Serotonin syndrome (serotonin toxicity)

INTRODUCTION — Serotonin syndrome, also referred to as serotonin toxicity, is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. It is seen with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning [1]. 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".)

●(See "General approach to drug poisoning in adults".)

●(See "Initial management of the critically ill adult with an unknown overdose".)

DEFINITION — Serotonin syndrome (ie, serotonin toxicity) is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. It is seen with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning [1]. 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 older adults. 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], and even in post-cardiac arrest patients treated with therapeutic hypothermia [8].

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 [9]. Notably, SSRIs are less commonly associated with causing severe serotonin syndrome compared with medications that inhibit monoamine oxidase (MAO) (table 2) [10]. The serotonin-norepinephrine reuptake inhibitors (SNRIs; eg, desvenlafaxine, venlafaxine) are slightly more likely to cause serotonin syndrome compared with SSRIs, but several-fold less likely compared with an MAOI co-ingestion [11].

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. Ingestion of multiple stimulants (eg, amphetamine with serotonergic agents) can cause a combination of excitatory toxidromes (table 3) that might not be easily classified as pure serotonin toxicity. Many reports exist in the literature misattributing nonspecific signs and symptoms without a clear precipitating etiology to serotonin syndrome [10].

PHARMACOLOGY AND CELLULAR TOXICOLOGY — In the central nervous system, 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 [3]. 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 [12], but no single receptor is solely responsible [1]. 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 (MAOI) may be more severe and more often lead to adverse outcomes, including death [13,14]. Although counterintuitive, serotonergic agonists that have their effect directly on postsynaptic 5-HT receptors (eg, fentanyl, buspirone, LSD, triptans) are less likely to cause severe or classic serotonin toxicity as compared with drug-drug interactions or MAOIs [10].

CLINICAL FEATURES

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 [10]. Mental status changes can include anxiety, restlessness, disorientation, and agitated delirium [15]. Patients may startle easily. Autonomic manifestations can include diaphoresis, tachycardia, hyperthermia, hypertension, vomiting, and diarrhea [3]. Neuromuscular hyperactivity can manifest as tremor, 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 [3]. In severe cases, muscle rigidity may mask myoclonus and hyperreflexia. While uncommon, fatal cases of serotonin syndrome are associated with hyperthermia and seizure, the latter of which is often a preterminal event [16]. Should a seizure occur in what is thought to be mild or moderate serotonin syndrome, the clinician should consider other causes. (See 'Differential diagnosis' below.)

Questions remain regarding the exact point at which serotonergic signs associated with therapeutic drug administration become the toxic reaction known as serotonin syndrome [10]. 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, as compared with a selective serotonin reuptake inhibitor (SSRI), may be more severe and more often lead to adverse outcomes, including death [13,14].

A description of symptoms, their onset, and their rate of change is also important [1]. 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 [3].

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 [1]:

●Hyperthermia

●Agitation

●Slow, continuous, horizontal eye movements (referred to as ocular clonus)

●Dilated pupils

●Tremor

●Akathisia

●Deep tendon hyperreflexia (common)

●Inducible or spontaneous muscle clonus (common)

●Muscle rigidity

●Bilateral Babinski signs

●Dry mucus membranes

●Flushed skin and diaphoresis

●Increased bowel sounds  

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 [3]. 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 [3]. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults".)

In order to narrow the differential diagnosis and to monitor for potential complications, particularly in severely ill patients, the following studies may be necessary:

●Complete blood count

●Basic serum electrolytes

●BUN and creatinine

●Creatine phosphokinase

●Hepatic transaminase concentrations

●Coagulation studies

●Blood culture

●Urinalysis and urine culture

●Plain chest radiograph

●Cerebrospinal fluid analysis and culture

●Head computed tomography (CT)

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 (algorithm 1) [17]. To fulfill the Hunter Criteria, a patient must have the presence of a serotonergic agent and meet one of the following conditions:

●Spontaneous clonus

●Inducible clonus plus agitation or diaphoresis

●Ocular clonus plus agitation or diaphoresis

●Tremor plus hyperreflexia

●Hypertonia plus temperature above 38ºC PLUS ocular clonus or inducible clonus

Serotonin syndrome is typically not a diagnosis of exclusion if the Hunter Criteria are met. However, patients on a stable dose of a serotonergic agent are unlikely to develop serotonin syndrome. Therefore, authorities suggested that the "presence of serotonergic agent" be defined as one of the following to make a definitive diagnosis [10]:

●Overdose with a serotonergic agent except a direct serotonin receptor agonist (table 2)

●Drug-drug interaction of two serotonergic agents except when both are direct serotonin receptor agonists

●Initiation or increase in dose of a serotonergic agent or agent that decreases metabolism of serotonergic agent

If none of these are present, then serotonin syndrome should be considered a diagnosis of exclusion, and other etiologies should be excluded. A mixed excitatory toxidrome (table 3) may be responsible in the setting of a polysubstance ingestion.

