Serotonin syndrome
29500
223903347
2008-07-06T12:43:17Z
It Is Me Here
2552569
Replaced PNG with SVG
{{Infobox_Disease |
Name = Serotonin syndrome |
Image = Serotonin (5-HT).svg |
Caption = [[Serotonin]] |
DiseasesDB = 30044 |
ICD10 = |
ICD9 = {{ICD9|333.99}} |
ICDO = |
OMIM = |
MedlinePlus = |
eMedicineSubj = ped |
eMedicineTopic = 2786 |
MeshName = Serotonin+Syndrome |
MeshNumber = 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, inadvertent interactions between drugs, or the recreational use of certain drugs. It is an [[Iatrogenesis|iatrogenic]] (i.e. caused by medical treatment) [[toxidrome]] (from [[toxic]] + [[syndrome]]). 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 [[poison]]ing.<ref>{{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}}</ref><ref>{{cite web| author=Gillman PK | year= 2005 | title=Serotonin toxicity, serotonin syndrome: 2005 update, overview and analysis | url=http://www.psychotropical.com/1_st_intro.shtml | accessdaymonth=10 January | accessyear=2008}}</ref> 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 [[5-HT receptor|serotonin receptors]]. This excess serotonin activity produces a specific spectrum of clinical findings which may range from barely perceptible to fatal.<ref name="pmid15784664">{{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}}</ref>
==Mechanism==
Serotonin syndrome is caused by increased [[serotonin]] in the [[central nervous system]]. It is the result of overstimulation of [[5-HT receptor|5-HT1A]] receptors in central grey nuclei and the medulla and, perhaps, of overstimulation of [[5-HT receptor|5-HT2]] receptors.<ref name="pmid15784664"/><ref name="pmid10221364">{{cite journal |author=Gillman PK |title=The serotonin syndrome and its treatment |journal=J. Psychopharmacol. (Oxford) |volume=13 |issue=1 |pages=100–9 |year=1999 |pmid=10221364 |doi=}}</ref> These changes are more pronounced following supra-therapeutic doses and overdoses, and they merge in a continuum with the toxic effects.<ref>Whyte IM, Serotonin Toxicity (Syndrome). in Medical Toxicology, Dart RC, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 103–6.</ref><ref name="Isbister-JToxClinTox">{{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}}</ref><ref>{{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 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
===Drugs which may contribute===
A large number of drugs and drug combinations have been associated with the serotonin syndrome.
<center>
{| class="wikitable"
!Class
!Drugs
|-
|[[Herbs]]
|[[St John's Wort]], [[Yohimbe]], [[Boswellia]]
|-
|[[Antidepressant]]s
|[[Monoamine oxidase inhibitor]]s (MAOIs), [[Tricyclic antidepressant|TCA]]s, [[SSRI]]s, [[Serotonin-norepinephrine reuptake inhibitor|SNRI]]s, [[bupropion]]<ref name="pmid15602102">{{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 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
|-
|[[Opioid]]s
|[[tramadol]], [[pethidine]]
|-
|CNS [[stimulant]]s
|[[phentermine]], [[diethylpropion]], [[amphetamine]]s, [[substituted amphetamine]]s, [[sibutramine]], [[methylphenidate]], [[methamphetamine]], [[cocaine]]
|-
|[[5-HT receptor|5-HT<sub>1</sub>]] agonists
|[[triptan]]s
|-
|[[Phenethylamines]]
|[[MDMA]], [[MDA (drug)|MDA]], [[MDEA]], [[PMA]]
|-
|[[Indole]]s
|[[Psilocybin]], [[LSD]]
|-
|Others
|[[tryptophan]], [[montelukast]] (Singulair), [[buspirone]], [[Sceletium tortuosum|kanna]], [[lithium]], [[linezolid]], [[dextromethorphan]] (DXM), [[5-Hydroxytryptophan]], [[chlorpheniramine]], [[risperidone]]<ref name="pmid12639169">{{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 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
|-
| colspan="2" | Reference: Rossi, 2005;<ref name="AMH2005">Rossi S, editor. [[Australian Medicines Handbook]] 2005. Adelaide: Australian Medicines Handbook; 2005. ISBN 0-9578521-9-3</ref> National Prescribing Service, 2005<ref>{{cite web| year= 2005 | title=
Prescribing Practice Review 32: Managing depression in primary care | publisher=National Prescribing Service Limited | url=http://www.nps.org.au/site.php?content=/html/ppr.php&ppr=/resources/Prescribing_Practice_Reviews/ppr32 | accessdaymonth=16 July | accessyear=2006}}</ref>
|}
</center>
The combination of [[Monoamine oxidase inhibitor|MAOI]]s and other serotonin agonists or precursors poses a particularly severe risk of a life-threatening serotonin syndrome episode. Many [[Monoamine oxidase inhibitor|MAOI]]s 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.
===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).<ref>{{cite web| author=Gillman PK | year= 2006 | title=Serotonin toxicity: 3 Spectrum concept | url=http://www.psychotropical.com/ | accessdaymonth=17 November | accessyear=2006}}</ref>
==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 [[SSRI]]s 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.<ref name="Isbister-JToxClinTox"/> 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 SSRIs, have clinically significant potency as serotonin reuptake inhibitors, e.g. [[tramadol]], [[amphetamine]], and [[MDMA]].<ref>{{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 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
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.<ref>{{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}}</ref>
Specific weather patterns are also implicated in the genesis of serotonin syndrome.
