Serotonin syndrome#Cause

File:ClonusfromSS (edited).webm seen in a person with serotonin syndrome]]

Symptom onset is usually relatively rapid, and SS encompasses a wide range of clinical findings. Mild symptoms may consist of increased heart rate, shivering, sweating, dilated pupils, myoclonus (intermittent jerking or twitching), as well as hyperreflexia (overresponsive reflexes). Many of these symptoms may be side effects of the drug or drug interaction causing excessive levels of serotonin rather than an effect of elevated serotonin itself.

Tremor is a common side effect of MDMA's action on dopamine, whereas hyperreflexia is symptomatic of exposure to serotonin agonists. Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds, high blood pressure and hyperthermia; a temperature as high as {{convert|40|°C|°F}}. The overactive reflexes and clonus in moderate cases may be greater in the lower limbs than in the upper limbs. Mental changes include hypervigilance or insomnia and agitation. Severe symptoms include severe increases in heart rate and blood pressure. Temperature may rise to above {{convert|41.1|°C|°F}} in life-threatening cases. Other abnormalities include metabolic acidosis, rhabdomyolysis, seizures, kidney failure, and disseminated intravascular coagulation; these effects usually arising as a consequence of hyperthermia.{{cite journal |vauthors=Isbister GK, Buckley NA, Whyte IM |title=Serotonin toxicity: a practical approach to diagnosis and treatment |journal=Med J Aust |volume=187 |issue=6 |pages=361–5 |date=September 2007 |pmid=17874986 |url=http://www.mja.com.au/public/issues/187_06_170907/isb10375_fm.html |url-status=live |archive-url=https://web.archive.org/web/20090412024747/http://www.mja.com.au/public/issues/187_06_170907/isb10375_fm.html |archive-date=2009-04-12 |doi=10.5694/j.1326-5377.2007.tb01282.x |s2cid=13108173 }}

The symptoms are often present as a clinical triad of abnormalities and can be use to assess the severity of serotonin syndrome:

Numerous medications and street drugs can cause SS when taken alone at high doses or in combination with other serotonergic agents. The table below lists some of these.

Many cases of serotonin toxicity occur in people who have ingested drug combinations that synergistically increase synaptic serotonin.{{cite journal|vauthors=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=635–642 |date=September 2003 |pmid=12925718 |doi=10.1093/qjmed/hcg109 |doi-access=free }} It may also occur due to an overdose of a single serotonergic agent.{{cite journal |vauthors=Foong AL, Grindrod KA, Patel T, Kellar J |author2-link=Kelly Grindrod|title= Demystifying serotonin syndrome (or serotonin toxicity) |journal= Canadian Family Physician |date=October 2018 |volume=64 |issue=10 |pages=720–727 |pmid=30315014|pmc=6184959 }} The combination of monoamine oxidase inhibitors (MAOIs) with precursors such as {{nowrap|L-tryptophan}} or {{nowrap|5-hydroxytryptophan}} pose a particularly acute risk of life-threatening serotonin syndrome.{{cite journal|vauthors= Sun-Edelstein C, Tepper SJ, Shapiro RE |title=Drug-induced serotonin syndrome: a review |journal=Expert Opinion on Drug Safety |volume=7 |issue=5 |pages=587–596 |date=September 2008 |pmid=18759711 |doi= 10.1517/14740338.7.5.587 |s2cid=71657093 }} The case of combination of MAOIs with tryptamine agonists (commonly known as ayahuasca) can present similar dangers as their combination with precursors, but this phenomenon has been described in general terms as the cheese effect. Many MAOIs irreversibly inhibit monoamine oxidase. It can take at least four weeks for this enzyme to be replaced by the body in the instance of irreversible inhibitors.{{cite journal|author= Sternbach H |title=The serotonin syndrome |journal=American Journal of Psychiatry |volume=148 |issue=6 |pages=705–713 |date=June 1991 |pmid=2035713 |doi= 10.1176/ajp.148.6.705|s2cid=29916415 }} With respect to tricyclic antidepressants, only clomipramine and imipramine have a risk of causing SS.{{Cite journal|last=Gillman|first=P. Ken|date= 2006-06-01|title=A Review of Serotonin Toxicity Data: Implications for the Mechanisms of Antidepressant Drug Action| url= https://www.biologicalpsychiatryjournal.com/article/S0006-3223(05)01441-1/abstract|journal=Biological Psychiatry|language=en|volume=59|issue=11|pages=1046–1051|doi=10.1016/j.biopsych.2005.11.016|pmid= 16460699 |s2cid=12179122|issn=0006-3223}}

