Serotonin Toxicity


This case was chosen as serotonin toxicity is relatively uncommon (or at least its recognition is) but very important to recognize, particularly as Linezolid is increasingly being used to treat resistant staph aureus strains.

Clinical problem

A 75-year-old man was admitted to ICU with failure to breathe after a maxilofacial procedure. The differential diagnosis was muscle weakness secondary to hypokalaemia or suxamethonium apnoea. Over the next few days he failed to wean or recover consciousness after stopping sedation, became pyrexial and was noted to have myoclonic jerks and have generalized rigidity. He also developed a lactic acidosis, renal failure and a hepatic transaminitis. Review of the history revealed that he had developed agitation and confusion preoperatively on the surgical ward after being commenced on linezolid (a weak monoamine oxidase inhibitor and antibiotic) to treat osteomyelitis. Earlier in his admission he had been started on fluoxetine (an SSRI) for depression. Serotonin syndrome was suspected.


The linezolid and fluoxetine were stopped and supportive treatment continued. A CT brain was performed to rule out other causes of his reduced GCS which apart from generalized atrophy was normal. Over the next few days his acidosis, renal failure and liver function tests improved.


Serotonin (5HT) is a monoamine neurotransmitter synthesized in nerve terminals and stored in synaptic vesicles. It is found in the CNS, GI tract, platelets and mast cells. After release into the synaptic cleft it is taken up into the presynaptic membrane or metabolized by monoamine oxidase. The metabolite is excreted in the urine.
It acts on many 5HT receptor subtypes, 14 of which have been identified so far. Its main actions divided into systems are listed below:

  • Modulates descending inhibitory pain pathways
  • Chemoreceptor Trigger Zone
  • Arousal, muscle tone, mood, memory
  • Vasoconstriction
  • Increased vascular permeability
  • Platelet aggregation
  • Bronchoconstriction
  • Water and electrolyte secretion
  • Contractility
Toxicity results from excess agonism of 5HT receptors and the effects are predictable from the actions of serotonin above. It results in a wide spectrum of manifestations which can range from mild to mortal. The cause is typically an interaction of 2 serotinergic drugs (SSRI, TCA, MAOI, methylene blue) but can result from single drug administration in theraputic use or overdose. The diagnosis is clinical based on the diagnositc criteria below.

Sternbach’s criteria
Recent addition or increase in a known serotinergic agent
Absence of other possible aetiologies
No recent addition or increase of a neuroleptic agent
Plus at least 3 of the following:
  • Mental status changes (confusion, hypomania)
  • Agitation
  • Myoclonus
  • Hyperreflexia
  • Diaphoresis
  • Shivering
  • Tremor
  • Diarrhoea
  • Incoordination
  • Fever
Adaptation of Sternbach diagnostic criteria. Diagnosis requires 4 major or 3 major plus 2 minor.

Symptom groupMajorMinor
Altered mood
Hypo or hypertension

Laboratory abnormalities that can occur in severe cases include metabolic acidosis, rhabdomyolysis, raised ALT and creatinine, seizures, renal failure and DIC. Onset is often within 24h of commencement or increased dose of a drug and can even occur within minutes. However in a review of case histories of linezolid causing serotonin toxicity the mean time to onset after starting linezolid was 9.5 days.
The main differential is neuroleptic malignant syndrome which is slower in onset and has a higher mortality. Dopamine agonism produces bradykinesia whereas serotonin agonism produces hyperkinesia.
The condition typically resolves 24-72h after stopping the drug depending on the half lives and metabolites of the responsible drugs. The prognosis is generally good.
Treatment is largely supportive but can include benzodiazepines for agitation and muscle contraction (benzodiazepines improve survival in animal models) and 5HT2A antagonists.

Lessons learnt

This was the first case of serotonin toxicity I have encountered. While I had previously read about the condition, so was aware of it, I did not remember it in detail and it was not in the forefront of my mind. I knew linezolid was a MAOI but I thought it was benign compared to older MAOIs and therefore had minimal interactions with other serotonergic drugs. Linezolid is becoming a relatively common treatment for resistant or difficult to treat staph aureus infections because of its improved tissue penetration compared to vancomycin. SSRIs are very common drugs and in future I will review patients drugs carefully to avoid potential interactions with linezolid. I will also recognize the features of serotonin toxicity more easily having done this review.


Chinniah S, French J, Levy D. Serotonin and anaesthesia. CEACCP, April 2008; 8: 43 - 45.

Boyer E, Shannon M. The Serotonin Syndrome. N Engl J Med 2005; 352(11): 1112-1120.

Morales-Molina JA, Mateu-de Antonio J, Marín-Casino M, Grau S. J Antimicrob Chemother. 2005 Dec;56(6):1176-8. Epub 2005 Oct 13. Linezolid-associated serotonin syndrome: what we can learn from cases reported so far.

Linezolid-associated serotonin syndrome after concomitant treatment with citalopram and mirtazepine in a critically ill bone marrow transplant recipient. J Intensive Care Med. 2005 Nov-Dec; 20(6):351-3.

E.J.C. Dunkley, G.K. Isbister, D. Sibbritt, A.H. Dawson and I.M. Whyte. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Q J Med 2003; 96: 635-642