Hot dry winds such as the "mistral" and "scirocco" in Europe and cold dry winds such as the "chinook" in North America can produce symptoms of this syndrome.<ref> AJ Giannini, DA Malone,TA Piotrowski. The serotonin irritation syndrome--A new clinical entity? Journal of Clinical Psychiatry. 47:22-29,1986</ref>
This effect is produced by atmospheric cations and has been reproduced in the laboratory.<ref>{{Cite journal
| author = [[A. J. Giannini]], [[S. Castellani]] & [[A. E. Dvoredsky]]
| title = Anxiety states: relationship to atmospheric cations and serotonin
| journal = [[The Journal of Clinical Psychiatry]]
| volume = 44
| issue = 7
| pages = 262–264
| year = 1983
| month = July
| pmid = 6190795
}}</ref>
The symptoms thus produced can be alleviated by ambient anions.<ref>AJ Giannini, S Castellani, MC Giannini. Reversal of hyperserotonergic anxiety with generated anions in human subjects. Society for Neuroscience Abstracts. 8:76.9. 1982.</ref>
==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]] (sweating commonly associated with shock), [[mydriasis]] (dilated pupils), [[myoclonus]] (intermittent tremor or twitching), as well as [[hyperreflexia|overactive or overresponsive reflexes]]. In addition moderate intoxication includes abnormalities such as hyperactive bowel sounds, [[hypertension]] and [[hyperthermia]]; a temperature as high as 40 °C (104 °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 (emotion)|agitation]].<ref name="pmid15784664"/>
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]].<ref name="pmid15784664"/>
The symptoms are often described as a clinical triad of abnormalities:
*'''[[Cognitive|Cognitive effects]]''': [[mental confusion]], [[hypomania]], [[hallucinations]], [[agitation (emotion)|agitation]], [[headache]], [[coma]].
*'''[[Autonomic nervous system|Autonomic effects]]''': [[shivering]], [[sweating]], [[fever]], [[hypertension]], [[tachycardia]], [[nausea]], [[diarrhea]].
*'''[[Somatic nervous system|Somatic effects]]''': [[myoclonus]]/[[clonus]] (muscle twitching), [[hyperreflexia]], [[tremor]].
==Diagnosis==
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 [[virus| viral illness]], [[anxiety]], [[neurological disorder]], or worsening psychiatric condition.<ref>{{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}}</ref> 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.<ref>{{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=}}</ref>
==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 [[Receptor antagonist|antagonists]] ([[cyproheptadine]] or [[methysergide]]), the control of [[Autonomic Nervous System|autonomic]] instability, and the control of hyperthermia.<ref>{{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}}</ref><ref name="pmid15784664"/>
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 [[benzodiazepine]]s, and waiting for the symptoms to resolve. If the offending medication is discontinued, the condition will often resolve on its own within 24 hours.<ref>{{cite journal | author = Prator B | title = Serotonin syndrome | journal = J Neurosci Nurs | volume = 38 | issue = 2 | pages = 102–5 | year = 2006 | pmid = 16681290}}</ref><ref>{{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}}</ref> Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin antagonists (i.e. cyproheptadine). Critically ill patients should receive the above therapies as well as sedation, neuromuscular paralysis, and [[intubation]].<ref name="pmid15784664"/>
== 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.<ref>{{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}}</ref>
Features, classically present in NMS, that are useful for differentiating the two [[syndrome]]s are:<ref>{{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 | pmid = 12771076}} [http://www.cmaj.ca/cgi/content/full/168/11/1439 Full Free Text].</ref>
*Fever
*Muscle rigidity
*Laboratory values (increased WBC and CK)
==Notable cases==
The death of [[Libby Zion]] was due to serotonin syndrome caused by a combination of [[meperidine]] and [[phenelzine]].<ref name="pmid15784664"/><ref>{{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=}}</ref> This case had a profound impact on graduate medical education and residency work hour limitations.<ref name="pmid9757752">{{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=}}</ref>
==References==
{{reflist}}
==External links==
*[http://www.psychotropical.com/ Dr P K Gillman's site, 'PsychoTropicalResearch', devoted to Serotonin and 'Serotonin Syndrome' research.]
* {{FPnotebook|PSY184}}
*[http://www.uspharmacist.com/oldformat.asp?url=newlook/files/feat/acf2fa6.htm Great article with a plethora of information on the toxidrome]; its causes and statistics involving the subsidiation of the toxidrome.
[[Category:Pharmacology]]
[[Category:Syndromes]]
[[de:Serotonin-Syndrom]]
[[es:Síndrome serotoninérgico]]
[[fr:Syndrome sérotoninergique]]
[[it:Sindrome serotoninergica]]
[[ja:セロトニン症候群]]
[[no:Serotonin syndrome]]
[[pl:Zespół serotoninowy]]
[[ru:Серотониновый синдром]]
[[fi:Serotoniinioireyhtymä]]
[[sv:Serotonergt syndrom]]