies interact to influence this outcome. It is a highly undesireable outcome and one that persuades me that pharmaceutical companies should cease to have any direct involvement in either education or clinical research. Separation, as suggested by myself, Sotelo and Mansfield must be the preferred option (1-4).
The new MAOI drugs were assigned the epithet RIMAs (reversible inhibitors of monoamine oxidase-A). Moclobemide is the most widely known. They require treating as a special case in relation to serotonin toxicity; particularly moclobemide. This is because much emphasis has been placed on moclobemide’s differences from the old MAOIs— indeed that must be the presumed reason for the marketing decision to re-name them as RIMAs rather than calling them MAOIs. Most doctors were wary of the old MAOI drugs that were frequently (but inappropriately and incorrectly) referred to as ‘dangerous’ (5,6); an image one would not wish to be associated with. Indeed, the way that the pharmaceutical company, Roche, have dealt with the investigation and marketing of moclobemide may be considered as an exemplar of all those factors that make the drug development process what it is today. Also, the slowness which the medical profession have exhibited in understanding the drug and its interactions, and their naivety in accepting partisan data without sufficient critical analysis, is a model for much of what has been amiss in the medical scientific field for decades.
Moclobemide has a usefully reduced tyramine potentiation propensity. That means it does not generally require a tyramine restricted diet which constitutes a significant advantage over the old irreversible MAOIs; or at least it would be an advantage if moclobemide was a good antidepressant, which it is not. Also, the irreversible binding to monoamine oxidase is the reason old irreversible MAOIs take 2-4 weeks to loose their effect (this is the time taken for the body to synthesise new monoamine oxidase from the genome). Moclobemide, being competitive and reversible, has a much shorter duration of action (2-4 hours). This is expected to lessen the severity and duration of any adverse interactions, including serotonin toxicity with SRIs. Lastly moclobemide is selective for monoamine oxidase-A; whereas the old irreversible MAOIs block both monoamine oxidase-A and B (except selegiline- aka deprenyl, and pargyline and clorgyline).
Serotonin toxicity with therapeutic doses of moclobemide (not over-doses) + SRIs has been extensively documented. There are about 25 such cases with doses ranging from 150 mg to 750 mg daily (see below).
The position with the old irreversible MAOIs, although still misunderstood, is clear and incontrovertibly high risk. Doctors who combine the old irreversible MAOIs with any serotonin reuptake inhibitor may be, and probably should be, be considered negligent.
Opinion that it is safe to combine moclobemide with SSRIs has been repeatedly expressed, based on preliminary and incomplete evidence. Moclobemide is the most frequently used MAOI drug, and thus the one most likely to be mixed with an SRI, whether by accident or on purpose.
The CNS Drugs review (Bonnet 2003)
The opinion that the risk benefit ratio for patients may make moclobemide combined with (S)SRIs a reasonable prospect for the treatment of refractory cases of depressive illness continues to be put forward. As recently as 2003 Bonnet suggested:--
“Cases of refractory depression might improve with a combination of moclobemide with other antidepressants, such as clomipramine or a SSRI. Since this combination has rarely (KG’s italics) been associated with a potentially lethal serotonin syndrome, it requires lower entry doses, a slower dose titration and a more careful monitoring of patients.”
Bonnet cited the rather partisan Dingemanse papers (see below) from the makers, Roche, in support of his views. Both Freeman (a former editor of the Brit J Psychiatry who was not a psychopharmacologist at all) and DeBattista have quoted Dingemanse and made similar statements (7,8). Freeman’s view, especially, was expressed at a time when he was clearly unaware of various important facts and it should be disregarded. It shows that even people of Freeman’s principles and stature can be flattered into expressing opinions about subjects of which they know little.
DeBattista et al state, re combining the SSRIs and moclobemide "... moclobemide may hold promise for less problematic drug interactions. Usual therapeutic doses of the SSRIs have generally been well tolerated in combination with moclobemide". They also quote Dingemanse (9,10) in justification of this, but seem to have been unaware of Hawley’s prior work (11,12). They were more cautious in their advocacy of the combination and made appropriate note of the deaths with over-doses.
This is a contentious issue with ethical considerations. One is reminded of the American civil war general who did not think snipers were effective: he raised his head above the parapets and was rudely ‘cut short’ in his ultimate utterance: "Nonsense, they couldn't hit an elephant at this dist...." (13)
I have published a comment on Bonnet’s CNS Drugs review suggesting, inter alia, that these combinations are risky, “The above data indicates clearly that moclobemide/SRI combinations represent a predictably risky strategy” (14), to which Bonnet responded (15) :-- …“Dr. Gillman is correct in emphasizing the danger of SS and the predictive nature of the Hunter criteria, which could help us to identify and treat SS in early stages. It should be realized, however, that the use of a potentially hazardous combination therapy is sometimes unavoidable to overcome the burden of treatment-resistant affective and anxiety disorders. Usually, SS resolves within 24 h after discontinuation of the offending drug(s)”.
