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.
Pathophysiology
Tryptophan is a precursor of serotonin and must be ingested from foods, including meats, dairy, fruits, and seeds. About 90% of all serotonin is made in the gastrointestinal epithelium and is the major component of the brain-gut axis.26 Serotonin cannot cross the blood-brain barrier; therefore, it is synthesized and stored in presynaptic terminals around the midline of the brainstem.1,26 Transport of serotonin is provided by serotonin transporter (SERT).1,26,27 Once released, serotonin can either stimulate postsynaptic neuron receptors or is taken up into the presynaptic terminals for reuse. SSRI antidepressants, such as citalopram and paroxetine inhibit the reuptake of serotonin by binding to 2 different sites on the SERT thus allowing more available serotonin to be accessible to other neurons.27 There are 7 families of serotonin receptors, 5-HT1 to 5-HT7 and at least 15 mammalian subtypes.28,29 The majority of these receptors have been implicated in depression or depressive-like behavior as evidenced by the efficacy of increasing extracellular serotonin for the treatment of depression with SSRIs, SNRIs, TCAs, and MAOIs.29 Three of the most studied receptors include 5-HTIA,5-HT1B,and 5-HT2A.
Etiology
Most serotonin-induced drug fatalities occur when combining serotonergic drugs that work through different pathways (Table 2).30 The most toxic combination of serotonin-enhancing drugs includes MAOIs taken with SSRIs or SNRIs, or a combination of 2 MAOIs.5-9
Other potentially lethal combinations may includepolypharmacy with antidepressants, pain medications, OTC medications, and illicit drugs. Linezolid, a new synthetic antimicrobial, is considered to be a weak MAOI. Therefore, prescribing it with other serotonin-elevating agents has been reported to precipitate ST.18
Most cases of ST do not require hospitalization and can be managed by stopping the medication or decreasing the dose. Therapeutic doses of a single drug are highly unlikely to cause toxicity, although there have been reported cases of patients who are sensitive or more susceptible and develop symptoms after administration of a single agent and/or a dosage increase.
Delayed ST reactions have occurred because of a prolonged half-life of a drug, iron deficiency anemia, and coingestion of shorter acting serotonin antagonists.31 Most antidepressants have a short half-life (< 24 hours)except for fluoxetine. A decrease in iron may contribute to ST because iron is needed to process serotonin from tryptophan. An example of 2 shorter-acting serotonin antagonists include cyproheptadine and olanzapine. Cyproheptadine is used in the treatment of ST, and olanzapine is an antipsychotic.
Symptoms
Symptoms of ST range from mild to severe and include a combination of neuromuscular, autonomic, and mental status changes (Table 3).5,10 Mild symptoms of ST can start within 1 to 2 hours after ingesting a medication that increases serotonin to a toxic state unless the drug has a long half-life (eg, fluoxetine). Sometimes mild symptoms of ST can be difficult to distinguish from common drug AEs, flu symptoms, or viruses. Patients taking therapeutic doses of SSRIs can experience serotonin symptoms, such as lower limb hyperreflexia or a few beats of ankle clonus without being toxic. One thing to remember is that not all patients will start with mild symptoms and may present in moderate or severe distress.
