Serotonin Toxicity, Serotonin Syndrome

Introduction

There has been, and there remains, much misunderstanding and misinformation concerning serotonin toxicity, both in medical, and non-medical, texts. This includes prestigious medical journals and books that are usually revered as authoritative and accurate.

Important original research has been published during 2003 and 2004 (especially Professor Whyte's HATS data) that makes much of what has previously been written redundant (1-15).

Serotonin toxicity only occurs after the ingestion of drugs that increase brain serotonin levels. There is no other disease or a natural cause for this constellation of symptoms and signs. It is poisoning caused by serotonergic agents. The typical side effects caused by usual therapeutic doses of the SSRIs, which are the most widely known and used serotonergic drugs, increase with increasing dose. There is variation between individuals in the susceptibility to various typical side effects and also 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 (like fluoxetine and paroxetine) have 'non linear' pharmacokinetics. Side effects may include the agitation and increased suicidal propensity that is possibly experienced by some individuals and about which there has been much written lately. Another example is the quite marked muscular jerks that happen during sleep, they probably represent myoclonic phenomena which are usually considered as diagnostic of ST. (*the term side effects in this context is something of a misnomer because the effects being referred to are an inevitable consequence of the drugs main intended mechanism of action, i.e. reuptake inhibition of serotonin, resulting in increased serotonin levels. These inevitably cause, for instance, tremor, diarrhoea, retarded orgasm etc. Whether retarded orgasm is regarded as a side-effect or a benefit depends on what effect you wanted.)

These idiosyncratic responses do not alter the evidence that the general pattern of side effects gradually become worse with increasing 'dose', and reach a degree of severity which justifies calling them toxic effects, in a dose-related manner (16). The meaning of the word toxicity is 'poisoning', and that insinuates life threatening consequences. If we are being precise the term ST should be reserved for those cases sufficiently severe to require hospital admission and medical intervention. It is appropriate to remember that all of us tend to be careless in the use of words and terms, but nevertheless this distinction, if born in mind, will help to maintain clarity of thinking. 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. Probably the most relevant and objective criteria is body temperature. That is the change that mediates the severe life threatening effects of ST. A key goal of medical management is to predict those cases that may become sufficiently severe to necessitate active intervention. It is now beyond reasonable argument that the degree of serotonin toxicity exhibited in experimental animals, given combinations of drugs that elevate serotonin levels, gradually increases, eventually causing excessive body temperature (hyperpyrexia) and death as a result: this is a 'dose-related' phenomenon (15, 17, 18). When pharmacologists say 'dose-related' what they really mean it is related to the end effect of the drug. 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 animals. Serotonin toxicity illustrates this point further, because there are cumulative effects caused by the end effect of two different drugs producing an additive effect which is much larger than either individual drug is able to produce by itself. 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.

It is also now clearly established that drugs that block 5-HT2A post-synaptic receptors prevent deaths from hyperpyrexia in animals and very probably do the same in Humans (3, 5, 10, 14, 15, 17, 19, 20). Contrary to much published comment, 5-HT1A receptor antagonists (blockers) make serotonin toxicity worse, not better (21). This leads to the inescapable conclusion that the most important consequences of serotonin toxicity are mediated by 2A receptors. If this were more widely known and appreciated some of the recently reported deaths and serious cases may have been avoided (22-25).

The more recent papers mentioned above, particularly those from Professor Whyte's HATS research group, have now clearly established the typical clinical picture, the diagnostic features, and also validated clear diagnostic decision rules for serotonin toxicity (13).

One of the main reasons for using the term serotonin toxicity rather than serotonin syndrome is because this emphasizes that it is a form of poisoning, not an idiosyncratic syndrome: i.e. a syndrome usually implies something that occurs in some people, but not in others. Neuroleptic malignant syndrome is idiosyncratic and rarely occurs after over-dose of neuroleptics: rather it occurs in a very small proportion of patients who are taking average, or above average, therapeutic doses (4, 26). NMS is quite different to ST (26-29).

