How to Prevent Serotonin Syndrome from Drug-Drug Interactions

Ms. B, age 22, is brought to the emergency department (ED) by her roommate for evaluation of confusion. Ms. B has a history of migraines and major depressive disorder and has been taking fluoxetine, 40 mg/d, for 1 year. A week ago, she started amitriptyline, 50 mg/d, when her migraines became more frequent. According to her roommate, Ms. B experienced a migraine early in the morning and had taken 2 doses of sumatriptan, 50 mg. She later complained of nausea and vomiting, and when her roommate returned from work that evening Ms. B was disoriented and her leg muscles would not stop twitching. [ILLUSTRATION OMITTED] In the ED, Ms. B is diaphoretic and increasingly agitated. Blood alcohol and urine drug screens are negative. Blood glucose is 95 mg/dL Complete blood count, basic metabolic panel, liver function, and kidney function tests are within normal limits. Her physical examination reveals a blood pressure of 130/85 mm Hg, heart rate of 130 beats per minute, respiratory rate of 21 breaths per minute, and body temperature of 38.6[degrees]C (101.4[degrees]F). Myoclonus and hyperreflexia affect her lower extremities. Ms. B is admitted with a preliminary diagnosis of serotonin (5-HT) syndrome. Serotonin syndrome: What is it? Serotonin syndrome is a rare but potentially serious adverse event resulting from excess serotonergic activity at central and peripheral 5-HT2A and 5-HT1A receptors. Serotonin syndrome toxicity ranges from relatively mild to severe, and may be lethal. Symptoms develop rapidly--within hours--and may include altered mental status, clonus, tremor, hyperthermia, diaphoresis, tachycardia, mydriasis, and akathisia (Table 1). (1-3) Fortunately, if recognized promptly and offending agents are discontinued, serotonin syndrome often resolves within a couple of days. Table 1 Characteristics of serotonin syndrome * Recent addition or dose increase of a serotonergic agent Tremor plus hyperreflexia Muscle rigidity plus fever plus clonus Spontaneous clonus Ocular clonus plus agitation or diaphoresis Inducible clonus plus agitation or diaphoresis * A combination of these characteristics may indicate serotonin syndrome Source: References 1-3 The differential diagnosis includes neuroleptic malignant syndrome (NMS), anticholinergic toxicity, and malignant hyperthermia. (1) Differentiating serotonin syndrome from NMS can be difficult. NMS results from dopamine blockade; however, many NMS symptoms are similar to those experienced with serotonin syndrome. Obtaining a history of recent medication and/or illicit drug use, conducting a physical exam, and evaluating the patient's clinical course help clarify a likely diagnosis. NMS generally has a slower onset--within days--and patients demonstrate neuromuscular rigidity and bradykinesia rather than the neuromuscular hyperreactivity (myoclonus, hyperreflexia) seen with serotonin syndrome. Interactions that increase risk A drug interaction is a pharmacologic or clinical response to a combination of medications that differs from the agents' known effects if given on their own. In the context of serotonin syndrome, the serotonergic activity of a drug can be increased as a result of a pharmacokinetic (PK) interaction, a pharmacodynamic (PD) interaction, or a combination of both. PK interactions may result from the coadministration of a drug that alters absorption, distribution, metabolism, or elimination parameters of [greater than or equal to]1 other drugs. Serotonergic antidepressants usually are metabolized by cytochrome P450 (CYP450) enzymes. Any drug that inhibits a CYP450 enzyme responsible for biotransformation of 1 of these antidepressants may increase exposure to the antidepressant and raise the risk of serotonin syndrome. CYP450 inhibitors include prescription medications as well as seemingly benign over-the-counter (OTC) drugs. …