Serotonin syndrome is a rare, largely avoidable adverse drug reaction caused by drugs that increase serotonin in synapses in the brain. It occurs soon after a recent increase in dose (or overdose) or a new exposure to a serotonergic drug.
Serotonin syndrome is part of a spectrum from mild adverse effects of elevated serotonin to death from severe serotonin toxicity. It is not an idiosyncratic, unpredictable, serious reaction to a serotonergic drug that can occur at any time. Some experts recommend using the term “serotonin toxicity” instead of “serotonin syndrome” to highlight that serotonin syndrome is a toxidrome, akin to anticholinergic or lithium toxicity.
People who prescribe medications that increase serotonin (5-hydroxytryptamine, 5-HT) like SSRIs should be aware of serotonin syndrome/toxicity. However, it is hard to make clinical sense of the various lists of “risky” medications and their potential interactions. Here, I describe the signs, symptoms, and characteristic time course of serotonin syndrome/toxicity so that you can include it in your differential diagnosis when appropriate. A future PsychSnap will focus on identifying high-risk drug combinations and non-risky drug combinations that are sometimes listed as high-risk.
Lori is a 59 yo woman with heart failure, supraventricular tachycardia (SVT), and obesity (BMI 67) who is wheelchair bound. 9 months ago, she started taking fluoxetine for major depression (first episode). She responded well to fluoxetine 40mg daily and stopped the medication after her depression was in remission for 6 months.
Unfortunately, 1 week later, Lori developed chest pain and was admitted to the hospital with COVID infection. She was also bacteremic with Staph aureus and was started on IV linezolid due to a vancomycin allergy. Her vital signs normalized over 12 hours, but several hours later Lori developed severe anxiety and a bilateral tremor. She was tachycardic to 120 with a temperature of 102F, sweating profusely, agitated, and shouting at people. You are mostly concerned about a spreading infection. You also know that linezolid is a weak monoamine oxidase inhibitor (MAOi), so you check Lori’s reflexes in her legs. She is hyperreflexic and exhibits six beats of clonus at her ankles.
How do you recognize the spectrum of serotonin syndrome/toxicity?
The diagnosis of serotonin toxicity is based on the triad of neuromuscular hyperactivity, altered mental status, and autonomic hyperactivity in the context of a recent medication change that elevates serotonin in the brain. There are no lab tests that can confirm excessive synaptic serotonin. Serotonin syndrome presents within hours of starting a new serotonergic medication or increasing the dose of an existing serotonergic medication. 60% of people develop symptoms of toxicity within 6 hours of the precipitating event (Chiew 2022).
A patient with mild serotonin toxicity could present anxious but alert, with tremor and hyperreflexia, usually in the legs more than the arms. Ankle clonus may be inducible. Symptoms of moderate serotonin syndrome include spontaneous, generalized clonus, autonomic symptoms like tachycardia, sweating, low-grade hyperthermia, and mydriasis, and agitation. Someone who intentionally overdoses on an SSRI has a 15% chance of developing moderate serotonin syndrome, but it is unlikely to progress to severe serotonin syndrome. There is a ceiling effect on the level of serotonin toxicity that can be caused by an overdose of SSRIs alone. Severe serotonin toxicity is usually caused by the combination of a monoamine oxidase inhibitor (MAOi) and another highly serotonergic drug, like an SSRI (Buckley 2014). Severe serotonin syndrome is characterized by hyperthermia, rigidity, confusion/coma, and sometimes death.
Clinical Evaluation
History – Look for a change in serotonergic medication exposure.
To put serotonin syndrome on your differential diagnosis, there must be a recent change in serotonergic medication exposure – a dose change (or a drug-drug interaction or liver failure that changes the plasma concentration), an overdose, or a drug change.
Get a careful medication history, including drugs that were recently stopped and might still be in the body. Fluoxetine sticks around for ~5 weeks after it is stopped due to its long half-life. The clinical effect of irreversible inhibitors like the MAOis used in depression lasts for 2 weeks after the drug is stopped because the body needs time to make new protein. Ask specifically about herbal medications like St. John’s wort, any sort of cough or cold medications (specifically chlorpheniramine and dextromethorphan), and recreational drugs, in particular MDMA.
Exam – Focus on vitals and the motor exam.
Clonus, including inducible, ocular, and spontaneous clonus, is the most specific symptom in serotonin toxicity. Clonus generally affects the lower extremities first and then becomes more generalized. In severe serotonin syndrome, truncal rigidity rather than clonus may be the main neuromuscular finding.
