Serotonin Toxicity: Introduction

by | Last updated Oct 17, 2021 | Published on Nov 13, 2014 | Serotonin Toxicity, Anti-Depressants

Au: P Ken Gillman
PsychoTropical Research, Bucasia, Qld
Orchid ID 0000-0001-8277-3397
Researchgate
https://www.researchgate.net/profile/Ken_Gillman 

Summary

This updated introductory commentary outlines this complex topic of serotonin toxicity (ST): it describes the features of the condition, the drugs that can induce it (with a genuinely evidence-based table), the patho-physiology, and the medical management. The spectrum concept, and the features associated with increasing degrees of severity, are delineated with figures illustrating how, and to what extent, different drugs are capable of elevating serotonin with explanations of their potential interactions.

Preface

Even now, in 2021, more than three decades after key research and reviews that demonstrated the essentials of the interactions relevant to ST, there remains a great deal of misinformation and misunderstanding both in medical and non-medical texts. The latest egregious example of misinformed writing from persons of minimal knowledge or experience (a supposed ‘meta-analysis’ of the last decades-worth of case reports [1] illustrates the low-point in medical publishing that has been reached [2] and the very poor refereeing standards now prevalent. For detailed comment on Werneke et al. see: Update on recent case reports of ST

Indeed, right on cue, as I was in the process of checking and updating this commentary in June 2021, a Medscape article with a quiz about serotonin syndrome (the first giveaway for a poor article is calling it SS and not ST) appeared. It contains multiple errors and misinformation and is clearly written by a doctor with no expertise, and little knowledge*, in the relevant scientific disciplines required to understand this subject — indeed the person who alerted me to it warned me that it would cause me to have an apoplectic fit. It did.

*A little bird, who knows said author well, told me that the author is renowned for his obstinate persistency in pontificating about things of which he knows little.

Such lack of knowledge and misunderstanding are reflected in advice and warnings concerning ST issued by ‘official’ agencies such as the World Health Organisation (WHO), the American FDA, the UK MHRA, Health Canada and the Australian TGA: their comments and advice have frequently been incorrect and misinformed. See, for detailed comment on the FDA, TGA etc. Serotonin Toxicity (Serotonin Syndrome) with 5-HT3 antagonists

Much of what is wrong, or in dispute, is not a question of opinion, but a question of want of knowledge of established scientific facts.

If you are wondering, ‘who is this, who thinks his opinion is superior to the FDA?’ The first answer is, I am a widely recognized world expert on the topic — and am not alone in my views or criticisms. The second answer is that much of what is wrong, or in dispute, is not a question of interpretation or opinion, but a question of want of knowledge of established scientific facts.

Most recently my criticisms have been reinforced by several Australian toxicologists, all professors, and all associated with the group here in Australia who have produced most of the quality prospectively gathered data relating to this subject [3]. Indeed, these eminent Australian toxicologists recently stated (2014) in the British Medical Journal that: ‘product information is a major impediment to sensible decision support in this area’ [3, 4] and of course product information is dictated more by medico-legal defensiveness and the regulatory agencies, not by practicing clinical pharmacologists/toxicologists.

Product information is a major impediment to sensible support of decision-making concerning ST

The complex topic of ST requires an understanding of many aspects of medical science, including methodology and logic, but especially pharmacology, drug interactions and toxicology. Evidently, not all commentators and writers have such an understanding. Many of the publications about ST are published by younger and less experienced doctors eager to get a few ‘runs on the board’ by publishing something — case reports and mini reviews, submitted to minor journals, are a popular conduit for such ambition.

Unfortunately, in the last few years, there has been a burgeoning of the number of journals devoted to publishing case reports (from < 10 on 2005 to nearly 200 in 2016, see Akers), almost all on an ‘author pays’ publishing model, accompanied by little or no refereeing. All but the most sophisticated of readers or researchers are probably unaware of this and how it has negatively affected the overall quality of medical publishing. Medical science has been seriously degraded in an insidious manner. To ascribe the same value to what non-experts write in such publications, as one should ascribe to the writings of experts, such as the professors referenced above, is mistaken and is wasteful of ones’ intellectual energy.

Most readers are unaware that many papers are subjected to little or no expert refereeing

However, general readers are not usually able to assess the expertise and experience of the authors of published papers, nor the quality of refereeing and cannot factor that into an assessment of a papers’ possible value.

Caveat lector!