Many medications may have been incorrectly thought to cause SS. For example, some case reports have implicated atypical antipsychotics in SS, but it appears based on their pharmacology that they are unlikely to cause the syndrome.{{cite journal|vauthors=Isbister GK, Downes F, Whyte IM |title=Olanzapine and serotonin toxicity |journal=Psychiatry and Clinical Neurosciences |volume=57 |issue=2 |pages=241–42 |date=April 2003 |pmid=12667176 |doi=10.1046/j.1440-1819.2003.01110.x |s2cid=851495 }} It has also been suggested that mirtazapine has no significant serotonergic effects and is therefore not 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= Human Psychopharmacology |volume=21 |issue=2 |pages=117–125 |year=2006 |pmid=16342227 |doi=10.1002/hup.750|s2cid=23442056 }} Bupropion has also been suggested to cause SS,{{cite journal|author=Munhoz RP |title=Serotonin syndrome induced by a combination of bupropion and SSRIs |journal=Clinical Neuropharmacology |volume=27 |issue=5 |pages=219–222 |year=2004 |pmid= 15602102 |doi=10.1097/01.wnf.0000142754.46045.8c}}{{cite journal|vauthors=Thorpe EL, Pizon AF, Lynch MJ, Boyer J |title=Bupropion induced serotonin syndrome: a case report |journal=Journal of Medical Toxicology |volume=6 |issue=2 |pages=168–171 |date=June 2010 |pmid=20238197 |doi=10.1007/s13181-010-0021-x|pmc=3550303}} although as there is no evidence that it has any significant serotonergic activity, it is thought unlikely to produce the syndrome.{{cite journal|author=Gillman PK |title=Bupropion, bayesian logic and serotonin toxicity |journal=Journal of Medical Toxicology |volume=6 |issue=2 |pages=276–77 |date=June 2010 |pmid=20440594 |doi=10.1007/s13181-010-0084-8|pmc=3550296}} In 2006 the US Food and Drug Administration (FDA) issued an alert suggesting that the combined use of either SSRIs or SNRIs with triptan medications or sibutramine could potentially lead to severe cases of SS.{{cite journal |author= Evans RW |title=The FDA alert on serotonin syndrome with combined use of SSRIs or SNRIs and Triptans: an analysis of the 29 case reports |journal= MedGenMed |volume=9 |issue=3 |page=48 |year=2007 |pmid=18092054 |pmc=2100123 }} This has been disputed by other researchers, as none of the cases reported by the FDA met the Hunter criteria for SS.{{cite journal|vauthors= Wenzel RG, Tepper S, Korab WE, Freitag F |title=Serotonin syndrome risks when combining SSRI/SNRI drugs and triptans: is the FDA's alert warranted? |journal=Annals of Pharmacotherapy |volume=42 |issue=11 |pages=1692–1696 |date= November 2008 |pmid=18957623 |doi=10.1345/aph.1L260 |s2cid= 24942783 }} The condition has however occurred in surprising clinical situations, and because of phenotypic variations among individuals, it has been associated with unexpected drugs, including mirtazapine.{{cite journal |vauthors=Duggal HS, Fetchko J |title=Serotonin syndrome and atypical antipsychotics |journal=American Journal of Psychiatry |volume=159 |issue=4 |pages=672–73 |date=April 2002 |pmid=11925312 |doi=10.1176/appi.ajp.159.4.672-a |doi-access= }}Boyer and Shannon's reply to {{cite journal|author= Gillman PK |title=The serotonin syndrome |journal=New England Journal of Medicine |volume=352 |issue=23 |pages=2454–2456 |date=June 2005 |pmid=15948272 |doi=10.1056/NEJM200506093522320 }}