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 [10,17].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of serotonin syndrome includes neuroleptic malignant syndrome (NMS), anticholinergic toxicity, malignant hyperthermia, intoxication from sympathomimetic agents, sedative-hypnotic (eg, alcohol, benzodiazepine, clonidine, baclofen) withdrawal, thyroid storm, acute extrapyramidal syndromes (eg, dystonic reaction), 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 4) [12]. NMS develops over days to weeks [12], whereas serotonin syndrome develops over 24 hours [3]. 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 [12]. In addition, resolution of NMS typically requires an average of nine days, compared with less than 24 hours (usually) for resolution of serotonin syndrome [12]. 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 3). (See "Anticholinergic poisoning".)

Extrapyramidal syndromes, such as an acute dystonic reaction, involve involuntary contraction of major muscle groups. Acute dystonia precipitated by antipsychotic medications is usually rapid in onset and is characterized by torticollis, retrocollis, oculogyric crisis, and opisthotonos. Compared with serotonin syndrome, dystonic reactions have sluggish neuromuscular responses (ie, rigidity) and muscle contractions that are asymmetric (eg, torticollis is not directed towards midline) and rapidly improve with diphenhydramine or benztropine administration. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Movement and motor symptoms' and "First-generation (typical) antipsychotic medication poisoning", section on 'Acute extrapyramidal syndromes'.)

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 [18]. (See "Malignant hyperthermia: 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, sedative-hypnotic withdrawal, or infections of the central nervous system typically lack these findings. (See "Cocaine: Acute intoxication", section on 'Clinical manifestations' and "Acute amphetamine and synthetic cathinone ("bath salt") intoxication", section on 'Clinical features of overdose' and "Alcohol withdrawal: Epidemiology, clinical manifestations, course, assessment, and diagnosis", section on 'Clinical presentation and course' and "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Clinical features' and "Viral encephalitis in adults", section on 'Clinical manifestations' and "Benzodiazepine withdrawal".)

The symptoms and signs of serotonin syndrome and thyroid storm can overlap. In most cases, the two conditions are readily distinguished based on the history and clinical findings, and no additional testing is necessary. Patients in thyroid storm typically have a known history of thyroid disease and a discrete inciting event (eg, surgery, infection) along with clinical findings suggesting the diagnosis, such as hyperpyrexia, palpable goiter, cardiovascular dysfunction (eg, tachydysrhythmia, signs of heart failure), agitated mental state, and tremor. In the rare circumstance when it is difficult to distinguish between the two conditions (eg, patient with a history of thyroid disease also taking a serotonergic medication), obtaining thyroid studies may be helpful. (See "Thyroid storm".)

MANAGEMENT

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:

●Discontinuation of all serotonergic agents (table 2)

●Supportive care aimed at normalization of vital signs

●Sedation with benzodiazepines

●Administration of serotonin antagonists

●Assessment of the need to resume use of causative serotonergic agents after resolution of symptoms

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. In a patient with an excitatory toxidrome (table 3), managing agitation and neuromuscular hyperactivity is required even if the patient does not meet strict diagnostic criteria for serotonin syndrome.

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 [1]. 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 [19]. 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 (IV) 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 [1]. 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 [20]. 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 IV benzodiazepines (eg, lorazepam 2 to 4 mg IV or diazepam 5 to 10 mg IV; pediatric dosing of lorazepam 0.05 to 0.1 mg/kg IV or intramuscular). 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, nicardipine, or nitroprusside [1]. 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 [1]. 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 [1].

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) [12]. Standard treatments for hyperthermia are discussed separately. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults", section on 'Cooling measures and temperature monitoring'.)

Patients whose temperature is above 41.1°C require immediate sedation, paralysis, and tracheal intubation [1]. 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 for emergency medicine and critical care" and "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, 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 [1]. In cases where the etiology of the patient's hyperthermia is unclear initially and infection remains a possibility, empiric administration of an initial dose of antibiotics, following collection of appropriate cultures, is prudent while cooling measures are implemented.

