Serotonin syndrome is a potentially life-threatening condition precipitated by the use of serotonergic drugs. It may be a consequence of therapeutic medication use, accidental interactions between medications or recreational drugs, or intentional overdose. Symptoms can range from mild to fatal and classically include altered mental status, autonomic dysfunction, and neuromuscular excitation. Several criteria exist for making this clinical diagnosis, but the Hunter criteria are generally accepted as the most accurate. The diagnosis can be made in patients with a history of exposure to a serotonergic drug plus one or more of the following: spontaneous clonus, inducible clonus with agitation and diaphoresis, ocular clonus with agitation and diaphoresis, tremor and hyperreflexia, hypertonia, temperature over 38 C with ocular or inducible clonus. Management consists of immediate discontinuation of serotonergic agents, hydration, and supportive care to manage blood pressure, hyperpyrexia, and respiratory and cardiac complications. Sedation is best facilitated with benzodiazepines. Refractory cases may respond to the antidote, cyproheptadine, which must be given orally or via gastric tube. The effectiveness of cyproheptadine is unproven, but multiple case reports support its use in patients who do not respond to sedation and supportive care.
Serotonin syndrome may occur as a consequence of therapeutic medication use, drug interactions, or intentional overdose. Multiple drugs may precipitate serotonin toxicity by a variety of mechanisms. SSRIs such as citalopram, escitalopram, fluoxetine, fluoxetine, paroxetine, and sertraline impair reuptake of serotonin from the synaptic cleft into the presynaptic neuron. Many other drugs also impair serotonin reuptake including meperidine, tramadol, pentazocine, metoclopramide, valproate, carbamazepine, dextromethorphan, and cyclobenzaprine. Serotonin modulators, such as trazodone, and dopamine-norepinephrine reuptake inhibitors, such as bupropion, also impair serotonin reuptake. Tri-cyclic antidepressants and St. John’s wort, a popular supplement, also inhibit serotonin reuptake. Monoamine oxidase inhibitors (MAOIs) inhibit serotonin metabolism and tend to produce the most severe and prolonged cases. MAOIs include phenelzine, tranylcypromine, isocarboxazid, selegiline, the antibiotic, linezolid, and methylene blue. Direct serotonin agonists include buspirone, ergot derivatives, fentanyl and lysergic acid diethylamide (LSD). Tryptophan, as a supplement or dietary source, increases serotonin formation and can be particularly dangerous in patients on other serotonergic drugs, especially MAOIs. Amphetamines, cocaine, MDMA (Ecstacy) and levodopa all increase serotonin release. Cocaine and MDMA also inhibit serotonin reuptake. Serotonin syndrome is often precipitated by the addition of one or more of these medications in patients who were previously stable on a serotonergic agent. Since there are so many drugs that may cause serotonin syndrome, it is important for providers to take a careful medication history when adding new medications.
The true incidence of serotonin syndrome is unknown, most likely because mild cases are frequently overlooked or dismissed. Even more serious cases may frequently be attributed to other causes. There is no confirmatory test or specific laboratory findings, and the syndrome has a broad spectrum of severity ranging from barely perceptible to lethal. Serotonin syndrome occurs in all age groups, and incidence is increasing with the increased use of serotonergic agents. SSRIs are the most common class of medications implicated in serotonin syndrome due to widespread use.
Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter that is biochemically derived from tryptophan. Serotonin is found primarily in the gastrointestinal tract, the central nervous system and in platelets. It is metabolized by monoamine oxidase in the liver. Serotonin modulates attention, mood, appetite, and sleep as well as some cognitive functions, making serotonin modulation a common mechanism of action for many antidepressants. Serotonin also modulates thermoregulation and promotes platelet aggregation, uterine contraction, bronchoconstriction, vasoconstriction, and gastrointestinal motility. Stimulation of the postsynaptic 5-HT1A and 5-HT2A receptors from a single or combination of drugs produces serotonin syndrome.