I agree about the burden of treatment-resistant affective and anxiety disorders. I agree that treatments regarded by mainstream texts as ‘dangerous’, eg MAOIs + TCAs, are valuable and I use them extensively (according to figures available to me, 10 times more frequently than the ‘average’ psychiatrist). Indeed I have published the opinion that the term ‘dangerous’ is quite inappropriate when used, as it not infrequently is, in association with MAOIs (5).
When describing moclobemide + SSRIs as a ‘predictably risky strategy’ I am not labelling that as dangerous in an absolute sense; but I do wish to emphasise that those who engage in such attempts will serve their patients best if they are as well informed as possible. The apparent level of knowledge about which drugs can be predicted to cause serious and life-threatening toxicity is well illustrated by numerous examples where many researchers, most of them from reputable hospitals and teaching institutions, have gained ethical approval to perform studies that exposed participants to risks that those researchers appear not to have had the knowledge to analyse or to quantify. It is unlikely such studies would have gained ethical approval (or volunteers to participate in them) had a fully informed estimate of the risks been available. It is evident from the citations in the references quoted below that a proportion of these authors were unaware of relevant published material that would and should have allowed them to develop a more critically informed view (10, 12, 16-31).
I am not so positive about the evidence for effectiveness or safety of moclobemide + SSRIs; but I think more work could be done. I am not sure who will do it, I hope they are experienced and well informed about serotonin toxicity.
In 1995 I published the following warning: “Whether or not moclobemide will exhibit the same propensity as the older MAOIs for causing the SS in man is still uncertain… In relation to the serious interactions of moclobemide with SRIs it is notable that, despite reports from 1962 onwards of ‘serotonin syndrome’ in animals, no cases were noted in humans for twenty years, until Insel’s report of 1982 (they certainly ocurred, but were not recognised). It is important to ensure that this mistake is not repeated with moclobemide, SRIs and opioids like meperidine (pethidine)” (32).
I also criticised Freeman’s Lancet review; I was informed that his review generated some angst in the Lancet editorial office, especially since Freeman was not a psychopharmacologists (33). “There are an increasing number of reports of SS; a computer search located 6 in 1991 and 25 in 1995. Some of them were fatalities after overdose, and near fatalities with therapeutic doses; and so it is salutary to observe that some twenty years elapsed between the original animal work on SS, and its recognition in humans. Indeed it is still under recognised and under reported and the mechanism of the interaction poorly appreciated; so much so that a major journal published a drug profile of moclobemide (a reversible inhibitor of MAO A) which said it had no interactions with SSRIs or TCAs, despite a pre-existing report in the same journal.”
I was referring to the report from Neuvonen that Freeman did cite but appears to have discounted, perhaps because they were over-doses? (34). However there were other reports he did not cite and was presumably unaware of (35,36).
In my Biological Psychiatry paper I have summarised my view: “These interactions are complex, especially when phamacokinetic factors influence drug levels, which then have further pharmacodynamic interactions. The misunderstanding of drug interactions played a part in the demise of mixed treatment regimes using the old MAOIs plus TCAs (37,38). Adequate trials of these various combinations have not been undertaken, so valuable data concerning potentially effective treatments may remain undiscovered. Sargent's words from 40 years ago are still worth noting: 'We are never going to learn how to treat depression in an MRC statistician's office' (39). Most current antidepressant agents produce small improvements that require clarification utilizing statistics, but only because the clinical effect is small. Sargent meant that when the treatment effect is large statistics become a refinement, rather than a necessity” (40).
The ‘Dingemanse’ papers
It is important to document this part of the moclobemide story because of the lessons it can teach us about the influence and bias of pharmaceutical companies and how that influences the literature. The view that moclobemide is a safe, and that it may be a useful treatment strategy, when combined with SSRIs, has been promulgated repeatedly in various papers published (mostly) by Roche personnel like Dingemanse. These papers are still being quoted to support this view despite the preliminary nature of the observations, and what has subsequently become a large body of contradictory evidence (as detailed here) (9, 10, 29, 41-43).
The potentially misleading view that there is probably no interaction between SSRIs and moclobemide has been reiterated by Dingemanse most recently in 1998; when the conclusion was offered:--‘Combination treatment with fluoxetine and moclobemide did not provide any indication of development of the serotonin syndrome’.
