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INTRODUCTION — Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system (CNS). It is seen with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning . Although classically described as the triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities, serotonin syndrome is actually a spectrum of clinical findings ranging from benign to lethal [1-4]. A summary table to facilitate the emergent management of serotonin syndrome is provided (table 1).
This review will discuss serotonin syndrome. A discussion of selective serotonin reuptake inhibitor (SSRI) intoxication and a general approach to management of the poisoned patient are found elsewhere. (See "Selective serotonin reuptake inhibitor poisoning" and "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose".)
DEFINITION — Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system (CNS). It is seen with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning . Serotonin syndrome may involve a spectrum of clinical findings, which often include mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. (See 'Clinical features' below.)
EPIDEMIOLOGY — Serotonin syndrome has been observed in all age groups, including newborns and the elderly. The increasing incidence of this condition is thought to parallel the increasing use of serotonergic agents in medical practice [1,3,5]. The syndrome has been described following intentional overdose [6,7].
The selective serotonin reuptake inhibitors (SSRIs) are perhaps the most commonly implicated group of medications associated with serotonin syndrome. The United States’ Toxic Exposure Surveillance System consistently reports tens of thousands of exposures to SSRIs, many of which involve serotonin syndrome .
However, the true incidence of serotonin syndrome may be under-represented in such figures for a number of reasons. Manifestations may be wrongly attributed to another cause, mild cases may be dismissed, or clinicians may not suspect the condition.
PHARMACOLOGY AND CELLULAR TOXICOLOGY — In the central nervous system (CNS), serotonin modulates attention, behavior, and thermoregulation. In the peripheral nervous system, serotonin is produced primarily by intestinal enterochromaffin cells and is involved in regulating gastrointestinal motility, vasoconstriction, uterine contraction, and bronchoconstriction . Serotonin is also found in platelets where it promotes platelet aggregation.
Stimulation of the postsynaptic 5-HT1A and 5-HT2A receptors has been implicated in serotonin syndrome , but no single receptor is solely responsible . Serotonin syndrome may result from any combination of drugs that has the net effect of increasing serotonergic neurotransmission (table 2). The syndrome is classically associated with the simultaneous administration of two serotonergic agents, but it can occur after initiation of a single serotonergic drug or increasing the dose of a serotonergic drug in individuals who are particularly sensitive to serotonin. Episodes of serotonin syndrome involving a monoamine oxidase inhibitor may be more severe and more often lead to adverse outcomes, including death [10,11].
Overview and principles of evaluation — The diagnosis of serotonin syndrome is made solely on clinical grounds. Therefore, a detailed history and thorough physical and neurologic examinations are essential.
Serotonin syndrome encompasses a spectrum of disease where the intensity of clinical findings is thought to reflect the degree of serotonergic activity. Mental status changes can include anxiety, agitated delirium, restlessness, and disorientation . Patients may startle easily. Autonomic manifestations can include diaphoresis, tachycardia, hyperthermia, hypertension, vomiting, and diarrhea . Neuromuscular hyperactivity can manifest as tremor, muscle rigidity, myoclonus, hyperreflexia, and bilateral Babinski sign. Hyperreflexia and clonus are particularly common; these findings, as well as rigidity, are more often pronounced in the lower extremities .
Questions remain regarding the exact point at which serotonergic signs associated with therapeutic drug administration become the toxic reaction known as serotonin syndrome. The transition point likely depends upon an assessment of the risks and benefits of therapy. As an example, an individual treated for major depression with a serotonergic agent may develop mild tremor and hyperreflexia. Although technically meeting the diagnostic criteria for serotonin syndrome, the patient may benefit more (ie, be significantly less depressed) with continued administration of the agent, even though it produces obvious but tolerable signs of serotonergic excess. However, clinicians should be extremely careful not to add other serotonergic drugs to the regimen of such a patient, and must remain vigilant for any worsening in condition.
History — The patient's history should include a detailed description of prescription drugs, over-the-counter medications, illicit substances, and dietary supplements used, as well as any change in dosing and schedule (table 2). Clinicians should ask about the dose, formulation (eg, sustained release), and any recent changes in medications. Episodes of serotonin syndrome involving a monoamine oxidase inhibitor may be more severe and more often lead to adverse outcomes, including death [10,11].
