Serotonin syndrome

Serotonin syndrome

Name = Serotonin syndrome

Caption = Serotonin
DiseasesDB = 30044
ICD10 =
ICD9 = ICD9|333.99
MedlinePlus =
eMedicineSubj = ped
eMedicineTopic = 2786
MeshName = Serotonin+Syndrome
MeshNumber = C21.613.276.720

Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, or the recreational use of certain drugs. It is most commonly referred to as serotonin syndrome, but the terms serotonin toxicity or serotonin toxidrome are more accurate as they reflect the fact that it is a form of poisoning. [cite journal | author = Gillman P | title = Comment on: Serotonin syndrome due to co-administration of linezolid and venlafaxine. | journal = J Antimicrob Chemother | volume = 54 | issue = 4 | pages = 844–5 | year = 2004 | doi= 10.1093/jac/dkh404 | pmid = 15317745] [cite web| author=Gillman PK | year= 2005 | title=Serotonin toxicity, serotonin syndrome: 2005 update, overview and analysis | publisher = PsychoTropical Research| url= | accessdaymonth=10 January | accessyear=2008] Rarely it may also be called serotonin storm, hyperserotonemia, or serotonergic syndrome.

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.cite journal |author=Boyer EW, Shannon M |title=The serotonin syndrome |journal=N. Engl. J. Med. |volume=352 |issue=11 |pages=1112–20 |year=2005 |pmid=15784664 |doi=10.1056/NEJMra041867]


Serotonin is a neurotransmitter, discovered in 1948, [cite journal |author=Rapport MM, Green AA, Page IH |title=Serum vasoconstrictor, serotonin; isolation and characterization |journal=J. Biol. Chem. |volume=176 |issue=3 |pages=1243–51 |year=1948 |month=December |pmid=18100415 |doi= |url=] it is involved in multiple states including aggression, pain, sleep, appetite, anxiety, depression, migraine, and emesis. Serotonin syndrome is caused by increased serotonin in the central nervous system. It appears to be the result of overstimulation of primarily the 5-HT2A receptors and not by 5-HT1A receptors in central grey nuclei and the medulla as originally suspected.cite book |last=Whyte| first= Ian M. |chapter=Serotonin Toxicity/Syndrome|title=Medical Toxicology |publisher=Williams & Wilkins| location=Philadelphia |year=2004|pages=103–6| isbn=0-7817-2845-2] Serotonin excess was first noted in humans in 1960. [cite journal |author=Oates JA, Sjoerdsma A |title=Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor |journal=Neurology |volume=10 |issue= |pages=1076–8 |year=1960 |month=December |pmid=13730138 |doi= |url=] Serotonin toxicity is more pronounced following supra-therapeutic doses and overdoses, and they merge in a continuum with the toxic effects of overdose.cite journal | author = Isbister G, Bowe S, Dawson A, Whyte I | title = Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose | journal = J Toxicol Clin Toxicol | volume = 42 | issue = 3 | pages = 277–85 | year = 2004 | pmid = 15362595 | doi = 10.1081/CLT-120037428] [cite journal | author = Whyte I, Dawson A, Buckley N | title = Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants | journal = QJM | volume = 96 | issue = 5 | pages = 369–74 | year = 2003 | pmid = 12702786 | doi = 10.1093/qjmed/hcg062]

Drugs which may contribute

A large number of drugs and drug combinations have been reported to produce serotonin syndrome.Rossi S, editor. Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook; 2005. ISBN 0-9578521-9-3] [cite web| year= 2005 | title=Prescribing Practice Review 32: Managing depression in primary care | publisher=National Prescribing Service Limited | url= | accessdaymonth=16 July | accessyear=2006] cite journal |author=Munhoz RP |title=Serotonin syndrome induced by a combination of bupropion and SSRIs |journal=Clinical neuropharmacology |volume=27 |issue=5 |pages=219–22 |year=2004 |pmid=15602102| doi = 10.1097/01.wnf.0000142754.46045.8c] cite journal |author=Karki SD, Masood GR |title=Combination risperidone and SSRI-induced serotonin syndrome |journal=The Annals of pharmacotherapy |volume=37 |issue=3 |pages=388–91 |year=2003 |pmid=12639169| doi = 10.1345/aph.1C228] [cite journal |author=Verre M, Bossio F, Mammone A, "et al" |title=Serotonin syndrome caused by olanzapine and clomipramine |journal=Minerva Anestesiol |volume=74 |issue=1-2 |pages=41–5 |year=2008 |pmid=18004234 |doi= |url=] [cite journal |author=Bijl D |title=The serotonin syndrome |journal=Neth J Med |volume=62 |issue=9 |pages=309–13 |year=2004 |month=October |pmid=15635814 |doi= |url=] [cite journal |author= Francis B, Harchelroad F |title=LSD/Fluoxetine induced serotonin syndrome|journal= Journal of Toxicology: Clinical Toxicology |volume= 34|issue= 5|pages= 560 |year=1996 |month= |pmid= |doi=10.3109/15563659609028019 |url=]

