Serotonin Syndrome/Serotonin Toxicity
Objecti ve: This review of serotonin syndrome or serotonin toxicity covers the years 2014 to 2019, including information on pathophysiology, etiology, and diagnosis, 3 criteria for diagnosing serotonin syndrome, and criteria for neuroleptic malignant syndrome.
Importance: The review highlights the potential lethal combinations of commonly prescribed medications used to treat both veteran and nonveteran patients and includes the latest information on offending medications.
Conclusions: Prevention of serotonin toxicity includes informed clinicians, patient education, careful prescribing and monitoring, and avoidance of multidrug regimens.
Treatment
Mild-to-moderate symptoms usually resolve on their own 1 to 3 days after decreasing or stopping the offending drug. The timing will depend on the half-life or active metabolites of the drug. Treatment is largely supportive and may require treatment for control of agitation with benzodiazepines and IV fluids for dehydration/hypotension.14 In cases not responding to supportive care, treatment with oral cyproheptadine is recommended.14
There are other medications that have been used in treatment such as olanzapine, chlorpromazine, propranolol, bromocriptine, dantrolene, droperidol, and haloperidol, but their efficacy is unproven and not recommended.10 Chlorpromazine can cause hypotension and increase hyperthermia. Propranolol has a long duration of action, may cause a prolonged hypotension, and can mask tachycardia that can be used to monitor the effectiveness of treatment.10 Bromocriptine is a serotonin agonist and may exacerbate symptoms. Dantrolene has no effect on survival in animal models.10 Droperidol and haloperidol can worsen hyperthermia by inhibiting sweating.38
Mechanical ventilation should be considered especially if muscle rigidity progresses and depressed respiratory function occurs. If the temperature starts to rise, immediate sedation, paralysis, mechanical ventilation, and cyproheptadine are administered.The overall goal is prevention of hyperthermia, which leads to multiorgan failure. A core temperature of ≥ 104°F is associated with neurologic cell death, and recovery is minimal.32 Consultation with an experienced toxicologist is strongly recommended.Antipyretics should not be used, because elevated temperature is centrally mediated from muscle rigidity. If presentation occurs within 1 hour, activated charcoal can be used for detoxification of potentially lethal amounts.
Warning Label Controversies
In 2006, the US Food and Drug Administration (FDA) issued an advisory warning against concurrently using a tryptan antimigraine drug and serotonin-mediated medications.39 In 2018, a research team conducted a 14-year retrospective analysis on 20,000 patients who were coprescribed a tryptan drug with SSRIs or SNRIs.40 The study reported that the risk of ST was rare and suggested that the FDA reconsider their advisory. There are several other controversial medications with a ST FDA warning label due to their mechanisms of action and inaccurate case reports.41
Human Poisonings
Consistent with the 2017 American Association of Poison Control Centers Toxic Exposure report, antidepressants continue to be in the top 5 substance classes most frequently involved in human exposures.42 Most accidental ingestions of antidepressants occur in toddlers, whereas intentional ingestions are usually done by adolesents.43 Over the past 10 years, antidepressants are the No. 1 fastest growing category of human exposures in all age groups.42
ST in the Pediatric Population
ST in the pediatric population mirrors that in adults.Differences include the inability of the child to report symptoms, lack of clinician awareness, and reluctance of adolescents to disclose recreational drug use.Management is the same as for adults, including discontinuing the offending drug, supportive care, adequate sedation, oxygen, IV fluids, and continuous cardiac monitoring. Sedation is weight based for benzodiazepines. Mild-to-moderate reactions require admission for observation. Severe reactions require admission to the ICU.
There have been at least 4 published case reports of children aged < 6 years with moderate-to-severe ST secondary to acute vilazodone ingestion.44 The dosages included 5.5 to 37 mg/kg. All 4 patients had altered mental status, seizures, hyperthermia, mild clonus, tachycardia, and hypertension. They all survived with intensive care treatment, including intubation, sedation, cyproheptadine in 2 cases, activated charcoal and IV lorazepam in the other cases.
Direk and colleagues reported a case of a 12-year-old girl who was brought to the emergency department by her stepmother for seizurelike activity and was diagnosed with epilepsy and status epilepticus.45 In the pediatric ICU she developed tachycardia, fever, agitation, dilated pupils, tremors, increased deep tendon reflexes, spontaneous clonus, and horizontal ocular movements. A detailed clinical history was retaken and revealed that the child had been prescribed risperidone 1 week before by the psychiatric clinic due to behavioral problems, including stealing money, lying, and running away from home and school. On further investigation, the stepmother was taking clomipramine and discovered 9 missing pills.
