| Serotonin syndrome | |
|---|---|
| Other names | Serotonin toxicity, serotonin toxidrome, serotonin sickness, serotonin storm, serotonin poisoning, hyperserotonemia, serotonergic syndrome, serotonin shock |
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| Serotonin | |
| Specialty | Critical care medicine,psychiatry |
| Symptoms | High body temperature, agitation,increased reflexes,tremor,sweating,dilated pupils,diarrhea[1][2] |
| Usual onset | Within a day[2] |
| Causes | Selective serotonin reuptake inhibitor (SSRI),serotonin norepinephrine reuptake inhibitor (SNRI),monoamine oxidase inhibitor (MAOI),tricyclic antidepressants (TCAs),amphetamine,methylene blue,pethidine (meperidine),tramadol,dextromethorphan,ondansetron,cocaine[2] |
| Diagnostic method | Based on symptoms and medication use[2] |
| Differential diagnosis | Neuroleptic malignant syndrome,malignant hyperthermia,anticholinergic toxicity,heat stroke,meningitis[2] |
| Treatment | Active cooling[1] |
| Medication | Benzodiazepines,cyproheptadine[1] |
| Frequency | Unknown[3] |
Serotonin syndrome (SS) consists of a group of symptoms that may occur with the use of certainserotonergic medications ordrugs.[1] The symptoms can range from mild to severe, and are potentially fatal.[4][5][2] Symptoms in mild cases includehigh blood pressure and afast heart rate, usually without afever.[2] Symptoms in moderate cases includehigh body temperature,agitation,increased reflexes,tremor,sweating,dilated pupils, anddiarrhea.[1][2] In severe cases,body temperature can increase to greater than 41.1 °C (106.0 °F).[2] Complications may includeseizures andextensive muscle breakdown.[2]
Serotonin syndrome is typically caused by the use of two or more serotonergic medications or drugs.[2] These may includeselective serotonin reuptake inhibitors (SSRIs),serotonin norepinephrine reuptake inhibitors (SNRIs),monoamine oxidase inhibitors (MAOIs),tricyclic antidepressants (TCAs),amphetamines,pethidine (meperidine),tramadol,dextromethorphan,buspirone,L-tryptophan,5-hydroxytryptophan,St. John's wort,triptans,MDMA,metoclopramide, orcocaine.[2] It occurs in about 15% of SSRIoverdoses.[3] It is a predictable consequence of excessserotonin on thecentral nervous system.[6] Onset of symptoms is typically within a day of the extra serotonin.[2]
Diagnosis is based on a person's symptoms and history of medication use.[2] Other conditions that can produce similar symptoms such asneuroleptic malignant syndrome,malignant hyperthermia,anticholinergic toxicity,heat stroke, andmeningitis should be ruled out.[2] As of 2013, no laboratory tests exist that can confirm the diagnosis.[2]
Initial treatment consists of discontinuing medications which may be contributing.[1] In those who are agitated,benzodiazepines may be used.[1] If this is not sufficient, aserotonin antagonist such ascyproheptadine may be used.[1] In those with a high body temperature,active cooling measures may be needed.[1] The number of cases of serotonin syndrome that occur each year is unclear.[3] With appropriate medical intervention the risk of death is low, likely less than 1%.[7] The high-profilecase of Libby Zion, who is generally accepted to have died from serotonin syndrome, resulted in changes to graduate medical school education inNew York State.[6][8]
Symptom onset is usually relatively rapid, and serotonin syndrome encompasses a wide range of clinical findings. Mild symptoms may consist ofincreased heart rate, shivering,sweating,dilated pupils, andmyoclonus (intermittent jerking or twitching), as well ashyperreflexia (overresponsive reflexes).[6] 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 ofMDMA's action ondopamine, whereas hyperreflexia is symptomatic of exposure toserotonin agonists. Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds,high blood pressure andhyperthermia; a temperature as high as 40 °C (104 °F). The overactive reflexes andclonus in moderate cases may be greater in the lower limbs than in theupper limbs. Mental changes includehypervigilance orinsomnia andagitation.[6] Severe symptoms include severe increases in heart rate and blood pressure. Temperature may rise to above 41.1 °C (106.0 °F) in life-threatening cases. Other abnormalities includemetabolic acidosis,rhabdomyolysis,seizures,kidney failure, anddisseminated intravascular coagulation; these effects usually arising as a consequence of hyperthermia.[6][9]
The symptoms are often present as a clinical triad of abnormalities and can be used to assess the severity of serotonin syndrome:[6][10]
| Severity | Autonomic effects | Neurological (somatic) signs | Mental status | Other symptoms |
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| mild |
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| moderate |
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| severe |
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| as above |