Many of the poorly informed comments that I see are by doctors who appear to have little research background in pharmacology and who are mainly commenting about case reports. These are often misleading — these writers do not understand the extensive background of animal experimentation and pharmacological research which informs us about the properties of drugs and their ability to alter levels of serotonin in the brain — that is an essential property they must possess if they are going to be implicated in ST. There is also widespread failure to distinguish between what are essentially side-effects, as opposed to potentially fatal toxicity, which is also adding to the extensive confusion.

ST requires extensive background knowledge of animal experimentation and pharmacological research to understand the properties of drugs and their ability to alter levels of serotonin in the brain

Recommended Recent Reviews

Enough of negatives. The following reviews are recommended.

Buckley et al. [3-5]

All of the authors of this paper are experienced toxicologists with special knowledge of ST. It does not get much better than this. There is also a link to a video showing how to elicit clonus properly and what it actually looks like. http://curriculum.toxicology.wikispaces.net/serotonin_video

2) Gillman, 2011 [6]

This is a review paper in which I set out the current understanding of ST which allows us to make accurate predictions about the properties of drugs. It summarises in diagrammatic form the severity of serotonin-mediated symptoms caused by therapeutic doses, and overdoses, of the various different drugs, and the interactions between them, that are capable of affecting the system to a clinically significant extent in humans. This paper draws on data provided by Prof Whyte from the ‘HATS’ database.

3) Gillman 2009 [7]

Above I have alluded to the various misleading warnings about ST issued by the WHO, the FDA etc. implicating a range of different drugs. This paper is a detailed analysis of why their warning about the dangers of triptans is mistaken. I have published similar papers about opioids (12), mirtazapine (13) etc. and I could write similar papers about several other drugs, but life is short, and I have other things I wish to do in my retirement.

4) Whyte, Buckley, Isbister, Dawson et al. [8-13] (7-9, 14-16):

Prof Whyte’s group and other Australian toxicologists have done the lion’s share of original research in this area. Any serious student will benefit from reading all their papers. These authors are experienced toxicologists who look after patients with ST and neuroleptic malignant syndrome etc. when they are sufficiently severe to be admitted to hospital.

5) Boyer 2005 [14]

This is a good paper with useful pictures and diagrams, which draws extensively on Prof Whyte’s, and my, work. The table of drugs causing ST is a little less reliable, for instance, it includes nefazodone: note that Boyer et al. agree (with Prof Whyte and me), that usually NMS and ST are clearly distinguishable, and not similar and easy to confuse, as is so tediously and frequently repeated.

6) Gillman [6, 7, 15-26]

I have published various other reviews on and around the subject of ST, particularly concerning the pharmacology and interactions of the main protagonist drugs, the ‘dramatis personae’ as it were. Despite the clear evidence that mirtazapine is not an SRI, which I set out in this review [21] it is still stated to be a ‘serotonergic’ drug by most writers. Remember Santayana: ‘Progress, far from consisting in change, depends on retentiveness. … Those who cannot remember the past are condemned to repeat it’.

So, read also ‘History and Risk’ [15]. That paper is a reminder of how psychiatry misunderstood these reactions for decades, despite clear evidence from the basic science literature. Students of history will not be surprised to learn that many writers continue to make these same mistakes today. The enduring confusion concerning TCAs is a case in point, with some writers still stating that all TCAs are contraindicated with MAOIs, whilst others, particularly on the European continent, contend that imipramine is safe.

7) Baldo [27, 28]

Baldo is a research immunologist (I do not think he is a qualified physician) who has taken an interest in ST in his retirement.

Whilst the content of his two papers is of a much higher scientific standard than most of those that I find myself criticising, nonetheless I think they suffer from significant errors and distortions which relate to over-reliance on case reports and his inexperience in clinical medicine, pharmacology, and toxicology. He says [27]:

Although the opioids most often associated with serotonin toxicity in humans inhibit human SERT in vitro, fentanyl and oxycodone are not inhibitory even though their clinical involvement has been reported. This suggests some SERT-independent effects on the serotonin system in vivo*. Heightened clinician awareness of the possibility of serotonin toxicity among patients taking opioids and serotonergic antidepressants is called for

*No, such a small number of reports of a such a long period of time with commonly co-prescribed drugs suggests they are false positives. This is as unsound as saying that 1 million visitors have been to the old, ruined Abbey — one of them has reported seeing a ghost, therefore ghosts must exist.

It is not logical or scientific to use poor quality data to negate good quality data

Baldo gives too much credence to poor quality case reports (cf. Guo below), of which there are many. These go against the basic pharmacological knowledge that we have, as above — poor quality data cannot negate good quality data, as I keep repeating: this is well exemplified by Guo’s case [29] that Baldo cites in support of his ideas, Guo was almost certainly not a case of ST — and even if it had been classifiable as probable ST it would not be useful or strong evidence to support the speculation he makes. More consequentially, he also omits to note that the danger is only with opioids combined with MAOIs, not with opioids combined with other serotonin reuptake inhibitors — this is a fundamental misconception and mistake.

