Serotonin toxicity (also known as the serotonin syndrome) is a drug-induced toxidrome (from toxic syndrome) related to synaptic serotonin (5-HT) concentrations. Current evidence indicates that serotonin toxicity will occur in everyone who accumulates excess intrasynaptic 5HT. It is possible that individual susceptibility will vary to some degree, for instance as a result of genetic variation in cytochrome P450 enzymes, serotonin transporter properties or receptor structure.

Clinical description of serotonin toxicity
The onset of severe toxicity is usually rapid following the troduction of a second serotonergic drug. The patient is initially alert/agitated, with tremor and hyperreflexia. The HATS database* has produced a clear picture of features that are associated with serotonin toxicity (Table 1), which may be characterised 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, mydriasis, fever, tachycardia and tachypnoea.
3) Altered mental status: agitation, excitement and (only in the advanced stage) confusion. [1, 2, 3]

*HATS database is a large series of consecutive poisonings from a toxicology unit with a defined catchment area. It has been compiled over a number of years by Professor Ian Whyte and his team (Faculty of Medicine and Health Sciences, University of Newcastle, NSW, Australia. mdimw@cc.newcastle.edu.au).

 Table 1. Serotonin related signs stratified by severity

Severity	Typical causes	Signs
Mild	SSRI + lithium, L-tryptophan or buspirone	Shivering, occasional myoclonus, tremor, hyperreflexia, fever (>37.5°C but <38.5°C)
Moderate	Over-dose of SSRI	Alertness, agitation, regular myoclonus, inducible ankle clonus, hyperreflexia, fever (>38.5°C but <39.5°C)
Severe	MAOI + SSRI	Severe agitation, generalised myoclonus, hyperreflexia, sustained ankle clonus, fever (>39.5°C), hypertonia/rigidity

SSRI = selective serotonin reuptake inhibitor; MAOI = monoamine oxidase inhibitor

Implicated drugs
The most important mechanism in relation to severe serotonin toxicity is serotonin reuptake inhibition when associated with monoamine oxidase inhibitors. Many drugs, not usually considered to be serotonin reuptake inhibitors do, in fact, have this activity.

Table 2. Serotonergic drugs (modified from [4])

Serotonin reuptake inhibitors (selective and non-selective)	paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram
Dual serotonin noradrenaline reuptake inhibitors (SNRI)	venlafaxine, milnacipran, duloxetine, sibutramine
Tricyclic antidepressants (TCA)	clomipramine, imipramine
Other antidepressants	St John's Wort (Hypericum perforatum)
Analgesics*	tramadol, pethidine (meperidine), fentanyl, methadone, dextromethorphan, dextropropoxyphene, pentazocine
Antihistamines	chlorpheniramine, brompheniramine
Monoamine oxidase inhibitors (irreversible)	tranylcypromine, phenelzine, nialamid isoniazid, iproniazid, isocarboxazid, pargyline, selegiline (deprenyl), clorgyline, furazolidone, procarbazine, linezolid
Monoamine oxidase inhibitors (reversible)	moclobemide, toloxatone

* Fatalities from serotonin toxicity involving analgesics have been seen with pethidine, tramadol, dextromethorphan and fentanyl.

The dose-effect relationship
Serotonin toxicity is a progression of effects from serotonin-related side-effects (at therapeutic doses) through to toxicity (in over-dose). There is now clear evidence that the number of fatalities resulting from monoamine oxidase inhibitors (MAOI) + serotonin reuptake inhibitors (SRI) is related to the increase in 5-HT levels. There are more deaths with MAOI + paroxetine (the most potent SRI than with MAOI + fluoxetine (a weaker SRI), and least deaths with MAOI + imipramine (the weakest SRI). Table 3 shows the close relationship between the affinities for cloned human 5-HT transporter and the severity of serotonin toxicity when the SRIs are mixed with MAOIs. A clear dose-effect relationship of clonus and hyperreflexia with MAOIs and ascending doses of L-tryptophan, from 20 up to 50 mg / kg /day has also been demonstrated [5].

Table 3. Serotonin transporter affinity (Ki in nmol) and serotonin toxicity

	affinity (Ki nM)
Paroxetine	0.13	Most potent - frequent serotonin toxicity + MAOIs
Other SSRIs	0.13	Frequent serotonin toxicity + MAOIs
Clomipramine	0.28	Frequent serotonin toxicity + MAOIs
Imipramine	1.4	Intermediate potency - less frequent serotonin toxicity + MAOIs
Amitriptyline	4.3	Less potent- no serotonin toxicity + MAOIs
Other TCAs	>5	Even less potent, no serotonin toxicity + MAOIs
Venlafaxine	~8	The exception, serotonin toxicity more frequent than SSRIs in spite of lower affinity

data taken from http://kidb.cwru.edu/pdsp.php

Note:The frequency of serotonin toxicity also correlates with serotonin reuptake inhibitor potency for narcotic analgesics although there is no systematic data on serotonin reuptake inhibitor potency of narcotic analgesics using human cloned receptors [6]. For more extensive tables see http://www.psychotropical.com/SerotoninToxicity.doc

In humans the evidence from the HATS database and elsewhere indicates that serotonin toxicity occurs more frequently with larger doses of selective serotonin reuptake inhibitors (SSRIs) and more frequently in overdose [7, 8, 9]. Interestingly over-dose of venlafaxine is associated with a greatly increased risk of serotonin toxicity compared to all other SSRIs [8], this may suggest an additional mechanism of serotonergic action. Clomipramine over-dose, on the other hand, is less likely to cause serotonin toxicity, possibly because of its potency as a 5-HT_2A receptor antagonist [10].