Numerous medications and street drugs can cause serotonin syndrome 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.[10] It may also occur due to an overdose of a single serotonergic agent.[28] The combination ofmonoamine oxidase inhibitors (MAOIs) with precursors such asL-tryptophan or5-hydroxytryptophan pose a particularly acute risk of life-threatening serotonin syndrome.[29] The case of combination of MAOIs with tryptamine agonists (commonly known asayahuasca) can present similar dangers as their combination with precursors, but this phenomenon has been described in general terms as thecheese effect. Many MAOIs irreversibly inhibitmonoamine oxidase. It can take at least four weeks for this enzyme to be replaced by the body in the instance of irreversible inhibitors.[30] With respect totricyclic antidepressants (TCAs), onlyclomipramine andimipramine have a risk of causing serotonin syndrome.[31]
Many medications may have been incorrectly thought to cause serotonin syndrome. For example, some case reports have implicatedatypical antipsychotics in serotonin syndrome, but it appears based on their pharmacology that they are unlikely to cause the syndrome.[32] It has also been suggested thatmirtazapine has no significant serotonergic effects and is therefore not a dual action drug.[33] Bupropion has also been suggested to cause serotonin syndrome,[34][35] although as there is no evidence that it has any significant serotonergic activity, it is thought unlikely to produce the syndrome.[36] In 2006 the USFood 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 serotonin syndrome.[37] This has been disputed by other researchers, as none of the cases reported by the FDA met the Hunter criteria for serotonin syndrome.[37][38] 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.[39][40]
Despite acting asnon-selectiveserotonin receptor agonists, majorserotonergic psychedelics likelysergic acid diethylamide (LSD) andpsilocybin do not cause serotonin syndrome even in the context of extremeoverdose.[41][20][42] This is thought to be due to the fact that they act aspartial agonists ofserotonin receptors like the serotonin5-HT2A receptor, in contrast to serotonin itself which is afull agonist.[41][42] Combination of psychedelics like LSD and psilocybin with antidepressants such as SSRIs is also not thought to pose a risk of serotonin syndrome.[42] A 2018 retrospective analysis of 3,554 LSD-only exposures reported topoison control centers in theUnited States between 2000 and 2016 found that serioustoxicity was infrequent.[20][43] On the other hand,NBOMe psychedelics like25I-NBOMe are moreefficacious at the serotonin 5-HT2A receptor and have been uniquely associated with serotonin syndrome-like toxicity.[20] In addition, serotonergic psychedelics additionally acting asserotonin releasing agents likemethylenedioxyamphetamine (MDA) andα-methyltryptamine (AMT) or additionally acting as MAOIs likeayahuasca or AMT can cause serotonin syndrome.[44][20][15][6][45]
The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. Serotonin syndrome has been reported in patients of all ages, including the elderly, children, and even newborn infants due toin utero exposure.[46][47][48][49] The serotonergic toxicity of SSRIs increases with dose, but even in overdose, it is insufficient to cause fatalities from serotonin syndrome in healthy adults.[50][51] Elevations ofcentral nervous system (CNS) serotonin will typically only reach potentially fatal levels when drugs with differentmechanisms of action are mixed together.[9] Various drugs, other than SSRIs, also have clinically significant potency as serotonin reuptake inhibitors, (such astramadol,amphetamine, and MDMA) and are associated with severe cases of the syndrome.[6][52] Severe and life-threatening serotonin syndrome has been said to almost exclusively be due to a combination ofantidepressants, for instance an MAOI with an SSRI.[44] However, combination of an MAOI and aserotonin releasing agent (SRA) likeMDMA can also consistently result in severe and life-threatening serotonin syndrome.[41]
Although the most significant health risk associated withopioid overdoses isrespiratory depression,[53] it is still possible for an individual to develop serotonin syndrome from certain opioids without theloss of consciousness. However, most cases of opioid-related serotonin syndrome involve the concurrent use of aserotergenic drug such asantidepressants.[54] Nonetheless, it is not uncommon for individuals taking opioids to also be taking antidepressants due to the comorbidity of pain and depression.[55] Cases where opioids alone are the cause of serotonin syndrome are typically seen with tramadol, because of its dual mechanism as aserotonin-norepinephrine reuptake inhibitor.[56][57] Serotonin syndrome 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 aneurotransmitter involved in multiple complex biological processes including aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting.[10] In humans the effects of excess serotonin were first noted in 1960 in patients receiving an MAOI andtryptophan.[58] The syndrome is caused by increased serotonin in the CNS.[6] It was originally suspected thatagonism of serotonin5-HT1A receptors incentral grey nuclei and themedulla oblongata was responsible for the development of the syndrome.[59] Further study has determined that overstimulation of primarily the serotonin5-HT2A receptors appears to contribute substantially to the condition, while the serotonin 5-HT1A receptor seems to play little role.[44][59] However, the serotonin 5-HT1A receptor may still contribute through apharmacodynamic interaction in which increased synaptic concentrations of a serotonin agonist saturate all receptor subtypes.[6] Additionally, noradrenergic CNS hyperactivity may play a role as CNSnorepinephrine concentrations are increased in serotonin syndrome and levels appear to correlate with the clinical outcome. Other neurotransmitters may also play a role;NMDA receptor antagonists andγ-aminobutyric acid have been suggested as affecting the development of the syndrome.[6] Serotonin toxicity is more pronounced following supra-therapeutic doses andoverdoses, and they merge in a continuum with the toxic effects of overdose.[50][60]