There are other serious errors in this paper including, among others, categorising bupropion, amitriptyline, and nortriptyline as SRIs, which they most certainly are not.

There is much good data in his papers, it is a shame that is spoilt by errors and conclusions which are unsupported by the evidence he adduces.

In his second paper [28] he concludes that the many patients on SRIs produce:

… increased possibility of ST in some opioid-treated patients, an outcome suggested in the recently issued 2016 FDA Drug Safety Communication warning 55 for ‘the entire class of opioid pain medicines’

The FDA data is, of course, based on the same kind of poor case reports as his paper, so hardly constitutes any kind of supporting evidence.

This FDA warning, like others they have issued, has serious misconceptions and errors, inter tot alia, listing doxepin and mirtazapine as drugs that increase serotonin, when in fact they are serotonin antagonists — it is profoundly disappointing to find such serious and basic errors from a supposedly authoritative source

https://www.fda.gov/media/96472/download

I have discussed elsewhere why this kind of false-positive data is producing a great deal of difficulty with computerised drug interaction warning systems that are causing Pharmacist and others to object to fill scrips for drugs which are not going to cause any harm through interactions. The harm to the patient will result from denying them the potential improvement that good, combined pharmacotherapy may produce.

False-positive data has produced many erroneous drug interaction warnings

I trust most of you will understand why I hold my head in despair, gulping like a stunned goldfish, whilst reading these numerous erroneous comments.

Sternbach [30]

This seminal paper was the first to attempt to describe and define ST. It relied on case reports and was therefore only an initial step in delineating the problem. Its pharmacological basis was shaky. It is now of mainly historical interest rather than being of scientific or clinical use or relevance. In my opinion this paper should now only be cited in the context of the history of serotonin syndrome. It no longer has clinical or pharmacological value.

Definition and Occurrence

ST can only occur after the ingestion of drugs that substantially increase brain serotonin levels. There is no other disease or a natural cause for this constellation of signs and symptoms. It is poisoning caused by drugs that have serotonin-mediated effects, so-called ‘serotonergic’ agents. The typical side effects caused by usual therapeutic doses of the (S)SRIs, which are the most widely known and used serotonin-elevating drugs, increase with increasing dose. There is variation between individuals in the susceptibility to various typical side effects, and the actual blood level (and therefore ‘end-effect’) goes up more rapidly with some drugs than with others as the dose is increased. This is because some drugs have ‘non-linear’ pharmacokinetics (they inhibit their own metabolism, so that their blood level increases out of proportion to the increase in dose — not an ideal characteristic).

ST can only occur after the ingestion of drugs, or combinations, that substantially increase brain serotonin levels

The general pattern is that side effects gradually become worse with increasing dose, but only occasionally reach a degree of severity which justifies calling them toxic effects.

The meaning of the word toxicity is ‘poisoning’, and poisoning insinuates life threatening severity. If we are being precise and logical the term ST should be reserved for those cases where hospital admission and medical intervention is mandated. There will sometimes be dispute about whether a given clinical case is most appropriately described as ‘severe’ or ‘atypical’ side effects, or as ‘toxic’ effects. The most relevant and objective criterion of severe ST is body temperature. Excessively elevated temperature, hyperthermia, is the main change that mediates the severe life-threatening effects of ST (‘pyrexia’ refers to infection-mediated temperature elevation which is different — the terms pyrexia or hyperpyrexia and hyperthermia are not interchangeable).

The most relevant and objective criterion of severe ST is body temperature

If core body temperature exceeds 39-40°c it is generally referred to as hyperthermia (NB the definition and use of this term is imprecise, see [31]. Regrettably, for such a clear-cut physical quantity, temperature is frequently not measured accurately and reliably. My NMS review paper [31] contains detailed comment about the lack of scientific rigour in reported temperature measurements and devices.

Understanding Medical Management

A key goal of medical management is to predict those small proportion of cases that may become sufficiently severe to necessitate rapid decisive active intervention (intensive supportive care, active cooling and possibly drugs). It is now beyond reasonable argument that the degree of ST exhibited in experimental animals, given combinations of drugs that elevate serotonin levels, gradually increases, eventually causing hyperthermia and death as a result: this is a ‘dose-related’ phenomenon. When pharmacologists say ‘dose-related’ what they really mean that it is related to the end effect of the drug(s). In human beings there are intervening variables relating to metabolism that cause large variations in the actual level of the drug at the sight of action. This means that the direct relationship between dose and effect is less precise than it is in inbred laboratory (i.e. genetically very similar) animals.