The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. SS has been reported in patients of all ages, including the elderly, children, and even newborn infants due to in utero exposure.{{cite journal| vauthors=Laine K, Heikkinen T, Ekblad U, Kero P |title=Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations |journal= Archives of General Psychiatry |volume=60 |issue=7 |pages=720–726 |date=July 2003 |pmid=12860776 |doi=10.1001/archpsyc.60.7.720 |doi-access= }}{{cite journal|vauthors=Isbister GK, Dawson A, Whyte IM, Prior FH, Clancy C, Smith AJ |title=Neonatal paroxetine withdrawal syndrome or actually serotonin syndrome? |journal= Archives of Disease in Childhood. Fetal and Neonatal Edition |volume=85 |issue=2 |pages= F147–48 |date= September 2001 |pmid=11561552 |doi=10.1136/fn.85.2.F145g |pmc= 1721292}}{{cite journal|vauthors=Gill M, LoVecchio F, Selden B |title=Serotonin syndrome in a child after a single dose of fluvoxamine |journal=Annals of Emergency Medicine |volume=33 |issue=4 |pages=457–459 |date=April 1999 |pmid=10092727 |doi=10.1016/S0196-0644(99)70313-6}} The serotonergic toxicity of SSRIs increases with dose, but even in overdose, it is insufficient to cause fatalities from SS in healthy adults.{{cite journal|vauthors=Whyte IM, Dawson AH |title=Redefining the serotonin syndrome [abstract] |journal=Journal of Toxicology: Clinical Toxicology |volume=40 |issue=5 |pages=668–69 |year=2002 |doi=10.1081/CLT-120016866 |s2cid=218865517 }} Elevations of central nervous system (CNS) serotonin will typically only reach potentially fatal levels when drugs with different mechanisms of action are mixed together. Various drugs, other than SSRIs, also have clinically significant potency as serotonin reuptake inhibitors, (such as tramadol, amphetamine, and MDMA) and are associated with severe cases of the syndrome.{{cite journal|vauthors=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=365–368 |year=2003 |pmid=12603236 |doi=10.1046/j.1360-0443.2003.00292.x}}

Although the most significant health risk associated with opioid overdoses is respiratory depression,{{cite journal|vauthors=Boyer EW|date=July 2012|title=Management of opioid analgesic overdose|journal=The New England Journal of Medicine|volume= 367|issue=2|pages=146–155|doi=10.1056/NEJMra1202561|pmc=3739053|pmid= 22784117}} it is still possible for an individual to develop SS from certain opioids without the loss of consciousness. However, most cases of opioid-related SS involve the concurrent use of a serotergenic drug such as antidepressants.{{Cite journal |last1=Rickli |first1=Anna |last2= Liakoni |first2=Evangelia |display-authors=1 |date=2018 |title= Opioid-induced Inhibition of the Human 5-HT and Noradrenaline Transporters in Vitro: Link to Clinical Reports of Serotonin Syndrome |journal=British Journal of Pharmacology |volume=175 |issue=3 |pages=532–543 |doi=10.1111/bph.14105 |pmid=29210063 |pmc=5773950 }} Nonetheless, it is not uncommon for individuals taking opioids to also be taking antidepressants due to the comorbidity of pain and depression.{{cite journal|vauthors=Bair MJ, Robinson RL, Katon W, Kroenke K |date=November 2003 |title=Depression and pain comorbidity: a literature review |journal=Archives of Internal Medicine|volume=163|issue=20|pages=2433–2445|doi=10.1001/archinte.163.20.2433 |doi-access=free |pmc=3739053|pmid=14609780}}

Cases where opioids alone are the cause of SS are typically seen with tramadol, because of its dual mechanism as a serotonin-norepinephrine reuptake inhibitor.{{cite web|title=Tramadol Hydrochloride | website= drugs.com|url= https://www.drugs.com/monograph/tramadol-hydrochloride.html |publisher= The American Society of Health-System Pharmacists|access-date=12 December 2020}}{{cite journal|vauthors= Takeshita J, Litzinger MH|date=2009|title=Serotonin Syndrome Associated With Tramadol|journal=Primary Care Companion to the Journal of Clinical Psychiatry|volume=11|issue= 5|page=273|doi=10.4088/PCC.08l00690|pmc=2781045 |pmid=19956471}} SS caused by tramadol can be particularly problematic if an individual taking the drug is unaware of the risks associated with it and attempts to self-medicate symptoms such as headache, agitation, and tremors with more opioids, further exacerbating the condition.