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. Thedose-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.[61][62] Some experts prefer the terms serotonin toxicity or serotonin toxidrome, to more accurately reflect that it is a form ofpoisoning.[9][62]
There is no specific test for serotonin syndrome. Diagnosis is by symptom observation and investigation of the person's history.[6] Several criteria have been proposed. The first evaluated criteria were introduced in 1991 by Harvey Sternbach.[6][30][63] Researchers later developed the Hunter Toxicity Criteria Decision Rules, which have bettersensitivity and specificity, 84% and 97%, respectively, when compared with the gold standard of diagnosis by a medical toxicologist.[6][10] As of 2007, Sternbach's criteria were still the most commonly used.[9]
The most important symptoms for diagnosing serotonin syndrome are tremor, extreme aggressiveness,akathisia, or clonus (spontaneous, inducible and ocular).[10]Physical examination of the patient should include assessment ofdeep tendon reflexes and muscle rigidity, the dryness of themucosa of the mouth, the size and reactivity of the pupils, the intensity of bowel sounds, skin color, and the presence or absence of sweating.[6] The patient's history also plays an important role in diagnosis, investigations should include inquiries about the use of prescription andover-the-counter drugs, illicit substances, anddietary supplements, as all these agents have been implicated in the development of serotonin syndrome.[6] To fulfill the Hunter Criteria, a patient must have taken aserotonergic agent and meet one of the following conditions:[10]
Serotonin toxicity has a characteristic picture which is generally hard to confuse with othermedical conditions, but in some situations it may go unrecognized because it may be mistaken for aviral illness,anxiety disorders,neurological disorder,anticholinergic poisoning,sympathomimetic toxicity, or worsening psychiatric condition.[6][9][64] The condition most often confused with serotonin syndrome isneuroleptic malignant syndrome (NMS).[65][66] The clinical features of neuroleptic malignant syndrome and serotonin syndrome share some features which can make differentiating them difficult.[67] In both conditions,autonomic dysfunction and alteredmental status develop.[59] 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.[10] Serotonin toxicity has a rapid onset after the administration of a serotonergic drug and responds to serotonin blockade such as drugs likechlorpromazine andcyproheptadine.Dopamine receptor blockade (NMS) has a slow onset, typically evolves over several days after administration of aneuroleptic drug, and responds to dopamine agonists such asbromocriptine.[6][59]
Differential diagnosis may become difficult in patients recently exposed to both serotonergic and neuroleptic drugs.Bradykinesia andextrapyramidal "lead pipe" rigidity are classically present in NMS, whereas serotonin syndrome causeshyperkinesia and clonus; these distinct symptoms can aid in differentiation.[23][68]
Management is based primarily on stopping the usage of the precipitating drugs, the administration ofserotonin antagonists such ascyproheptadine (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[69]),[70] and supportive care including the control of agitation, the control of autonomic instability, and the control of hyperthermia.[6][71][72] Additionally, those who ingest large doses of serotonergic agents may benefit from gastrointestinal decontamination withactivated charcoal if it can be administered within an hour of overdose.[9] 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, givingbenzodiazepines 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 nocontrolled trials demonstrating its efficacy for serotonin syndrome.[9][73][74] Despite the absence of controlled trials, there are a number of case reports detailing apparent improvement after people have been administered cyproheptadine.[9] Animal experiments also suggest a benefit from serotonin antagonists.[75] Cyproheptadine is only available as tablets and therefore can only be administered orally or via anasogastric tube; it is unlikely to be effective in people administered activated charcoal and has limited use in severe cases.[9] Cyproheptadine can be stopped when the person is no longer experiencing symptoms and the half life of serotonergic medications already passed.[2]