ST illustrates this point further because there are (usually) cumulative effects caused by the interaction of two drugs, with different mechanisms of action, producing an effect which is much larger than either individual drug can produce by itself. SSRIs raise serotonin by a few hundred percent above baseline, whereas a combination of MAOI and SRI raises it by a few thousand percent, see [20].

SSRIs raise serotonin by a few hundred percent above baseline, whereas a combination of MAOI and SRI raises it by a few thousand percent

For these reasons the term ‘dose-effect’ relationship needs to be understood as the cumulative effect of all drugs taken on the relevant measure, which in this case is the intra-synaptic serotonin level (see figure STT below). It is also now clearly established that drugs that block 5-HT2A post-synaptic receptors prevent deaths from hyperthermia in animal models of ST and almost certainly do the same in Humans — the decision about the risk of using them in humans, who are physiologically unstable and severely ill, relates mainly to the potential side-effects, because none of the available drugs are sufficiently specific as 5HT2A antagonists.

Although it is frequently suggested that 5-HT1A receptors may be important for mediation of ST in fact 1A antagonists (blockers) have little effect, possibly making ST a little worse, rather than better. This leads to the conclusion that the important consequences of ST are mediated by 2A receptors. That conclusion is cemented by the confirmatory animal experimental evidence.

See Isbister [32], for the seminal analysis of animal and human serotonin toxicity patho-physiology

If this were more widely known and appreciated some of the recently reported deaths and serious cases may have been avoided by more timely use of 5-HT2A antagonists e.g., chlorpromazine and cyproheptadine.

Recent papers, particularly those from Professor Whyte’s HATS research group and associates, have now clearly established the typical clinical picture, the diagnostic features, and validated clear research diagnostic criteria for ST.

It is important to understand that research diagnostic criteria are not necessarily applicable in routine clinical practice and cannot replace clinical experience and judgment.

There are many case reports which have applied these rules without sufficient understanding of what constitutes a ‘serotonergic’ drug and what constitutes significant signs and symptoms, especially clonus. Indeed, many reports appear to confuse clonus with myoclonus. There is no substitute for clinical experience and an understanding of the time-course of the progression of the signs and symptoms — this is well exemplified by the fact that in serious cases that have progressed to rigidity, clonus may not have been elicited prior to the onset of rigidity and is obscured by it.

It is often stated that ST is difficult to diagnose and has no clear diagnostic features: that is wrong. One of the main reasons for using the term ST rather than serotonin syndrome is because this clarifies that it is a form of poisoning, just as Lithium toxicity is a form of poisoning. It is not an idiosyncratic syndrome: a syndrome is usually understood to mean something that occurs in some people, but not in others.

Neuroleptic malignant syndrome is such a condition, it is idiosyncratic and rarely occurs after an over-dose of neuroleptics: rather it occurs in a very small proportion of patients who are taking therapeutic doses [31].

No-one would suggest using the term ‘lithium syndrome’, so why the term ‘serotonin syndrome’ persists is hard to see.

It is also often stated that ST & NMS are similar, or even hard to distinguish: that is wrong, NMS is quite different to ST [33-37].

The usefulness of conceptualising the condition as ST, rather than SS, is made evident in a variety of ways. For instance, consider the frequent comment one sees that ‘serotonin syndrome is rare…’ and now the statement ‘poisoning is rare’: it is true that poisoning is rare, except in those who take poisons. However, neither statement is more helpful, or revealing, than saying ‘it never rains if the sky is blue’. This point is consonant with Bayesian theory: this states that the probability of an ‘experiment’ cannot be properly calculated without factoring in our estimate of the prior probability. So, if you feel something like rain falling on you when the sky is clear and blue ‘natural common sense’ (a form of Bayesian reasoning) tells you it may be your neighbour with an over-exuberant garden sprinkler, rather than a miracle.

This important logical principle was emphasised more recently by the astronomer Carl Sagan as, ‘extraordinary claims require extraordinary evidence’. This line of thought originates from the Scottish philosopher David Hume (1711-1776) who launched an effective critique of miraculous claims. This sceptical rationalism was (and still is) a major challenge to religious belief.

