Serotonin syndrome

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**Serotonin syndrome**
*Classification & external resources*

Serotonin
ICD-9	333.99
DiseasesDB	30044
eMedicine	ped/2786
MeSH	C21.613.276.720

Serotonin syndrome is a rare, but potentially life-threatening adverse drug reaction that results from intentional self-poisoning, therapeutic drug use, or inadvertent interactions between drugs. It is an iatrogenic (i.e. caused by medical treatment) toxidrome. It is most commonly referred to as serotonin syndrome, however, serotonin toxicity or serotonin toxidrome (from toxic + syndrome) are more accurate as it reflects the fact that it is a form of poisoning.^[1]^[2] Rarely it may also be called serotonin storm.

Serotonin syndrome is not a spontaneous drug reaction, it is a consequence of excess serotonergic activity at central nervous system (CNS) and peripheral serotonin receptors. This excess serotonin activity produces a specific spectrum of clinical findings which may range from barely perceptible to fatal.^[3]

1 Mechanism
- 1.1 Drugs which may contribute
- 1.2 Spectrum concept
2 Risk and severity
3 Symptoms
4 Diagnosis
5 Management
6 Neuroleptic malignant syndrome and serotonergic syndrome
7 Footnotes
8 External links

[edit] Mechanism

Serotonin syndrome is caused by increased serotonin in the central nervous system. It is the result of overstimulation of 5-HT1A receptors in central grey nuclei and the medulla and, perhaps, of overstimulation of 5-HT2 receptors.^[3]^[4] These changes are more pronounced following supra-therapeutic doses and overdoses, and they merge in a continuum with the toxic effects.^[5]^[6]^[7]

[edit] Drugs which may contribute

A large number of drugs and drug combinations have been associated with the serotonin syndrome.

Class	Drugs
antidepressants	MAOIs, TCAs, SSRIs, mirtazapine, venlafaxine, St John's Wort
opioids	tramadol, pethidine, oxycodone, morphine...
CNS stimulants	phentermine, diethylpropion, amphetamines, sibutramine, methylphenidate
5-HT₁ agonists	triptans
illicit drugs	methylenedioxymethamphetamine (MDMA or ecstasy), lysergic acid diethylamide (LSD), cocaine
others	selegiline, tryptophan, buspirone, kanna, lithium, linezolid, dextromethorphan (DXM), 5-HTP, chlorpheniramine
Reference: Rossi, 2005;^[8] National Prescribing Service, 2005^[9]

The combination of MAOIs and other serotonin agonists or precursors poses a particularly severe risk of a life-threatening serotonin syndrome episode. Many MAOIs inhibit monoamine oxidase irreversibly, so that the enzyme cannot function until it has been replaced by the body, which can take at least two weeks. A dangerous serotonin syndrome reaction can occur unless serotonin agonists and even serotonin precursors such as foods containing tryptophan are strictly avoided until the monoamine oxidase has been replaced.

[edit] Spectrum concept

A recently postulated ‘spectrum concept’ of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. The dose effect relationship is the term used to describe the effects of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug (which may produce large elevations in serotonin levels).^[10]

[edit] Risk and severity

The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. The serotonergic toxicity of SSRIs increases with dose, but even in over-dose it is insufficient to cause fatalities from serotonin syndrome in healthy adults. The syndrome occurs in approximately 14 to 16 percent of persons who overdose on SSRIs.^[6] It is usually only when drugs with different mechanisms of action are mixed together that elevations of central nervous system serotonin reach potentially fatal levels. The most frequent (and perhaps the only) combination of therapeutic drugs likely to elevate serotonin to that degree is the combination of monoamine oxidase inhibitors with serotonin reuptake inhibitors (Various drugs, other than the selective serotonin reuptake inhibitors (SSRIs), have clinically significant potency as serotonin reuptake inhibitors, e.g. tramadol and sibutramine). Serotonin releasers such as amphetamine and the street drug MDMA, known as "ecstasy" can cause fatalities if mixed with MAOIs^[11]

The relative risk of serotonin toxicity provides some clues and insights about the nature and extent of drugs’ serotonergic effects. For example, it suggests mirtazapine, which has no serotonergic toxicity, has no significant serotonergic effects at all, and is not in fact a dual action drug.^[12]

[edit] Symptoms

Symptom onset is usually rapid, often occurring within minutes after self-poisoning or a change in medication. Serotonin syndrome encompasses a wide range of clinical findings. Mild symptoms may only consist of tachycardia, and shivering, diaphoresis, mydriasis, intermittent tremor or myoclonus, as well as overactive or overresponsive reflexes. Moderate intoxication includes abnormalities such hypertension and hyperthermia; a temperature as high as 40°C (104° F)is common in moderate intoxication. As well as the mild symptoms other features include hyperactive bowel sounds. The overactive reflexes and clonus in moderate cases may be greater in the lower limbs than in the upper limbs. Mental status changes include hypervigilance and agitation.^[3]

Severe symptoms include severe hypertension and tachycardia that may lead to shock. Severe case often have agitated delirium as well as muscular rigidity and high muscular tension. Temperature may rise to above 41.1°C (105.98° F) in life-threatening cases. Other abnormalities include metabolic acidosis, rhabdomyolysis, seizures, renal failure, and disseminated intravascular coagulation.^[3]

The symptoms are often described as a clinical triad of abnormalities:

Cognitive effects: mental confusion, hypomania, hallucinations, agitation, headache, coma.
Autonomic effects: shivering, sweating, fever, hypertension, tachycardia, nausea, diarrhea.
Somatic effects: myoclonus/clonus (muscle twitching), hyperreflexia, tremor.