Antidote: Cyproheptadine — If benzodiazepines and supportive care fail to improve agitation and correct vital signs, we suggest antidotal therapy with cyproheptadine [21]. Cyproheptadine is a histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-HT2A antagonistic properties [21]. It also has weak anticholinergic activity.

Cyproheptadine is available in 4 mg tablets or 2 mg/5 mL syrup [12]. 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 [1]. 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 IV fluids. Based on limited observational evidence, treatment with cyproheptadine during pregnancy is not associated with an increased risk of congenital abnormalities [12].

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 [22]. In addition, many reports describe the successful use of cyproheptadine to treat serotonin syndrome [21,23-28]. 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 [1]. 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 [1]. Dantrolene has no effect on survival in animal models and is ineffective in patients with severe temperature elevation not caused by skeletal muscle receptor abnormalities. (See "Malignant hyperthermia: Diagnosis and management of acute crisis" and "Neuroleptic malignant syndrome", section on 'Medical therapy'.)

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 [1]. 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.

SPECIAL POPULATIONS

Pediatrics — 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 [29-32]. 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 [15]. (See "MDMA (ecstasy) intoxication" and "Dextromethorphan misuse and poisoning: Clinical features and diagnosis".)

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 (IV) 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:

●Children younger than two years can be given approximately 0.06 mg/kg per dose every six hours, if needed (not to exceed 0.25 mg/kg/day).

●Children two to six years can be given 2 mg every six hours, if needed (not to exceed 12 mg/day).

●Children 7 to 14 years can be given 4 mg every six hours, if needed (not to exceed 16 mg/day).

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 effects [33]. The most prominent findings were restlessness, tremor, and rigidity; myoclonus and hyperreflexia occurred less often. Symptoms appeared to subside quickly without any specific treatment [33].

Older adults — Management of serotonin toxicity in older adults is similar to other populations. However, older adults are at potentially increased risk of developing serotonin toxicity due to drug interactions from polypharmacy. General issues with polypharmacy in older adults are discussed separately. (See "Drug prescribing for older adults", section on 'Polypharmacy'.)  

Older adults who take multiple medications that increase serotonergic neurotransmission (table 2) are at increased risk [34,35]. In United States adults, antidepressant use increases with age; 19 percent of adults 60 years and older reported taking an antidepressant during 2015 to 2018 [36]. In a study that reviewed the medication lists of 6545 ambulatory patients 60 years and older followed in one clinic, the prevalence of potential multidrug interactions was 1.3 percent [37]. Among those, psychotropics were the most common (35 percent) medications that could contribute to interactions, and serotonin toxicity would be the outcome in approximately 20 percent.

Tramadol, a strongly serotonergic opioid that can cause serotonin toxicity by itself or combined with other serotonergic agents, is often prescribed to older adults. A study of the United States National Hospital Ambulatory Medical Care Survey found that from 2007 to 2018, tramadol prescribing during emergency department visits increased from 1.7 to 2.9 percent [38]. Patients 55 years and older had the largest increase, which was almost threefold. Multiple case reported describe tramadol precipitating serotonin toxicity in older adults [39-43].

As compared with other age groups, older adults who develop serotonin toxicity may be more likely to go undiagnosed. Many of the signs and symptoms of serotonin excess, such as generalized weakness, confusion, hallucinations, fever, diaphoresis, tachypnea, and tachycardia, are nonspecific and can be misattributed to infection, dehydration, and other metabolic processes in older adults. Tremor can be mistaken for rigors [44]. A study of 309 consecutive patients admitted to one intensive care unit found that 8 percent (mean age 52 years; 14/24 were ≥55 years) met the Hunter Toxicity Criteria (algorithm 1) for serotonin syndrome; none of the patients were recognized to have this diagnosis until examined by the investigators [45].  

In an older adult taking one or more serotonergic agents who presents with altered mental status, fever, or signs of autonomic hyperactivity, we examine the lower extremities specifically for tremor, hyperreflexia, and clonus. The same diagnostic criteria, characterized by increased neuromuscular activity, are used in older adults. Tremor and hyperreflexia are important findings and common in older adults with serotonin excess [34]. (See 'Diagnosis and diagnostic criteria' above.)  

PREVENTION — Serotonin syndrome can be avoided by applying pharmacologic principles, educating clinicians, and modifying prescription practices [1]. Multi-drug regimens should be avoided, if possible. Tramadol, meperidine, and dextromethorphan are strongly serotonergic opioids and should be avoided in patients taking other serotonergic agents [10].