Those who enjoy a good chortle might care to read the splendid essay on miracles by Darwin’s cousin, Sir Francis Galton (the extraordinary Victorian polymath) on the effect of prayers on missionary ships vs. merchant ships: see http://galton.org/essays/1870-1879/galton-1872-fortnightly-review-efficacy-prayer.html

Accordingly, it is difficult to suffer from poisoning if you have not taken a poison. Therefore, an important piece of information for doctors to know if they are dealing with a possible case of ST is: what drugs have been ingested? The ingested drugs determine the form of poisoning and large enough doses may produce poisoning in all people, even if there is some inter-individual variation in susceptibility. This is what has led to the first research diagnostic decision rule from the HATS data which is: a definite prediction of impending ST can be confidently made if, but only if, a known potently serotonin-elevating drug has been ingested and the single physical sign of clonus is present.

That is where so many case reports go wrong, ondansetron, amitriptyline, and mirtazapine (etc) are not powerfully serotonin-elevating drugs, nor do a couple of twitches of the ankle represent pathological clonus.

Conversely, one can state that if an overdose of a mixture of MAOIs and SSRIs is known to have been ingested there is a high probability of life-threatening ST: even if the patient currently appears well, one would be well-advised to observe them in an intensive care unit. In order to understand the complexities of this issue it is necessary first to remember that ST is mediated by an increase in the level of serotonin in synapses in the central nervous system, which then excessively stimulates all types of serotonin receptors.

Because there are several types of drugs, with different mechanisms of action, each of which can increase serotonin levels to differing degrees (see [20], there is a characteristic degree of severity of serotonin-mediated effects, or toxicity, associated with each type of drug when taken by itself, either in normal therapeutic doses, or in over-dose. For instance, over-doses of selective serotonin reuptake inhibitors (SSRIs) alone do not produce dangerous toxicity or temperatures in excess of 38.5℃; however, an overdose of an MAOI like tranylcypromine-alone will sometimes produce hyperthermia, and even death, but over-dose of the RIMA moclobemide does nothing.

Over-doses of SSRIs-alone do not produce dangerous toxicity or temperatures in excess of 38.5℃

This demonstrates that the maximum elevation of serotonin produced by these mechanisms is significantly different, being greater with the old irreversible MAOIs (study the figure ST triangle below and refs. [6, 20]. NB. Because serotonin is unable to cross the blood brain barrier conditions such as carcinoid syndrome that involve considerable increases in peripheral serotonin do not cause CNS symptoms.

The bodies capacity to break down serotonin is so rapid that it seems to be difficult to raise levels sufficiently high to cause death (from ST) by taking only one type of drug (e.g., MDMA (ecstasy) rarely causes death from ST).

It is almost always the case that serious toxicity and death is associated with combining two different types of drugs with different mechanisms of action.

Almost all human fatalities have been associated with a combination of MAOIs and (S)SRIs*.

*Remember, the term SRI includes various drugs not normally thought of to be antidepressants, such as some of the opioid analgesics, which also possess the property of serotonin reuptake.

The great majority of human fatalities have been associated with a combination of MAOIs and (S)SRIs. So far, just about the only other combination capable of causing fatalities is MAOIs with serotonin releasers (‘indirect agonists’) e.g. MDMA (but not methylphenidate). Over-doses of SSRIs-alone cause a marked increase in serotonin-mediated side effects which, in about 15 per cent of typical over-dose cases, leads to a degree of symptoms sufficient to cross an arbitrary threshold of severity which is now commonly referred to as ST.

SRIs-alone do not cause a sufficient degree of toxicity to require admission to an intensive care facility

It is more helpful to understand that there is a gradually increasing degree of severity of serotonin-mediated effects, which, at some point on the severity spectrum, it is appropriate to call ‘toxicity’: the spectrum concept.

The Spectrum Concept

One important reason for trying to understand all this is because some patients die. The question is, can we predict which patients are likely to die without treatment? The answer is unequivocally yes, as a result of the information and concepts above.

The only severe life-threatening ST you are ever likely to see is as a result of taking an MAOI and an SRI together

We know that even very large over-doses of SSRIs-alone rarely or never cause life threatening ST. The dramatic illustration of the usefulness of the ‘dose-effect’ idea (the spectrum concept) is contained in the story of methylene blue (MB). In 2006 I noticed that there were several reports that appeared to be severe ST following surgery for parathyroid conditions [6, 38-41]. It was soon apparent that it was only patients who had previously been taking SRIs who were getting this reaction. The only common link in terms of drugs was methylene blue, so this suggested that it must be a monoamine oxidase inhibitor, although this had not previously been recognised despite the fact that it has been in use for 50 years. I initiated research that provided strong evidence that this was indeed the case [25]: other details are contained in the MB commentary [see left-hand menu]. Similar reasoning led to the identification of metaxalone as a weak MAOI, see: https://psychotropical.com/metaxalone-skelaxin-potential-serotonin-toxicity/

Diagnostic Features

ST has now been clearly characterized as a triad of neuro-excitatory features. 1) Neuromuscular hyperactivity (hyperkinesia, the opposite of NMS which shows bradykinesia); tremor, hyperreflexia, and clonus in that order), and (in the advanced severe stage) pyramidal rigidity.

