Mystery Diagnosis: Recognizing Serotonin Syndrome

Submitted by Wendy Blatchley, RN, BSN

Tags: advanced practice hunter serotonin toxicity criteria recognition serotonin syndrome serotonin toxicity treatment

Mystery Diagnosis: Recognizing Serotonin Syndrome

Share Article:

Written by Wendy Blatchley, RN, BSN, PACU Clinical Nurse at The University of Tampa


Serotonin syndrome (SS) is a rare condition that is believed to be induced by ingestion of serotonergic medications, leading to an increased serotonin level. Although many medications are thought to be responsible, some of the more common are antidepressants and opioids. There are no definitive tests to confirm SS, therefore diagnosis is based on clinical findings and can be somewhat difficult. A triad of symptoms, neuromuscular hyperactivity, altered mental status, and autonomic hyperactivity, are considered the hallmark signs, but are not present in all cases. Symptoms can vary from mild and almost undetectable to severe and life threatening. Three diagnostic systems are currently utilized to assist with diagnosis if SS is suspected: the Hunter, Sternbach, and Radomski criteria. A diagnosis of SS should prompt discontinuation of the suspected offending agent. Increased awareness of this issue is needed, including symptoms and risk factors, so that the advanced practice registered nurse (APRN) may promptly recognize and diagnosis this condition to avoid further complications. Completing a thorough history and physical, along with accurate medication reconciliation can assist the APRN in identifying high risk patients. While there is still so much about SS that remains unknown, current information and education on this issue will ensure the APRN is providing safe and high-quality care. Databases utilized were CINAHL, PubMed, and ScienceDirect. These databases provide access to numerous nursing, biomedical, and scientific journals and were useful in locating up-to-date, peer reviewed research on this subject.

Mystery Diagnosis: Recognizing Serotonin Syndrome

Serotonin syndrome (SS) is a clinical syndrome that is exclusively drug‑induced and can range from mild to life-threatening. Diagnosis is sometimes difficult as there is no definitive test and it is diagnosed based on symptoms. SS can also mimic a variety of other medical conditions. Many commonly prescribed medications can increase the risk of developing this condition. Advanced practice registered nurses (APRNs) in all areas of patient care need to be vigilant in screening for SS. Awareness of causes, familiarity with screening criteria, and rapid diagnosis are essential to offering patients the safest and highest quality of care.

Clinical Focus

The exact mechanism of serotonin syndrome (SS) is still not completely understood. Based on available information, it is believed to be drug induced, causing an excess amount of serotonin in the central nervous system. Treatment is supportive and involves discontinuation of the offending agent. Antidotal therapies, such as cyproheptadine, an antihistamine that can rapidly reduce intensity of symptoms, do exist but studies verifying them exclusively for this purpose are limited (Bartlett, 2017). Monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly linked medications, especially if used concurrently (Bartlett, 2017; Lam, 2015). While some medications are more obviously responsible for the development of toxicity, others are less common, but still important to consider. A study recognized methylene blue (MB), commonly used in surgical procedures, as a causative agent; serotonin is metabolized by monoamine oxidase (MAO) in the liver and MB is a known inhibitor of MAO, thus causing toxicity in patients receiving MB (Zuschlag, Warren, & Schultz, 2018). While it is important to become aware of what medications can contribute to toxicity, it is equally as important to know associated symptoms and screening tools used.

A triad of symptoms is used to diagnose this condition which include neuromuscular hyperactivity, altered mental status, and autonomic hyperactivity (Prakash & Rathore, 2016). Three sets of criteria have been established for diagnosis of SS: Sternbach, the Hunter serotonin toxicity criteria, and Radomski, with the Hunter criteria being the most widely accepted and accurate tool (Ansari & Kouti, 2016). None of the previously mentioned diagnostic tools are completely accurate. In a study completed by Werneke, Jamshidi, Taylor, and Ott, APRNs were urged not to rely solely on the Hunter criteria to diagnose patients, even if the Hunter criteria are not met, a diagnosis of serotonin toxicity is still possible (2016). This point is further illustrated in a study focusing on patients with peripheral neuropathy: the patients had areflexia due to neuropathy and did not meet the Hunter criteria for SS but were diagnosed using the Sternbach criteria based on neuromuscular and autonomic hyperactivity, along with altered mental status (Prakash, Gosai, Brahmbhatt, & Shah, 2014). This should not discredit the Hunter criteria, as it remains useful in the diagnosis of SS, but practitioners should be aware of all available diagnostic tools and ensure completion of a thorough history and physical, including medications and symptoms.