The usefulness of conceptualising the problem as serotonin toxicity, rather than serotonin syndrome, is made evident in a variety of ways. For instance, consider the frequent comment 'serotonin syndrome is rare', and then the statement 'poisoning is rare'; it is true that poisoning is rare, except in those who ingest poisons. However, neither statement is much 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 (30). 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 (31, 32). This important logical principle was popularised more recently by the astronomer Carl Sagan as ''extraordinary claims require extraordinary evidence' (33). This line of thought originates from the Scottish philosopher David Hume (1711-1776) who launched an effective critique of miraculous claims (34). This sceptical rationalism was a major challenge to religious belief throughout the later 18th and 19th centuries. Those who enjoy a good chortle might care to read the splendid essay by Darwin's cousin, Francis Galton, funded by Wedgewood potteries, 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

It is difficult to suffer from poisoning if you haven't taken a poison. This is a slightly trite way of expressing the idea that the most important piece of information for doctors to know if they are dealing with a possible case of serotonin toxicity is: what drugs have been ingested? The ingested drugs determine the form of poisoning and large enough doses will produce poisoning in all people, even if there is some inter-individual variation in susceptibility. This is what has led to the first diagnostic decision rule from the HATS data which is: a definite prediction of impending serotonin toxicity can be confidently made if a known potently serotonergic drug has been ingested and the single physical sign of clonus is present (13). Similarly one can state that if a mixture of MAOIs and SSRIs has been ingested there is (at least) a 50 per cent probability of life threatening serotonin toxicity (6, 12): even if the patient currently appears well they must be observed in an intensive care unit (35).

In order to understand the more subtle complexities of this issue it is necessary first to remember that serotonin toxicity is mediated by an increase in the level of serotonin in synapses in the central nervous system*, which then excessively stimulate all types of post synaptic serotonin receptors. Because there are several types of drug with different mechanisms of action, each of which can increase serotonin levels to differing degrees, there is a characteristic degree of severity 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 38.5c (5); however, an overdose of an MAOI like tranylcypromine-alone will produce hyperpyrexia, and even death (2), but over-dose of the RIMA moclobemide-alone does nothing. This demonstrates that the maximum elevation of serotonin produced by these mechanisms is significantly different, being greater with the old irreversible MAOIs.

*Because serotonin is unable to cross the blood brain barrier conditions such as carcinoid syndrome that involve considerable increases in peripheral serotonin cannot 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 serotonin toxicity) by taking only one type of drug (e.g. MDMA, ecstasy (3,4-methylenedioxymethamphetamine)). It is almost always the case that serious toxicity and death is associated with combining two different types of drug with a different mechanisms of action. A great majority of human fatalities are 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. Amphetamine (but not methylphenidate) and MDMA.

Over-Doses of SSRIs-alone cause a marked increase in serotonergic side effects which, in about 15 per cent of typical over-dose cases, leads to a degree of symptoms sufficiently severe to cross an arbitrary threshold of severity which has been commonly referred to as 'serotonin syndrome'. However, as argued above, the term serotonin syndrome is unhelpful and it is more helpful to understand that there is a gradually increasing degree of severity of serotonergic effects, which at some point on the severity spectrum, it is appropriate to call 'toxicity'.

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. We now know that even very large over-doses of SSRIs rarely or never cause life threatening serotonin toxicity (5). The dramatic illustration of the usefulness of the 'dose-effect' idea (the spectrum concept) is that about 50 per cent of patients who take an overdose of a mixture of MAOIs (of the RIMA sub-type) and SSRIs experience serious serotonin toxicity which is life threatening, and often requires treatment with 5-HT2A antagonists (12) (the old MAOIs + SSRIs are even more likely to precipitate severe ST).

The only other combination that can produce life threatening toxicity is that of an MAOI and a serotonin releaser. This means a combination of moclobemide (or older MAOIs like tranylcypromine) with either Amphetamine or MDMA. Such combinations are almost exclusively a result of the illicit drugs scene, although they could occur if a doctor used amphetamine and moclobemide or tranylcypromine etc together (see table).

Fatalities do occur with larger single drug over-doses of the old irreversible MAOIs, such as tranylcypromine. There is some uncertainty about whether this is from purely serotonergic effects, or from other effects (i.e. dopamine and noradrenaline). This is in dramatic contrast the newer RIMA moclobemide which does not even cause significant serotonergic side effects when taken in over-dose by itself, never mind serious serotonin toxicity (12). This illustrates the large difference in the effect on brain serotonin levels of these two types of drug. In my opinion, this may also explain the substantial difference in their effectiveness for the treatment of depression (tranylcypromine good, moclobemide poor).