Serotonin is a neurotransmitter involved in multiple complex biological processes including aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting. In humans the effects of excess serotonin were first noted in 1960 in patients receiving an MAOI and tryptophan.{{cite journal|vauthors=Oates JA, Sjoerdsma A |title=Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor |journal=Neurology |volume=10 |issue=12 |pages=1076–8 |date=December 1960 |pmid=13730138 |doi=10.1212/WNL.10.12.1076 |s2cid=40439836 }} The syndrome is caused by increased serotonin in the CNS. It was originally suspected that agonism of 5-HT_1A receptors in central grey nuclei and the medulla oblongata was responsible for the development of the syndrome. Further study has determined that overstimulation of primarily the 5-HT_2A receptors appears to contribute substantially to the condition.{{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=978-0-7817-2845-4}} The 5-HT_1A receptor may still contribute through a pharmacodynamic interaction in which increased synaptic concentrations of a serotonin agonist saturate all receptor subtypes. Additionally, noradrenergic CNS hyperactivity may play a role as CNS norepinephrine concentrations are increased in SS and levels appear to correlate with the clinical outcome. Other neurotransmitters may also play a role; NMDA receptor antagonists and γ-aminobutyric acid have been suggested as affecting the development of the syndrome. 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|vauthors=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|s2cid=43121327 }}{{cite journal|vauthors=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|doi-access= }}

A 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-response relationship is the effect 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 journal|author=Gillman PK |title=The spectrum concept of serotonin toxicity |journal=Pain Med |volume=5 |issue=2 |pages=231–2 |date=June 2004 |pmid=15209988 |doi=10.1111/j.1526-4637.2004.04033.x|doi-access= }} Some experts prefer the terms serotonin toxicity or serotonin toxidrome, to more accurately reflect that it is a form of poisoning.{{cite journal|author=Gillman PK |title=A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action |journal=Biol Psychiatry |volume=59 |issue=11 |pages=1046–51 |date=June 2006 |pmid=16460699 |doi=10.1016/j.biopsych.2005.11.016 |s2cid=12179122 }}

There is no specific test for SS. Diagnosis is by symptom observation and investigation of the person's history. Several criteria have been proposed. The first evaluated criteria were introduced in 1991 by Harvey Sternbach.{{cite journal |vauthors=Hegerl U, Bottlender R, Gallinat J, Kuss HJ, Ackenheil M, Möller HJ |title=The serotonin syndrome scale: first results on validity |journal=Eur Arch Psychiatry Clin Neurosci |volume=248 |issue=2 |pages=96–103 |year=1998 |pmid=9684919 |doi=10.1007/s004060050024 |s2cid=37993326 |url=http://link.springer.de/link/service/journals/00406/bibs/8248002/82480096.htm |url-status=dead |archive-url=https://web.archive.org/web/19991011013705/http://link.springer.de/link/service/journals/00406/bibs/8248002/82480096.htm |archive-date=1999-10-11 }} Researchers later developed the Hunter Toxicity Criteria Decision Rules, which have better sensitivity and specificity, 84% and 97%, respectively, when compared with the gold standard of diagnosis by a medical toxicologist. As of 2007, Sternbach's criteria were still the most commonly used.

The most important symptoms for diagnosing SS are tremor, extreme aggressiveness, akathisia, or clonus (spontaneous, inducible and ocular). Physical examination of the patient should include assessment of deep tendon reflexes and muscle rigidity, the dryness of the mucosa of the mouth, the size and reactivity of the pupils, the intensity of bowel sounds, skin color, and the presence or absence of sweating. The patient's history also plays an important role in diagnosis, investigations should include inquiries about the use of prescription and over-the-counter drugs, illicit substances, and dietary supplements, as all these agents have been implicated in the development of SS. To fulfill the Hunter Criteria, a patient must have taken a serotonergic agent and meet one of the following conditions:

• Spontaneous clonus, or
• Inducible clonus plus agitation or diaphoresis, or
• Ocular clonus plus agitation or diaphoresis, or
• Tremor plus hyperreflexia, or
• Hypertonism plus temperature > {{convert|38|°C|°F}} plus ocular clonus or inducible clonus

