#479: Serotonin Syndrome – Signs, Symptoms & Nursing Interventions

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Your patient was just started on linezolid for a staph infection. Three hours later, you notice some concerning findings – agitation, tremors, diarrhea, and a temperature of 102.8. You take a look at the patient’s medical history and see she takes sertraline for depression and Tramadol for pain. Is something going on here? 

In this article, you’ll review the key things you need to know about serotonin syndrome, a condition that occurs when there is an overabundance of serotonergic activity in the CNS. Serotonin syndrome can range from mild to severe, and if left untreated, can be fatal.

What is serotonin?

Serotonin is a neurotransmitter that plays an important role in mood, attention, behavior, and temperature regulation. While we tend to think of antidepressants when we look at sources of exogenous serotonin, it can also be found in supplements and illicit drugs. Additionally, excess serotonin can occur due to drug interactions. 

When does serotonin syndrome occur? 

Serotonin syndrome usually manifests within 24 hours of the impending event – this could be a dose adjustment, a new medication, a drug interaction, supplements, or illicit drug use. 

What medications and supplements increase serotonergic activity?

Antidepressant medications that impact serotonin are the most likely triggers for serotonin syndrome. These include: 

• SSRIs – Selective serotonin reuptake inhibitors such as sertraline (Zoloft) and escitalopram (Lexapro)
• SNRIs – Serotonin and norepinephrine reuptake inhibitors such as venlafaxine (Effexor) and duloxetine (Cymbalta).
• TCAs – Tricyclic antidepressants such as amitriptyline.
• MAOIs – Monoamine oxidase inhibitors such as phenelzine (Nardil) pose the highest risk for serotonin syndrome.
• Other antidepressants – Bupropion (Wellbutrin), trazodone (which is often prescribed as a sleep aid), and mirtazapine.

Other substances that can also increase serotonergic activity include: 

• Dextromethorphan – Over-the-counter cough medications containing dextromethorphan can lead to serotonin syndrome, especially when taken with a serotonergic medication or supplement.
• Migraine medications – Carbamazepine (Tegretol) and sumatriptan (Imitrex), among others.
• Pain medications – Codeine, fentanyl, hydrocodone, oxycodone, meperidine, and tramadol.
• Antinausea medications – Metoclopramide (Reglan) and ondansetron (Zofran).
• Linezolid (Zyvox)
• Lithium 
• Supplements – Ginseng, nutmeg and St. John’s Wort.
• Illicit drugs – Examples include cocaine, amphetamines, LSD, and ecstasy.

It’s important to note that polypharmacy is a significant risk factor for serotonin syndrome. For example, a patient may take a therapeutic dose of sertraline and have no adverse effects. But if trazodone is added as a sleep aid and they also take cough syrup containing dextromethorphan, they could potentially develop serotonin syndrome. This is why patient education is such a critical component when starting a new medication or increasing the dose. And one of the key things to teach your patient is to recognize signs of serotonin syndrome. We’ll get into that next using the Straight A Nursing LATTE Method.

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L: How does the patient LOOK? 

The classic triad of symptoms for serotonin syndrome are:

• Mental status changes – agitation, confusion, anxiety, restlessness
• Autonomic instability – hypertension, tachycardia, hyperthermia, diaphoresis, diarrhea, nausea
• Neuromuscular abnormalities – tremor, hyperreflexia, clonus (especially on lower extremities, specifically the ankle), muscle rigidity, lack of coordination (ataxia), ocular clonus

Note that symptoms can range from mild (diarrhea, nausea, shivering) to severe (fever, muscle rigidity, and seizures). Left untreated, serotonin syndrome can lead to rhabdomyolysis (due to extreme muscle rigidity), metabolic acidosis, renal failure, myoglobinuria, DIC, ARDS, and death. It is vital to notice the condition early and intervene quickly.

 A: How do you ASSESS a patient with suspected or confirmed serotonin syndrome? 

• Monitor and trend vital signs – Rising heart rate, blood pressure, and temperature are cause for concern. Note that hyperthermia with serotonin syndrome can be significant, with temperatures at or above 106° F. 
• Neurological – Assess LOC, level of agitation or anxiety
• Neuromuscular – Observe for tremors, ocular clonus, ataxia, and muscle rigidity
• GI – Assess bowel sounds (will be hyperactive), monitor the patient for diarrhea and nausea/vomiting
• Cardiac – Cardiac monitoring is essential due to the autonomic instability associated with serotonin syndrome
• Medications – Do a full medication reconciliation, looking at all medications. This includes scheduled meds, PRN medications, herbal supplements, OTC medications, and illicit drugs.

T: What TESTS are utilized?

There is no single lab test to confirm serotonin syndrome and diagnosis is primarily achieved through clinical examination of the patient.  Labs may be ordered to identify complications and rule out other causes. 

• WBC – May be increased
• Electrolytes – Electrolyte imbalances can occur in severe cases; electrolyte imbalances can also mimic some of the signs of serotonin syndrome
• Creatinine, BUN – Assess renal function and monitor for AKI
• Sodium bicarbonate – Decreased in acidotic states
• Creatine phosphokinase (CPK) – Increased due to muscle rigidity/damage
• Liver function tests – Liver injury can occur and cause these labs to be elevated
• Coagulation studies – DIC can occur in severe cases
• Urine studies – Examination of the urine may reveal blood in the urine which is a red flag for rhabdomyolysis; a toxicology panel can identify substances that can contribute to serotonin syndrome
• Serum lactate – Will be elevated in metabolic acidosis associated with severe toxicity
• Blood cultures – Utilized to rule out infection/sepsis
• ABG – In severe cases, patient will be acidotic; if respiratory function is affected, an ABG will show the level of hypoxemia
• Specific labs to rule out other causes – Other conditions that have assessment findings in common with serotonin syndrome include anticholinergic toxicity, malignant hyperthermia, neuroleptic malignant syndrome, acute dystonic reactions, meningitis, substance withdrawal, and thyroid storm. Various tests may be utilized to rule these out as causes for the patient’s signs and symptoms.