[edit] Diagnosis

There is no lab test for serotonin syndrome, so diagnosis is by symptom observation and the patient’s history. Serotonin toxicity is a toxidrome (i.e. has a characteristic picture). It is unique and hard to confuse with other medical conditions but in some situations it may go unrecognized because it may be mistaken for a viral illness, anxiety, neurological disorder, or worsening psychiatric condition.^[13] Much confusion has been produced by muddling it with side effects from serotonergic drugs. These rarely, if ever, become dangerous or fatal. Clinicians must also differentiate between serotonin syndrome and neuroleptic malignant syndrome, which has similar symptoms. Patients taking serotonergic drugs and who have sudden onset of symptoms should immediately seek medical care.

[edit] Management

There is no antidote to the condition itself, and management involves the removal of the precipitating drugs, the initiation of supportive care, the control of agitation, the administration of serotonin antagonists (cyproheptadine or methysergide), the control of autonomic instability, and the control of hyperthermia.^[14]^[3]

The intensity of therapy depends on the severity of symptoms, If the symptoms are mild, treatment may only consist of discontinuation of the offending medication or medications, offering supportive measures, giving benzodiazepines, and waiting for the symptoms to resolve. If the offending medication is discontinued, the condition will often resolve on its own within 24 hours.^[15]^[16] Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotoinin antagonists (i.e. cyproheptadine). Critically ill patients should receive the above therapies as well as sedation, neuromuscular paralysis, and be intubated.^[3]

[edit] Neuroleptic malignant syndrome and serotonergic syndrome

The clinical features of neuroleptic malignant syndrome (NMS) and serotonergic syndrome are very similar. This can make differentiating them very difficult.^[17]

Features, classically present in NMS, that are useful for differentiating the two syndromes are:^[18]

Fever
Muscle rigidity

[edit] Footnotes

^ Gillman P (2004). "Comment on: Serotonin syndrome due to co-administration of linezolid and venlafaxine.". J Antimicrob Chemother 54 (4): 844-5. PMID 15317745.
^ Gillman PK (2005). Serotonin toxicity, serotonin syndrome: 2005 update, overview and analysis. Retrieved on 17 November 2006.
^ ^a ^b ^c ^d ^e ^f Boyer EW, Shannon M (2005). "The serotonin syndrome". N Engl J Med 352 (11): 1112-20. PMID 15784664.
^ Gillman P (1999). "The serotonin syndrome and its treatment". J Psychopharmacol 13 (1): 100-9. PMID 10221364.
^ Whyte IM, Serotonin Toxicity (Syndrome). in Medical Toxicology, Dart RC, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 103–6.
^ ^a ^b Isbister G, Bowe S, Dawson A, Whyte I (2004). "Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose". J Toxicol Clin Toxicol 42 (3): 277-85. PMID 15362595.
^ Whyte I, Dawson A, Buckley N (2003). "Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants". QJM 96 (5): 369-74. PMID 12702786.
^ Rossi S, editor. Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook; 2005. ISBN 0-9578521-9-3
^ Prescribing Practice Review 32: Managing depression in primary care. National Prescribing Service Limited (2005). Retrieved on 16 July 2006.
^ Gillman PK (2006). Serotonin toxicity: 3 Spectrum concept. Retrieved on 17 November 2006.
^ Vuori E, Henry J, Ojanperä I, Nieminen R, Savolainen T, Wahlsten P, Jäntti M (2003). "Death following ingestion of MDMA (ecstasy) and moclobemide". Addiction 98 (3): 365-8. PMID 12603236.
^ Gillman P (2006). "A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status". Hum Psychopharmacol 21 (2): 117-25. PMID 16342227.
^ Fennell J, Hussain M (2005). "Serotonin syndrome:case report and current concepts.". Ir Med J 98 (5): 143-4. PMID 16010782.
^ Sporer K (1995). "The serotonin syndrome. Implicated drugs, pathophysiology and management". Drug Saf 13 (2): 94-104. PMID 7576268.
^ Prator B (2006). "Serotonin syndrome". J Neurosci Nurs 38 (2): 102-5. PMID 16681290.
^ Jaunay E, Gaillac V, Guelfi J (2001). "[Serotonin syndrome. Which treatment and when?]". Presse Med 30 (34): 1695-700. PMID 11760601.
^ Christensen V, Glenthøj B (2001). "[Malignant neuroleptic syndrome or serotonergic syndrome]". Ugeskr Laeger 163 (3): 301-2. PMID 11219110.
^ Birmes P, Coppin D, Schmitt L, Lauque D (2003). "Serotonin syndrome: a brief review.". CMAJ 168 (11): 1439-42. PMID 12771076. Full Free Text.