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Key points
- Serotonin syndrome (SS): severe, life-threatening condition due to increased serotonin activity in the CNS; can range from mild to severe.
- Aetiology: occurs with single serotonergic drug, combinations, or overdose; implicated drugs include SSRIs, SNRIs, TCAs, MAOIs, triptans, and St John’s wort.
- Pathophysiology: caused by increased serotonin production (e.g. tryptophan), decreased metabolism (MAOIs), increased release (amphetamines), or receptor overstimulation (LSD, lithium).
- Clinical features: triad of altered mental state (e.g. agitation, confusion), autonomic hyperactivity (e.g. tachycardia, hyperthermia), and neuromuscular abnormalities (e.g. hyperreflexia, clonus).
- Differential diagnoses: neuroleptic malignant syndrome (slower onset, severe rigidity), anticholinergic syndrome (dry mouth, urinary retention), and heat stroke.
- Diagnosis: clinical, using Hunter Serotonin Toxicity Criteria (e.g. clonus, hyperreflexia, hypertonia plus hyperthermia).
- Investigations: basic observations, ECG (prolonged QTc), FBC (raised WBC), creatine kinase (elevated in severe cases), and drug screening for toxins.
- Management: discontinue serotonergic agent, supportive care (fluids, cooling, benzodiazepines), cyproheptadine if severe; ICU care for hyperthermia or instability.
- Complications: seizures, rhabdomyolysis, renal failure, respiratory distress, coma, and death; prognosis improves with prompt management.
Introduction
Serotonin syndrome (SS) or serotonin toxicity is a severe and potentially life-threatening condition caused by increased serotonin activity in the central nervous system (CNS).1 Although known to have its classic features, it is often considered a spectrum ranging from mild to severe.
Serotonin syndrome can occur with a single serotonergic drug at a therapeutic dose, a combination of serotonergic drugs, or in overdose.2 Its onset typically occurs within a few hours of intake of a new serotonergic agent or following a change in dose.Â
The incidence of SS is challenging to quantify as it is a relatively uncommon drug reaction and mild cases probably go unreported. It can occur in all ages and without sex preference.3
Aetiology
Several drugs have been linked to the development of SS, particularly those that increase serotonin levels (serotonergic agents). SS can occur with exposure to a single serotonergic agent, however, the risk is increased if multiple medications are co-prescribed.
Serotonergic drugs include:4
- Selective serotonin reuptake inhibitors (SSRIs), e.g. citalopram, fluoxetine, sertraline
- Serotonin and norepinephrine reuptake inhibitors (SNRIs), e.g. venlafaxine, duloxetine
- Tricyclic antidepressants (TCAs), e.g. amitriptyline, clomipramine
- Monoamine oxidase inhibitors (MAOIs), e.g. selegiline, phenelzine
- Bupropion
- Anti-migraine medications, e.g. triptans, carbamazepine
- Analgesics, e.g. meperidine, tramadol
- Antiepileptics/mood stabilisers, e.g. lamotrigine, valproate, lithium
- Illicit substances, e.g. ecstasy, cocaine, amphetamines, LSD
- Herbal supplements such as St John’s wort
Most fatal cases of serotonin syndrome involve an MAOI plus an SSRI, so concurrent use is contraindicated. Caution is advised when switching between serotonergic agents. Concurrent use of an SSRI and St John’s wort is also to be avoided.5
Pathophysiology
Various mechanisms can potentially affect the quantity or activity of serotonin. These include:3, 6
- Increased production of serotonin due to increased availability of precursors by L-tryptophan-containing substances
- Reduced metabolism of serotonin by MAOIs, St John’s wort
- Increased release of stored serotonin by substances like amphetamines, cocaine, MDMA
- Reuptake inhibition by SSRIs, TCAs, SNRIs
- Direct stimulation of serotonin receptors by agents like buspirone, lysergic acid diethylamide (LSD), triptans, lithium
Clinical features
History
A detailed history and thorough physical and neurologic examinations are essential.7 In suspected SS, it is important to determine:8
- Medication use, supplements, and illicit substances, including names, doses, schedules, and any recent changes
- Duration of symptoms, which typically appear within 6 to 24 hours of a dose change or new substance intake
Intentional overdoses are typically more severe than accidental ones, so it’s crucial to ask if the overdose was premeditated.