2) Autonomic hyperactivity; diaphoresis, hyperthermia, tachycardia and tachypnoea.

3) Altered mental status; characterised by ‘over-arousal’ typified by agitation, excitement, ‘mania’ and (only in the advanced stage) confusion.

Professor Whyte’s group have applied decision tree rules (CART) to their large data set and shown that only the symptoms of clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia are needed for accurate diagnosis of ST. Their research diagnostic rules are in their various papers. They demonstrate, for instance, that if in the presence of a drug known to produce potent serotonin-mediated effects (see table for clinically relevant drugs), the sole sign of spontaneous clonus is present, then ST may be reliably diagnosed.

Clinically, the onset of toxicity is usually rapid, because it results from drug combinations and starts when the second drug reaches effective blood levels. The clinical picture is often alarming and rapidly progressive after the first or second dose of the second serotonergic drug in the patient’s regime. The patient is often alert, with tremor and hyperreflexia. Ankle clonus is usually demonstrable, progressing to generalised repetitive spontaneous clonus. Neuromuscular signs are initially greater in the lower limbs, then become more generalized as toxicity increases. Patients may exhibit pronounced tremors. Other symptoms may include shaking, shivering often including chattering of the teeth and sometimes trismus. Pyramidal rigidity is a late development in severe cases, and when it affects the truncal muscles then rigidity impairs respiration. A body temperature steadily increasing above 39ºC, rigidity, and increasing PaCO2, heralds life-threatening toxicity.

Diagnostic decision rules intended for research cannot, and should not, replace clinical experience and judgment

There is no substitute for clinical experience and an understanding of pharmacology and, especially, the speed and time-course of progression of symptoms. The above information indicates that it is important to have an accurate well validated list of drugs that possess significant clinical potency for elevating serotonin in humans.

It is important to clarify the speed and time-course of the progression of symptoms

A definitive table of the relevant drugs is below, the justification for why a particular drug is included, or excluded, is based on in vitro HCR data, in silico data, animal experiments and human toxicology data. Understanding that properly requires extensive and detailed study (see my published papers and other commentaries).

Most published lists or tables of ‘serotonergic’ drugs contain errors and misinformation.

In brief, one simple example of this is mirtazapine, which is included by almost everyone in their lists; it is in fact a drug which reduces serotonin effects by blocking 5HT2A receptors, it reduces manifestations of severe ST in experimental animal models. It therefore poses no risk whatsoever of inducing ST in humans [21].

The term ‘serotonergic’ is generally misused because, strictly speaking, it means a drug affecting the serotonin system, which may therefore be either pro-serotonergic or anti-serotonergic. That is why I try to use the terms ‘serotonin-mediated’, and ‘serotonin-elevating’ in preference.

Drugs with clinically relevant serotonin-elevating effects

Serotonin reuptake inhibitors (selective and non-selective)

Paroxetine, sertraline, fluoxetine, fluvoxamine, (es)citalopram, and vortioxetine. (des)venlafaxine, (levo)milnacipran, duloxetine, clomipramine, imipramine (but not other TCAs) and sibutramine (not generally available any more).

Analgesics

Tramadol, pethidine, methadone, dextromethorphan, dextropropoxyphene, and pentazocine.

We can now be confident fentanyl (and congeners) are not significant elevators of serotonin.

Antihistamines

chlorpheniramine brompheniramine (but not other anti-histamines)

Miscellaneous

Ziprasidone (an anti-psychotic with some SRI action)

Serotonin releasers

MDMA (not Methylphenidate), fenfluramine (withdrawn)

Monoamine oxidase inhibitors

Tranylcypromine, phenelzine, isocarboxazid, (nialamid, iproniazid generally unavailable, isoniazid is too weak as MAOI)

MAO-A selective drugs do ppt. ST: methylene blue, clorgyline, Moclobemide, (befloxatone & toloxatone, if ever re-introduced), linezolid (probably only a danger in high doses)

MAO-B selective drugs do not precipitate ST: viz. selegiline, rasagiline ladostigil

Weak MAOIs

Possibly rarely a risk with high/IV dosing: linezolid, metaxalone (but not furazolidone or procarbazine).

