3. Serotonin Toxicity Contrasted with Neuroleptic Malignant Syndrome

The distinction between NMS and ST continues to generate much poorly informed and confused debate in the literature. Why remains a bit of a puzzle, because the evidence is clear that typically they are quite different and usually straightforward to distinguish between.

Fundamental Differences

Before discussing the controversies and misconceptions surrounding this subject it may be best to start by stating what one would consider to be the basics which make it obvious that the two conditions are different. ST has a rapid onset (hours) and progression, it happens exclusively and predictably in association with potently serotonergic drugs, but not with DA antagonists. NMS has a slow onset and progression (hours to days), non-predictably, and only rarely in association with neuroleptics: it also happens in the complete absence of neuroleptics, but notwith typical ‘serotonergic’ drugs like SSRIs. ST is a well delineated and clearly recognisable condition (best called a ‘toxidrome’) showing the signs and symptoms of hyperkinesia (increased physical activity) and increased mood/mental activity with hyperreflexia and marked clonus. Conversely, NMS is defined by bradykinesia (decreased physical activity) and bradyphrenia (slowed mentation) in the absence of clonus, but with fever or hyperpyrexia and extrapyramidal rigidity. ST is clearly a manifestation of toxicity (it is predictable and common with specific drug combinations), whereas NMS is a rare idiosyncratic reaction to essentially normal doses and very rarely occurs after over-doses. That suggests the underlying patho-physiology of the two conditions is very different. This is because ST is clearly linked to the known mechanism of action of the precipitating drugs, whereas NMS is not, and there is no known or established mechanism to explain the possible connection. ST typically resolves rapidly within hours after the cessation of the relevant drugs, depending on their respective half-lives, whereas NMS resolves slowly over some/many days. Also there is a specific effective antidote for ST, 5-HT2A receptor antagonists, whereas NMS tends to improve with Dopamine agonists such as bromocriptine and apomorphine. There is doubt that NMS is unitary syndrome, rather it seems to be a heterogenous collection of symptoms with variable contributing factors and causes (see (1). Indeed, the fact that after 50 years there are still no generally accepted diagnostic criteria (2) probably tells us something important. Furthermore, the course of hyperthermia may be different in the two conditions. In hyperthermic (i.e. > 39°C) serotonin toxicity (which is usually only seen with combinations of MAOI+SRI) body temperature increases rapidly and reaches levels in excess of 40°C and, without aggressive treatment, death from the consequences of hyperthermia is frequent within a few hours. In NMS the temperature increases slowly and infrequently exceeds 39°C (1) and also morbidity and mortality are significant in the absence of serious hyperthermia (1, 3). The usually clinical picture is typically very different. NMS is preceded by increasingly severe Parkinsonian symptoms, often with a severe degree of bradykinesia amounting to immobility, stupor and mutism. Typically suffers are delirious, fearful, prostrate and mute (4). Contrary-wise, the early stages of ST involve excitability, overactivity and can resemble a manic state. In other words, although the vague term ‘changes in mental state’ is used for both conditions, the reality is that the characteristics of these mental state changes are quite different. The excitability often precedes the development of overt neurological symptoms like hyperreflexia and clonus. It is only if, and when, ST reaches the severe state that clonus shades into rigidity , which paralyses chest wall muscles leading to > PaCO2 & the complications that may bring on confusion and coma. Various other symptoms are often recognisably different. For instance, shivering is quite frequent in ST but never occurs in NMS. The tremor in ST tends to be more marked and of the intention type, whereas in NMS it is extra-pyramidal like a typical Parkinsonian tremor. Autonomic instability tends to be rather worse in NMS as does diaphoresis. Tachycardia, flushing and diarrhoea are usually more prominent in ST. Thus, in NMS, bradykinesia and rigidity are prodromal symptoms but in ST bradykinesia does not occur and rigidity (if and when it occurs in severe cases), is a terminal development. The aetiology, progression, symptoms, signs, patho-physiology and treatment response are all quite different and thus we can say confidently that the two conditions are usually clearly distinguishable.

Causation

In my 2010 review of neuroleptic malignant syndrome (1) I compared ST, NMS and malignant hyperthermia (MH), using the Hill criteria for causality. That exercise underlined the tenuous causal connection between neuroleptics and the presumed syndrome of NMS. This is thus an appropriate point at which to observe that NMS is a misnomer, a miss-named entity, because it is: a) not exclusively related to neuroleptics, b) it is not ‘malignant’, and c) it is doubtful that it is valid to regard it as a meaningful syndrome. From Gillman 2010: “Criteria for establishing cause-effect relationships in medical science, established by Sir Austin Bradford Hill (5) have recently been applied in several situations similar to NMS (6, 7) and refinements have been discussed (8, 9). These criteria or considerations are, as initially enumerated by Hill (5): “1) Strength, 2) consistency, 3) specificity, 4) temporality, 5) biological gradient (dose-effect), 6) plausibility, 7) coherence, 8) experiment and 9) analogy” (see references for a more detailed expositions of these points).”