Clinical examination
Features may vary and can range from mild symptoms to life-threatening ones, but typical clinical findings of SS include a triad of:6, 8-9
- Altered mental state: agitation, confusion, anxiety, and hypervigilance
- Autonomic hyperactivity: tachycardia, hypertension, hyperthermia, mydriasis, flushed skin, diaphoresis, shivering and increased bowel activity
- Neuromuscular abnormalities: ocular clonus, hyperreflexia, rigidity, tremor and myoclonus, especially in the lower limbs
In mild cases, the main features are mild hypertension and tachycardia, mydriasis, diaphoresis, shivering, tremor, myoclonus, and hyperreflexia.
In moderate cases, patients have the above symptoms, plus hyperthermia ≥ 40°C, hyperactive bowel sounds, horizontal ocular clonus, mild agitation, hypervigilance, and pressured speech.
In severe cases, all of the above symptoms are present, plus hyperthermia ≥ 41.1°C, fluctuations in pulse rate and blood pressure, delirium, and muscle rigidity.
 HARD features
Think of serotonin syndrome with any combination of HARD features:Â 10
- Hyperthermia
- Autonomic instability
- Rigidity
- Drowsiness/delirium
Differential diagnoses
The differential diagnoses for SS include:7-8
- Neuroleptic malignant syndrome (NMS): fever, confusion, unstable vital signs, elevated creatine kinase level, and muscle rigidity
- Catatonia: agitation, stupor, autonomic abnormality, reduced oral intake, negativism, and posturing
- Anticholinergic syndrome: fever, dilated pupils, dry mouth and eyes, decreased sweating, delirium, and urinary retention
- Heat stroke: fever, headache, dizziness, excessive sweating, abdominal cramps, and tachycardia
Table 1. Distinguishing between SS and NMS7
| Features | Serotonin syndrome (SS) | Neuroleptic malignant syndrome (NMS) |
| Causative agent | Serotonergic agents (overdose/drug combinations) | Antipsychotic agents (idiosyncratic/normal dose) |
| Onset | Rapid (within 24 hours) | Slow (days to weeks) |
| Neuromuscular findings | Tremor, myoclonus, ocular clonus, hyperreflexia | Severe muscular rigidity (lead pipe), hyporeflexia |
| Pupils | Mydriasis (dilated) | Normal |
| Bowel sounds | Hyperactive | Normal/decreased |
| Creatine kinase | Normal/slightly raised | Raised |
| Treatment agents | Benzodiazepines, cyproheptadine | Bromocriptine, dantrolene |
| Resolution | Within 24 hours | Days to weeks |
Investigations
Serotonin syndrome is diagnosed clinically, with no specific laboratory investigations required. However, investigations can clarify the clinical picture, assess the severity of the condition, monitor for complications and guide management.11
Bedside investigations
Relevant bedside investigations include:
- Basic observations: to assess for fever, tachypnoea, tachycardia, hypertension, altered level of consciousness, pupil size
- Urine dipstick: to exclude urinary infection
- Urine drug screen: to identify illicit substances taken
- ECG: may show prolonged QRS or prolonged QTc interval (typical with serotonin toxicity)
Laboratory investigations
Relevant laboratory investigations with non-specific findings include:
- Full blood count: may show elevated white blood cells
- Urea and electrolytes: may show renal impairment in severe cases
- Creatine kinase: may be slightly increased
- Drug toxicology: to assess possible accidental or intentional overdose or poisoning
- Blood cultures: if sepsis is suspected
Imaging
Relevant imaging includes:
- Chest X-ray: if in respiratory failure
Diagnosis
The Hunter Serotonin Toxicity Criteria (HSTC) is the most accurate and highly recommended diagnostic criteria among several. There must be the presence of a serotonergic agent and one of the following:7Â
- Spontaneous clonus
- Inducible clonus plus agitation or diaphoresis
- Ocular clonus plus agitation or diaphoresis
- Tremor plus hyperreflexia
- Hypertonia plus temperature above 38°C plus ocular clonus or inducible clonus
