Serotonin Syndrome

Introduction

Serotonin syndrome is the clinical manifestation of excess serotonin at central and peripheral serotonergic receptors. It can be seen following intentional overdose of one or more serotonergic agents, or even with therapeutic doses of more than one serotonergic agent.

Onset of symptoms is usually rapid, within minutes to hours of ingesting the serotonergic agent(s). Clinical features may consist of the “classic triad” of;

  1. Altered mental status

  2. Neuromuscular hyperactivity

  3. Autonomic instability

Whilst antidepressants are commonly implicated in this syndrome, it is important to recognise that there are a number of other drugs, both prescribed and illicit, that can contribute to a serotonin syndrome.

Clinical severity can range anywhere from mild discomfort to a fulminant life-threatening syndrome with multi-organ failure. Treatment is largely supportive with a focus on withdrawal of  the precipitating agent, supportive care and psychiatric review.

Risk Factors

Serotonin syndrome can be caused by agents that increase serotonergic receptor activation. This can occur via a number of mechanisms and it is important to appreciate the breadth of medicines that may be implicated:

  • Decreased serotonin metabolism:

    • e.g. MAO inhibitors, linezolid, methylene blue.

  • Increased serotonin release:

    • e.g. Amphetamines, MDMA,

  • Decreased serotonin uptake:

    • SSRIs, TCAs, SNRIs, St John’s Wort, synthetic piperidine opioids (tramadol, methadone, pethidine, fentanyl) and some anti-emetics (metoclopramide, ondansetron).

  • Serotonin receptor agonism:

    • e.g Lithium, sumatriptan, LSD.

The greater number of agents involved, taken at higher doses, results in an increased risk of developing serotonin syndrome. The combination of a MAO inhibitor with an SSRI/SNRI/TCA, imparts a particularly high risk for developing serotonin syndrome.

In an acute single-drug overdose, serotonin syndrome occurs in approximately 15% of SSRI and 30% of venlafaxine (SNRI) overdoses.

Clinical Features

Rapid onset of symptoms, usually within hours of overdose/medication change. Approximately 60% of patients present will present to ED within 6 hours of overdose therefore it is important to remember that symptoms may develop after initial presentation to hospital.

 

Altered Mental Status

  • Confusion

  • Agitation

  • Anxiety

  • Drowsiness and potentially coma

Neuromuscular Hyperactivity

  • Clonus especially occular and ankle.

    • Spontaneous or inducible

  • Tremor

  • Hypertonia

  • Hyper-reflexia

Autonomic Instability

  • Hyperthermia

  • Hypertension

  • Tachycardia

  • Mydriasis

  • Diaphoresis

  • Diarrhoea

In severe cases, hyperthermia may be seen with complications such as seizures, rhabdomyolysis, acute renal failure, disseminated intravascular coagulation (DIC), multi-organ failure and death.

 

Differential Diagnosis

 

Toxicology

  • Other Toxidromes

    • Anticholingeric Syndrome. Distinguishing features from serotonin syndrome = dry skin (vs. sweating), decreased bowel sounds (vs. hyperactive) and a lack of neuromuscular findings

    • Neuroleptic Malignant Syndrome. Distinguishihing features = slower onset, mutism, lead-pipe rigidity and bradyreflexia.

  • Alcohol or illicit drug intoxication

  • Withdrawal

 

Neurological

  • Stroke

  • Cavernous sinus thrombosis

  • Intracranial haemorrhage

  • Seizure/post-ictal

Infectious

  • CNS

    • e.g. meningitis, encephalitis,

  • Other sources of sepsis

 

Metabolic

  • Hypoglycaemia

  • Hyponatraemia

  • Uraemia

  • Hypercalcaemia

  • Hyperthyroidism

Clinical Investigations

There is no reliable test to diagnose serotonin syndrome. It is a clinical diagnosis that should be suspected if there is a history of serotonergic drug intake with associated clinical features. Hunter’s criteria is a diagnostic criteria that was developed to assist the diagnosis of serotonin syndrome in patients following overdose

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As with all poisonings, a number of standard investigations are important. Particularly those performed at the bedside

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Bedside

  • ECG

    • Particularly looking at QRS and QT intervals. TCAs can cause a serotonin syndrome, as well as sodium channel blockade, resulting in QRS widening.

  • VBG

    • Particularly looking at pH and blood sugar.

  • Urine hCG in all females of child-bearing age

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Laboratory

  • FBC, U&E and LFTs

    • looking for evidence of end organ dysfunction especially if hyperthermic

  • Paracetamol Levels

    • paracetamol OD is common, toxic and reversible. Patient may not disclose that they have taken it so have high degree of suspiscion.

  • CoAg

    • elevated INR indicating liver dysfunction or coagulopathy secondary to hyperthermia

  • CK

    • ? rhabdomyolysis in hyperthermia or severe neuromuscular excitation

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Radiology

  • Often not required in stable patients

  • CT Brain if altered mental state or decreased GCS

    • looking for other causative pathology

Management and Disposition

The precipitating drug should be withheld. Management of serotonin syndrome is largely supportive and focused on preventing significant hyperthermia and it’s complications.

 

Resuscitation

  • Attend to ABC as clinically indicated

  • Patient with clinically significant OD need to be in a high observation area with cardiac monitoring

  • PO or IV Benzodiazepines

    • first line treatment for agitation, seizures, tachycardia and hypertension

  • Seek and treat hypoglycaemia

  • 50g PO activated charcoal only has a role in those patients who present within 1 - 2 hours of clinically significant OD and who are alter and co-operative.

  • Commence active cooling immediately if hyperthermic.

Specific Treatment

  • Monitor for and aggressively treat hyperthermia. Severe hyperthermia may lead to multi-organ failure, neurological injury and death

    • Hyperthermia results from excessive muscle activity so anti-pyretics are not useful.

    • Tepid sponging, cooled IV fluids and fanning

    • Control agitation/seizures with IV benzodiazepines

    • If ongoing significant hyperthermia despite the above sedation with neuromuscular paralysis and ventilation may be required

  • Lack of evidence base but there may be a role for serotonin specific antagonists in mild-moderate serotonin syndrome

    • Cyproheptadine 8mg PO/NG

Disposition

  • If the patient has no features of serotonin syndrome, but is at risk, consider monitoring for at least 8 hours for the emergence of clinical features

  • Mild to moderate cases of serotonin syndrome will usually require as short medical admission. Abrupt resolution of symptoms within 24 hours can be expected with good supportive care.

  • Severe serotonin syndrome cases requiring paralysis and ETT will require ICU admission for ongoing organ support

  • All deliberate self poisonings require Psychiatry review prior to discharge.

 

References

  1. Houchens, NW (2016) 'Serotonin Syndrome: Preventing, Recognizing, and Treating It', Cleveland Clinic Journal of Medicine , 83(11), pp. 810-17

  2. Bateman, N., Jefferson, R., Thomas, S., Thompson, J., Vale, A. (2014) Toxicology (Oxford Desk Reference), : Oxford University Press

  3. Murray, L., Daly, F., Little, M., Cadogan, M. (2007) Toxicology Handbook, Australia: Elsevier Australia.

  4. Thanacody, R. (2007) 'Serotonin Syndrome', Medicine, 35(10), pp. 556-7.

This blog was written by Dr Ruadhán O’Laoi and was last updated in February 2021

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