Table 1 Hill Criteria for MH, NMS and ST

Hill CriterionMHNMSST
StrengthStrongWeakStrong
ConsistencyStrongEquivocalStrong
SpecificityStrongAbsentStrong
TemporalityStrongWeakStrong
Biological gradientStrongEquivocalStrong
PlausibilityStrongEquivocalStrong
CoherenceStrongWeakStrong
ExperimentStrongAbsentStrong
AnalogyStrongAbsentStrong
Legend Table 1

The evidence for criteria is rated as: Strong, Equivocal, Weak, or Absent (see Gillman (1) for explanation of ratings). Abbreviations: MH malignant hyperthermia, NMS neuroleptic malignant syndrome, ST serotonin toxicity

Case Reports and Other Publications

Profs Whyte and Buckley and Isbister (professors of toxicology, who look after these kinds of patients regularly in intensive care units), and I, are among the few experts who have published reviews on the subject of both serotonin toxicity and neuroleptic malignant syndrome. We all agree about the clear distinction between these two conditions (10-14). It is probably fair to say that confusion is more prominent among psychiatrists and in psychiatric journals than it is in journals covering neurology or medicine. Over the years various authors have put forward a view that these two conditions are ‘similar’, ‘alike’, share ‘a common [final] pathway’, or are ‘indistinguishable’. However, ignorance of some established facts (as above) and the fallaciousness of the ‘evidence’ on which such propositions are based (poor single cases reports) render these arguments ill-founded and weak. I would say that clinicians who state that ST and NMS are usually ‘indistinguishable’ probably have little or no practical experience of these conditions. Only recently I had a brief correspondence with Steele & Keltner, the authors of a recent paper that suggested ST and NMS are similar (15). Do not forget, this is a complex topic which requires more than a nodding acquaintance with advanced psycho-pharmacology, toxicology etc. as well as significant background clinical experience in medicine, neurology and intensive care medicine. This sort of expertise is usually only accumulated by quite experienced doctors in relevant disciplines. The main author of this particular contribution is Keltner, a professor, not of medicine but of nursing, in the United States of America. I do not intend to deride or belittle Prof Keltner when I suggest that his knowledge and experience in these matters cannot be weighed equally with persons such as Profs Whyte and Buckley, nor indeed myself. However, many people reading this kind of material will not be aware of this distinction, nor of the modest status of the journal in question, nor of the fact that many key references are missing from the paper and that some of the references quoted have been rebutted (although he does not appear to recognise this). The paper contains a number of misconceptions and superficial oversimplifications and I will not unnecessarily expand his commentary by going into them in detail. It is merely sufficient to illustrate the justification for my points above with one example from their table 1 (p. 59) and associated text. Here they compare the features of the two conditions. They highlight that hyperthermia, altered consciousness, motor symptoms, and autonomic instability are shared by both. However that does not indicate there is any meaningful commonality between them, and to imagine so is unscientific. Their term ‘motor symptoms’ is not a precise medical term but a general category covering many different specific symptoms that may occur in many different conditions (e.g. clonus is a ‘motor’ sign, it is highly characteristic of ST but does not occur in NMS). This specific ‘motor’ symptom of clonus that is characteristic of ST is completely different to the motor symptoms that occur in NMS and Parkinson’s disease. To offer this comparison as a justification that they are similar is either naĂŻve, ignorant or a disingenuous obfuscation of the issues. It is a bit like saying it is difficult to tell the difference between cars and trucks because they both have an engine, four wheels and a steering wheel. Their assumptions and logic are patently absurd. Enough said, lets move on.

Accumulated Reports

Here is my collection, over the years, of case reports (mostly dubious) relevant to this discussion, along with published comments, associated material and rebuttals etc. (1, 11, 13-54). This does not claim to be a definitive or all-inclusive list, but it is extensive and will assist any researchers who wish to locate relevant reports, comment and material. Below I will use one or two of them to illustrate what I think are some relevant or important points.

Reports Illustrating Other Salient Points

Prof Max Fink of catatonia fame (55, 56) proposed a general neurotoxic syndrome encompassing both ST and NMS. This was on the basis of one highly unsatisfactory case report (31) which was stated to involve serotonergic drugs and appeared (at least to them) to be indistinguishable from NMS (but reported no proper description of a medical examination of the patient and seemed to be a second-hand report). The drugs being administered were nortriptyline and trazodone and the patient had recently ceased l-Dopa. The data in this report are unreliable and neither nortriptyline nor trazodone are ‘serotonergic’ drugs. It is difficult to understand the rationale of this report and the whole basis and idea is groundless and illogical. They did not even discuss l-dopa withdrawal as a possible precipitator of this NMS-like state, which would be the most parsimonious explanation. This is not competent science and did not deserve publication in a scientific journal. Other authors have picked up this and similar notions and run with them. Fink resurrected his argument (57) in response to a report by Haddow in the BMJ years later (58). This Haddow case is one of the few interesting case reports and illustrates one important and fundamental observation: it is neither logical nor wise to generalise or extrapolate in the case of adverse drug reactions occurring with CNS-active drugs in patients who are known to have significant brain disease, frequently some kind of dementia or brain damage. This is because it is recognised that such patients frequently exhibit exaggerated, atypical and paradoxical responses to CNS drugs. In my research as an expert in serotonin toxicity I have read, reviewed and refereed many hundreds of reports concerning CNS drug reactions and in my opinion it is striking that nearly all the genuinely anomalous and atypical cases occur in patients with cerebral pathology. The other key consideration is this: it has not been established that NMS is in fact a unitary homogenous syndrome. Indeed, much evidence indicates that it is not. Thus it is obviously even more risky or invalid to generalise and extrapolate about cases that are labeled as, or proposed to be, NMS. Some suggest that serotonin toxicity occurs with olanzapine and other ‘atypical’ neuroleptics. Kontaxakis argued (from a selective review of 17 case reports, always a dubious enterprise) that neuroleptic malignant syndrome cases with olanzapine exhibit serotonin toxicity-like symptoms (59-61). Like Fink, they suggest that NMS and ST share a common patho-physiology and represent some sort of generic non-specific neuro-toxic syndrome. There are so many basic flaws in the assumptions and logic of this report that it is difficult to know where to start any criticism of it. Firstly, picking on olanzapine because it has significant activity at 5-HT2A receptors, as if that was some special property, is mistaken and absurd. Many neuroleptics, including many of the older neuroleptics like chlorpromazine, have this property. It is not special to the so-called second generation drugs. Nevertheless, it appears to be the reason they have chosen this drug, although that is not clearly and explicitly stated: “Olanzapine is an atypical antipsychotic, which exhibits greater affinity to serotonin (5-HT2A) receptors than to dopamine (D2) receptors [9].” I also note that this reference [9] that they give contains no original data relevant to the claim they make (re receptor affinity), which is poor scholarship. To cite references which do not provide the data claimed is only one step away from scientific fraud. There is no more delicate way of stating that. Their report uses the non-specific and out-dated Sternbach criteria *** for serotonin toxicity which automatically makes it of limited validity. Whyte, Buckley, Isbister and I have pointed out the strong evidence that contradicts these ideas in various publications (see refs above). The idiosyncratic nature of NMS precludes patho-physiological comparison with ST in relation to the mechanism of action of the precipitating drugs even if the symptoms (as is proposed by Kontaxakis) were like ST. They are not (see above, and especially my published response ‘Defining toxidromes: serotonin toxicity and neuroleptic malignant syndrome: A comment on Kontaxakis et al’ (37)) so the proposal is doubly flawed. Consider also that neither olanzapine, nor any other ‘atypical’ neuroleptics show evidence of ‘serotonergic’ effects, they neither produce serotonin-mediated side effects in therapeutic trials, nor do they produce serotonin-mediated effects, nor symptoms of ST, when taken by themselves in over-dose. *** Sternbach made suggestions (62), long ago, about diagnostic criteria, which were reasonable initially, but were non-validated proposals derived from a selected (non-random) sample. Sternbach’s review was superseded many years ago by the more reliable data from Professor Whyte’s HATS data published in a series of seminal papers. Sternbach noted the likelihood of reporting bias in his series, but that qualification has received insufficient subsequent attention.