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 disorders, neurological disorder, anticholinergic poisoning, sympathomimetic toxicity, or worsening psychiatric condition.{{cite journal|vauthors=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 condition most often confused with serotonin syndrome is neuroleptic malignant syndrome (NMS).{{cite book|vauthors=Nisijima K, Shioda K, Iwamura T |title=Neurobiology of Hyperthermia |chapter=Neuroleptic malignant syndrome and serotonin syndrome |journal=Prog Brain Res |volume=162 |pages=81–104 |year=2007 |pmid=17645916 |doi=10.1016/S0079-6123(06)62006-2 |series=Progress in Brain Research |isbn=9780444519269}}{{cite book |last1=Tormoehlen |first1=LM |last2=Rusyniak |first2=DE |title=Thermoregulation: From Basic Neuroscience to Clinical Neurology, Part II |chapter=Neuroleptic malignant syndrome and serotonin syndrome |series=Handbook of Clinical Neurology |date=2018 |volume=157 |pages=663–675 |doi=10.1016/B978-0-444-64074-1.00039-2 |pmid=30459031|isbn=9780444640741 }} The clinical features of neuroleptic malignant syndrome and SS share some features which can make differentiating them difficult.{{cite journal|vauthors=Christensen V, Glenthøj B |title=[Malignant neuroleptic syndrome or serotonergic syndrome] |journal=Ugeskrift for Lægerer |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, 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 and neuroleptic drugs. Bradykinesia and extrapyramidal "lead pipe" rigidity are classically present in NMS, whereas SS causes hyperkinesia and clonus; these distinct symptoms can aid in differentiation.{{cite journal|vauthors=Birmes P, Coppin D, Schmitt L, Lauque D |title=Serotonin syndrome: a brief review |journal=CMAJ |volume=168 |issue=11 |pages=1439–42 |date=May 2003 |pmid=12771076 |pmc=155963 |url=http://www.cmaj.ca/cgi/pmidlookup?view=long&pmid=12771076}}{{cite journal|vauthors=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 |date=September 2001 |pmid=11582830 |doi= 10.1177/070674370104600718|doi-access=free }}

Management is based primarily on stopping the usage of the precipitating drugs, the administration of serotonin antagonists such as cyproheptadine (with a regimen of 12 mg for the initial dose followed by 2 mg every 2 hours until clinical, while some claim that a higher initial dose up to 32 mg has more benefit{{cite journal | last=Prakash | first=Sanjay | last2=Shah | first2=Chetsi S. | last3=Prakash | first3=Anurag | title=Serotonin syndrome controversies: A need for consensus | journal=World Journal of Critical Care Medicine | volume=13 | issue=2 | date=2024-06-09 | issn=2220-3141 | pmid=38855279 | pmc=11155509 | doi=10.5492/wjccm.v13.i2.94707 | doi-access=free | page=94707}}),{{cite journal | last1=Scotton | first1=William J | last2=Hill | first2=Lisa J | last3=Williams | first3=Adrian C | last4=Barnes | first4=Nicholas M | title=Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions | journal=International Journal of Tryptophan Research | publisher=SAGE Publications | volume=12 | year=2019 | issn=1178-6469 | doi=10.1177/1178646919873925 | page=117864691987392| pmid=31523132 | pmc=6734608 }} and supportive care including the control of agitation, 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 |doi=10.2165/00002018-199513020-00004|s2cid=19809259 }}{{cite journal | title=Recognition and treatment of serotonin syndrome | author=Frank, Christopher | pmc=2464814 | pmid=18625822 | volume=54 | issue=7 | year=2008 | journal=Can Fam Physician | pages=988–92}} Additionally, those who ingest large doses of serotonergic agents may benefit from gastrointestinal decontamination with activated charcoal if it can be administered within an hour of overdose. 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. The serotonin antagonist cyproheptadine is the recommended initial therapy, although there have been no controlled trials demonstrating its efficacy for SS.{{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=10.1177/026988119901300111|s2cid=17640246 |url=https://zenodo.org/record/844143 }} Despite the absence of controlled trials, there are a number of case reports detailing apparent improvement after people have been administered cyproheptadine. Animal experiments also suggest a benefit from serotonin antagonists.{{cite journal|vauthors=Nisijima K, Yoshino T, Yui K, Katoh S |title=Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome |journal=Brain Res. |volume=890 |issue=1 |pages=23–31 |date=January 2001 |pmid=11164765 |doi=10.1016/S0006-8993(00)03020-1|s2cid=29995925 }} Cyproheptadine is only available as tablets and therefore can only be administered orally or via a nasogastric tube; it is unlikely to be effective in people administered activated charcoal and has limited use in severe cases. Cyproheptadine can be stopped when the person is no longer experiencing symptoms and the half life of serotonergic medications already passed.

