Published: December 2010

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Serotonin syndrome/toxicity - reminder

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Prescriber Update 31(4): 30-31
December 2010

Serotonin syndrome, more correctly termed serotonin toxicity, is a set of predictable type A dose dependent adverse reactions caused by increased intra-synaptic/extracellular serotonin.¹

Since serotonin toxicity can be fatal after a single dose of an inappropriate medicine (or combination) it is vitally important to be familiar with both the causal agents and signs and symptoms.

A number of diagnostic criteria have been suggested, the most commonly quoted are Sternbach's² (based on a review of 38 case reports) and the Hunter criteria (derived from Australian toxicology data).³ The Hunter criteria are generally considered to be preferable as they are based on a larger sample size (2222 cases) and have been shown to be simpler, more sensitive and more specific.⁴

The Hunter criteria can be grouped into a triad of clinical features:

Neuromuscular effects	Autonomic effects	Mental state changes
Hyperreflexia	Tachycardia	Agitation
Clonus (spontaneous or inducible)	Hyperthermia (mild<8.5°C, severe ≥ 38.5°C	Hypomania
Myoclonus	Diaphoresis	Anxiety
Shivering	Flushing	Confusion
Hypertonia/rigidity

The most robust diagnostic feature of serotonin toxicity is clonus (spontaneous, inducible or ocular) and this differentiates serotonin toxicity from other toxic drug states.³

The severity of serotonin toxicity can generally be classified as: mild, moderate or severe. Severe toxicity is characterised by rapidly increasing body temperature associated with muscle rigidity; this is a medical emergency. The patient may deteriorate to multiorgan failure and death without treatment. Recommended treatment is generally supportive. Serotonin receptor antagonists such as chlorpromazine and cyproheptadine have been used to treat serotonin toxicity; sedation, muscle paralysis and ventilation may be required in severe cases. Although cases of moderate toxicity are unlikely to be fatal, symptoms can cause significant distress to the patient and supportive treatment should be provided.³

The three pharmacological mechanisms contributing to serotonin toxicity are: serotonin reuptake inhibition (SRI), presynaptic serotonin release and monoamine oxidase (MAO) inhibition. Overdose with single agents causing SRI or reversible inhibition of MAO (RIMAs) rarely cause serotonin toxicity; however overdoses of MAOIs alone can result in serotonin toxicity. Although the serotonergic toxicity of SSRIs increases with dose, SSRIs alone generally do not precipitate life threatening toxicity. Life threatening toxicity has occurred when MAOIs are combined with other serotonergic medicines.¹

Whilst the pharmacology of serotonin toxicity is relatively simple, it is important to remember that it is not only prescription antidepressant medicines that can cause this toxicity. Non-prescription medicines, some illicit drugs and some complementary medicines can also affect serotonin concentrations. Therefore prescribers are advised to check with patients about use of over-the-counter or complementary medicines before prescribing serotonergic medicines.

A summary of serotonergic medicines is given in Table 1 below. Please be aware that this will change with time and is not exhaustive.

Table 1: Serotonergic substances

Serotonin Reuptake Inhibitors
SSRIs	fluoxetine paroxetine sertraline	fluvoxamine citalopram escitalopram
Tricyclic antidepressantsa	clomipramine	imipramine
SNRIs	velafaxine sibutramineb	duloxetine
Opioid Analgesics	pethidine tramadol dextropropoxyphene	fentanyl methadone dextromethorphanc
Herbal (complementary)	St John's wort
Monamine oxidase Inhibitorsd
Irreversible	phenelzine	tranylcypromine
Reversible	selegilene	moclobemide
Antibiotics	linezolid	isoniazid
Others	methylene blue (methylthioninium chloride)
Serotonin Releasing Agents
	Fenfluraminee	Amphetaminesf
	MDMA(ecstacy)
Others
Antihistaminesg	chlorphenamine	bromphenamine
Miscellaneoush	lithium	tryptophan

1. Only these tricyclic antidepressants have serotonergic activity.
2. Sibutramine although indicated for weight loss was an SNRI. Although this medicine has been withdrawn it has been found in 'herbal' weight loss products.
3. Dextromethorphan is used as an anti-tussive and is available in supermarkets.
4. Only MAOIs approved for use in New Zealand are listed here.
5. Fenfluramine is not approved for use in New Zealand but has been found in 'herbal' weight loss products.
6. Methylphenidate is not serotonergic, but methamphetamine ("P") may be.
7. Not all commentators include these antihistamines as serotonergic.
8. The evidence that triptans are serotonergic is controversial. The FDA has previously issued an alert but the pharmacology is not suggestive of an ability to provoke serotonin toxicity.

References

1. Gillman PK 2006 'A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action'. Biol Psychiatry 59: 1046-1051.
2. Sternbach H 1991 'The serotonin syndrome' Am. J. Psychiatry 148: 705-713.
3. Isbister GK, Buckley NA and Whyte IM 2007 'Serotonin toxicity: a practical approach to diagnosis and treatment' Med J Aus 187: 361-365.
4. Dunkley EJC, Isbister GK, Sibbritt D et al 2003 'The Hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity'. Q J Med 96: 635-642.