A description of symptoms, their onset, and their rate of change is also important . The majority of cases of serotonin syndrome present within 24 hours, and most within six hours, of a change in dose or initiation of a drug .
Patients with intentional ingestions often develop greater toxicity than those with accidental exposures, so it is important to ask the patient directly about his or her intent. Information obtained from the overdose patient is often unreliable, however, and confirmation should be sought. Additional history, including comorbid conditions and signs and symptoms, should be elicited from the patient, family members, friends, emergency medical services (EMS) personnel, and police. A general approach to management of the poisoned patient is found elsewhere. (See "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose".)
Physical examination — Typical vital sign abnormalities include tachycardia and hypertension, but severe cases may develop hyperthermia and dramatic swings in pulse and blood pressure. Pertinent physical examination findings may include :
Neuromuscular findings are typically more pronounced in the lower extremities.
LABORATORY EVALUATION — Serotonin syndrome is a clinical diagnosis; serum serotonin concentrations do not correlate with clinical findings, and no laboratory test confirms the diagnosis . Nevertheless, some nonspecific laboratory findings may develop, including an elevated white blood cell count, elevated creatine phosphokinase, and decreased serum bicarbonate concentration.
Patients with severe disease may develop severe complications, including disseminated intravascular coagulation, rhabdomyolysis, metabolic acidosis, renal failure, myoglobinuria, and acute respiratory distress syndrome . (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults" and "Clinical manifestations and diagnosis of rhabdomyolysis" and "Acute respiratory distress syndrome: Epidemiology; pathophysiology; pathology; and etiology".)
In order to narrow the differential diagnosis and to monitor for potential complications, particularly in severely ill patients, the following studies may be necessary:
In patients whose overdose was intentional, acetaminophen and salicylate concentrations should be measured and an electrocardiogram evaluated for signs of toxicity from other agents. (See "General approach to drug poisoning in adults", section on 'Electrocardiography' and "General approach to drug poisoning in adults", section on 'Other laboratory studies'.)
DIAGNOSIS AND DIAGNOSTIC CRITERIA — Serotonin syndrome is diagnosed on the basis of clinical findings. We suggest diagnosing serotonin syndrome using the Hunter Toxicity Criteria Decision Rules . To fulfill the Hunter Criteria, a patient must have taken a serotonergic agent and meet ONE of the following conditions:
Several sets of diagnostic criteria have been developed to define serotonin syndrome, of which the Hunter Criteria are most accurate (84 percent sensitive and 97 percent specific when compared with the gold standard of diagnosis by a medical toxicologist). In a comparison with the original Sternbach Criteria, the Hunter Criteria performed with greater accuracy and were less likely to miss early, mild, or subacute forms of serotonin syndrome.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of serotonin syndrome includes neuroleptic malignant syndrome (NMS), anticholinergic toxicity, malignant hyperthermia, intoxication from sympathomimetic agents, sedative-hypnotic withdrawal, meningitis, and encephalitis.
Serotonin syndrome is often misdiagnosed as NMS, but the two can readily be distinguished on the basis of history, examination findings, and clinical course (table 3) . NMS develops over days to weeks , whereas serotonin syndrome develops over 24 hours . Serotonin syndrome is characterized by neuromuscular hyperreactivity (tremor, hyperreflexia, myoclonus), while NMS involves sluggish neuromuscular responses (rigidity, bradyreflexia). Hyperreflexia and myoclonus are rare in NMS . In addition, resolution of NMS typically requires an average of nine days, compared with less than 24 hours (usually) for resolution of serotonin syndrome . Hyperthermia, altered mental status, muscle rigidity, leukocytosis, elevated creatine phosphokinase, elevated hepatic transaminases, and metabolic acidosis are seen in severe cases of both conditions, which highlight the necessity of a thorough history and physical examination. (See "Neuroleptic malignant syndrome".)