Notes Although clomipramine and imipramine do precipitate ST, none of the other TCAs are able to because they are too weak as SRIs. Trazodone, nefazodone, mianserin, mirtazapine are not significant SRIs (they block 5-HT2A receptors). Fatalities from ST involving opioids have been with pethidine, tramadol and dextromethorphan, but not fentanil. Methylphenidate is not a serotonin releaser. See other commentaries for detailed information about other drugs of interest.

Figure 1: The Serotonin Toxicity Triangle STT Insert fig. here

The figure illustrates the severity of drug interactions between the three important classes of drugs that precipitate ST: MAOIs, SRIs, and ‘releasers’ like MDMA, as represented by the small centre triangle, the corners of which represent the three classes. ST is a concentration related phenomenon that increases with dose (and mixtures of different types of serotonergic drugs), Each class of drug has a maximum level to which it can elevate 5-HT. Numbers in boxes indicate potency: e.g. 1) Tranylcypromine, Phenelzine 2) Methylene Blue, 3) RIMAs, indicates that, in a given situation, TCP is a more potent precipitator of ST than is a RIMA *amphetamines: serious reactions and deaths do occur from hypertension, but probably not from ST, because they are DA releasers much more than 5-HT releasers. Figure 2 Degree of ST Typical with Drug Classes

Legend The bars depict ‘overdose’ and ‘high therapeutic dose’, which reflects the full effect of the drug as used for refractory illness. MAO-AB = non-selective irreversible inhibitors e.g. tranylcypromine and phenelzine; MAO-A = moclobemide; REL = 5-HT releasers like MDMA (the only one in therapeutic use, fenfluramine, has been withdrawn); SRI = all serotonin reuptake inhibitors, selective and non-selective and SNRIs.  Amphetamine is a releaser, but mainly of dopamine more than 5-HT.  The typical sequence of signs at their approximate initial appearance is shown. Note the clear ‘ceiling’ effects: e.g. SRIs alone rarely or never induce severe signs or temperatures of > 38.5°C Moclobemide overdose does not induce ST of even moderate degree, mirtazapine has no serotonergic side effects, and no serotonergic toxicity at all. The data on which this figure is based were checked and verified with the signs documented in the HATS database of thousands of overdoses (last checked March 2012), with the assistance of Professor Ian Whyte.

References

1. Werneke, U., et al., Conundrums in neurology: diagnosing serotonin syndrome–a meta-analysis of cases. BMC Neurology, 2016. 16(1): p. https://doi.org/10.1186/s12883-016-0616-1.

2. Akers, K.G., New journals for publishing medical case reports. Journal of the Medical Library Association: JMLA, 2016. 104(2): p. 146 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816468/.

3. Buckley, N.A., A.H. Dawson, and G.K. Isbister, Serotonin syndrome. BMJ, 2014. 348: p. 10.1136/bmj.g1626.

4. Buckley, N.A., et al., A prospective cohort study of trends in selfpoisoning, Newcastle, Australia, 1987–2012: plus ça change, plus c’est la même chose. Medical Journal of Australia, 2015: p. https://www.mja.com.au/journal/2015/202/8/prospective-cohort-study-trends-self-poisoning-newcastle-australia-1987-2012-plus.

5. Isbister, G.K., N.A. Buckley, and I.M. Whyte, Serotonin toxicity: a practical approach to diagnosis and treatment. Medical Journal of Australia, 2007. 187(6): p. 361-5.

6. Gillman, P.K., CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of Psychopharmacology, 2011. 25(3): p. 429-3.

7. Gillman, P.K., Triptans, Serotonin Agonists, and Serotonin Syndrome (Serotonin Toxicity): A Review. Headache, 2009. 50(2): p. 264-272.

8. Reith, D.M., et al., Clinical features of self-poisoning with monoamine oxidase inhibitors and / or serotonin reuptake inhibitors. Proceedings of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1996. 3( (Abstract)): p. 29.

9. Whyte, I.M. and A.H. Dawson, Relative toxicity of venlafaxine and serotonin specific reuptake inhibitors in overdose. Journal of Toxicology. Clinical Toxicology, 2001. 39: p. 255.

10. Whyte, I.M. and A.H. Dawson, Redefining the serotonin syndrome. Journal of Toxicology Clinical Toxicology, 2002. 40: p. 668-669.

11. Dunkley, E.J.C., et al., Hunter Serotonin Toxicity Criteria: a simple and accurate diagnostic decision rule for serotonin toxicity. Quarterly Journal of Medicine, 2003. 96: p. 635-642.

12. Isbister, G.K., et al., Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. British Journal of Clinical Pharmacology, 2003. 56: p. 441-450.

13. Whyte, I.M., Serotonin Toxicity (Syndrome). in Medical Toxicology, R.C. Dart, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 103–106.

