see also:

• neuroleptic malignant syndrome
• SSRI/SNRI antidepressants

• Serotonin syndrome is due to excess activation of post-synaptic 5HT1A in lower brain stem & spinal cord, perhaps with some dopaminergic involvement.
• 5HT is derived from L-tryptophan via tryptophan hydroxylase which converts it to 5-OH tryptophan which is then decarboxylated to form 5HT (5-OH tryptamine or serotonin).
• 5HT is degraded by monoamine oxidase A & is actively absorbed by circulating platelets.
• see also Serotonin physiology physiology.

• may be caused by one or more of the following:
  • increased substrate supply:
    • high doses of L-tryptophan or 5-OH tryptophan
  • inhibition of serotonin metabolism:
    • MAOI & a serotonin precursor combination (eg. tryptophan)
    • MAOI & either SSRI or tricyclic
      • NB. even if SSRI/TCA stopped < 2wks ago or fluoxetine in past 5wks!
  • inhibition of serotonin reuptake
    • SSRI/SNRI antidepressants, TCA's
  • potentiation of serotonin activity
  • activation of serotonin receptors by agents other than serotonin
    • full 5HT1A agonist (8-OH DPAT, 5 Me ODMT) but not partial agonist (buspirone)
    • 5HT agonists:
      • clomipramine
      • dextromethorphan (Actifed)
      • fenfluramine (Ponderax) (no longer sold in Australia as of Sept 1997 as assoc. with valvulopathies)
      • pentazocine (Fortral)
      • pethidine
• Risk increased in pts with:
  • ? disease states with decreased serotonin metabolism
  • genetically slow metabolisers of serotonin (7% pop.)

• recent addition or increase in dosage of an agent that enhances serotonin activity or availability
• absence of abused substances or other causes of hyperthermia
• no recent addition or increase in the dose of a neuroleptic (otherwise consider neuroleptic malignant syndrome (NMS))
• presence of at least 3 of:
  • altered mental state
  • agitation
  • tremor
  • shivering
  • diarrhoea
  • hyperreflexia (legs > UL)
  • myoclonus - esp. ocular
  • ataxia
  • fever

• sepsis / septicaemia (esp. meningitis)
• drug abuse/withdrawal (esp. delirium tremens)
• malignant hyperthermia due to general anaesthesia
• neuroleptic malignant syndrome:
  • NMS presents in a more toxic state, with more severely impaired consciousness, more likely to be febrile and at higher temperature than serotonin syndrome, with lead-pipe rigidity rather than myoclonus with raised WCC, LFT's & CK more likely, but nystagmus and diarrhoea is rare.
  • hyper-reflexia tends to be UL > LL in contrast to serotonin syndrome
• sympathomimetic or anticholinergic overdose
• heat illness and heat stroke - exposure to heat, dehydration
• baseline psychiatric symptoms
• lethal catatonia
  • akinetic, frequently exhibit rigidity and even fever +/- bizarre choreoform movements & torsion spasms.
  • usually preceded by 2-3wks increasing depression & withdrawal

• stop all serotoninergic drugs
• do not give antiemetics which will exacerbate the serotonin syndrome such as ondansetron, granisetron, and metoclopramide (Maxolon) (which is a 5-HT3 antagonist + 5-HT4 agonist + CNS dopamine antagonist)
• oxygen to maintain SaO2 > 93%
• IV fluids to treat volume depletion and hyperthermia
• sedate with benzodiazepines such as diazepam
• patients whose temperature is above 41.1ºC require immediate sedation, paralysis, and endotracheal intubation
• patients with severe hypertension and tachycardia should be treated with short-acting agents, such as esmolol or sodium nitroprusside - avoid long acting beta adrenergic blockers
• hypotension from MAOIs should be treated with low doses of direct-acting sympathomimetic amines such as phenylephrine, epinephrine, or norepinephrine
  • Indirect agents (eg, dopamine) should be avoided because they are metabolized to epinephrine and norepinephrine; when monoamine oxidase is inhibited, epinephrine and norepinephrine production at the cellular level is not controlled, possibly leading to an exaggerated hemodynamic response
• Mx VT & seizures as per usual
• limit muscle contractions (else risk of fever, rhabdomyolysis & resp. compromise):
  • if mild: consider benzodiazepines, home & r/v 1 day
  • if mod/severe: benzodiazepine ( consider lorazepam o/IV, or clonazepam as useful in myoclonus)
  • if very severe: consider muscle paralysis & sedation with intubation
• other options:
  • cyproheptadine orally
    • cyproheptadine is a histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-HT2A antagonistic properties. It also has weak anticholinergic activity.
    • when administered as an antidote for serotonin syndrome, an initial dose of 12 mg is recommended, followed by 2 mg every two hours until clinical response is seen¹⁾.
    • cyproheptadine is only available in an oral form, but it may be crushed and given through a nasogastric tube.
  • propranolol, bromocryptine or dantrolene are NOT recommended²⁾.
  • chlorpromazine (Largactil) , although having 5-HT2A antagonist activity, is currently NOT recommended as risk of hyperthermia³⁾.
  • there is NO role for antipyretic agents, such as paracetamol (acetaminophen) - the increase in body temperature is not due to an alteration in the hypothalamic temperature set point, but rather an increase in muscular activity
• 40% require ICU
• 70% resolve within 24hrs