Clinical evaluation of the patient can be bolstered by using a tool such as the Hunter Serotonin Toxicity Criteria. It is used to diagnose serotonin syndrome when a causative agent is in use and the patient has at least one of the following: 

• Spontaneous clonus
• Inducible clonus + agitation or diaphoresis
• Ocular clonus + agitation and diaphoresis
• Tremor + hyperreflexia
• Hypertonia + temp > 38° C (100.4° F) + ocular or inducible clonus

T: How is serotonin syndrome TREATED?

The most important action to take when treating serotonin syndrome is to stop the offending agent(s) immediately. Since the syndrome is a result of toxicity, the condition will resolve once the serotonergic medication is discontinued.  Note that symptoms can persist for several days, especially when the patient is taking a medication with a long half-life such as fluoxetine. 

Secondary to discontinuing serotonergic substances, supportive care is utilized to bring the body back into balance and treat any complications. This can include: 

• Hydration with IV fluids – Hyperthermia can cause fluid losses, aim for UO > 0.5 ml/kg/hr. Additionally, IV fluids are critical in cases of rhabdomyolysis in order to protect the kidneys from AKI.
• Oxygen therapy (goal > 94%).
• Short-acting antihypertensives such as esmolol and nicardipine.
• In cases of hypotension related to MAOIs, vasopressors such as norepinephrine are utilized.
• Cooling measures such as cooling blankets, ice packs to the groin/axilla, and cool IV fluids – Note that antipyretics are ineffective in serotonin syndrome because the main causes of hyperthermia are increased muscle activity and central deregulation. Some patients will need to be sedated to prevent excess muscle activity.
• Sedation with benzodiazepines to decrease muscle contractions (added benefit of reducing heart rate and blood pressure).
• Intubation may be needed in severe cases and when heavy sedation or neuromuscular blockade is utilized to decrease muscular activity.
• Serotonin antagonist – If supportive measures do not treat the syndrome adequately, a serotonin antagonist, cyproheptadine, may be utilized.

Things to avoid include:

• Physical restraints – increase muscle rigidity and hyperthermia risk
• Haloperidol – may worsen rigidity and interfere with temperature regulation
• Succinylcholine – risk of severe hyperkalemia if rhabdomyolysis is present

E: How do you EDUCATE the patient/family?

The most important thing to teach the patient who is prescribed a serotonergic agent is to avoid substances that increase serotonin levels. This includes cough syrup containing dextromethorphan, herbal supplements such as St. John’s Wort and illicit/recreational drugs. 

In addition, it’s important the patient communicates all medications and supplements to each physician to avoid the over-prescribing of serotonergic medications. Along with that, encourage the patient to use a single pharmacy so potential drug interactions can be flagged by the pharmacist as well. 

It’s also vital that patients know the early signs of serotonin syndrome so they can seek medical care quickly. Things to watch for when increasing dosage or adding a new medication include: 

• Sudden restlessness, agitation or confusion
• A rapid heart rate
• Fever
• Muscle twitching, stiffness, or lack of coordination
• Heavy sweating, diarrhea, nausea/vomiting
• Dilated pupils

Case Study (do we need a graphic or something to separate this out?) We have that cute graphic that looks like a clipboard…would that work?

Patient Presentation

Margaret is a 58-year-old woman admitted to the medical floor for a methicillin-resistant Staphylococcus aureus (MRSA) wound infection. Her PMH includes major depressive disorder, fibromyalgia, and type 2 diabetes. Her home medications include sertraline 100 mg daily, tramadol 50 mg every 6 hours PRN, and metformin.

The hospitalist orders linezolid 600 mg IV every 12 hours for MRSA coverage. Three hours after the first dose, her nurse notes she is increasingly restless, sweating through her gown, and complaining of ‘jumping legs.’

Nursing Assessment Findings

• Alert but agitated; repeatedly pulling at IV tubing
• Pupils 6 mm and reactive bilaterally
• Inducible ankle clonus bilaterally
• Diaphoretic; skin flushed and warm
• Reports: “I can’t stop my legs from twitching and I feel like I’m going to throw up.”

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Nurses are often the first and best defense against medication toxicity. Your head-to-toe assessment and clinical curiosity save lives. Stay sharp out there!

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References:

Mayo Clinic. (2024, September 12). Serotonin syndrome-Serotonin syndrome—Symptoms & causes. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/serotonin-syndrome/symptoms-causes/syc-20354758

Simon, L. V., Torrico, T. J., & Keenaghan, M. (2026). Serotonin Syndrome. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK482377/

Wang, Y., Lin, Y., Lin, Q., Liange, H., Cai, W., & Jiang, D. (2023). Exploring the association between selective serotonin reuptake inhibitors and rhabdomyolysis risk based on the FDA pharmacovigilance database (Pt. 12257). Scientific Reports, 13(1). https://pmc.ncbi.nlm.nih.gov/articles/PMC10382477/