14. Boyer, E.W. and M. Shannon, The serotonin syndrome. New England Journal of Medicine, 2005. 352(11): p. 1112-20.

15. Gillman, P.K., Serotonin Syndrome: History and Risk. Fundamental and Clinical Pharmacology, 1998. 12(5): p. 482-491.

16. Gillman, P.K., The serotonin syndrome and its treatment. Journal of Psychopharmacology, 1999. 13(1): p. 100-9.

17. Gillman, P.K., Moclobemide and the risk of serotonin toxicity (or serotonin syndrome). Central Nervous System Drug Reviews, 2004. 10: p. 83-85.

18. Gillman, P.K., Making sense of serotonin toxicity reports. A comment on Chopra et al. World Journal of Biological Psychiatry, 2004. 5: p. 166-167.

19. Gillman, P.K., Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British Journal of Anaesthesia, 2005. 95(4): p. 434-441.

20. Gillman, P.K., A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biological Psychiatry, 2006. 59(11): p. 1046-51.

21. Gillman, P.K., A systematic review of the serotonergic effects of mirtazapine: implications for its dual action status. Human Psychopharmacology. Clinical and Experimental, 2006. 21(2): p. 117-25.

22. Gillman, P.K., Extracting value from case reports: lessons from serotonin toxicity. Anaesthesia, 2006. 61: p. 419-422.

23. Lawrence, K.R., M. Adra, and P.K. Gillman, Serotonin Toxicity Associated with the Use of Linezolid: A Review of Postmarketing Data. Clinical Infectious Diseases, 2006. 42: p. 1578-83.

24. Gillman, P.K., Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology 2007. 151(6): p. 737-48.

25. Ramsay, R.R., C. Dunford, and P.K. Gillman, Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol, 2007. 152(6): p. 946-51.

26. Gillman, P.K., Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. Journal of Clinical Psychopharmacology, 2011. 31(1): p. 66-74.

27. Baldo, B.A., Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects. Arch Toxicol, 2018. 92(8): p. 2457-2473.

28. Baldo, B.A. and M.A. Rose, The anaesthetist, opioid analgesic drugs, and serotonin toxicity: a mechanistic and clinical review. Br J Anaesth, 2020. 124(1): p. 44-62.

29. Guo, S.L., et al., Meperidine-induced serotonin syndrome in a susceptible patient. British Journal of Anaesthesia, 2009.

30. Sternbach, H., The serotonin syndrome. American Journal of Psychiatry, 1991. 148: p. 705-713.

31. Gillman, P.K., Neuroleptic Malignant Syndrome: Mechanisms, Interactions and Causality. Movement Disorders, 2010. 25(12): p. 1780-1790.

32. Isbister, G.K. and N.A. Buckley, The Pathophysiology of Serotonin Toxicity in Animals and Humans: Implications for Diagnosis and Treatment. Clinical Neuropharmacology, 2005. 28(5): p. 205-214.

33. Isbister, G.K. and N. Buckley, Adverse reactions to psychotropic medication: the literature continues to confuse. British Medical Journal, 2005: p. http://bmj.bmjjournals.com/cgi/eletters/329/7478/1333.

34. Gillman, P.K., NMS and ST: chalk and cheese. British Medical Journal, 2005: p. http://bmj.bmjjournals.com/cgi/eletters/329/7478/1333.

35. Gillman, P.K., Defining toxidromes: serotonin toxicity and neuroleptic malignant syndrome: A comment on Kontaxakis et al. Archives of General Hospital Psychiatry, 2004: p. http://www.general-hospital-psychiatry.com/content/2/1/10/comments#41454.

36. Gillman, P.K., Comments on “Serotonin syndrome during treatment with paroxetine and risperidone”. Journal of Clinical Psychopharmacology, 2001. 21(3): p. 344-5.

37. Whyte, I.M., Serotonin syndrome complicating the treatment of recurrent depression. Current Therapeutics, 1999. 40: p. 6-7.

38. Gillman, P.K., Methylene Blue implicated in potentially fatal serotonin toxicity. Anaesthesia, 2006. 61: p. 1013-1014.

39. Gillman, P.K., Methylene Blue: A Risk for Serotonin Toxicity. Australian and New Zealand College of Anaesthetists Bulletin, 2008. 17: p. 36.

40. Gillman, P.K., Methylene blue is a potent monoamine oxidase inhibitor. Can J Anaesth, 2008. 55(5): p. 311-2.

41. Gillman, P.K., Methylene Blue and Serotonin Toxicity: Definite Causal Link. Psychosomatics, 2010. 51(5): p. 448-9.

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