ST has now been more clearly characterized as a triad of neuro-excitatory features.

  1. Neuromuscular hyperactivity; tremor, clonus, myoclonus, hyperreflexia, and (in the advanced stage) pyramidal rigidity.
  2. Autonomic hyperactivity; diaphoresis, fever, tachycardia and tachypnoea.
  3. Altered mental status; agitation, excitement and (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 serotonin toxicity. Their diagnostic rules are in their paper, which should be consulted (13). They demonstrate that if, in the presence of a serotonergic drug (see table for what is a clinically significant serotonergic drug), spontaneous clonus is present 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 and myoclonus are usually demonstrable. 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 truncal muscles that impairs respiration. Rigidity, decreasing PaCO2, and a fever of >38.5ÂșC heralds life-threatening toxicity.

The above information indicates that one of the most important things is to have an accurate list of drugs with significant clinical potency on the serotonin system in humans. A brief table of the important drugs is below, but the detailed justification of why particular drugs are included or excluded requires much more extensive and detailed study of other references.

Drugs with clinically relevant serotonergic potency

From reference:--(36, 37)

Serotonin reuptake inhibitors (selective and non-selective)

  • Paroxetine sertraline fluoxetine fluvoxamine citalopram vilazodone 
  • venlafaxine milnacipran [& now re-badged as levomilnacipran (Fetzima)
    duloxetine sibutramine.
  • clomipramine imipramine (but not other TCAs).
  • tramadol pethidine fentanil (and congeners) methadone dextromethorphan dextropropoxyphene pentazocine (but not other opioids).
  • chlorpheniramine brompheniramine (but not other anti-histamines).

Serotonin releasers

  • Amphetamine MDMA.

Monoamine oxidase inhibitors

  • Tranylcypromine phenelzine nialamid iproniazid isocarboxazid.
  • pargyline selegiline clorgyline.
  • moclobemide toloxatone.
  • furazolidone procarbazine linezolid.
  • Methylene Blue

Table 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 neither SRIs nor significantly serotonergic. Also, they do not precipitate serotonin toxicity with MAOIs see (21).

Fatalities from ST involving opioids have been with pethidine, tramadol and dextromethorphan and, possibly fentanil. See (21).

Methylphenidate appears insufficiently potent as a serotonin releaser to precipitate serotonin toxicity.

Despite one or two odd reports tryptans do not appear to be associated with ST.

For the Methylene Blue story see (38).

References

1. Whyte, IM, Serotonin uptake inhibitors, in Medical Toxicology, R.C. Dart, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 843-851.

2. Whyte, IM, Monoamine oxidase inhibitors, in Medical Toxicology, R.C. Dart, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 823-834.

3. Whyte, IM, Serotonin Toxicity (Syndrome). in Medical Toxicology, R.C. Dart, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 103-106.

4. Whyte, IM, Neuroleptic malignant syndrome., in Medical Toxicology, R.C. Dart, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 101-103.

5. Isbister, GK, et al., Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. Journal of Toxicology. Clinical Toxicology, 2004. 42(3): p. 277-85.

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

7. Gillman, PK, Making sense of serotonin toxicity reports, a comment on Chopra et al. (World J Biol Psychiatry 2004, 5: 114-115). World Journal of Biological Psychiatry, 2004. 5: p. 167-8.

8. Gillman, PK, Serotonin toxicity. www.depression-webworld.com, 2004. www.depression-webworld.com/serotox.htm.

9. Gillman, PK, The spectrum concept of serotonin toxicity. Pain Medicine, 2004. 5(2): p. 231-2.

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22. Otte, W, Birkenhager, TK, and van den Broek, WW, Fatal interaction between tranylcypromine and imipramine. European Psychiatry, 2003. 18: p. 264-265.

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

28. Gillman, PK, Misleading cases. Journal of the American Medical Directors Association, 2005. 6(6): p. 422-3.

29. Gillman, PK, More misleading case reports. Anaesthesia, 2005: p.

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31. Buckley, NA, Whyte, IM, and Dawson, AH, Diagnostic data in clinical toxicology--should we use a Bayesian approach? Journal of Toxicology. Clinical Toxicology, 2002. 40(3): p. 213-22.

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34. Hume, D, An Enquiry Concerning Human Understanding, ed. L.A.S. Bigge. 1902: Oxford: Clarendon Press. 114-16.

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