Many cases of serotonin toxicity occur in patients who have ingested drug combinations that synergistically increase synaptic serotonin.cite journal |author=Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM |title=The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity |journal=QJM |volume=96 |issue=9 |pages=635–42 |year=2003 |month=September |pmid=12925718 |doi= |url=] It may also occur in patients following ingestion of a single serotonergic agent. [cite journal |author=Fraser J, South M |title=Life-threatening fluvoxamine overdose in a 4-year-old child |journal=Intensive Care Med |volume=25 |issue=5 |pages=548 |year=1999 |month=May |pmid=10401959 |doi= |url=] The combination of MAOIs and other serotonin agonists or precursors poses a particularly severe risk of a life-threatening serotonin syndrome. 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 four weeks.cite journal |author=Sternbach H |title=The serotonin syndrome |journal=Am J Psychiatry |volume=148 |issue=6 |pages=705–13 |year=1991 |month=June |pmid=2035713 |doi= |url=]

Many medications may have been incorrectly thought to cause serotonin syndrome. For example some case reports have implicated atypical antipsychotics in serotonin syndrome but it appears based on their pharmacology that they are unlikely to cause serotonin syndrome. [cite journal |author=Isbister GK, Downes F, Whyte IM |title=Olanzapine and serotonin toxicity |journal=Psychiatry Clin. Neurosci. |volume=57 |issue=2 |pages=241–2 |year=2003 |month=April |pmid=12667176 |doi= |url=]

pectrum 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). [cite web| author=Gillman PK | year= 2006 | title=Serotonin toxicity: 3 Spectrum concept | publisher = PsychoTropical Research| url= | accessdaymonth=17 November | accessyear=2006]

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. [cite journal |author=Whyte IM, Dawson AH|title=Redefining the serotonin syndrome [abstract] |journal=J Toxicol Clin Toxicol |volume=40 |issue=5 |pages=668–9 |year=2002 |month= |pmid=|doi=10.1081/CLT-120016859 |url=] 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; concerns have also been expressed in combining SSRIs with the herbal remedy St John's wort. Various drugs, other than SSRIs, have clinically significant potency as serotonin reuptake inhibitors, e.g. tramadol, amphetamine, and MDMA. [cite journal | author = Vuori E, Henry J, Ojanperä I, Nieminen R, Savolainen T, Wahlsten P, Jäntti M | title = Death following ingestion of MDMA (ecstasy) and moclobemide | journal = Addiction | volume = 98 | issue = 3 | pages = 365–8 | year = 2003 | pmid = 12603236 | doi = 10.1046/j.1360-0443.2003.00292.x] 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. [cite journal | author = Gillman P | title = A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status | journal = Hum Psychopharmacol | volume = 21 | issue = 2 | pages = 117–25 | year = 2006 | pmid = 16342227 | doi = 10.1002/hup.750]


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, shivering, diaphoresis (sweating), mydriasis (dilated pupils), myoclonus (intermittent tremor or twitching), as well as overactive or overresponsive reflexes. Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds, hypertension and hyperthermia; a temperature as high as convert|40|°C|°F is common in moderate intoxication. 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. Severe symptoms include severe hypertension and tachycardia that may lead to shock. Severe cases often have agitated delirium as well as muscular rigidity and high muscular tension. Temperature may rise to above convert|41.1|°C|°F in life-threatening cases. Other abnormalities include metabolic acidosis, rhabdomyolysis, seizures, renal failure, and disseminated intravascular coagulation, these effects usually arise as a consequence of hyperthermia.

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.


There is no lab test for serotonin syndrome, so diagnosis is by symptom observation and the patient's history. Serotonin toxicity has a characteristic picture which is generally 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. [cite journal | author = Fennell J, Hussain M | title = Serotonin syndrome:case report and current concepts. | journal = Ir Med J | volume = 98 | issue = 5 | pages = 143–4 | year = 2005 | pmid = 16010782] The patients history and clonus (spontaneous, inducible and ocular) are the most important sign in the diagnosing serotonin syndrome. Researchers in Australia have developed the Hunter Serotonin Toxicity Criteria for diagnosing serotonin syndrome.

The Hunter Serotonin Toxicity Criteria suggests that in the presence of a serotonergic agent the patient has:
* Spontaneous clonus, or
* Inducible clonus or ocular clonus with agitation or diaphoresis, or
* Tremor and hyperreflexia, or
* Hypertonic and temperature > convert|38|°C|°F and ocular clonus or inducible clonusThen the diagnosis is serotonin syndrome. If these are not met then it is not serotonin syndrome.

Differential diagnosis

The condition most often confused with serotonin syndrome is neuroleptic malignant syndrome (NMS). [cite journal |author=Nisijima K, Shioda K, Iwamura T |title=Neuroleptic malignant syndrome and serotonin syndrome |journal=Prog. Brain Res. |volume=162 |issue= |pages=81–104 |year=2007 |pmid=17645916 |doi=10.1016/S0079-6123(06)62006-2 |url=] The clinical features of neuroleptic malignant syndrome and serotonin syndrome share some features which can make differentiating them difficult. [cite journal | author = Christensen V, Glenthøj B | title = [Malignant neuroleptic syndrome or serotonergic syndrome] | journal = Ugeskr Laeger | volume = 163 | issue = 3 | pages = 301–2 | year = 2001 | pmid = 11219110] In both conditions, autonomic dysfunction and altered mental status develop.