There is still so much about serotonin syndrome (SS) that is unknown. The presentation of SS varies from case to case, with numerous medications being the cause. Education and increased awareness of how to recognize SS is relevant to APRNs and other healthcare providers to ensure a proper diagnosis. Misdiagnosis is not only potentially harmful to the patient, but it could lead to unnecessary costs or increased length of stay if hospitalized. Research provided by Prakash, Makwana, Rathore, and Dave (2016), highlighted 3 cases that initially presented as febrile encephalopathy; all patients were ultimately diagnosed with SS using the Hunter criteria. An additional study completed by Prakash, Patel, Kakked, Patel, and Yadav followed 12 patient cases of mild SS, highlighting the importance of recognizing symptoms early- if overlooked, the offending drug may be continued, or the patient may even receive a second serotonergic drug, ultimately putting the patient’s life in danger (2015). As the APRN caring for these patients, these are important points to consider- misdiagnosis could be potentially harmful.


Recognizing serotonin syndrome and becoming familiar with this diagnosis is essential for all healthcare providers. Because it is a drug induced condition, it is highly preventable. In addition to serotonergic drugs being one of the most obvious, use of opiod analgesics is increasingly recognized as a risk factor. Two studies indicated similar findings of increased risk of developing SS with administration of opiod analgesics; chances of this complication increased when taken in combination with pre-hospital prescribed antidepressants (Ansari and Kouti, 2016; Pedavally, Fugate, & Rabinstein, 2014). Antidepressants and opioid analgesics are commonly prescribed medications. It is important that the APRN educates patients to familiarize them with the medications prescribed, potential side effects, as well as symptoms of SS so that early recognition and treatment is possible. Not only is it the APRN’s responsibility to know if their patient is at risk for SS and to be able to recognize the signs and symptoms, they should also ensure familiarity with diagnostic criteria systems to assist with diagnosis. While there is still much to learn about SS, established information and education can be helpful in correctly diagnosing and treating the patient appropriately while providing the best quality of care.

Signs and Symptoms

Diagnosing SS remains difficult as there is no definitive test and the diagnosis is based on the clinical presentation of symptoms and using diagnostic criteria systems. Clinically it is characterized by a triad of neuromuscular hyperactivity, autonomic hyperactivity, and mental status changes and can range from mild and barely perceptible symptoms to severe and life threatening (Prakash et al., 2015). While this triad of symptoms is important to diagnosis, presentations vary from case to case and are often nonspecific. To make diagnosis even more challenging, other conditions such as anticholinergic poisoning, malignant hyperthermia, and neuroleptic malignant syndrome, can all mimic SS (Bartlett, 2017).

The onset of signs and symptoms varies, with occurrences ranging from within a few hours of exposure to the responsible agent, up to 24 hours or longer (Bartlett, 2017). In mild to moderate cases, anxiety, diaphoresis, and tachycardia are common, while in more severe cases, acidosis, hepatitis, rhabdomyolysis, hyperthermia, seizures, and even coma have been reported (Bartlett, 2017). It is imperative that the APRN is aware of patient history, risk factors, current medications, and symptoms that could possibly be indicative of SS.

Diagnostic Criteria Systems

The Hunter, Sternbach, and Radomski classifications are the 3 systems currently used to diagnose SS (Werneke et al., 2016). One of the most commonly used diagnostic criteria systems is the Hunter criteria. The Hunter criteria requires that one of the following features or groups of features are present in addition to the patient receiving a known serotonergic agent: spontaneous clonus, inducible clonus/ocular clonus with agitation or diaphoresis or rigidity with a temperature above 100.4 degrees Fahrenheit and tremor and hyperreflexia (Prakash et al., 2016). The Hunter criteria is the most recent system used and appears to be the most reliable in diagnosis of SS, but other systems utilized prior are still helpful in diagnosis. The first classification system used was the Sternbach criteria, which focused mainly on mental status changes and could indicate SS without neuromuscular symptoms; The Radomski criteria refined Sternbach and differentiated between major and minor symptoms and added rigidity to the neuromuscular symptoms (Werneke et al., 2016). It is important that the APRN is aware of the different systems used to diagnose SS. None of the criteria systems can be relied upon exclusively and a thorough patient history is helpful if SS is suspected. If the patient is placed on a serotonergic agent, or if another is added to their regimen, and the patient develops symptoms soon after initiation, it would be appropriate to suspect SS.


