Question 1(p.2)

Describe the physiological basis of the effects seen in the serotonin  syndrome (80% marks). List the classes of drugs that may cause the serotonin syndrome (20% marks).

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College Answer

For a good answer candidates were expected to mention the role of serotonin (5 
hydroxytryptamine) is an important neurotransmitter, a local hormone in the GIT and 
involved in platelet reactions. It is formed from tryptophan and metabolised by MAO 
(thus the potential effect of a combination SSRI with MAO inhibitor, or concurrent 
use of several serotonin affecting drugs). Typically the serotonin syndrome is a 
predictable effect of increased CNS levels of serotonin with a consequence of hyper 
reflexia, tremor, clonus, skeletal muscle contraction and hyperthermia (but in 
serotonin syndrome these effects are probably CNS mediated), hypertension, and 
The expected list of drugs included the SSRI’s themselves, combination of SSRI’s 
and MAOI’s, antidepressants (2nd generation [e.g Venlafaxine]) ,Tramadol (blocks 
serotonin re-uptake), pethidine, fentanyl, ondansetron, sumatriptan (5-HT1 agonist).
Syllabus: M3
References: Basic and Clinical Pharmacology, Katsung pg 264 – 269


This appears to be a question none of the trainees could answer. This makes perfect sense, as the international scientific community is still unclear on this, and Francescageli et al, writing in 2019, did not report any clearly established molecular mechanisms. The college answer  itself is also weirdly lacking in detail, offering irrelevant factoids like "important neurotransmitter, a local hormone in the GIT and involved in platelet reactions" and listing some clinical features but not explaining them other than to say that "in serotonin syndrome these effects are probably CNS mediated". This disappointing performance by both the trainees and the examiners highlights one important point which should be comforting to the trainee preparing for the CICM primaries: neither the candidate nor the faculty knew how to explain serotonin syndrome physiologically, and both groups are now successful intensivists, i.e. this does not seem to have been much of an impediment to any of their careers.

Also, ondansetron is a 5-HT3 antagonist, and therefore should not be expected to produce serotonin syndrome (Rojas-Fernandez, 2014)

Anyway. If one were trying to explain serotonin syndrome in ten minutes or less, one would be forced to take some shortcuts. One would certainly not be able to reproduce the spectacular table of serotonin syndrome causative agents from  Francescangeli et al, 2019. Instead a shorter leaner version of the same thing is offered here. Wherever one sees a confident statement to the tune of "...and this receptor subtype is responsible for this effect", the source for the information is Deka et al, 2020. 

  • Specific serotonin receptors are involved:
    • 5-HT1A and 5-HT2A receptors are the most responsible
  • Stimulation of these receptors exceeds safe thresholds when:
    • Serotonin synthesis is increased (eg. dietary tryptophan, soft cheese etc.)
    • Serotonin release is enhanced (pethidine, dextromethorphan)
    • Serotonin reuptake is inhibited (SSRIs, MDMA)
    • Serotonin metabolism is impaired (MAOIs, linezolid, methylene blue)
    • Serotonin receptor agonists are present (eg. sumatriptan, LSD, fentanyl)
    • Or any combination of the above.
  • The result of this hyperstimulation is:
    • Altered function of other neurotransmitter systems for which serotonin is a neuromodulator (usually, an inhibitory influence)
    • For the majority of these, serotonin excess leads to the disinhibition of presynaptic release of these mediators
    • They include noradrenaline, acetylcholine, dopamine and glutamate
  • Clinically, this manifests as:
    • Confusion (possibly due to the effect on cholinergic neurotransmission)
    • Pupillary dilatation (a 5-HT1A effect)
    • Hypertension (a 5-HT2A effect)
    • Hyperthermia (a 5-HT2A effect)
    • Diarrhoea (the effect of increased serotonin activity on the GIT)
    • Muscle rigidity and clonus (probably related to dopamine disinhibition)


Francescangeli, James, et al. "The serotonin syndrome: from molecular mechanisms to clinical practice." International journal of molecular sciences 20.9 (2019): 2288.

Simon, Leslie V., and Michael Keenaghan. "Serotonin syndrome." StatPearls [Internet] (2021).

Deka, Satyendra, et al. "Pharmacology of Serotonin and Its Receptors." Frontiers in Pharmacology of Neurotransmitters. Springer, Singapore, 2020. 183-212.

Rojas-Fernandez, Carlos H. "Can 5-HT 3 Antagonists Really Contribute to Serotonin Toxicity? A Call for Clarity and Pharmacological Law and Order." Drugs-real world outcomes 1.1 (2014): 3-5.

Camilleri, Michael. "Serotonin in the gastrointestinal tract." Current opinion in endocrinology, diabetes, and obesity 16.1 (2009): 53.