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- A potentially life-threatening adverse drug reaction that results from excessive stimulation of peripheral and CNS serotonergic receptors
- It is a concentration-dependent toxicity that can develop in any individual who has ingested drug combinations that synergistically increase synaptic 5-hydroxytryptamine (HT).
- Serotonin toxicity occurs in three main settings: (i) therapeutic drug use, which often results in mild to moderate symptoms; (ii) intentional overdose of a single serotonergic agent, which typically leads to moderate symptoms; and (iii) as the result of a drug interaction between numerous serotonergic agents (most commonly, selective serotonin reuptake inhibitors [SSRIs] and monoamine oxidase inhibitors [MAOIs]), most often associated with severe serotonin toxicity.
- Classically characterized by a triad of symptoms that include mental status change, neuromuscular hyperactivity, and autonomic instability
- Onset is usually within 24 hours with 60% of cases occurring within 6 hours of exposure to, or change in, dosing of a serotonergic agent. Rarely, cases have been reported weeks after discontinuation of serotonergic agents.
Elderly are at increased risk given use of polypharmacy.
- Serotonin syndrome has similar manifestations in children and adults.
- General management is unchanged in children, other than medication dosing.
- 3rd-trimester exposure to SSRIs has been associated with transient neonatal complications that may reflect either acute drug withdrawal or serotonergic toxicity.
- Symptoms in neonates may include tremors, increased muscle tone, jitteriness, shivering, feeding/digestive disturbances, irritability, agitation, sleep disturbances, increased reflexes, excessive crying, and respiratory disturbances.
Seen in about 14–16% of SSRI overdose patients
- About 100,000 adverse events reported with antidepressant use including some deaths, annually. Most associated with SSRIs, either alone or in combination with other drugs. In a 2008 study, SSRIs alone were responsible for adverse events in 18.8% of cases, with 55.7% due to intentional causes, 39.5% unintentional, and remainder of causes unknown. Of patients reporting adverse effects with SSRIs, 46.6% had symptoms requiring hospitalization, and significant toxic effects occurred in 90 patients with two resultant deaths (1)[A].
- The incidence of serotonin syndrome is rising because serotonergic agents are increasingly used in clinical practice and in combination with other serotonergic agents.
- Predominant age: affects all age groups
- Predominant sex: male = female
Etiology and Pathophysiology
- The result of excessive stimulation in peripheral and CNS serotonergic receptors
- Risk is mediated in a dose-related manner to the action of 5-HT/5-HT agonists on 5-HT1A and/or 5-HT2A receptors. The development mechanism of the syndrome is unknown.
- It is hypothesized that the degree of serotonin elevation in blood plasma has to be 10–15% times above baseline levels to result in serotonin toxicity (2)[A].
- A number of drugs are associated with the serotonin syndrome, which usually involves combination with an SSRI. These include SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline); MAOIs; SNRIs (duloxetine, venlafaxine, desvenlafaxine); tricyclic antidepressants (e.g., amitriptyline); other antidepressants (nefazodone, trazodone); anxiolytic (buspirone); lithium; triptans; anticonvulsants (Depakote); analgesics (fentanyl, meperidine, pentazocine, tramadol); antibiotics (linezolid, tedizolid [weak MAOI], ritonavir); over-the-counter (OTC) cough medications (dextromethorphan); some antipsychotics (risperidone, olanzapine); antiemetics (ondansetron, granisetron); other medications, such as metoclopramide, cyclobenzaprine, L-dopa; dietary supplements (tryptophan); herbal supplements (St. John’s wort, nutmeg); methylene blue; and drugs of abuse (e.g., methylenedioxymethamphetamine [MDMA], cocaine, D-lysergic acid diethylamide [LSD], and amphetamine).
- Initially, patients can develop a peripheral tremor, confusion, and ataxia; systemic signs are next (e.g., agitation, diaphoresis, hyperreflexia, and shivering). If it worsens, the severe signs of fever, jerking, and diarrhea may develop. Serotonin syndrome can last from hours to days after the offending agents are stopped and supportive care is initiated.
- Drug interactions are most often the cause of severe cases of serotonin syndrome. Many of the same classes of medications listed earlier are involved, especially MAOIs (including linezolid) with SSRIs.
- Serotonergic agents
- Reported following ingestion of a single agent
- The greatest number of adverse events has been shown to be associated with SSRIs in combination with other substances, and the combination of SSRIs and MAOIs carries the greatest risk of developing serotonin toxicity.
- Consider drug–drug interactions when a multidrug regimen is required and avoid if possible.
- Caution patients about taking SSRIs with OTC medications (e.g., dextromethorphan) or herbal supplements (e.g., St. John’s wort) prior to consulting a physician.
- Clinician education
- Continual improvement in use of health information technology