Additional pharmacological treatment for severe case includes administering atypical antipsychotic drugs with serotonin antagonist activity such asolanzapine orasenapine.[6] Critically ill people should receive the above therapies as well as sedation or neuromuscular paralysis.[6] People who have autonomic instability such as lowblood pressure require treatment with direct-acting sympathomimetics such asepinephrine, norepinephrine, orphenylephrine.[6] Conversely, hypertension or tachycardia can be treated with short-actingantihypertensive drugs such asnitroprusside oresmolol; longer acting drugs such aspropranolol should be avoided as they may lead to hypotension and shock.[6] The cause of serotonin toxicity or accumulation is an important factor in determining the course of treatment. Serotonin is catabolized bymonoamine oxidase A in the presence ofoxygen, 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 serotonin syndrome 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.[6]Physical restraints are not recommended for agitation or delirium as they may contribute to mortality by enforcing isometricmuscle contractions that are associated with severelactic acidosis and hyperthermia. If physical restraints are necessary for severe agitation they must be rapidly replaced with pharmacologicalsedation.[6] The agitation can cause a large amount of muscle breakdown. This breakdown can cause severe damage to the kidneys through a condition calledrhabdomyolysis.[76]
Treatment for hyperthermia includes reducing muscle overactivity via sedation with a benzodiazepine. More severe cases may require muscular paralysis withvecuronium,intubation, and artificial ventilation.[6][9]Suxamethonium is not recommended for muscular paralysis as it may increase the risk of cardiac dysrhythmia from hyperkalemia associated with rhabdomyolysis.[6]Antipyretic agents are not recommended as the increase inbody temperature is due to muscular activity, not ahypothalamic temperature set point abnormality.[6]
Upon the discontinuation of serotonergic drugs, most cases of serotonin syndrome resolve within 24 hours,[6][9][77][78] although in some casesdelirium may persist for a number of days.[30] Symptoms typically persist for a longer time frame in patients taking drugs which have a long eliminationhalf-life, active metabolites, or a protracted duration of action.[6]
Cases have reported persisting chronic symptoms,[79] andantidepressant discontinuation may contribute to ongoing features.[80] Following appropriate medical management, serotonin syndrome is generally associated with a favorable prognosis.[81]
Epidemiological studies of serotonin syndrome are difficult as many physicians are unaware of the diagnosis or they may miss the syndrome due to its variable manifestations.[6][82] In 1998 a survey conducted in England found that 85% of thegeneral practitioners that had prescribed the antidepressantnefazodone were unaware of serotonin syndrome.[47] 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.[73] Onepostmarketing surveillance study identified an incidence of 0.4 cases per 1000 patient-months for patients who were taking nefazodone.[47] Additionally, around 14 to 16% of persons who overdose on SSRIs are thought to develop serotonin syndrome.[50]
Serotonin syndrome, or serotonin toxicity, was first reported in humans in 1982.[44][83] It had previously been observed in animals.[44][83][84] However, serotonin syndrome-like toxicity had previously been reported as early as the 1960s, but these cases were not recognized as serotonin toxicity.[44] Serotonin syndrome was first defined as a distinct clinical entity and formally given the name "serotonin syndrome" in 1991.[44][85]
The most widely recognized example of serotonin syndrome was the death ofLibby Zion in 1984.[86] Zion was a freshman atBennington College at her death on March 5, 1984, at age 18. She died within 8 hours of her emergency admission to theNew 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 seemeddisoriented at times. The emergency room physicians were unable to diagnose her condition definitively but admitted her forhydration and observation. Her death was caused by a combination ofpethidine andphenelzine.[87] A medical intern prescribed the pethidine.[88] The case influenced graduate medical education and residency work hours. Limits were set onworking hours for medical postgraduates, commonly referred to as interns or residents, in hospital training programs, and they also now require closer senior physician supervision.[8]
Importantly, the idea of increased risk for developing serotonin syndrome and/or serotonin toxicity, when [antidepressants (ADs)] are co-administered with high doses of psychedelics, has recently been challenged, in part because classic psychedelics are partial agonists of the 5-HT2A receptor and would also compete for serotonin binding (Malcolm and Thomas, 2022; Rickli et al., 2016; Sarparast et al., 2022). Based on this clinical rationale, the concomitant use of ADs and classic psychedelics may be preferred, or patients could temporarily reduce the dose of ADs around dosing days with psychedelics to have minimal interactions. Simultaneously, the competition for 5-HT2A receptors could impede the biological action of psychedelics during concomitant use of ADs and potentially limit efficacy (Halman et al., 2024), particularly as the 5-HT2A receptor induces neuroplasticity (Cameron et al., 2023; Ly et al., 2018; Vargas et al., 2023).
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