Most data on moclobemide has been derived from studies using doses of 300-450 mg in normal healthy volunteers; its propensity to cause serotonin toxicity at doses of 600 mg or greater has not been extensively or well studied. In the 1998 Dingemanse paper all subjects selected were cytochrome P450 2D6 extensive metabolisers, tending to make them have lower blood levels and be lower risks for interactions. The authors did not explain or discuss the reason for that odd choice. The period of 5 days on the usual minimum dose of fluoxetine 20 mg, combined with moclobemide 600 mg daily in 12 subjects, does not give confidence in the conclusion the paper offers. Dingemanse’s statement that moclobemide + fluoxetine… ‘did not provide any indication of development of the serotonin syndrome’ is seriously misleading to all but the most sophisticated of readers.
The usual minimum dose of fluoxetine 20 mg daily is frequently exceeded in primary care practice, and doses of 60 mg or more are common in specialist practice. The use of fluoxetine 20 mg daily, in a sample of extensive metabolisers (EMs) of 2D6 dependant drugs, renders the Dingemanse study of diminished value because it is unrepresentative of the clinical situations that will frequently and inevitably occur. There was limited indication of how these important factors might affect the outcome. Because extrapolation from this data to a clinical population is of doubtful scientific validity, this paper will mislead clinicians who are not well informed (i.e. the great majority of clinicians) and who do not read it very critically and carefully. Fluoxetine pharmacokinetics are non-linear, so the frequently used doses of 40-60 mg and more will produce disproportionately higher blood levels and an elevated risk of inducing serotonin toxicity. Also at those levels it will be even more likely to precipitate a pharmacokinetic interaction, thus also elevating moclobemide levels. Dingemanse, using fluoxetine at a dose of only 20 mg, found “markedly elevated moclobemide levels”. Unless contrary evidence becomes available it must be assumed that higher fluoxetine doses will be more risky by virtue of this combined pharmacokinetic and pharmacodynamic interaction. Indeed, pharmacokinetic and pharmacodynamic interactions between moclobemide and fluoxetine serve as a teaching model for educating doctors about importance of these aspects of pharmacology.
This interaction problem is further compounded by the dangerous potential of the long elimination half-life for fluoxetine***, of up to 5 days, and for norfluoxetine up to 20 days. The role of 2D6 in fluoxetine’s elimination is still uncertain; it seems the R and S enantiomers are converted to nor-fluoxetine by 2C19 and 2D6, but the elimination of norfluoxetine, which is active both as an SRI and a cytochrome P450 enzyme inhibitor, is less well elucidated (44-47).
*** dangerous potential of the long elimination half-life of fluoxetine— note, in the first series of deaths (total of 7 deaths) from serotonin toxicity in the fluoxetine trials back in the 1980s some deaths occurred when MAOIs were started more than 30 days after ceasing fluoxetine (17).
Prior to the Dingemanse paper, there had been at least 15 publications, reporting serotonin toxicity with moclobemide and SRIs (up to the end of 1996). Most, but by no means all, were with over-doses (note- Dingemanse paper was accepted October 1997): none of them were cited in the 1998 paper, neither was there any mention or discussion of these extensively documented and serious problems, which included deaths involving moclobemide.
Moclobemide data sheet / PI / MIMS
In my opinion the current warnings in relation to the risk of morbidity and death from serotonin toxicity with moclobemide + (S)SRIs * in the, data sheet / PI / MIMS type texts, is incomplete, potentially misleading and out of date. Firstly, it fails to recognise or explain the link between narcotic analgesics, imipramine / clomipramine, SSRIs and other drugs like sibutramine, being implicated by virtue of their common property of serotonin reuptake inhibition. Secondly, there is insufficient emphasis or explanation of the now established probability of severe side effects blending into serotonin toxicity and fatalities with mixtures of SRIs and MAOIs of all types. Thirdly, there is no adequate description of the now established characteristic features of serotonin toxicity which would facilitate clinicians being able to recognise serotonin toxicity when it occurs. Fourthly, there is inadequate information or guidance about the need for urgent assessment and treatment of symptoms that indicate life-threatening toxicity in relation to the established high risk of severe serotonin toxicity, and the possibility of fatalities, with moclobemide and SRI combinations.
In my opinion this may place companies (Roche with moclobemide, and Pfizer with linezolid, and maybe others) in a weak position to defend themselves if they are sued for damages. The risk of serious adverse effects is now a matter of fact and is beyond any argument; the only question is the extent of that risk. The legal concept of ‘failure to warn’ seems relevant. See http://www.justiceseekers.com/ (48)
It may be noted that some Roche data sheets (PI) contain misleading and contradictory information that indicates a flawed understanding the problem, especially with clomipramine, TCAs and SSRIs. One Roche PI states: ‘In a clinical study designed to test the interaction between MANERIX and a tricyclic antidepressant (clomipramine), severe adverse reactions emerged and the study was terminated. Data involving other tricyclic antidepressants are limited. Consequently, the concomitant use of MANERIX and tricyclic antidepressants is contraindicated. Clinical data are not available on the concomitant use of MANERIX and selective serotonin reuptake inhibitors or conventional MAO inhibitors. Therefore, until such data become available, MANERIX should not be administered in combination with these agents.’