Serotonin syndrome is diagnosed clinically and requires a thorough review of medications and a careful physical exam. Symptoms tend to develop rapidly after exposure to the precipitating drug: 30% within one hour, 60% within 6 hours, and nearly all patients with toxicity developing symptoms within 24 hours of exposure. The spectrum may range from barely perceptible tremor to life-threatening hyperthermia and shock. Signs and symptoms include agitation, anxiety, restless, disorientation, diaphoresis, hyperthermia, tachycardia, nausea, vomiting, tremor, muscle rigidity, hyperreflexia, myoclonus, dilated pupils, ocular clonus, dry mucous membranes, flushed skin, increased bowel sounds, and a bilateral Babinski sign. Clonus and hyperreflexia are particularly common. Neuromuscular findings tend to be more pronounced in the lower extremities. As compared to the neuroleptic malignant syndrome, patients with serotonin syndrome are more likely to have associated gastrointestinal symptoms and clonus.
Several criteria exist for making the diagnosis: Sternbach, Radomski, and Hunter. The Hunter test is accepted as the most accurate, but the criteria were designed specifically for patients with SSRI overdose, not serotonin syndrome from other agents; therefore, it may not reveal the disease in patients with minor symptoms.
The following tests may be useful in assessing patients with serotonin syndrome and narrowing the differential diagnosis: complete blood count, electrolytes, creatinine and BUN, creatine phosphokinase, hepatic transaminases, coagulation studies, urinalysis, drug screen, neuroimaging, and lumbar puncture. No laboratory test confirms the diagnosis, but patients may have leukocytosis, elevated creatine phosphokinase, and decreased serum bicarbonate concentration. Patients may develop labile blood pressure, heart rate and cardiac dysrhythmias, disseminated intravascular coagulation, rhabdomyolysis, renal failure, metabolic acidosis, myoglobinuria, and respiratory failure.
Most cases of serotonin syndrome are mild and will resolve with removal of the offending drug alone. After stopping all serotonergic drugs, management is largely supportive and aimed at preventing complications. Patients frequently require sedation, which is best facilitated with benzodiazepines. Antipsychotics should be avoided because of their anticholinergic properties, which may inhibit sweating and heat dissipation. Vital signs should be normalized with intravenous (IV) fluids and cooling measures. Antipyretics such as acetaminophen are ineffective because increased muscular activity causes the hyperthermia in serotonin syndrome. Severe hyperthermia may require sedation, paralysis, and intubation for mechanical ventilation. Autonomic instability may require antihypertensive agents or vasopressors, depending on presentation, and may be quite labile and difficult to manage. Short-acting agents such as esmolol are recommended if antihypertensive are required. Most cases with hypotension can be managed with IV fluids alone, but in refractory cases, direct-acting sympathomimetics such as phenylephrine, norepinephrine, and epinephrine are preferable.
Cyproheptadine is a histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-Ht2A antagonistic properties. While strong evidence to support its use is lacking, it is widely used as an antidote for serotonin syndrome. Side effects may include sedation, which may be desirable, and hypotension, which in most cases will respond to IV fluids. The usual starting dose is 12 mg, followed by an additional 2 mg every two hours as long as symptoms persist. As the patient improves, cyproheptadine is usually continued at a dose of 8 mg every 6 hours until symptoms resolve.
Patients with abnormal vital signs require admission to a monitored setting, and severe cases warrant intensive care unit care.
Mild cases of serotonin syndrome, with subtle symptoms such as tremor or restlessness, are often overlooked completely or attributed to anxiety or the underlying psychiatric condition. When gastrointestinal symptoms are present, symptoms often are attributed to food poisoning or the flu. Serious cases share many common features with the neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic toxicity, sympathomimetic toxicity, or infectious causes such as meningitis or encephalitis. A careful medication history and diagnostic testing will help delimitate the cause.
Most cases of serotonin syndrome will resolve completely within 24 to 72 hours without sequelae if recognized and treated with removal of the precipitating agent and appropriate supportive care. Patients who are asymptomatic 6 to 8 hours following an overdose are unlikely to develop significant toxicity. SSRIs are rarely associated with death, even in overdose, when used alone. Most fatalities associated with SSRIs are due to co-ingestion with other drugs. Fatalities, when they occur, tend to happen within the first 24 hours and are more likely in patients on MAOIs than SSRIs.
Serotonin syndrome is best managed by a multidisciplinary team that includes the pharmacist. Since many cases are drug-related, the physician and pharmacist must be aware of potential drug interactions. Drug-induced serotonin syndrome is usually mild and will resolve spontaneously but it is best to prevent the disorder in the first place. Cases that are diagnosed and managed have a good outcome.
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