Anticholinergic toxicity classically presents with hyperthermia, agitation, altered mental status, mydriasis, dry mucous membranes, urinary retention, and decreased bowel sounds after the use of an anticholinergic agent. In contrast with serotonin syndrome, muscular tone and reflexes are normal in anticholinergic poisoning (table 4). (See "Anticholinergic poisoning".)
Malignant hyperthermia occurs in susceptible individuals exposed to halogenated volatile anesthetics and depolarizing muscle relaxants (eg, succinylcholine). It classically presents with increased concentrations of end-tidal carbon dioxide, rigor mortis-like muscle rigidity, tachycardia, hyperthermia, and acidosis . (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis" and "Susceptibility to malignant hyperthermia: Evaluation and management".)
Serotonin syndrome may be distinguished from other causes of agitated delirium on the basis of neuromuscular findings. Whereas patients with serotonin syndrome show signs of neuromuscular activation (eg, tremor, hyperreflexia and clonus that are greater in the lower extremities, ocular clonus, and increased muscle tone), patients with sympathomimetic toxicity or infections of the central nervous system lack these findings.
Key principles — A summary table to facilitate the emergent management of serotonin syndrome is provided (table 1). Five principles are central to the management of serotonin syndrome:
Application of these principles varies with the severity of illness. In mild cases, discontinuation of inciting medications, supportive care, and sedation with benzodiazepines are generally sufficient. Moderately ill patients require more aggressive treatment of autonomic instability and possibly treatment with a serotonin antagonist (see 'Antidote: Cyproheptadine' below). Hyperthermic patients (>41.1°C) are critically ill and often require neuromuscular paralysis and tracheal intubation.
Common management pitfalls include failure to recognize serotonin syndrome, misdiagnosis, and failure to understand serotonin syndrome's potentially rapid rate of progression (see 'Clinical features' above). Even if the diagnosis remains unclear, the clinician should withhold serotonergic agents and provide aggressive supportive care, anticipating the need for interventions before the patient's condition deteriorates.
Serotonin syndrome often resolves within 24 hours of discontinuing the serotonergic agent and initiating care, but drugs with long half-lives or active metabolites may cause symptoms to persist . Irreversible monoamine oxidase inhibitors (MAOIs) carry the greatest risk, and symptoms can persist for several days. Selective serotonin reuptake inhibitors (SSRIs) may contribute to the development of serotonin syndrome up to several weeks after the drug has been discontinued; the half-life of fluoxetine is one week and that of its metabolite norfluoxetine is up to 2.5 weeks . Although the patient may not exhibit symptoms of serotonin syndrome while taking fluoxetine, care should be taken when administering another serotonergic agent after discontinuing this or any other SSRI.
As with any toxic exposure, consultation with a medical toxicologist, clinical pharmacologist, or poison control center can provide valuable assistance with clinical decision-making. (See 'Additional resources' below.)
Supportive care and sedation — Supportive care is the mainstay of therapy and includes the administration of oxygen and intravenous fluids, continuous cardiac monitoring, and correction of vital signs. Clinicians should provide sufficient oxygen to maintain the oxygen saturation ≥ 94 percent, and give IV crystalloid to treat volume depletion, and to some extent hyperthermia.
Chemical restraint is greatly preferred to physical restraint for agitated patients; physical restraints may cause isometric muscle contractions leading to profound lactic acidosis and hyperthermia . Sedation with benzodiazepines is important for controlling agitation as well as correcting mild increases in blood pressure and heart rate. Diazepam prolongs survival in a rat model of serotonin syndrome, but no specific agent has been studied in humans . Regardless of the benzodiazepine selected, the clinician should give standard doses to begin therapy and titrate further treatment to effect, the goals being adequate patient sedation (not somnolence) and normal vital signs.
We treat patients with significant agitation (eg, those who do not respond immediately to verbal interventions) with intravenous (IV) benzodiazepines (eg, lorazepam 2 to 4 mg IV or diazepam 5 to 10 mg IV). These doses can be repeated every 8 to 10 minutes based upon patient response. Butyrophenones (eg, droperidol and haloperidol) should be avoided; these drugs have anticholinergic properties that inhibit sweating and dissipation of body heat.