Can Previous Neuroleptic Administration ‘Trump’ ST

There is also a widespread perception that neuroleptic malignant syndrome symptoms somehow ‘trump’ or override symptoms of serotonin toxicity, and that serotonin toxicity cannot be diagnosed in the presence of neuroleptics. The origin and logic for this ipse dixit(‘because I say so’) assertion is unclear and has never been adequately articulated, yet it has become widely and uncritically accepted. This may be because of the misinformation perpetuated by poor case reports: readers who wish to learn about NMS and ST are advised, in additional to information on this web site, to start with the major recent reviews by Caroff, Whyte et al and Gillman (1, 38, 63-69). Special evidence is required to logically justify assigning one illness or toxidrome a hierarchical precedence over another; one cannot claim that previous intake of neuroleptics goes against or negates a diagnosis of ST without such special evidence. No-one has ever advanced such evidence. There are good reasons for rejecting that supposition and assuming the exact opposite. That is because ST is much more strongly and predictably associated with serotonergic drugs than NMS is with neuroleptics, because NMS is unpredictable and rare (i.e. idiosyncratic).

ST and NMS: Chalk and Cheese

As alike as chalk and cheese is how I summarised it (13) and Professor Whyte wrote some time ago re NMS and ST: (43, 46) “In my capacity as a general physician to the local psychiatric hospital and as a clinical pharmacologist who takes referrals of drug related problems, I have managed over 50 patients with Neuroleptic Malignant Syndrome over the last 12 years. From this clinical experience and the literature, I have compiled a table comparing the clinical features of Serotonin Syndrome with those of Neuroleptic Malignant Syndrome
.. “From this comparison it can be seen that while there are several features in common, a full physical examination and clinical assessment makes it almost impossible to confuse the two diagnoses. A similar table and conclusions have been recently published by Gillman (Gillman, PK., The Serotonin Syndrome at its treatment. Journal of Psychopharmacology. Vol 13 (1): 1999, pp 100-109)”.

  1. From more recent conversations with Prof Whyte I would estimate that the numbers referred to above are much higher and his confidence in his opinion remains the same.

It seems that it is mostly psychiatrists who subscribe to the opinion that NMS and ST are ‘virtually indistinguishable’ and this may be because they do not usually have involvement in the care of these seriously ill patients in the intensive care units where they are treated by physicians and toxicologists. Thus their opinions are essentially ultracrepidarian, that is to say, those opinions go well beyond their level of expertise.

Postscript: Why is There so Much Misinformation in the Medical Literature?

A brief diversion may be educative. Although the peer review system in scientific publishing is an excellent and laudable idea in principle, in practice it is far from perfect. There are many journals that are not in the top division who are unable to get quality reviewing of their material and often accept and publish papers with limited or no meritorious content. Many of them are just substandard scholarship. Much of this kind of material gets published as case reports which are inherently of lesser scientific standard, and are often very misleading. There has been much debate about whether journals should publish case reports at all and many more eminent journals elect not to do so. Such short reports and mini reviews usually require the authors to make a stab at reviewing the literature on the subject in question. For complex topics like ST and NMS that is a nearly impossible exercise (due to the constraints of time and space and the inexperience of most authors) and frequently leads to pointless and erroneous publications that are then inadequately refereed). There are various other comments on my website in relation to the whole business of substandard and biased publications, for those with the time and interest to read about it. Most people are aware of the importance of the old expression ‘buyer beware’ (caveat emptor) and it is also helpful to realise that even in the scientific literature one should remember the sister phrase ‘caveat lector’, that is, ‘reader beware’.

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69. Gurrera, R, Neuroleptic malignant syndrome controversies revisited-what is the incidence of neuroleptic malignant syndrome? Pharmacoepidemiol Drug Saf, 2011. 20(6): p. 659.

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– Dr Ken Gillman

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Dr Ken Gillman

My collaborators and I recently showed that Methylene Blue MB (aka Methylthioninium chloride) is an extremely potent monoamine oxidase inhibitor (MAOI) in vitro [i.e. in test tube experiments] and that in humans it causes potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (1, 2). There have been a number of deaths in humans due to serotonin toxicity precipitated by this interaction.

