Serotonin Syndrome · What It Is, Causes, Signs, Symptoms, and More

Serotonin syndrome is caused by serotonergic drugs, which overstimulate 5HT-1A and 5HT-2A receptors in the central nervous system. Any drug that increases serotonin levels in the body may carry a risk of serotonin syndrome. Excess serotonin synthesis as a result of phentermine (i.e., weight loss medication) or L-tryptophan (i.e., amino acid) can upregulate the production of serotonin. Medications that increase the release of serotonin from the body, such as illicit drugs (e.g., cocaine) or amphetamines, can result in serotonin toxicity. Many medications decrease serotonin reuptake, thereby increasing the amount of serotonin available. Such medications include antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs) like sertraline, escitalopram, and fluoxetine. In addition, tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline); serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine, duloxetine); dietary supplements (e.g., St. John’s Wort); and certain opioids (e.g., tramadol) also decrease serotonin reuptake. 

Some atypical antidepressants (e.g., buspirone), triptans (e.g., sumatriptan), and other medications, like metoclopramide (i.e., prokinetic medication), may act by activating serotonin receptors. Meanwhile, monoamine oxidase inhibitors (e.g., phenelzine, isocarboxazid) decrease serotonin metabolism by inhibiting an enzyme responsible for its breakdown. Finally, medications such as dextromethorphan reduce certain CYP450 enzymes, which affect serotonin metabolism.  

The signs and symptoms of serotonin syndrome may range from mild to fatal and typically begin about 24 hours after exposure to excess serotonin. Serotonin syndrome symptoms may be remembered with the “the 3 A’s” mnemonic: altered mental status, neuromuscular abnormalities, and autonomic hyperactivity. Altered mental status refers to changes in temperament such as agitation, restlessness, or anxiety. Neuromuscular abnormalities may present as ocular clonus (i.e., involuntary muscle contraction of the eye), hyperreflexia, tremors, and rigidity of muscles. Meanwhile, signs of autonomic hyperactivity may include tachycardia (i.e., elevated heart rate), hypertension (i.e., elevated blood pressure), diaphoresis (i.e., sweating), mydriasis (i.e., pupillary dilation), flushed skin, arrhythmias (i.e., irregular heart rhythm), vomiting, or diarrhea.

 Those with mild cases may experience tremors, sweating, tachycardia, hypertension, and nausea, among other milder symptoms. Individuals with more moderate serotonergic toxicity may also experience fever, often greater than 40 degrees Celsius or 104 degrees Fahrenheit; hyperactive bowel sounds; clonus; and agitation. More severe symptoms may include worsening hyperthermia and delirium. As an individual’s condition worsens, other complications may develop, including rhabdomyolysis (i.e., rapid muscle breakdown), myoglobinuria (i.e., myoglobin in urine), respiratory failure, and kidney failure. Eventually, if left untreated, it may lead to coma or death.

A healthcare professional may diagnose serotonin syndrome after a thorough history and a physical examination. There is no specific diagnostic test that leads to a serotonin syndrome diagnosis. Instead, diagnosing serotonin syndrome is based on clinical presentation and excluding other possible causes. Individuals who use prescription or over-the-counter medications (e.g., serotonergic medications); use illicit drugs (e.g., LSD, cocaine, amphetamines, ecstasy), dietary supplements (e.g., St. John’s Wort); have a history of depression or chronic pain, or have renal failure may be key findings that alert a provider to a diagnosis of serotonin syndrome. 

The Hunter Serotonin Toxicity Criteria (HSTC), a more recent set of criteria, outline two factors an individual must meet to be diagnosed with serotonin syndrome. The first states an individual must take a serotonergic medication. The second criterion includes experiencing one of the following: spontaneous clonus.

Lab findings, although not specific to serotonin syndrome, lab findings may show leukocytosis (i.e., elevated white blood cell count), elevated creatinine, elevated transaminases, or low bicarbonate levels. Of note, measuring levels of serotonin is not an effective diagnostic method.

When diagnosing serotonin syndrome, it is essential to rule out neuroleptic malignant syndrome (NMS). Like serotonin syndrome, an individual with NMS may experience altered mental status, fever, and autonomic instability. An individual with neuroleptic malignant syndrome may show muscle rigidity and hyporeflexia. Additionally, neuroleptic malignant syndrome is typically caused by antipsychotics, which would be present in their history. Neuroleptic malignant syndrome may also develop gradually rather than acutely, as seen in serotonin syndrome.

Other conditions such as malignant hyperthermia, anticholinergic toxicity, sympathomimetic toxicity, heat stroke, meningitis, and central hyperthermia may also be considered and excluded.