The Serotonin Syndrome Scaries
…the patient’s ability to provide history is limited
ingested a “PILL”…
case
The patient is a 33-year-old female with a medical history of ADHD and depression presenting with altered mental status. Per emergency medical services (EMS), the patient’s friend called for an episode of unresponsiveness. The patient’s ability to provide history is limited, but the friend reported that shortly prior to this event, the patient ingested a “pill” which he believed to be alprazolam (a medication she is prescribed). While awaiting evaluation, the patient had witnessed seizure-like activity in the waiting room, lasting approximately 30 seconds and was brought to a critical care room. Attempts were made to contact the patient’s friend and brother for collateral information, but all listed numbers were out of service. Per the patient’s medication dispense records, the patient is prescribed bupropion, alprazolam, and levetiracetam.
VITALS:
HR: 143 BP: 118/54 RR: 18 T: 97.5F spO2: 98% on room air
PHYSICAL EXAM:
General: Ill-appearing female, unable to answer questions
Neuro: Pupils 6 mm, sluggishly reactive; inducible clonus (3–5 beats), opsoclonus, myoclonus, hypertonia without rigidity, hyperreflexia of ankle plantar flexion and knee extension
CV: Tachycardic, regular rhythm, no murmurs
Pulm: Lungs clear to auscultation
GI: Soft, non-distended
Skin: Warm, well-perfused
Other: Mucous membranes dry; no signs of trauma
diagnosis
Serotonin Syndrome
discussion
Serotonin syndrome is a condition characterized by a spectrum of clinical findings resulting from increased serotonergic activity in the central nervous system. The neurotransmitter serotonin plays a role in mood, temperature regulation, vomiting, and pain perception (1). As a result, the adverse effects of this condition can range from mild to severe depending on the extent of serotonin toxicity. Serotonin syndrome can result from therapeutic use, overdose, or drug interactions involving serotonergic agents (2). The diagnosis of this condition is largely clinical, without a specific laboratory test to confirm the diagnosis. Although a comprehensive drug screen can help support the diagnosis, it often takes days to result and should not delay clinical decision making. Frequently, a triad of neuromuscular hyperactivity (clonus, hyperreflexia, myoclonus), autonomic instability (tachycardia, hyperthermia, diaphoresis), and altered mental status (agitation, delirium, coma) is seen (2). However, not all these symptoms have to be present to diagnose this condition.
The Hunter criteria, a set of clinical guidelines, has largely replaced the Sternbach criteria as an aid in diagnosing serotonin syndrome due to its increased sensitivity and specificity (3). The Hunter criteria detail that the diagnosis of serotonin syndrome can be made in the presence of a serotonergic agent and one of the following clinical features: spontaneous clonus, inducible clonus plus agitation or diaphoresis, ocular clonus plus agitation of diaphoresis, tremor plus hyperreflexia, or hypertonia with a temperature above 38 degrees Celsius and ocular or inducible clonus (3).
The history in this case was extremely limited due to the patient’s mental status, as is frequently seen with toxicologic cases. This can contribute to the high rate of underdiagnosis and under- reporting of serotonin syndrome (4). The diagnosis in this case was made primarily through physical exam findings as the patient demonstrated key features of serotonin syndrome: hyperreflexia, inducible clonus, opsoclonus, and agitation with a prescribed serotonergic medication (bupropion). Although bupropion is a norepinephrine and dopamine reuptake inhibitor (NDRI), multiple case reports have implicated bupropion as a cause of serotonin syndrome, either alone or in combination with other serotonergic agents (5,6). This is due to an indirect increase in serotonergic activity (5).
When diagnosing a patient with serotonin syndrome it is prudent to maintain a broad differential. This includes neuroleptic malignant syndrome (NMS), malignant hyperthermia, anticholinergic toxicity, toxic metabolic encephalopathy, and seizure-related encephalopathy to name a few. NMS typically presents with rigidity, hyperthermia, and history of antipsychotic use which this patient did not have (7). Malignant hyperthermia can present similarly to NMS but usually involves recent use of anesthetic agents. Anticholinergic toxicity has a toxidrome including dry mucous membranes, delirium, and mydriasis. However, clonus is usually absent (7). NMS and malignant hyperthermia are life threatening conditions that involve treatment with dantrolene, and therefore should always be considered before initiating treatment for serotonin syndrome.