As I write this updated version [amended June 2012] of the story about MB the reverberations of the American FDA warning are beginning to echo around the Internet spreading significant mis-information. It is enough to say that the FDA warning is unlikely to result in much useful increase in anyone’s knowledge or understanding because it contains significant mistakes and lists many drugs as being a danger which are not involved in serotonin toxicity. This is counter-productive.

I have not posted anything on MB since 2009 is because I have been concentrating on getting scientific papers published in the peer-reviewed literature in order to make the scientific community more aware of this problem. I have now published a number of contributions to the medical literature about this which I list here for completeness, and the historical record.

Publications concerning MB, up to June 2012: (1-14).

 Summary: Essential Basic Knowledge

Methylene blue is a potent monoamine oxidase inhibitor (MAOI) that interacts with all serotonin reuptake inhibitors of all sorts (selective and non-selective, SRI/SSRI) to induce severe potentially fatal serotonin toxicity ST (serotonin syndrome): a severe reaction is likely with therapeutic doses of such MAOI/SRI combinations and can frequently be fatal.

I have recently published a review of human cases of ST with MB and SRIs which establishes that this toxic reaction is ST (1) beyond reasonable doubt, even thought the regulatory agencies [in UK, USA and Europe] have not got up to speed with this yet. The theoretical underpinning of the pharmacology of the interaction is both well established and well understood and there is little or no room for doubt or equivocation. The MHRA and the FDA warnings have been/are poor and unhelpful, they have been amended once and may have been amended again by the time you read this (15, 16)).

Key Symptoms and The Effect of Anaesthesia

Progressively: Tremor, then hyperreflexia (especially lower limbs), clonus (inducible, spontaneous, ocular), rigidity, hyperthermia. Autonomic overactivity (diaphoresis, BP, mydriasis, gut) and mental state change (excitement, confusion in late stage).

But: anaesthesia changes the emerging signs and symptoms because anaesthesia itself treats ST. It lowers brain temperature and disguises and or suppresses symptoms like tremor & hyperreflexia. So, post anaesthesia ST may present after 30-60 minutes as agitation/confusion and the hyperreflexia etc. may be muted and only noted on careful examination. As the cooling effect of anaesthesia wears off hyperthermia can increase rapidly (over a few hours) leading to death (12, 17).

History

I am an acknowledged authority on serotonin toxicity (ST), sometimes called serotonin syndrome (SS), and also an expert on other sorts of drug interactions, side effects and adverse effects. Hence my interest in, and recognition of, this problem of serotonin toxicity with Methylthioninium chloride (methylene blue).

Since my initial ‘alert’ (18) and web site posting in 2006 about serotonin toxicity from combinations of MB + (selective) serotonin reuptake inhibitor interactions ((S)SRIs), further serious cases, and several fatalities from probable or definite ST have been reported/recognised. It is usual in such circumstances for reported cases to be only a proportion of actual cases, and the questions to my website and cases reported to me also indicate that. There are two retrospective case series of relevance, Kartha (19) & Sweet (20).

There are now [Oct 2014] around 20 case reports. Indeed, there are unlikely to be many further case reports that are sufficiently interesting to be worthy of publication, as many journal editors have already concluded. Reports that have been submitted, which do not add anything to the existing literature, are likely to be rejected on the basis that they are of insufficient novelty value or interest. That somewhat lengthy explanation of the current status is appropriate because it represents a straw poll of opinion among the experts in the field. In other words what they are saying is it is well documented and more case reports probably will not add anything of value.

The UK MHRA data also contains several cases, including one typical case of ST that was fatal. However, most of the MHRA data is of little value for assessing ST, particularly because there is no definite information about previous and current drug treatment: it merely confirms that most cases of CNS toxicity look like ST even from the minimal information available.

The in vitro study I initiated, courtesy of Rona Ramsay in St Andrews, yielded data unequivocally demonstrating that Methylene Blue is a potent inhibitor of monoamine oxidase A (MAO-A) in vitro (2) with a Ki of 27 nM — that is very potent. This clarifies why it precipitates serious and potentially fatal serotonin toxicity if combined with (S)SRIs (3, 21), just as moclobemide and the old monoamine oxidase inhibitors (MAOIs) do.

SSRIs include all ‘Prozac’ like drugs as well as other drugs that act as SRIs like the  tricyclic antidepressant (TCA) clomipramine, the opioids tramadol and meperidine (aka pethidine), and sibutramine, venlafaxine, duloxetine, chlorpheniramine etc. See (18) Table 2, or my web site, for an authoritative list. NB many published lists contain multiple errors and mis-information (that includes the MHRA, FDA, WHO, EMA, TGA, Health Canada which all contain elementary errors and muddled thinking).

Mixtures of MAOIs (in this instance Methylthioninium [aka methylene blue]) combined with SRIs (of any sort, specific or non-specific) are the only likely cause of serious (i.e. potentially fatal) serotonin toxicity. Such mixtures produce a high risk of toxicity and should be studiously avoided.

This new finding of potent MAO-A inhibition by MB is important because it is used intra-venously in surgery for thyroid operations at doses of 2-10 mg/kg, for methaemaglobinuria (1-2 mg/kg) and for resistant hypotension in septic shock and anaphylaxis (22-24); cardiac surgery (25-28); ifosfamide encephalopathy (29); priapism (30); also trials in dementia ((31), abstract only) and manic-depressive illness have just been completed (Alda, M, Dalhousie Nova Scotia, (32)) and malaria (see http://clinicaltrials.gov) and chromo-endoscopy (33).

And then there is the odd, and seemingly mostly forgotten story of its use in amniocentesis (34-36) where it caused fetal abnormalities like ileal atresia, and possible deaths: the deaths seem to have been skated over. Even more alarmingly the same mistakes appear to be being repeated with toluidine blue (Tolonium Chloride) (37) and Azure B (38). It is also used for various other staining biopsy purposes by various routes and doses, e.g. it is injected into inter-vertebral discs, up fallopian tubes, into ileostomies etc.