Additional pharmacological treatment for severe case includes administering atypical antipsychotic drugs with serotonin antagonist activity such as olanzapine or asenapine. Critically ill people should receive the above therapies as well as sedation or neuromuscular paralysis. People who have autonomic instability such as low blood pressure require treatment with direct-acting sympathomimetics such as epinephrine, norepinephrine, or phenylephrine. Conversely, hypertension or tachycardia can be treated with short-acting antihypertensive drugs such as nitroprusside or esmolol; longer acting drugs such as propranolol should be avoided as they may lead to hypotension and shock. The cause of serotonin toxicity or accumulation is an important factor in determining the course of treatment. Serotonin is catabolized by monoamine oxidase A in the presence of oxygen, so if care is taken to prevent an unsafe spike in body temperature or metabolic acidosis, oxygenation will assist in dispatching the excess serotonin. The same principle applies to alcohol intoxication. In cases of SS caused by MAOIs, oxygenation will not help to dispatch serotonin. In such instances, hydration is the main concern until the enzyme is regenerated.

Specific treatment for some symptoms may be required. One of the most important treatments is the control of agitation due to the extreme possibility of injury to the person themselves or caregivers, benzodiazepines should be administered at first sign of this. Physical restraints are not recommended for agitation or delirium as they may contribute to mortality by enforcing isometric muscle contractions that are associated with severe lactic acidosis and hyperthermia. If physical restraints are necessary for severe agitation they must be rapidly replaced with pharmacological sedation. The agitation can cause a large amount of muscle breakdown. This breakdown can cause severe damage to the kidneys through a condition called rhabdomyolysis.{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004531/ |title=Serotonin syndrome – PubMed Health |publisher=Ncbi.nlm.nih.gov |access-date=2013-01-28 |url-status=live |archive-url=https://web.archive.org/web/20130201070649/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004531/ |archive-date=2013-02-01 }}

Treatment for hyperthermia includes reducing muscle overactivity via sedation with a benzodiazepine. More severe cases may require muscular paralysis with vecuronium, intubation, and artificial ventilation. Suxamethonium is not recommended for muscular paralysis as it may increase the risk of cardiac dysrhythmia from hyperkalemia associated with rhabdomyolysis. Antipyretic agents are not recommended as the increase in body temperature is due to muscular activity, not a hypothalamic temperature set point abnormality.

Upon the discontinuation of serotonergic drugs, most cases of SS 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 |doi=10.1097/01376517-200604000-00005}}{{cite journal|vauthors=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 in some cases delirium may persist for a number of days. Symptoms typically persist for a longer time frame in patients taking drugs which have a long elimination half-life, active metabolites, or a protracted duration of action.

Cases have reported persisting chronic symptoms,{{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 |date=February 2002 |pmid=11889332 |doi=10.1097/00003246-200202000-00033 |s2cid=28908329 }} and antidepressant discontinuation 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=10.2165/00002018-200124030-00003 |s2cid=26897797 }} Following appropriate medical management, SS is generally associated with a favorable prognosis.{{cite journal|vauthors=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 |date=July 2000 |pmid=10941349 |doi=10.1097/00005792-200007000-00001 |s2cid=41036864 |doi-access=free }}