To induce clonus, briskly dorsiflex the patient’s foot and look for involuntary, rhythmic beating of the foot at the ankle. Ocular clonus, also called opsoclonus, is involuntary, multidirectional eye movements that can be continuous or triggered by rapid eye movements. If clonus is spontaneous, look for rhythmic, large muscle contractions, sometimes triggered by minor movement or vibration (as opposed to rapid myoclonic jerks). Spontaneous clonus can sometimes look like seizures.
This video shows inducible clonus at the ankle and ocular clonus.
Diagnosis
The Hunter Criteria for Serotonin Toxicity are the most commonly used diagnostic criteria for serotonin toxicity (Dunkley 2003).
They require the presence of a serotonergic agent and one of the following:
-spontaneous clonus
-inducible or ocular clonus + (agitation or diaphoresis)
-inducible or ocular clonus + hypertonia + temp >38C
-tremor and hyperreflexia
The Hunter Criteria are 84% sensitive and 97% specific. They may miss cases of severe serotonin syndrome when rigidity masks clonus. Chiew et al recently recommended that the criteria be updated to include a recent change in serotonergic medication rather than the “presence” of any serotonergic agent (Chiew 2024).
The differential diagnosis of serotonin toxicity commonly includes alcohol or benzodiazepine withdrawal, drug intoxication (with MDMA, synthetic cannabinoids, or stimulants), anticholinergic toxicity, and encephalitis.
Management
If you are concerned about a possible case of serotonin toxicity, stop the serotonergic medication(s). Mild to moderate serotonin syndrome usually resolves within 1-3 days of stopping the serotonergic drugs. For patients who have benefited from a serotonergic medication, restarting the medication at a lower dose or without other serotonergic medications may be justifiable. Remember – this is toxicity, not a dangerous idiosyncratic drug reaction.
Severe serotonin toxicity is a medical emergency that requires ICU-level care and can lead to severe hyperthermia, rhabdomyolysis, disseminated intravascular coagulation (DIC), and death. In addition to stopping the serotonergic agents, treat severe serotonin toxicity with active cooling with ice packs and cooling blankets, chemical sedation with benzodiazepines (lorazepam or diazepam) to reduce muscle hyperactivity, and paralysis and ventilation if necessary. Serotonin antagonists to the 5H2A receptor reduce hyperthermia in animal studies (Zhang 2009). IV chlorpromazine or oral cyproheptadine both act as 5HT2A antagonists and are commonly used to treat people with moderate or severe serotonin syndrome, although there is no strong evidence to support this practice in humans.
Back to Lori –
Lori had an inadvertent exposure to both linezolid (a weak MAOi) and fluoxetine (a highly serotonergic agent that takes 5 weeks to wash out). Within hours of starting linezolid, she developed tremor, hyperreflexia, inducible clonus, agitation, tachycardia, and sweating, meeting the Hunter Criteria for Serotonin Toxicity. The linezolid was immediately stopped. The fluoxetine will remain in her body for another month. With close monitoring and diazepam to treat agitation, Lori fully recovered in 2 days.
Note: We will revisit the risk of serotonin toxicity from specific drugs in a future PsychSnap. Until then, please know that linezolid can reasonably be prescribed to a person taking an SSRI or SNRI if there are limited antibiotic options. The absolute risk of serotonin toxicity with this combination remains <1% (Bai, 2022).
Key Points
- Serotonin syndrome/toxicity is caused by a recent increase in serotonergic drug exposure, usually an increase in dose (or overdose) or the addition of a new serotonergic drug.
- Serotonin syndrome is defined by the clinical triad of neuromuscular excitation, altered mental status, and autonomic excitation.
- Hyperreflexia/clonus are the most specific symptoms for serotonin syndrome and anchor the Hunter Serotonin Toxicity Criteria.
References:
Bai, Anthony D., et al. “Association of linezolid with risk of serotonin syndrome in patients receiving antidepressants.” JAMA Network Open 5.12 (2022): e2247426-e2247426.
Buckley, Nicholas A., Andrew H. Dawson, and Geoffrey K. Isbister. “Serotonin syndrome.” Bmj 348 (2014).
Chiew, Angela L., and Nicholas A. Buckley. “The serotonin toxidrome: shortfalls of current diagnostic criteria for related syndromes.” Clinical Toxicology 60.2 (2022): 143-158.
Dunkley, E. J. C., et al. “The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.” Qjm 96.9 (2003): 635-642.
Malcolm, Benjamin, and Kelan Thomas. “Serotonin toxicity of serotonergic psychedelics.” Psychopharmacology 239.6 (2022): 1881-1891.
Zhang, Gongliang, et al. “Assessment of 5-hydroxytryptamine efflux in rat brain during a mild, moderate and severe serotonin-toxicity syndrome.” European journal of pharmacology 615.1-3 (2009): 66-75.
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