New Human Data, May 2009 and Onward

The dangerous irony is that, although thought of as merely a dye by non-pharmacologically orientated surgeons, it is a very potent drug. As of May 2009 there are good new studies of its human pharmacokinetics, reviewed by Stanford and Gillman (9). The Ramsay and Gillman paper on in vitro activity (2) established that MB is a very potent inhibitor of MAO-A with a Ki of 27 nM and that it binds in the active site of MAO-A. The most recent human data established MB plasma concentrations after an IV dose of 0.75 mg kg-1 (usual therapeutic doses are 1-7 mg kg-1) as being a peak of 500-600 ng ml-1 in plasma (33, 39, 40). The mean T1/2was 13.6±3.7 h. The peak value of 500 ng ml-1 represents a concentration of 1.6 ”M in plasma, indicating that the concentration inside cells is likely to reach a level that inhibits MAO-A, even at the low dose of 0.75 mg kg-1. At higher concentrations MB also inhibits Nitric Oxide synthase (NOS): the formation of L-citrulline by NOS is completely inhibited by 30 ”M MB (41, 42), and it inhibits soluble guanylate cyclase (cGC) (43, 44). I have a case reported to me via the website of definite ST with only 1 mg kg-1,which fits the above estimate. That has now been published (8).

Various evidence suggests MB helps memory and neuronal degeneration (45-49). It may also have (like some other MAOIs, see Youdim) acetylcholinesterase antagonist activity (50). Wischik also proposes MB dissolves Tau polymers isolated from Alzheimer disease brains, and prevents Tau aggregation in cell models in the high nM concentration range (150 – 580 nM) and also reverses Tau pathology in the brain (31, 51). MAO-A inhibition probably occurs at a lower concentration than Tau inhibition. In view of previous evidence about MAOIs and Parkinson disease and dementia (52, 53) it will be interesting to learn to what extent this is related to its MAOI activity.

The older studies of its pharmacokinetics (54, 55) are probably outdated (see above) but suggested: an estimated terminal half-life of 5.25 h (recent estimates 14 hrs); the area under the concentration-time curve was, oral dose, 9 nmol/min/ml vs. IV 137 nmol/min/ml. i.v. IV probably results in much higher concentrations in brain. See also (56, 57). The LD50 in sheep is ~40mg kg-1. However, there is some doubt about the accuracy of some of these older estimations.

For some clinical situations it may be relevant to note that MB appears to prevent the febrile response: Riedel has demonstrated MB completely blocked the febrile response to lipopolysaccharide  (LPS) (58).

I said before “My guess is that at > 0.5 – 1 mg per kg intra-venously it will be active as an MAOI.” And it seems that was a good guess. When injected into tissues the systemic availability may be less, and the dose probably lower, so these situations are  less likely to give rise to ST interactions. Please contact me if you have any views or experience on this so I can update this doc as needed. Try to remember to fill out adverse drug reaction reports for the authorities in your country, it is clear this is often forgotten about.

Summary of The Current Evidence

  • We have irrefutable evidence that mixing MAOIs and SRIs, in therapeutic doses, gives a high risk of severe ST, and definitely does precipitate fatalities.
  • We have very strong evidence that Methylthioninium chloride (methylene blue) is a very potent (at nanomolar concentrations) MAO-A inhibitor in vitro, and also very strong evidence it is active in vivo.
  • We know that many of the cases in question have exhibited symptoms typical of ST (and ST is not easily confused with other conditions), and of a severity only seen with mixtures of MAOI + SSRI  (ipso facto, this is very strong evidence that MB is an MAOI in humans, not just in test tubes).
  • We know paralysis and anaesthesia are good effective treatment for ST, and therefore modify the symptoms (particularly hyperthermia), so we would expect these post-operative cases to be atypical.
  • We know that in Sweet’s & Kartha’s series of 325 patients only those on SSRIs pre-operatively got symptoms, and not a single patient of the 280 who were not on SRIs got symptoms.

This constitutes very strong presumptive evidence that serotonin toxicity is the most likely explanation, and also constitutes a very strong cause-effect link to explain all the observations. I cannot see, nor have I seen proposed, any remotely plausible alternative explanation.

If MB [aka Methylthioninium] is judged to be indicated cessation of SRIs must be accorded a very high priority indeed (with due consideration of elimination half-life), prior to treatment/procedure/surgery. Other types of drugs with serotonin-mediated actions (the word “serotonergic” is very mis-used and I do not like it) are not implicated in significant toxicity e.g. tryptans, mirtazapine, bupropion,, tricyclic antidepressants (except clomipramine) etc. See (18).

How the Story Started

In 2005 David Bogod, the editor of the journal Anaesthesia, invited me to write an editorial concerning case reports and serotonin toxicity (3). Anaesthesia had already published an interesting case report by Martindale et al of ‘Neurological sequelae following methylene blue injection for parathyroidectomy’, although that report had not then been recognised as a possible example of ST (59). One of my routine Google searches for SS/ST in early 2006 led me to an unpublished report on the internet by Rosenbaum (60), who, most astutely in my opinion, suggested the symptoms and signs observed in that patient might be serotonin toxicity (ST) resulting from an interaction between methylene blue and a serotonin reuptake inhibitor (SSRI). Rosenbaum noted the similarities to the Martindale report: medical.mhaus.org see link  (still available as of June 2012). I immediately corresponded with Rosenbaum, in order to encourage him to publish his case in a peer reviewed Journal (he never got round to it), and to let him know that in my opinion he was correct, and furthermore that this strongly suggested (because of the severity of symptoms) that methylene blue must be a monoamine-oxidase inhibitor. I searched for information concerning methylene blue and MAOI activity, with some success, and submitted a comment to Bogod (Anaesthesia) concerning this (3), particularly because the case illustrated the problems and potential of case reports, the subject of my previous Anaesthesia editorial. As they were preparing to go to press with my letter the editor contacted me to say they had received another report that he thought I might wish to comment on. Indeed, it seemed very likely that this was indeed another case of ST (61). All subsequently discovered/recognised published reports, as of May 2012, are tabulated below.