Treatment of SS is supportive and involves discontinuing or removing the responsible agents and treating symptoms that arise. Cyproheptadine is an antihistamine often used as a treatment for SS and can dramatically improve intensity of signs and symptoms in a short time frame, and in some cases provides complete resolution (Bartlett, 2017). Anxiety, fever, tachycardia, and hyperthermia are symptoms that are commonly seen with a diagnosis of SS. Administration of benzodiazepines helps to control agitation and has the additional benefits of lowering heart rate, temperature, and decreasing muscle activity (Bartlett, 2017). In more severe cases of muscle rigidity and hyperthermia, paralysis with non-depolarizing blockers and mechanical ventilation may be necessary (Pedavally et al., 2014). Treatment regimens will vary amongst patients based on the severity of signs and symptoms. The APRN should be aware of medications that can cause SS and advise patients to report new onset of symptoms immediately. Early and rapid diagnosis will help lessen the severity of signs and symptoms and improve patient outcomes.


There is a need to increase awareness of SS. Prakesh et al. (2015) estimates that as many as 85% of healthcare providers are not aware of SS as a clinical entity. Nonspecific symptoms and lack of definitive tests make diagnosis even more difficult. Sudden progression from mild signs and symptoms to severe is common if left unrecognized and untreated, and while rare, fatalities do occur and usually involve monoamine oxidase inhibitors (Bartlett, 2017). The APRN can play a vital role in early recognition of SS if they are aware of what risk factors their patient has and monitor them closely if on a serotonergic agent. It is suggested that every patient placed on a serotonergic drug should be examined for the presence of tremor, hypertonia, hyperreflexia, and clonus (Prakash et al., 2015). The APRN should become aware of medications associated with SS, know signs and symptoms, as well as diagnostic criteria. Patient education is also necessary. These steps will help ensure patient safety and high quality of care.


  1. Ansari, H., & Kouti, L. (2016). Drug interaction and serotonin toxicity with opioid use: Another reason to avoid opioids in headache and migraine treatment. Current Pain and Headache Reports, 20(8), 1-7. doi:10.1007/s11916-016-0579-3
  2. Bartlett, D. (2017). Drug-induced serotonin syndrome. Critical Care Nurse, 37(1), 49-54. doi:10.4037/ccn2017169 Lam, Y. W. (2015). Serotonin toxicity from co-administration of escitalopram and mirtazapine.
    The Brown University Psychopharmacology Update, 26(6), 2-3. doi:10.1002/pu.30051
  3. Pedavally, S., Fugate, J. E., & Rabinstein, A. A. (2014). Serotonin syndrome in the intensive care unit: Clinical presentations and precipitating medications. Neurocritical Care, 21(1), 108-113. doi:10.1007/s12028-013-9914-2
  4. Prakash, S., Gosai, F., Brahmbhatt, J., & Shah, C. (2014). Serotonin syndrome in patients with peripheral neuropathy: A diagnostic challenge. General Hospital Psychiatry, 36(4), 450.e9-450.e11. doi:10.1016/j.genhosppsych.2014.03.012
  5. Prakash, S., Makwana, P., Rathore, C., & Dave, A. (2016). Serotonin syndrome presenting as febrile encephalopathy with CSF pleocytosis: A report of three cases. Neurological Sciences, 37(9), 1561-1564. doi:10.1007/s10072-016-2638-2
  6. Prakash, S., Patel, V., Kakked, S., Patel, I., & Yadav, R. (2015). Mild serotonin syndrome: A report of 12 cases. Annals of Indian Academy of Neurology, 18(2), 226-230. doi:10.4103/0972-2327.150612
  7. Prakash, S., & Rathore, C. (2016). Serotonin syndrome presenting as surgical emergency: A report of two cases. Indian Journal of Critical Care Medicine, 20(2), 120-122. doi:10.4103/0972-5229.175944
  8. Werneke, U., Jamshidi, F., Taylor, D. M., & Ott, M. (2016). Conundrums in neurology: Diagnosing serotonin syndrome – A meta-analysis of cases. BioMed Central Neurology, 16(1), 1-9. doi:10.1186/s12883-016-0616-1
  9. Zuschlag, Z. D., Warren, M. W., & Schultz, S. K. (2018). Serotonin toxicity and urinary analgesics: A case report and systematic literature review of methylene blue-induced serotonin syndrome. Psychosomatics, 59(6), 539-546. doi:10.1016/j.psym.2018.06.012