Epidemiological studies of SS are difficult as many physicians are unaware of the diagnosis or they may miss the syndrome due to its variable manifestations.{{cite journal|vauthors=Sampson E, Warner JP |title=Serotonin syndrome: potentially fatal but difficult to recognize |journal=Br J Gen Pract |volume=49 |issue=448 |pages=867–8 |date=November 1999 |pmid=10818648 |pmc=1313553 }} In 1998 a survey conducted in England found that 85% of the general practitioners that had prescribed the antidepressant nefazodone were unaware of SS.{{cite journal |vauthors=Mackay FJ, Dunn NR, Mann RD |title=Antidepressants and the serotonin syndrome in general practice |journal=Br J Gen Pract |volume=49 |issue=448 |pages=871–4 |date=November 1999 |pmid=10818650 |pmc=1313555 }} The incidence may be increasing as a larger number of pro-serotonergic drugs (drugs which increase serotonin levels) are now being used in clinical practice.{{cite journal|vauthors=Graudins A, Stearman A, Chan B |title=Treatment of the serotonin syndrome with cyproheptadine |journal=J Emerg Med |volume=16 |issue=4 |pages=615–9 |year=1998 |pmid=9696181 |doi=10.1016/S0736-4679(98)00057-2 }} One postmarketing surveillance study identified an incidence of 0.4 cases per 1000 patient-months for patients who were taking nefazodone. Additionally, around 14–16% of persons who overdose on SSRIs are thought to develop SS.

File:Phenelzine.svg is a MAOI which contributed to SS in the Libby Zion case]]

The most widely recognized example of SS was the death of Libby Zion in 1984.{{cite news |first=Jane |last=Brody |author-link=Jane Brody |title=A Mix of Medicines That Can Be Lethal |url=https://www.nytimes.com/2007/02/27/health/27brody.html?n=Top/News/Health/Diseases,%20Conditions,%20and%20Health%20Topics/Antidepressants |work=New York Times |date=February 27, 2007 |access-date=2009-02-13 |url-status=live |archive-url=https://web.archive.org/web/20131113094550/http://www.nytimes.com/2007/02/27/health/27brody.html?n=Top%2FNews%2FHealth%2FDiseases%2C%20Conditions%2C%20and%20Health%20Topics%2FAntidepressants |archive-date=November 13, 2013 }} Zion was a freshman at Bennington College at her death on March 5, 1984, at age 18. She died within 8 hours of her emergency admission to the New York Hospital Cornell Medical Center. She had an ongoing history of depression, and came to the Manhattan hospital on the evening of March 4, 1984, with a fever, agitation and "strange jerking motions" of her body. She also seemed disoriented at times. The emergency room physicians were unable to diagnose her condition definitively but admitted her for hydration and observation. Her death was caused by a combination of pethidine and phenelzine.{{cite journal|vauthors=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 |date=March 1988 |pmid=3347226 |doi=10.1056/NEJM198803243181209}} A medical intern prescribed the pethidine.{{cite news |url=https://query.nytimes.com/gst/fullpage.html?sec=health&res=990CE4DC1230F932A35752C0A963958260 |title=Doctors' Accounts Vary In Death of Libby Zion |author=Jan Hoffman |newspaper=The New York Times |date=January 1, 1995 |access-date=2008-12-08 |url-status=live |archive-url=https://web.archive.org/web/20090816081427/http://query.nytimes.com/gst/fullpage.html?sec=health |archive-date=August 16, 2009 }} The case influenced graduate medical education and residency work hours. Limits were set on working hours for medical postgraduates, commonly referred to as interns or residents, in hospital training programs, and they also now require closer senior physician supervision.

• Carcinoid syndrome

{{Reflist}}

• [http://www.nejm.org/action/showImage?doi=10.1056%2FNEJMra041867&iid=f02 Image demonstrating findings in moderately severe serotonin syndrome] {{Webarchive|url=https://web.archive.org/web/20210829054104/https://www.nejm.org/action/showImage?doi=10.1056%2FNEJMra041867&iid=f02 |date=2021-08-29 }} from {{cite journal|vauthors=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|s2cid=37959124 }}

{{Medical condition classification and resources

| DiseasesDB = 30044

| ICD11 = {{ICD11|8D85}}

| ICD10 =

| ICD9 = {{ICD9|333.99}}

| ICDO =

| OMIM =

| MedlinePlus = 007272

| eMedicineSubj = ped

| eMedicineTopic = 2786

| MeshName = Serotonin+Syndrome

| MeshNumber = C21.613.276.720

}}

{{CNS diseases of the nervous system}}

{{Poisoning and toxicity}}

{{Good article}}

{{DEFAULTSORT:Serotonin Syndrome}}

Category:Neuropharmacology

Category:Clinical pharmacology

Category:Rare syndromes

Category:Adverse effects of psychoactive drugs

Category:Wikipedia medicine articles ready to translate

Category:Wikipedia neurology articles ready to translate