Description

• A potentially life-threatening drug-induced syndrome that results from synaptic increase in serotonin (5-hydroxytryptamine [5-HT]) concentrations and stimulation of peripheral and CNS serotonergic receptors
• Classic triad of symptoms that include mental status changes, neuromuscular hyperactivity, and autonomic instability
• Onset is usually within 24 hours with the majority occurring within 6 hours of exposure to, or change in, dosing of a serotonergic agent; rarely, reported weeks after discontinuation of serotonergic agents
• It is a concentration-dependent toxicity that can develop in any individual who has ingested drug combinations that synergistically increase synaptic 5-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], serotonin noradrenergic reuptake inhibitors [SNRIs], and monoamine oxidase inhibitors [MAOIs]), most often associated with severe serotonin toxicity.

Geriatric Considerations
Increased risk through polypharmacy given frequent use of serotonergic analgesics, antibiotics, and antidepressants

Pediatric Considerations

• Similar manifestations and management in children and adults
• Consider toxic ingestion of serotonergic agents prescribed to caregivers of pediatric patients.
• 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.

Pregnancy Considerations
Serotonin levels are increased from baseline during an uncomplicated pregnancy with preeclamptic patients demonstrating a 10-fold increase in serotonin levels.

Epidemiology

Seen in approximately 14–16% of SSRI overdose patients

Incidence
In a 2008 study, SSRIs 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. 46.6% had symptoms requiring hospitalization, and significant toxic effects occurred in 90 patients with two resultant deaths (1).

Etiology and Pathophysiology

• Increased synaptic 5-HT or agonist concentration as a result of one or more of the following mechanisms: (i) decreased 5-HT breakdown (e.g., MAOI), (ii) decreased 5-HT reuptake (e.g., SSRI), (iii) increased 5-HT agonists (e.g., tryptophan), (iv) increased 5-HT release (e.g., amphetamines), and (v) CYP2D6 and CYP3A4 inhibitors (e.g., erythromycin)
• Risk is mediated in a dose-related manner to the action of 5-HT/5-HT agonists on 5-HT_1A and/or 5-HT_2A receptors.
• A number of drugs are associated with 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, clomipramine); other antidepressants (nefazodone, trazodone, mirtazapine); anxiolytic (buspirone); lithium; triptans; anticonvulsants (divalproex [Depakote]); analgesics (fentanyl, meperidine, pentazocine, tramadol); antibiotics/antivirals (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 wort, nutmeg); methylene blue; and drugs of abuse (e.g., methylenedioxymethamphetamine [MDMA], cocaine, D-lysergic acid diethylamide [LSD], amphetamine) (2)[A]

Risk Factors

• Recent dose adjustments or overdose of drugs associated with serotonin syndrome
• The greatest number of adverse events are associated with SSRIs in combination with other substances, and the combination of SSRIs and MAOIs carries the greatest risk of developing serotonin toxicity.

General Prevention

• 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 wort) prior to consulting a physician.
• Avoid serotonergic agents for nonpsychiatric disorders (e.g., tramadol for pain relief).