Autonomic instability — Management of autonomic instability may be difficult since severely intoxicated patients often exhibit large and rapid changes in blood pressure and heart rate. Consequently, patients with severe hypertension and tachycardia should be treated with short-acting agents, such as esmolol or nitroprusside . Dosing of these short-acting cardiovascular agents should be titrated to maintain autonomic stability; longer-acting agents, such as propranolol, should be avoided.
Hypotension from MAOIs in patients with serotonin syndrome should be treated with low doses of direct-acting sympathomimetic amines, such as phenylephrine, epinephrine, or norepinephrine . Indirect agents (eg, dopamine) should be avoided because they are metabolized to epinephrine and norepinephrine; when monoamine oxidase is inhibited, epinephrine and norepinephrine production at the cellular level is not controlled, possibly leading to an exaggerated hemodynamic response .
Hyperthermia — Control of hyperthermia is critical and involves eliminating excessive muscle activity. Aggressive and effective control of hyperthermia can potentially minimize several severe complications of serotonin syndrome (eg, seizures, coma, disseminated intravascular coagulation, hypotension, ventricular tachycardia, and metabolic acidosis) . Standard treatments for hyperthermia are discussed separately. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults", section on 'Cooling measures'.)
Patients whose temperature is above 41.1ºC require immediate sedation, paralysis, and tracheal intubation . Standard rapid sequence intubation (RSI) using an induction and paralytic agent should be performed. Etomidate (0.3 mg/kg IV) and succinylcholine (1.5 to 2 mg/kg IV) can generally be used; succinylcholine should be avoided in patients with possible hyperkalemia (as may occur in patients with acute renal failure or rhabdomyolysis). After intubation, paralysis can be maintained with a longer-acting nondepolarizing agent, such as vecuronium. Clinicians must provide adequate sedation, typically with a benzodiazepine, while the patient is paralyzed. (See "Rapid sequence intubation in adults" and "Sedative-analgesic medications in critically ill patients: Selection, initiation, maintenance, and withdrawal".)
In hyperthermia associated with serotonin syndrome, there is no role for antipyretic agents, such as acetaminophen; the increase in body temperature is not due to an alteration in the hypothalamic temperature set point, but rather an increase in muscular activity .
Antidote: Cyproheptadine — If benzodiazepines and supportive care fail to improve agitation and correct vital signs, we suggest antidotal therapy with cyproheptadine . Cyproheptadine is a histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-HT2A antagonistic properties . It also has weak anticholinergic activity.
Cyproheptadine is available in 4 mg tablets or 2 mg/5 mL syrup . When administered as an antidote for serotonin syndrome, an initial dose of 12 mg is recommended, followed by 2 mg every two hours until clinical response is seen. Cyproheptadine is only available in an oral form, but it may be crushed and given through a nasogastric or orogastric tube.
Cyproheptadine may lead to sedation, but this effect is consistent with the goals of management . Furthermore, as a nonspecific serotonin antagonist, cyproheptadine may produce transient hypotension due to the reversal of serotonin-mediated increases in vascular tone. Such hypotension usually responds to intravenous fluids. Cyproheptadine is rated category B for safety in pregnancy by the US Food and Drug administration (FDA) (table 5) .
Definitive evidence of cyproheptadine's effectiveness is lacking. A small study used PET scan to assess 5-HT2 blockade in two volunteers after taking cyproheptadine (12 mg and 18 mg per day for six days). At 12 mg/day, there was 85 percent blockade and at 18 mg/day there was over 95 percent blockade of 5-HT2 receptors in the prefrontal cortex . In addition, many reports describe the successful use of cyproheptadine to treat serotonin syndrome [17,19-24]. The majority of these patients received cyproheptadine at an initial dose of 8 mg, while fewer patients responded to as little as 4 mg and some had no response to as much as 16 mg.
Other antidotes — Antipsychotic agents with 5-HT2A antagonist activity, such as olanzapine and chlorpromazine, have been considered for antidotal treatment, but their efficacy is unproven and we do NOT recommend their use . Chlorpromazine can cause orthostatic hypotension, although this is generally not an issue with serotonin syndrome, in which hypertension is common. Chlorpromazine can also increase hyperthermia.
