Serotonin syndrome

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Not to be confused with
SSRI discontinuation syndrome
.
Serotonin syndrome
Other namesSerotonin toxicity, serotonin toxidrome, serotonin sickness, serotonin storm, serotonin poisoning, hyperserotonemia, serotonergic syndrome, serotonin shock
anticholinergic toxicity, heat stroke, meningitis[2]
TreatmentActive cooling[1]
MedicationBenzodiazepines, cyproheptadine[1]
FrequencyUnknown[3]

Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain

body temperature can increase to greater than 41.1 °C (106.0 °F).[2] Complications may include seizures and extensive muscle breakdown.[2]

Serotonin syndrome is typically caused by the use of two or more serotonergic medications or drugs.

St. John's wort, triptans, MDMA, metoclopramide, or cocaine.[2] It occurs in about 15% of SSRI overdoses.[3] It is a predictable consequence of excess serotonin on the central 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.

anticholinergic toxicity, heat stroke, and meningitis should be ruled out.[2] No laboratory tests can confirm the diagnosis.[2]

Initial treatment consists of discontinuing medications which may be contributing.

New York State.[6][8]

Signs and symptoms

Clonus seen in a person with serotonin syndrome

Symptom onset is usually relatively rapid, SS encompasses a wide range of clinical findings. Mild symptoms may consist of

high blood pressure and hyperthermia; a temperature as high as 40 °C (104 °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.[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 include metabolic acidosis, rhabdomyolysis, seizures, kidney failure, and disseminated intravascular coagulation; these effects usually arising as a consequence of hyperthermia.[6][9]

The symptoms are often present as a clinical triad of abnormalities:[6][10]

Causes

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.

Class Drugs that can induce serotonin syndrome
Antidepressants
SNRIs,[6] nefazodone,[11] trazodone[11]
Opioids Dextropropoxyphene,[12] tramadol,[6] tapentadol, pethidine (meperidine),[6] fentanyl,[6] pentazocine,[6] buprenorphine[13] oxycodone,[14] hydrocodone[14]
Central nervous system stimulants
hallucinogenic substituted amphetamines,[12] sibutramine,[6] methylphenidate,[12] cocaine[12]
5-HT1 agonists Triptans[6][12]
Psychedelics
LSD[20]
Herbs
yohimbe[22]
Others
chlorpheniramine,[12] risperidone,[25] olanzapine,[26] ondansetron,[6] granisetron,[6] metoclopramide,[6] ritonavir,[6] metaxalone[6]

Many cases of serotonin toxicity occur in people who have ingested drug combinations that synergistically increase synaptic serotonin.

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.[29] With respect to tricyclic antidepressants, only clomipramine and imipramine have a risk of causing SS.[30]

Many medications may have been incorrectly thought to cause SS. For example, some case reports have implicated

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.[36] This has been disputed by other researchers, as none of the cases reported by the FDA met the Hunter criteria for SS.[36][37] 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.[38][39]

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.[40][41][42][43] The serotonergic toxicity of SSRIs increases with dose, but even in overdose, it is insufficient to cause fatalities from SS in healthy adults.[44][45] Elevations of central nervous system (CNS) serotonin will typically only reach potentially fatal levels when drugs with different mechanisms of action are mixed together.[9] 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.[6][46]

Although the most significant health risk associated with

loss of consciousness. However, most cases of opioid-related SS involve the concurrent use of a serotergenic drug such as antidepressants.[48] Nonetheless, it is not uncommon for individuals taking opioids to also be taking antidepressants due to the comorbidity of pain and depression.[49]

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.[50][51]
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.

Pathophysiology

Serotonin is a

overdoses, and they merge in a continuum with the toxic effects of overdose.[44][54]

Spectrum concept

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.[55][56] Some experts prefer the terms serotonin toxicity or serotonin toxidrome, to more accurately reflect that it is a form of poisoning.[9][56]

Diagnosis

There is no specific test for SS. 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][29][57] 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.[6][10] As of 2007, Sternbach's criteria were still the most commonly used.[9]

The most important symptoms for diagnosing SS are tremor, extreme aggressiveness,

serotonergic agent and meet one of the following conditions:[10]

Differential diagnosis

Serotonin toxicity has a characteristic picture which is generally hard to confuse with other

neuroleptic drug, and responds to dopamine agonists such as bromocriptine.[6][53]

Bradykinesia and extrapyramidal "lead pipe" rigidity are classically present in NMS, whereas SS causes hyperkinesia and clonus; these distinct symptoms can aid in differentiation.[23][62]

Management

Management is based primarily on stopping the usage of the precipitating drugs, the administration of

nasogastric 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 as

nitroprusside or esmolol; longer acting drugs such as propranolol 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 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.

Agitation

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 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.[6] The agitation can cause a large amount of muscle breakdown. This breakdown can cause severe damage to the kidneys through a condition called rhabdomyolysis.[69]

Hyperthermia

Treatment for hyperthermia includes reducing muscle overactivity via sedation with a benzodiazepine. More severe cases may require muscular paralysis with

hypothalamic temperature set point abnormality.[6]

Prognosis

Upon the discontinuation of serotonergic drugs, most cases of SS resolve within 24 hours,[6][9][70][71] although in some cases delirium may persist for a number of days.[29] 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.[6]

Cases have reported persisting chronic symptoms,

antidepressant discontinuation may contribute to ongoing features.[73] Following appropriate medical management, SS is generally associated with a favorable prognosis.[74]

Epidemiology

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.[6][75] In 1998 a survey conducted in England found that 85% of the general practitioners that had prescribed the antidepressant nefazodone were unaware of SS.[41] 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.[66] One postmarketing surveillance study identified an incidence of 0.4 cases per 1000 patient-months for patients who were taking nefazodone.[41] Additionally, around 14–16% of persons who overdose on SSRIs are thought to develop SS.[44]

Notable cases

Libby Zion
case

The most widely recognized example of SS was the death of

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.[77] A medical intern prescribed the pethidine.[78] 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.[8]

See also

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External links

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