ADDITIONAL RESOURCES

Regional poison control centers — 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 are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Serotonin syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Pharmacology – Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system due to serotonergic agent therapeutic use, inadvertent interactions between drugs, and intentional self-poisoning. Monoamine oxidase inhibitors (MAOIs) are associated with the most severe cases and direct serotonin receptor agonists with the mildest cases. (See 'Pharmacology and cellular toxicology' above.)

●Clinical presentation – Serotonin syndrome encompasses a spectrum of disease where the intensity of clinical findings is thought to reflect the degree of serotonergic activity. Most cases of serotonin syndrome present within 24 hours of a change or initiation of a serotonergic drug (table 2). Typical vital sign abnormalities include tachycardia and hypertension, but severe cases may develop hyperthermia and rapid, dramatic swings in pulse and blood pressure. Patients can manifest agitation, ocular clonus, tremor, akathisia, deep tendon hyperreflexia, inducible or spontaneous clonus, muscle rigidity, dilated pupils, and diaphoresis. Neuromuscular findings are typically more pronounced in the lower extremities. (See 'Clinical features' above.)

●Diagnosis – Serotonin syndrome is a clinical diagnosis. The Hunter Criteria are the most accurate diagnostic criteria; a patient must have the presence of a serotonergic agent and meet one of the following conditions (see 'Diagnosis and diagnostic criteria' above):

•Spontaneous clonus

•Inducible clonus plus agitation or diaphoresis

•Ocular clonus plus agitation or diaphoresis

•Tremor plus hyperreflexia

•Hypertonia plus temperature above 38°C plus ocular clonus or inducible clonus

●Laboratory testing – No laboratory test confirms the diagnosis; serotonin concentrations do not correlate with clinical findings. Additional diagnostic studies are used to exclude other etiologies and monitor potential complications. (See 'Laboratory evaluation' above.)

●Management – Treatment depends on the severity of illness and starts with discontinuing all serotonergic agents. In mild cases, supportive care and sedation with benzodiazepines is generally sufficient. Moderately ill patients require more aggressive treatment of autonomic instability and possibly treatment with a serotonin antagonist. Hyperthermic patients are critically ill and often require paralysis and endotracheal intubation. (See 'Management' above.)

•Supportive care is the mainstay of therapy. All patients are treated with oxygen to maintain oxygen saturation (SpO₂) ≥94 percent, intravenous (IV) fluids for volume depletion, continuous cardiac monitoring, and correction of abnormal vital signs. Severely intoxicated patients often exhibit rapid, dramatic changes in vital signs. (See 'Supportive care and sedation' above.)

-In patients with severe hypertension and tachycardia, we suggest treatment with short-acting agents, such as esmolol, nicardipine, or nitroprusside (Grade 2C).

-In patients with hypotension from MAOIs, we suggest treatment with low doses of direct-acting sympathomimetic amines such as phenylephrine, epinephrine, or norepinephrine (Grade 2C). We recommend that indirect agents (eg, dopamine) not be used (Grade 1C). (See 'Autonomic instability' above.)

-Control of hyperthermia is critical and involves eliminating excessive muscle activity. In patients whose temperature is above 41.1°C, we recommend treatment with immediate sedation, paralysis, and tracheal intubation in addition to external cooling measures as compared with external cooling measures alone (Grade 1C). Antipyretic agents (eg, acetaminophen) are ineffective and should not be used for serotonin syndrome. (See 'Hyperthermia' above and "Severe nonexertional hyperthermia (classic heat stroke) in adults", section on 'Cooling measures and temperature monitoring'.)

•We suggest sedation with benzodiazepines for controlling agitation as well as correcting mild increases in blood pressure and heart rate (Grade 2C). (See 'Supportive care and sedation' above.)

•In patients for whom benzodiazepines and supportive care fail to improve agitation and correct vital signs, we suggest treatment with cyproheptadine, an antagonist at histamine and serotonin receptors (Grade 2C). The initial dose is 12 mg, 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 tube. (See 'Antidote: Cyproheptadine' above.)

●Disposition and prognosis – Symptoms usually resolve within 24 hours of discontinuing the serotonergic agent. Patients with mild or moderate symptoms should be monitored until symptoms resolve. Patients with severe serotonin toxicity (eg, hyperthermia, autonomic instability, agitated delirium) require care in an intensive care unit. (See 'Disposition and prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen J Traub, MD, former section editor of the toxicology program, for 20 years of dedicated service.