The key issue to grasp (see figure below, ST triangle) is that severe degrees of ST, involving therapeutic doses of (S)SRIs, only occur following combination with MAOIs (3), but not with other drugs (with other mechanisms of action (cf. the misinformation in the MHRA warning)). These few cases therefore indicated (one could almost say proved) that methylene blue must posses significant potency as an MAOI. See diagrams and figures below that illustrate the details of symptoms, interactions and severity.

 A search of the existing standard texts (Goodman and Gilman, Rang and Dale, British National Formulary, Martindale etc) revealed no information or suggestion that Methylene Blue is an MAOI: however other older, and some recent literature did support a degree of MAO inhibition (62-64), but one of uncertain potency and relevance in relation to humans. I therefore sought the assistance of Rona Ramsay at St Andrews, an expert in the field of assessing MAOI potency, who took on the task of assaying MAO inhibition by methylene blue. The rest, as they say, is history.

SRIs have been in use for more than three decades. Clomipramine has been in use since 1966- France, 1968- UK, well before fluoxetine, 1986-USA, 1988- UK. MB has been used for parathyroid surgery since ~ 1971. It would be astonishing if substantial numbers of patients taking them had not been operated on with procedures that utilize the infusion of methylene blue. Since (we now know) that it is a potent MAOI one would expect a large number of reports of toxicity; there are few. This is similar to the situation that pertained for decades with pethidine and imipramine (65, 66). In my opinion the most parsimonious explanation is that ST had occurred but had not been recognised, or the relevance of the reactions seen had not been appreciated: cf. pethidine, imipramine, linezolid (67). The fact that most of the cases now uncovered have been reported as ‘encephalopathy’ re-enforces my point. This is congruous with the well documented history of failure to recognise serotonin toxicity when it occurred frequently between 1955 and 1982 without recognition (68), usually caused by MAOIs + imipramine or clomipramine or pethidine.

It would be interesting to know if, in retrospect, experienced practitioners recognise that they have indeed seen ST symptoms (particularly clonus, hyperreflexia, pyrexia and agitation/confusion) in such cases (see Kartha (19) below). Patients are usually slightly hypothermic post-operatively. A recent study of 1300 patients found a mean aural temperature of 35.8°C (69). Anaesthetics greatly reduce both brain metabolism and temperature, inducing brain and body hypothermia (70-74). After a single pentobarbital dose of 50 mg/kg, i.p. brain temperature dropped 4.0-4.5 °C (75). So post-operative cases of ST are most unlikely to be hyperthermic by the usual criteria. Other signs may well be muted also. Careful and repeated examination for clonus (especially ocular), hyperreflexia and tremor (masked by post-op shivering) are recommended.

 Errors in Official Warnings: MHRA, FDA, EMA

[Also see posting Oct 2014 for explanation about further muddled thinking and ill-conceived advice by various international regulatory agencies concerning the warnings of supposed ST with 5-HT3 antagonists, like ondansetron etc. There seems to be something about committees which puts them at an insurmountable disadvantage when dealing with complex topics like this.] Serotonin Toxicity and 5-HT3 antagonists

The MHRA in the UK issued an incomplete and misleading warning (15) in Jan 2008, but have discounted the Ramsay paper, a copy of which they were provided with prior to its publication in May 2007. They have also failed to reference my 2006 paper, or use the term serotonin syndrome or serotonin toxicity (21). Both their warning and their response to my written communication to them, and to this web post, have been factually inaccurate and muddled. They have indicated they do not wish any further communications or information, and have declined to explain why they have deliberately chosen not to inform doctors of the potential for fatality from ST. Their further update of April 2009 does little to improve things (16), it again fails to mention MAO inhibition by MB, and also fails to mention the fatality in their own case data. One really has to wonder what on earth is going on in their heads; if anyone can throw any light on that, do let me know. They need to get their act together and get up to speed on this issue. NB I have also written to the FDA who did not even deign to reply: talk about hubris.

The FDA and EMA (European Medicines Agency) and MHRA materials for doctors (product information etc.) do not explain the entirely predictable incidence of ST nor mention MB is a potent MAOI. Doctors need to know this in order to understand what is going on and to treat patients correctly.

Failure to state MB is an MAOI and failure to warn by providing explicit information about potentially fatal ST is inexplicable, and, with our current knowledge, inexcusable.

Health Canada Get it Right

Health Canada have issued [Feb 2011] this succinct and correct information:

“Serotonin toxicity/serotonin syndrome has been reported when methylene blue was administered intravenously in patients also receiving other drugs with serotonin reuptake inhibition properties. Several of these cases required admission to intensive care unit.” (76).

So you see, it is possible. That is about all a well informed doctor needs to know in an emergency.

Currently Known Cases: Methylene Blue and ST

Currently known cases relevant to methylene blue and serotonin toxicity are: (12, 17, 19, 59-61, 77-86), this includes the old new case I have uncovered (77) about which Clare Stanford and I have published a ‘correction’ (see below) that also reviews MB pharmacology. Note: Patel (87) has been included in the paper by Ng (83), the case does not meet any criteria to justify a even a suggestion of ST, and no SSRI had been taken pre-op, so this case is irrelevant in this context. Ng says, of Patel, ‘Only one of the seven case reports did not meet the diagnostic criteria, as a serotonergic agent had not been administered’, his meaning is unclear. His report is really of six cases, most of which had been previously postulated to be ST and had already been commented on. His table assigning diagnosis contains multiple errors.