Diagnosis is the most difficult part of caring for a patient with serotonin syndrome. Management primarily involves discontinuing all serotonergic agents and providing supportive care, targeted toward the patient’s specific symptoms. This includes airway support, supplemental O2 as needed, intravenous fluids for hypovolemia, and aggressive external cooling for patients with hyperthermia. With treatment, symptoms of serotonin syndrome typically resolve in 24 hours (7). Furthermore, benzodiazepines are the cornerstone of treatment for autonomic symptoms and agitation. Currently, there is not a consensus on which benzodiazepines are the most effective for treatment of serotonin syndrome. However, diazepam has been shown to prolong survival in rat subjects (8).
Benzodiazepines are typically first line for seizures, as seen in the patient described in this case. If seizures are refractory to benzodiazepines, anti-epileptic drugs should be used as second line agents (7). Dexmedetomidine can also be used as an adjunctive therapy for controlling agitation and autonomic instability in severe serotonin syndrome refractory to benzodiazepines (9). Of note, dexmedetomidine can cause hyperthermia and should be avoided in patients with pre-existing hyperthermia. Furthermore, it should be discontinued if hyperthermia develops, as drug induced hyperthermia is usually resistant to traditional cooling methods (9). In moderate to severe cases of serotonin syndrome, cyproheptadine, a serotonin antagonist, can be administered to help mitigate symptoms (7).
In addition to seizures, other serious complications that can arise if this condition is untreated including hyperthermia, rhabdomyolysis, disseminated intravascular coagulation, and multiple organ failure (2). It is important to diagnose and treat this condition early. Patients with moderate to severe symptoms should be admitted to an intensive care unit (ICU) level of care for close monitoring.
case resolution
More history was obtained later in this patient’s clinical course from collateral sources . She had been experiencing multiple stressors and told her family she was “tired of it all.” The family sent a friend over to keep her company. While there, the patient told her friend she took a “bunch of xanax.” Soon after, the patient had an episode of seizure-like activity prompting the call to EMS.
While in the emergency department, the patient was given lorazepam for seizures and agitation. She had another epileptic event and was subsequently loaded with Keppra. She was started on a dexmedetomidine drip for agitation refractory to benzodiazepines with good response. The patient was admitted to the medical ICU. Approximately 12 hours later, the patient developed acute hypoxic respiratory failure (AHRF) ultimately requiring intubation. A chest x-ray showed new bilateral opacities concerning for multifocal aspiration/pneumonia. She was persistently hypoxemic despite maximal ventilator settings, requiring VV-ECMO. The patient was continued on benzodiazepines and a dexmedetomidine drip for treatment of serotonin syndrome. A comprehensive toxicology subsequently resulted in the following: lorazepam, alprazolam, levetiracetam, bupropion, hydroxybupropion, cotinine, caffeine.
After three days of VV-ECMO, the patient was decannulated and weaned to room air. She admitted to ingesting a large amount of bupropion to “feel numb.” On day six of her hospitalization, she was transferred to an inpatient psychiatric unit. After twenty-one days, the patient was discharged to a partial program. She is now doing well now in outpatient therapy on sertraline.
key take-aways
History may be unreliable or unavailable—a thorough physical exam is critical.
Keep a broad differential when evaluating altered mental status.
Classic toxidromes can guide early diagnosis.
Serotonin syndrome is a clinical diagnosis—do not delay treatment for lab confirmation.
Seizure complications (aspiration, AHRF, hypoxia) can escalate quickly.
Treatment includes benzodiazepines, sedation (e.g., dexmedetomidine), supportive care, and in severe cases, intubation/ECMO.
Ensure close follow-up for underlying psychiatric disease and substance use disorders.
AUTHOR: Maiya Cowan, MD is a fourth year emergency medicine resident at Brown Emergency Medicine.
FACULTY REVIEWER: Samuel Goldman, MD is an assistant professor and clinician educator at Brown Emergency Medicine.
References
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Boyer EW, Shannon M. “The serotonin syndrome.” N Engl J Med. 2005 Mar 17;352(11):1112–20.
Dunkley EJ, Isbister GK, Sibbritt D, et al. “The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.” QJM. 2003 Sep;96(9):635–42.
Ibrahim H, Maksod SA, Khorshed M, et al. “Serotonin syndrome: a rare undiagnosed cause of hyperpyrexia.” Egypt J Intern Med. 2023 Jun; 35(40).
Murray BP, Carpenter JE, Sayers J, et al. “Two Cases of Serotonin Syndrome After Bupropion Overdose Treated With Cyproheptadine.” J Emerg Med. 2021;60(4):e67-e71
Thorpe EL, Pizon AF, Lynch MJ, et al. “Bupropion induced serotonin syndrome: a case report.” J Med Toxicol. 2010 Jun;6(2):168-71.
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Rushton WF, Charlton NP. “Dexmedetomidine in the treatment of serotonin syndrome.” Ann Pharmacother. 2014 Dec;48(12):1651-4.