Treatment with propranolol, bromocriptine, or dantrolene is not recommended. Propranolol has a long duration of action, may cause prolonged hypotension, and can mask tachycardia that can be used to monitor the effectiveness of treatment. Bromocriptine, a serotonin agonist, may exacerbate serotonin syndrome . Dantrolene has no effect on survival in animal models.
DISPOSITION AND PROGNOSIS — Patients with severe serotonin syndrome (eg, hyperthermia, autonomic instability, agitated delirium) require care in an intensive care unit. Those with moderate symptoms should be admitted for observation and placed on a cardiac monitor until symptoms resolve. Symptoms usually resolve within 24 hours of discontinuing the serotonergic agent and initiating care, but drugs with long durations of action or active metabolites may cause prolonged symptoms . Mild cases may be observed for four to six hours. If during that period the patient's mental status and vital signs remain normal, there is no increase in clonus or deep tendon reflexes, and close follow-up is assured, the patient may be discharged home.
It merits reiteration that serotonin syndrome manifests a broad spectrum of clinical severity. Particularly in mild cases, clinicians must weigh benefits and risks when determining treatment and whether to continue the causative agent. (See 'Clinical features' above.)
Prognosis is generally favorable, as long as the entity is recognized and complications are treated appropriately.
PEDIATRIC CONSIDERATIONS — Serotonin syndrome in the pediatric population parallels that in the adult population, with similar pathophysiology and manifestations. Any drug or drug combination that increases serotonergic neurotransmission can produce the syndrome (table 2). The same diagnostic criteria, characterized by increased neuromuscular activity, are used in the pediatric population. Hyperreflexia, clonus, and hyperthermia remain important findings. (See 'Diagnosis and diagnostic criteria' above.)
Although multiple case reports have been published, several obstacles make the diagnosis of serotonin syndrome more difficult in pediatric patients [25-28]. Children may not be able to communicate vague symptoms; clinicians may not consider the syndrome a pediatric problem; and adolescents may be reluctant to disclose recreational drug use, which may include serotonergic agents, such as methylenedioxymethamphetamine (MDMA; "ecstasy") or dextromethorphan . (See "MDMA (ecstasy) intoxication" and "Dextromethorphan poisoning: Epidemiology, pharmacology and clinical features".)
The fundamental principles of serotonin syndrome management remain unchanged in pediatrics. Any serotonergic agent is discontinued. Supportive care is provided, the goals being adequate patient sedation and normal vital signs. Standard interventions include oxygen, intravenous fluids, and continuous cardiac monitoring. Autonomic instability and hyperthermia require aggressive treatment. Sedation with weight-based doses of benzodiazepines is recommended for the treatment of agitation. (See 'Management' above.)
In pediatric patients with severe symptoms, serotonergic antagonists can be given; cyproheptadine may be used in pediatric patients with a dose of 0.25 mg/kg/day divided every six hours. Doses should be titrated to maintain adequate sedation. General dosing is as follows:
Pediatric patients with severe serotonin syndrome require management in an intensive care unit. Pediatric patients with mild to moderate symptoms should be placed on a cardiac monitor and admitted for observation. If serotonin syndrome is recognized and complications are treated appropriately, the prognosis is generally favorable.
In addition to cases in the general pediatric population, there are rare reports of neonates with symptoms resembling serotonin syndrome. One small study showed that infants exposed to SSRIs late in pregnancy were at increased risk for adverse central nervous system (CNS) effects . The most prominent findings were restlessness, tremor, and rigidity; myoclonus and hyperreflexia occurred less often. Symptoms appeared to subside quickly without any specific treatment .
PREVENTION — Serotonin syndrome can be avoided by applying pharmacologic principles, educating clinicians, and modifying prescription practices . Multi-drug regimens should be avoided, if possible.
ADDITIONAL RESOURCES — Once serotonin syndrome occurs, a medical toxicologist, clinical pharmacologist, or poison control center should be consulted for assistance. Regional poison control centers in the United States (1-800-222-1222) are available at all times for consultation on patients who are critically ill, require admission, or have clinical pictures that are unclear. The World Health Organization provides a listing of international poison centers at its website: www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html
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