Table: Cases of ST with MB (up to June 2012): Certainty of Diagnosis and Severity

Case reference (chronological order)Certainty of diagnosis of STSeverity of clinical stateComments
1) Stanford (77)DefiniteSevereMB used, but not mentioned in original report
2) Martindale (59)DefiniteSevere‘Rotational nystagmus’, represents ocular clonus
3) Bach (79)ProbableModerate‘A suggestion of clonus, forced dorsiflexion of feet’ *
4) Majithia (80)Probable/definiteSevere‘Nystagmus’, was very probably ocular clonus *
5) Mathew (61)DefiniteSevereMH queried, tremor, agitation, temperature 40°C
6) Rosenbaum (60)DefiniteSevereThe first recognised case. ‘Agitated, tachycardic and diaphoretic 
 lower extremity rigidity’. T38.3°C
7) Khan (81)Probable/definiteSevere‘Confused, agitated, jerky movement of all four limbs’ *
8) Mihai (82)PossibleN/A‘Agitated and restless 
 unable to speak no response to verbal command 
 no limb weakness, 
 no focal neurological signs’
9) Ng (83)Probable/definiteSevere‘Agitated, disoriented, moving all limbs purposelessly 
 increased tone in all limbs’ and ‘rapid, fluid eye movements’ represents probable ocular clonus *
10) Shanmugam (84)DefiniteSevere‘confused and agitated 
 temperature 40°C, myoclonic jerks, fine tremors, dilated pupils, shivering, hyperactive reflexes, hypertonicity’
11) Khavandi (85)Probable/definiteModerate‘agitated and restless’, ‘myoclonic movements of the lower limbs, brisk reflexes’, T 37.5° C)
12) Schweibert (8)DefiniteSevere‘Confusion, agitation, aphasia, ocular clonus, mydriasis, hyperreflexia and arterial hypertension’. Dose 1 mg kg-1
13) Rowley (86)DefiniteSevere‘38.1°C (rectal), end-gaze nystagmus, hypertonia, diaphoresis, agitated, Duloxetine.
14) Heritier Barras (17)DefiniteSevereSevere hyperthermia 42.3°C, rigidity, shivering, inducible clonus, hyperreflexia, diaphoresis.
15) Top (12)DefiniteFatalSevere hyperthermia 43.1°C, ocular clonus, hyperreflexia, diaphoresis. Venlafaxine 150 mg daily, MB 9 mg/kg

Other cases have crossed my desk in various confidential contexts, none of them contradict anything stated herein. Sadly the WHO database is usually only accessible on payment of a fee (that I, personally, cannot afford), but they have told me they have 102 reports of toxicity. Anders Viklund is kindly trying to get more information for me, I will give more details if and when those are available. I am trying to help producers to update their product information texts (the Australians have already initiated that, to their credit). I am not aware of the WHO acting on this yet, it would be worth their serious consideration because in many areas of the world MB is apparently being issued to doctors without proper warnings. If you are aware of any cases that might be relevant please let me know via email

Case Series: Kartha and Sweet

It is noteworthy that two case series exist, in Nov 2006 Kartha (19) and in March 2007 Sweet (20). It might be useful to re-examine such series .

Kartha reported 12 cases of ‘toxic metabolic encephalopathy’ (which, in my opinion, are likely to represent serotonin toxicity) from a retrospective analysis of 193 patients operated on for parathyroidectomy using methylene blue: one patient died (possibly of serotonin toxicity). All 12 with ‘toxic metabolic encephalopathy’ were on SSRIs pre-operatively. I.e. Of the total of 28 patients who were on SSRIs (in the series of 193) 12/28 had ‘toxic metabolic encephalopathy’. It is almost certain that had these patients all been fully assessed for the symptoms of serotonin toxicity the % exhibiting significant serotonin toxicity symptoms would have been in excess of 50%. This paper was published just after my August 2006 review so I was unable to take its valuable data into account (I ‘found’ it 6/2008)

Sweet & Standiford report on a series of 132 cases, 17 had SSRIs pre-op. None of those who had no prior use of SSRIs got symptoms, 5/17 (30%) who did take SSRIs pre-op did get symptoms. They considered the possible explanation of serotonin toxicity but did not favour it because of the symptom profile. In my opinion the main reason for the different and varying symptom profile is treatment: i.e. these subjects were coming out of anaesthesia which is an effective treatment for serotonin toxicity. The rate at which various drugs are cleared, especially relaxants, probably plays a key role in suppressing hyperreflexia etc. Also, as Rosenbaum points out (personal communication) symptoms that obscure ST, such as shivering, are very common on emergence from anaesthesia. I would observe also that it is certain that a proportion of the patients on SSRIs were either on sub-therapeutic doses of SSRI or were non-compliant; so the real denominator in the fractions needs to be adjusted lower, in my opinion by at least 30%, i.e. ~12/20 not 12/28). The nominator is also certain to be too low (missed cases), so the real % experiencing a reaction is probably between 50 & 75%.

Both these series (totalling 325 patients) concur in the finding only those patients on SSRIs experienced symptoms. The odds are thousands to one that it is the pharmacological property of serotonin reuptake inhibition that is the key to this adverse interaction. There is no other known property these drugs posses in common that could explain things. Both these series also support my supposition that almost all these cases  had previously been going unrecognised/unreported. From my detailed knowledge of the history of serotonin toxicity that is exactly what I would predict. To restate it simply: Doctors do not see what they are not looking for. This is an important point to appreciate because it seems that a major stumbling block for many people who do not have a good understanding of serotonin toxicity (and the spectrum concept) is the comparative rarity of (reported) cases relative to the presumed large number of cases where Methylthioninium chloride (methylene blue) and SSRIs must have been used together.

The Stanford Report: History and Education

When I checked the fine details of all the various accumulated references (to update my web posting- viz this doc, in June 2008) my attention was drawn to the correspondence relating to Bach (79) from Siebert (89), Howard (90) and Palmer (78) that highlighted the apparent anomaly of the earliest potentially related report from (Clare & sister) Stanford in 1999 (77), which, although very similar, did not report the use of Methylthioninium chloride (methylene blue).