This information is wrong and not in keeping with current knowledge. Also, it is outrageous, unethical and immoral that the ‘severe adverse reactions emerged and the study was terminated (clomipramine)’, ocurred but was never communicated to doctors in any way, or published.
Another Roche data sheet (PI) statement is wrong: ‘Clinical data are not available on the concomitant use of MANERIX and selective serotonin reuptake inhibitors or conventional MAO inhibitors’. That is incorrect. The data from Hawley, analysed in detail herein, incontrovertibly contradicts that.
Serotonin toxicity reports prior to the 1998 Dingemanse paper
For completeness, the serotonin toxicity cases with moclobemide that might have been noted in the Dingemanse paper, are cited below. References up to the end of 1996 (Dingemanse paper was accepted Oct 1997, so I am being generous) (32, 34-36, 49-59).
Systematic data on moclobemide/SRI toxicity
The only systematic data concerning moclobemide/SRI toxicity is from the HATS team of an analysis of 106 moclobemide over-doses from their large data base. There were a total of 106 moclobemide ingestions
- 33-- moclobemide alone, of these 1/33 had ST (52 moclobemide + non-serotonergic drug; no further information given).
- 21-- moclobemide + SSRI. Of these 11/21 had ST. 6 were 'severe' with temp of > 38.5c needing paralysis and intubation.
The above data has now been fully published in peer reviewed form .
The risk with moclobemide (at therapeutic doses) and (S)SRIs combined is almost certainly much lower than with MAOIs like tranylcypromine and (S)SRIs combined. The studies below demonstrate a significant incidence of serotonergic side effects merging into serotonin toxicity, and Hawley discontinued such work because of toxicity concerns (see below) (10, 12, 22-24, 41, 43).
Moclobemide/SRI toxicity compared with MAOI/SRI toxicity
In contrast, Razani, using the same (low) tranylcypromine dose (20 mg) as Oefele, but combining it with amitriptyline, maximum dose 150 mg (a weak SRI), rather than clomipramine (a potent SRI), reported no serotonin toxicity in a four week trial with 20 patients. This accords with many other early studies (see other references) and years of clinical experience. My own is of the treatment of approximately 1000 patients with tranylcypromine, about half of whom have also been administered concurrently amitriptyline, nortriptyline or doxepin with no serotonin toxicity, nor even problems with significant serotonergic side effects (61-74).
Note: HATS contains some instances of combination over-doses with moclobemide + SRIs (see above; = ~ 30 as of 2003) but few of MAOI + SRI, so these are not (yet) amenable to statistical analysis to elucidate the relative risk of MAOI/SRI vs. Moc/SRI.
It seems that the nearly fatal / fatal cases have been more frequent with MAOI/SRI combinations than the Moc/SRI ones, which, although requiring intubation / paralysis ventilation / 5-HT 2A antagonists, may be somewhat less severe. Nevertheless deaths still occur with Moc / SRI combinations.
The pharmacokinetics of moclobemide
Moclobemide shows low affinity competitive, selective and reversible binding to MAO-A with a Ki in the high micro-molar range (200-400 µ mol). In vitro the half-life for reactivation of MAO-A is 90-120 minutes. In rat liver the ED 50 for MAO A and B inhibition are similar (8.4 vs. 6.6 µmol) but in the brain it appears selective for MAO-A (ED 50 7.6 µmol vs. MAO-B 78 µmol) (75, 76).
The pharmacokinetics of moclobemide itself is linear even in over-dose but levels are raised by interactions, eg with fluoxetine. The daily dose of moclobemide has escalated as the experience (or frustration?) of clinicians grows; although 600 mg is the stated maximum, doses of 2400 mg daily are used by some doctors in practice.
Moclobemide: suggested prescriber information / warning for patients
In my opinion the current warnings, in the moclobemide PI / data sheets (various English language ones vary a little), in relation to the risk of serious adverse effects and death from serotonin toxicity with moclobemide, when combined with all types of SRIs, does not adequately reflect the current knowledge and understanding of serotonin toxicity. I therefore suggest that doctors and pharmacists, who prescribe or supply moclobemide, do all they can to ensure that all non-current supplies of moclobemide and serotonin reuptake inhibitors of any sort are not present in the same household, and also to warn people of the serious risks. A child might only have to take a few (3 or 4?) tablets of each to kill themselves, in a rather horrible way.
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All text ©Dr Ken Gillman MRC Psych - PsychoTropical Research®
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