The tricyclic antidepressants (TCAs) exhibit widely varying potencies for serotonin reuptake inhibition (see Table 3). Although there has some confusion in the literature over the last fifty years [11] a re-analysis of the data demonstrates clearly that it is safe to combine amitriptyline, a weak SRI, with a MAOI. Amitriptyline in overdose does not exhibit serotonin toxicity (i.e. the features of neuromuscular hyperactivity; tremor, clonus, myoclonus, hyperreflexia). Other TCAs with weaker SRI potency than amitriptyline are not associated with serotonin toxicity, either in over-dose by themselves, or when combined with MAOIs [4]. Conversely the more potent TCA serotonin reuptake inhibitor, clomipramine, has serotonergic effects in over-dose and causes fatalities from serotonin toxicity with MAOIs, as do the SSRIs. The lack of significant serotonin toxicity with MAOIs when they are combined with drugs such as nefazodone or mirtazapine indicates the modest extent to which these drugs raise serotonin levels [12, 13].

The dangerous combinations, likely to give rise to fatalities, are irreversible MAOIs (eg tranylcypromine or phenelzine), or RIMAs such as moclobemide, when combined with any SRI (see Table 3). It is important to note that it is not just the SSRIs, but also other drugs that act as SRIs, such as some narcotic analgesics (especially tramadol and pethidine), venlafaxine and sibutramine. Moclobemide alone has low (possibly zero) propensity to cause serotonin toxicity, even with large over-doses [7], but the risk of serious serotonin toxicity and death when moclobemide is combined with SRIs is high. Thus, in spite of many claims to the contrary, moclobemide is NOT safe to combine with a drug that inhibits serotonin reuptake.
A detailed critical analysis of moclobemide and serotonin toxicity may be found at http://www.psychotropical.com/serotonintoxicity.doc

Diagnosis and treatment
Differentiating serotonin toxicity and neuroleptic malignant syndrome (NMS)
Contrary to comments that are sometimes heard it is not difficult to distinguish serotonin toxicity from NMS since their typical features are quite different (Table 4).

Table 4. Comparison of Serotonin Toxicity and Neuroleptic malignant syndrome

Serotonin toxicity	Neuroleptic malignant syndrome
Rapid onset and rapid progression in association with serotonergic drugs	Slow onset and progression, in association with neuroleptics
Hyperkinesia (agitation) and hyperreflexia / clonus, pyramidal rigidity.	Bradykinesia and extrapyramidal rigidity.
A manifestation of toxicity	An idiosyncratic reaction to therapeutic doses

Based on data in [4, 14]

Establishing a diagnosis of Serotonin Toxicity
Key information is:
1) The quantity and type of drugs ingested
2) The evolution of the symptoms and their rate of change, especially temperature > 38.5°C, severe upper body hyperreflexia accompanied by rising plasma CO₂ levels (secondary to impaired truncal muscle movement reducing respiration).

An overdose of a SSRI alone produces a moderate degree of serotonin toxicity in 10% - 20 % of cases (sufficient for admission and active medical treatment), but with no serious sequelae, and no fatalities have been reliably documented.

When both a MAOI and a SRI have been co-ingested (even in low doses) rapid deterioration is likely and early transfer to an emergency setting with a toxicologist is strongly recommended.

Treatment
If an MAOI or RIMA + SRI have been co-ingested then more than 50% of such cases experience severe potentially life-threatening serotonin toxicity. It is these combinations that are most likely to require active medical intervention including intensive care, cooling, 5HT_2A receptor antagonists such as cyproheptadine, intubation and neuromuscular paralysis. Benzodiazepines may also be a useful adjunctive treatment along with 5-HT_2A receptor antagonists [15, 16, 17].

Non-specific treatment, without an understanding the underlying concept, constitutes an ill-informed and dangerous over-simplification. The speed with which death ensues, if appropriate treatment is not urgently initiated, cannot be over-emphasised (see http://www.psychotropical.com/SerotoninToxicity.doc) .

Details of these treatments are outside the scope of this review but can be readily found in the medical literature.

Conclusion
Serotonin toxicity is one of the very rare instances in clinical medicine where it is possible that death will result from the addition of a drug at therapeutic doses (a SRI) whilst a patient is on a course of another drug (a MAOI or RIMA). Serotonin toxicity has been a clinical problem for 50 years. The increased use of serotonergic drugs has increased the risk. It is important that all physicians should appreciate the risk and have, at least, a minimal understanding of how to avoid them and treat them when they occur.

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