As I have argued case reports are usually unhelpful and often poor, but the exception proves the rule. The Stanford report is a paragon; it is so good, important, interesting and educative that I abridge the abstract below:

‘
 postoperative delirium 
 during recovery from anaesthesia. Features agitation, confusion, uncontrolled limb movements, abnormal ocular function (KG-probably horizontal ocular oscillations- not nystagmus), hypertension, pyrexia, brisk reflexes, ankle clonus and raised creatine kinase. 
 had been taking paroxetine. 
 had many features in common with problems associated with, the serotonin syndrome and the malignant neuroleptic syndrome. We offer several alternative explanations for this event, all of which rest on disruption of serotonergic and/or dopaminergic transmission.’

NB The bolded features are typical/pathognomonic of serotonin toxicity. This degree of severity could only result from MAOI + SSRI: ergo, the patient must have received an MAOI, somehow. (see diagram/figure).

The report does not mention Methylthioninium chloride (methylene blue) but does say the operation was a parathyroidectomy. That is why other commentators (Bach (79), Siebert (89), Howard (90) and Palmer (78)) ‘wrote it off’ as different. I hope readers will by this stage be sufficiently well informed about serotonin toxicity to guess the remainder of the story. I emailed Clare Stanford to ask her to check if MB had been used: and yes, it had been used. So this Stanford report was the 1st report involving Methylthioninium chloride (methylene blue) where the possibility of ST was considered in detail, even though we did not know MB was an MAOI at that time, and no-one appreciated the key role it played in the case for ten years.

All this illustrates the predictive power of the spectrum concept of serotonin toxicity, as detailed in my reviews (1, 18). To fully and properly understand the situation a brief review of serotonin toxicity is required. Look at the diagrams/figures in the other sections which will help). Don’t worry if it takes a minute or two to twig: there have been several peer reviewers of a couple of my published papers who have clearly not understood the intricacies of the spectrum concept of serotonin toxicity, despite being reviewers for quite eminent journals, and have made rather silly comments.

Other Data: Most Poor Case Reports

Ng (83) summarised some cases in 2008 and added, post hoc, his opinion that they may represent serotonin toxicity. He has insufficiently recognised the previous work (6), and the implications of the fact methylene blue is an MAOI on the risk of toxicity. Hence his contribution is incomplete, misleading and incorrect in some details. He has not acknowledged prior references which stated clearly that serotonergic mechanisms, specifically serotonin toxicity, had been concluded to be the explanation by other authors right from the start. In his introduction he states: ‘to consider this diagnosis [serotonin syndrome] in previ­ous, unexplained reports of adverse reactions amongst patients undergoing parathyroidectomy using methylene blue.’ Thus his introduction is disingenuous because the cases were not ‘unexplained’ at all; his contribution is not original or useful, indeed it probably meets the definition of plagiarism.

It is impossible, in this context, to avoid repeating my comment about poor case reports which is elaborated in detail in my editorial ‘Extracting value from case reports: lessons from Serotonin toxicity (serotonin syndrome)’(18). Poorly informed comment based on faulty case reports bedevils the whole issue and causes much confusion. ‘Plus ça change, plus c’est la mĂȘme chose’, as Alphonse said (88).

Several other commentators had previously speculated about serotonergic mechanisms, even if they did not quite make all the connections and appreciate the implication that Methylthioninium chloride (methylene blue) must be an MAOI. Since we have touched on the area of precedence, acknowledging prior contributions, plagiarism and learning from history, it is most appropriate to give due credit to Clare Stanford (77)(the 1st author is her sister), they came tantalisingly close to getting it right: A decade later I can now, with Clare’s help, complete the circle! (see (9).

Conclusions

1. Mixing methylene blue with SRIs frequently and predictably causes severe serotonin toxicity: cease SRIs, with appropriate washout periods, beforehand. This definitely applies to intra-venous use at doses of approximately 0.5 – 1 mg per kg or greater, the risk with smaller doses via other routes is still uncertain, but oral doses of 200-400 mg produce blood levels that would be predicted to be sufficient to cause an interaction.

2. Make sure you know the following drugs which are significant serotonin reuptake inhibitors from (7), table 2. Paroxetine, sertraline, fluoxetine, fluvoxamine, (es)citalopram. (des)Venlafaxine, milnacipran, duloxetine, sibutramine, Clomipramine, imipramine. Tramadol, meperidine (pethidine), dextromethorphan, dextropropoxyphene pentazocine, Chlorpheniramine, brompheniramine, (fentanyl is most unlikely to be significantly serotonergic in usual doses).

3. Remember patients may forget to mention drugs recently ceased. Because fluoxetine has an elimination half-life of up to 7+ days it may be present in significant amounts more than one month after cessation.

4. Be aware of the signs and symptoms of serotonin toxicity, especially hyperreflexia, clonus, and how to treat it and be aware that post-anaesthetic cases are expected to present with modified signs and symptoms.

5. The ‘corrected’ % of patients experiencing a reaction post operatively (see above) may be as high as 50% – 75%.

6. The question of interactions between opioid analgesics (pethidine, tramadol, fentanyl etc) and MAOIs is dealt with in detail in another of my reviews (91).

7. The UK MHRA & FDA & EMA warnings are only partially correct, rather unhelpful, and in need of significant revision. They do not explain the entirely predictable incidence of ST nor mention MB is a potent MAOI. Doctors need to know this in order to treat patients correctly.

8. Other agencies (including professional associations and colleges) might consider issuing information and guidance (some have done already (5, 92), well done).

9. Some suppliers of Methylthioninium chloride (methylene blue) have already modified their PIs to state MB is a potent MAOI and may precipitate lethal ST with SRI. Those that have not may be held to have failed to give due warning of material risks.

References

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