However, they are actually very different conditions with different underlying dysfunction (serotonin excess vs dopamine blockade). Both the time course and the clinical features of NMS differ significantly from those of serotonin toxicity. Serotonin toxicity has a rapid onset after the administration of a serotonergic drug and responds to serotonin blockade such as drugs like chlorpromazine and cyproheptadine. Dopamine receptor blockade (NMS) has a slow onset and typically evolves over several days after administration of a neuroleptic drug and responds to dopamine agonists such as bromocriptine. Differential diagnosis may become difficult in patients recently exposed to both serotonergic drugs and neuroleptic drugs. Features that are classically present in NMS, that are useful for differentiating the two are bradykinesia and extrapyramidal "lead pipe" rigidity, whereas serotonin syndrome causes hyperkinesia and clonus. [cite journal |author=Isbister GK, Dawson A, Whyte IM |title=Citalopram overdose, serotonin toxicity, or neuroleptic malignant syndrome? |journal=Can J Psychiatry |volume=46 |issue=7 |pages=657–9 |year=2001 |month=September |pmid=11582830 |doi= |url=] [cite journal |author=Birmes P, Coppin D, Schmitt L, Lauque D |title=Serotonin syndrome: a brief review |journal=CMAJ |volume=168 |issue=11 |pages=1439–42 |year=2003 |month=May |pmid=12771076 |pmc=155963 |doi= |url=]


There is no antidote to the condition itself, and management involves the removal of the precipitating drugs and the initiation of supportive care. Supportive care includes the control of agitation, the administration of serotonin antagonists (cyproheptadine or methysergide), the control of autonomic instability, and the control of hyperthermia. [cite journal | author = Sporer K | title = The serotonin syndrome. Implicated drugs, pathophysiology and management | journal = Drug Saf | volume = 13 | issue = 2 | pages = 94–104 | year = 1995 | pmid = 7576268] 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 for myoclonus, and waiting for the symptoms to resolve. Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin antagonists such as cyproheptadine. Critically ill patients should receive the above therapies as well as sedation, neuromuscular paralysis, and intubation with artifical ventilation.

Upon initiation of therapy and the discontinuation of serotonergic drugs most cases of serotonin syndrome resolve within 24 hours. [cite journal | author = Prator B | title = Serotonin syndrome | journal = J Neurosci Nurs | volume = 38 | issue = 2 | pages = 102–5 | year = 2006 | pmid = 16681290] [cite journal | author = Jaunay E, Gaillac V, Guelfi J | title = [Serotonin syndrome. Which treatment and when?] | journal = Presse Med | volume = 30 | issue = 34 | pages = 1695–700 | year = 2001 | pmid = 11760601] Although delirium may persist for a number of days. Cases have reported muscle pain and weakness persisting for months [cite journal |author=Chechani V |title=Serotonin syndrome presenting as hypotonic coma and apnea: potentially fatal complications of selective serotonin receptor inhibitor therapy |journal=Crit. Care Med. |volume=30 |issue=2 |pages=473–6 |year=2002 |month=February |pmid=11889332 |doi= |url=] although antidepressant withdrawal may contribute to ongoing features. [cite journal |author=Haddad PM |title=Antidepressant discontinuation syndromes |journal=Drug Saf |volume=24 |issue=3 |pages=183–97 |year=2001 |pmid=11347722 |doi= |url=] Following appropriate medical management, serotonin syndrome is generally associated with a favorable prognosis. [cite journal |author=Mason PJ, Morris VA, Balcezak TJ |title=Serotonin syndrome. Presentation of 2 cases and review of the literature |journal=Medicine (Baltimore) |volume=79 |issue=4 |pages=201–9 |year=2000 |month=July |pmid=10941349 |doi= |url=]

Notable cases

The death of Libby Zion was due to serotonin syndrome caused by a combination of meperidine and phenelzine. [cite journal |author=Asch DA, Parker RM |title=The Libby Zion case. One step forward or two steps backward? |journal=N. Engl. J. Med. |volume=318 |issue=12 |pages=771–5 |year=1988 |month=March |pmid=3347226 |doi= |url=] This case had a profound impact on graduate medical education and residency work hour limitations.cite journal |author=Brensilver JM, Smith L, Lyttle CS |title=Impact of the Libby Zion case on graduate medical education in internal medicine |journal=Mt. Sinai J. Med. |volume=65 |issue=4 |pages=296–300 |year=1998 |pmid=9757752 |doi=]


External links

* [ Dr P K Gillman's site, 'PsychoTropicalResearch', devoted to Serotonin and 'Serotonin Syndrome' research.]
* [ Serotonin Syndrome: Recognition and Management] ; its causes and statistics involving the subsidiation of the toxidrome.

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