ManagementÂ
Serotonin syndrome usually resolves within 24 hours of treatment, with the degree of intervention dependent on symptom severity.3, 9
Conservative management
- Immediate discontinuation of the serotonergic agent
- Activated charcoal if within 1 hour of intentional overdose
- Continuous monitoring, including telemetry
- Cooling with ice packs
- Early intensive care review
Medical management
- Intravenous fluids: for volume depletion in hyperthermia
- Benzodiazepines (e.g. lorazepam): for agitation, muscular rigidity and hypertension
- Cyproheptadine (serotonin antagonist): if supportive measures fail
- Short-acting antihypertensives (e.g. esmolol, nicardipine, nitroprusside): for hypertension and tachycardia. Avoid longer-acting agents (e.g. propranolol) due to autonomic instability
- Intubation and ventilation with neuromuscular paralysis: for significant hyperthermia and instability
Following the resolution of symptoms, a comprehensive assessment and thorough medication review should take place to identify the causative agent (if not determined) and how it can be prevented in future. Clear documentation and medication alert are necessary.Â
Table 2. Summary of symptom severity and management12
| Severity | Symptom | Management |
| Mild | Mild hypertension, tachycardia, mydriasis, diaphoresis, shivering, tremor, myoclonus, hyperreflexia |
|
| Moderate | Above plus temperature of at least 40°C, hyperactive bowel sounds, ocular clonus, agitation, hypervigilance |
|
| Severe | Above plus temperature >41.1°C, dramatic swings in pulse rate and blood pressure, delirium, muscle rigidity |
|
Complications
Severe cases may lead to complications such as seizures, rhabdomyolysis, myoglobinuria, metabolic acidosis, renal failure, acute respiratory distress syndrome, respiratory failure, diffuse intravascular clotting, coma, and death.12
The prognosis of serotonin syndrome varies on the degree of serotonin toxicity, depending on the dose and type of serotonergic agent. In most cases, symptoms usually start suddenly and resolve within 24-36 hours with proper care. After an SSRI overdose, if a patient remains symptom-free for several hours, further medical treatment is often unnecessary.
Reviewer
Dr Hal Abdullahi
Consultant Psychiatrist
Editor
Dr Jamie Scriven
References
- Francescangeli J, Karamchandani K, Powell M, et al. The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice. International Journal of Molecular Sciences. 2019. Available from: [LINK].
- Werneke U, Jamshidi F, Taylor DM, et al. Conundrums in neurology: diagnosing serotonin syndrome – a meta-analysis of cases. BMC Neurology. 2016. Available from: [LINK].
- Scotton WJ, Hill LJ, Williams AC, et al. Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions. International Journal of Tryptophan Research. 2019. Available from: [LINK].
- Mikkelsen N, Damkier P, Pedersen SA. Serotonin syndrome-A focused review. Basic & Clinical Pharmacology & Toxicology. 2023. Available from: [LINK].
- NICE CKS. Depression: Selective serotonin reuptake inhibitors (SSRIs). 2024 Available from: [LINK].
- Simon LV, Torrico TJ, Keenaghan M. Serotonin Syndrome. StatPearls. 2024. Available from: [LINK].
- UpToDate. Serotonin syndrome (serotonin toxicity). 2024. Available from: [LINK].
- Taylor DM, Gaughran F, Pillinger T. The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry. 2020.
- Boyer EW, Shannon M. The Serotonin Syndrome. New England Journal of Medicine. 2005. Available from: [LINK].
- Burnside A. Psychiatry: Breaking the Ice – Introductions, Common Tasks and Emergencies for Trainees. 1st ed. Chapter 67, p. 408. 2015. Available from: [LINK].
- Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine (Baltimore). 2000. Available from: [LINK].
- Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin Syndrome. Ochsner Journal. 2013. Available from: [LINK].
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