Serotonin syndrome (SS) is caused by the excess accumulation of serotonin and subsequent overactivity at 5-HT receptors.
The Patient
A 44-year-old female patient presented to the Mayo Clinic Depression Center. Significant past medical history included major depressive disorder, generalized anxiety disorder, opioid use disorder, and migraines. She was referred to the neurology department due to worsening anxiety and agitation, and neurology documentation noted complaints of diaphoresis, muscle twitches, and inattention difficulties over the past 2 to 3 months, as well as clonus. At the time of the psychiatric appointment, prescribed medications included fluoxetine 60 mg, buspirone 30 mg twice daily, buprenorphine 8 mg/naloxone 2 mg, and hydroxyzine 100 mg 3 times daily.
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Following consultation with the pharmacy, fluoxetine and buspirone doses were reduced and it was recommended to temporarily hold buprenorphine/naloxone. Hydroxyzine was discontinued and clonazepam 0.5 to 1 mg twice daily as needed was initiated. Physical symptoms reported by the patient resolved over the course of 5 days.
Serotonin Syndrome
Serotonin, or 5-hydroxytyptamine (5-HT), is a monoamine neurotransmitter involved in several important biological processes including learning, memory, mood, appetite, and sleep. Serotonin synthesis involves a 2-step conversion process, and its activity terminated in 1 of 2 ways: either metabolized by monoamine oxidase or recycled by the serotonin transporter.1
Serotonin syndrome (SS) is caused by the excess accumulation of serotonin and subsequent overactivity at 5-HT receptors. SS is usually induced by serotonergic agents, with monoamine oxidase inhibitors and selective serotonin reuptake inhibitors being the 2 most common drug classes.2 Other lesser-known SS-inducing drugs include fentanyl, tramadol, linezolid, and even OTC agents such as dextromethorphan and chlorphenaramine.3
Three hallmark signs of SS include neuromuscular hyperactivity, altered mental status, and autonomic dysfunction.4 Although SS is often thought of as an acute emergency when systemic symptoms such as hyperthermia and altered mental status are present, it should be considered on a spectrum of severity from mild to life-threatening.
Emergent SS is often diagnosed based on the Hunter Criteria which requires exposure to a serotonergic agent plus 1 of the following: spontaneous clonus; inducible clonus plus agitation or diaphoresis; ocular clonus with agitation or diaphoresis; tremor with hyperreflexia; or hypertonia with temperature above 38ºC plus ocular or inducible clonus.5 Other criteria to diagnose SS can include Sternbach’s criteria and Radomski’s criteria.6,7
Acute vs Chronic Serotonin Syndrome
SS usually manifests acutely within 24 hours of initiating a serotoninergic agent or following a dose escalation. It is less commonly described with stable dosing of a serotonergic agent. However, recent literature has called attention to chronic SS (CSS). Like acute onset SS, CSS displays the same triad of symptoms. However, notable differences lie in symptom duration and severity. Although there is no current standard definition of CSS, in a retrospective chart review, Prakash et al. categorized patients based on the presentation of symptoms for 6 or more weeks.3 Compared with SS, patients with CSS are more likely to present with generalized systemic symptoms of fatigue, insomnia, restlessness, and diaphoresis rather than hyperthermia.3 Gastrointestinal symptoms may also be seen. Complaints of limb stiffness, muscle twitches, and tremors often result in a neurology referral and medication causes may be overlooked. Due to the milder and more sustained symptoms, patients with CSS often present in an ambulatory care setting.
Treatment of SS, whether acute or chronic, involves discontinuation of the offending agent and supportive care (e.g. intravenous fluids and oxygen therapy) to normalize vitals as necessary. Benzodiazepines may also be used to treat agitation and muscle stiffness.8 Serotonin antagonists such as cyproheptadine, which binds to the 5-HT2A receptor, can be used in acute SS and also have been employed in cases of CSS.9 If treated adequately, SS resolution is expected to occur within 24 hours.8 In the chronic setting, however, improvement may take up to 14 days.2 Currently, there are no well-defined timelines nor diagnostic criteria that distinguish acute SS from CSS, which makes diagnosis of this condition difficult, especially in an outpatient setting.
With the commonality of antidepressant and other serotonergic medication prescribing, as well as polypharmacy, there is a need for increased recognition and understanding of CSS. Misdiagnosis of CSS can be attributed to the presentation of general, non-acute medical symptoms, leading to extensive work-up. Although generally not life threatening, CSS can negatively impact an individual’s quality of life and morbidity. Without recognition of potential CSS, symptoms likely do not resolve spontaneously if the offending serotonergic agent remains onboard. Therefore, discussion of this topic is important to raise clinician awareness.
Wen Jiang is a PharmD candidate in the University of Florida College of Pharmacy class of 2026.
Jon Leung, PharmD, is a preceptor.
