Serotonin Syndrome

Drug-induced over-stimulation of serotonin receptors in CNS, characterised by:

CNS dysfunction
Autonomic disturbance
Hyperreflexia

Serotonin syndrome is also:

Potentially fatal
Largely avoidable

Serotonin syndrome is subdivided into:

Mild
May be difficult to distinguish from underlying medical conditions, or supra-therapeutic use of an SSRI. Symptoms include:
- Brisk reflexes, inducible clonus
- Insomnia, anxiety
- Nausea, diarrhoea, hypertension, tachycardia
Moderate
May occur with overdose of single agent, or ↑ therapeutic doses. Symptoms include:
- Sustained clonus, ocular clonus
- Agitation
- Mydriasis, diaphoresis, fever ⩽38.5
Severe
Potentially fatal.
- Usually only occurs with two or more serotonergic drugs
- Usually requires one monoamine oxidase inhibitor
- Symptoms include:
  - Muscle rigidity, respiratory failure
  - Confusion, coma
  - Severe hyperthermia

Epidemiology and Risk Factors

Pathophysiology

Excessive serotonin activity at 5-HT₂ receptors in the CNS.

Aetiology

Drugs Associated with Moderate to Severe Serotonin Toxicity
Class	Subclass	Agents
Monoamine Oxidase Inhibitors	Irreversible inhibitors	Phenelzine Tranylcypromine Iproniazid Isocarboxazid
	Reversible inhibitors of MAO-A	Moclobemide
	Non-psychotropics	Linezolid Methylene blue
Serotonin Releasing Agents	SSRIs	Fentanyl Tramadol Pethidine Dextromethorphan
	Sympathomimetics	Ecstasy Amphetamines Bath salts
	Herbal	St John’s Wort
Other		Lithium Buspirone Tryptophan

Drugs without significant risk of toxicity include serotonin antagonists and drugs that do not agonise 5-HT₂, including:

Antipsychotics
Anxiolytics
Anti-migraine drugs
Antiemetics

Clinical Features

Severe and life-threatening cases almost always involve a monoamine oxidase inhibitor
Awareness of potent serotonergic agents is key to preventing reactions

Careful and detailed drug history is essential:

Many drugs influence serotonergic neurotransmitters
Many drugs listed with serotonin syndrome as a side effect will rarely cause
Many contributing drugs have:
- Persistent activity
  e.g. Irreversible MAO.
- Long half-lives
  May have been stopped weeks prior.
Use of herbal remedies
Use of illicit substances

Presentation:

Toxicity usually within hours of ingestion
Diagnosis requires:
- Overdose of serotonergic drug
- ↑ Dose of serotonergic drug
- Addition of a second serotonergic drug
Classic triad of:
- Neuromuscular excitation
  Hyperreflexia, myoclonus, rigidity.
  - Generalised clonus is classical, and may be:
    - Inducible
      Ankle dorsiflexion.
    - Spontaneous
      Generally rhythmic, large muscle contractions triggered by minor stimulus.
    - Ocular
      May be fine or coarse gaze oscillations.
- Autonomic nervous system excitation
  Nausea, diarrhoea, hypertension, tachycardia, hyperthermia, severe hyperthermia.
- Altered mental state
  Insomnia, anxiety, agitation, confusion, coma.
Severe serotonin toxicity is characterised by:
- Rapid hyperthermia
- Muscle rigidity

Investigations

Diagnosis is clinical. Investigations are targeted towards ruling out other causes, or identifying complications.

Laboratory:

Blood
- UEC and CMP
  Rhabdomyolysis.
- Coagulation screen
  DIC.

Imaging:

Other:

LP
Encephalitis.
EEG

Diagnostic Approach and DDx

Key differentials include:

Alcohol withdrawal
Drug withdrawal
Non-convulsive seizures
Encephalitis
Neuroleptic Malignant Syndrome

Diagnostic Criteria

Hunter Serotonin Toxicity Criteria:

Serotonergic agent
Dose ↑, overdose, or new agent.
- Spontaneous clonus
  - Yes
    Serotonin toxicity.
  - No
    Inducible clonus or Ocular Clonus?
    - Yes
      Agitation or diaphoresis or (hypertonia and temperature ⩾38°C)?
      - Yes
        Serotonin toxicity.
      - No
        Go to tremor and hyperreflexia.
    - No
      Tremor and hyperreflexia?
      - Yes
        Serotonin toxicity.
      - No
        No serotonin toxicity.

Neuroleptic Malignant Syndrome is a common differential for serotonin syndrome.

The key differentiating features are that:

Serotonin syndrome has an:
- Earlier onset
- Hyper-reflexia and clous
- Dilated pupils
- ↑ Bowel sounds
NMS has:
- A slow onset over days
- Extrapyramidal features
- Rigidity but no clonus
- Normal or ↓ bowel sounds

Management

Cease precipitants
Sedation
Prevention of hyperthermia is critical in severe toxicity
Consider specific antidotes
Although they lack evidence.

Resuscitation:

A
- Intubation may be required to control temperature
C
- Volume resuscitation
D
- Sedation
  - Reduces muscles activity
E
- Prevent hyperthermia
  - Beneficial as:
    - Reduces complications
    - Down regulates 5-HT_2a receptors
  - Methods:
    - Active cooling
    - Paralysis and ventilation

Specific Therapy:

Pharmacological
- Specific agents
  In severe cases, seek toxicology advice:
  - Chlorpromazine
    - Most commonly used
    - Requires pre-load with IV fluid
  - Cyproheptadine
    Serotonin and histamine antagonist.
    - No significant differences in severe cases in a retrospective review

Anaesthetic Considerations

Marginal and Ineffective Therapies

Complications

Include:

Hyperthermia related
- Rhabdomyloysis
- DIC
- Multiorgan failure
ARDS

Prognosis

Varies with severity:

Mild
Will not progress to severe toxicity without:
- Dose escalation
- Drug interactions
Moderate
Usually resolves over 1-3 days following cessation.
Severe
Medical emergency. Requires:
- Aggressive supportive care
- Consideration of specific reversal agents

References

Buckley NA, Dawson AH, Isbister GK. Serotonin syndrome. BMJ. 2014 Feb 19;348(feb19 6):g1626–g1626.
Nguyen H, Pan A, Smollin C, Cantrell LF, Kearney T. An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California Poison Control System. J Clin Pharm Ther. 2019 Apr;44(2):327–34.