1. The Serotonin Syndrome
Hunter Area Toxicology Service

2. Serotonin 5–hydroxytryptamine or 5–HT Discovered in 1948
Major role in multiple states
aggression, pain, sleep, appetite
anxiety, depression
migraine, emesis
Hunter Area Toxicology Service

3. Serotonin metabolism Dietary tryptophan
converted to 5–hydroxy– tryptophan by tryptophan hydroxylase
then to 5-HT by a non–specific decarboxylase
Specific transport system into cells
Degradation
mainly monoamine oxidase (MAO–A > MAO–B)
5–hydroxyindoleacetic acid (5-HIAA) in urine
Hunter Area Toxicology Service

4. Serotonin actions Serotonin causes the following effects
excitation/inhibition of CNS neurons
stimulation of peripheral nociceptive nerve endings
vascular effects
constriction (direct and via sympathetic innervation)
dilatation (endothelium dependent)
platelet aggregation
increased microvascular permeability
Hunter Area Toxicology Service

5. Serotonin actions increased gastrointestinal motility
direct excitation of smooth muscle and indirect action via enteric neurons
contraction of other smooth muscle eg bronchi, uterus
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6. Serotonin roles Peripheral peristalsis vomiting
platelet aggregation and haemostasis
inflammatory mediator
sensitisation of nociceptors
microvascular control
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7. Serotonin roles Central control of appetite sleep mood hallucinations
stereotyped behaviour
pain perception
vomiting
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8. Serotonin receptors 5–HT1 7 trans–membrane domains G protein linked
cAMP dependant
anxiolytic and antidepressant
subtypes
5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F
Hunter Area Toxicology Service

9. 5–HT1 5–HT1A 5–HT1B (rat) limbic system neocortex hypothalamus
regulation of emotions
neocortex
hypothalamus
substantia gelatinosa
proprioception
5–HT1B (rat)
Hunter Area Toxicology Service

10. 5–HT1 5–HT1D autoreceptors heteroreceptors
inhibitory feedback
heteroreceptors
modulate release
acetylcholine
glutamate
anti–migraine effect of sumatriptan
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11. 5–HT1 5–HT1E 5–HT1F ? functional role
distribution includes CNS, uterus, mesentery
inhibit cAMP
high affinity
sumatriptan, methysergide
Hunter Area Toxicology Service

12. Serotonin receptors 5–HT2 7 trans–membrane domains G protein linked
phospholipase C dependant
hallucinogens
subtypes
5–HT2A, 5–HT2B, 5–HT2C
Hunter Area Toxicology Service

13. 5–HT2
5–HT2A
Periphery
contraction of vascular/non–vascular smooth muscle
platelet aggregation
increased capillary permeability
modulation of the release of other neurotransmitters and hormones
ACh, adrenaline, dopamine, excitatory amino acids, vasopressin
Hunter Area Toxicology Service

14. 5–HT2 5–HT2A CNS motor behaviour head twitch wet dog shakes
sleep regulation
nociception
neuroexcitation
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15. 5–HT2 5–HT2B (rat) 5–HT2C stomach fundus CSF production locomotion
eating disorders
anxiety
migraine
Hunter Area Toxicology Service

16. Serotonin receptors 5–HT3 5-HT4 (rat) 5-HT5 (rat)
ligand gated cation channels
5-HT4 (rat)
coupled to adenylate cyclase
5-HT5 (rat)
subtypes
5–HT5A, 5–HT5B
Hunter Area Toxicology Service

17. 5–HT3 Peripheral Central
located exclusively on neurons and mediate neurotransmitter release - parasympathetic, sympathetic, sensory and enteric
cardiac inhibition/activation, pain, initiation of the vomiting reflex
Central
facilitate dopamine and 5–HT release, inhibit ACh and noradrenaline release
anxiety, depression, memory, tolerance and dependence
Hunter Area Toxicology Service

18. Serotonin receptors 5-HT6 (rat) 5-HT7 (rat and human)
coupled to adenylate cyclase
significance unknown
Hunter Area Toxicology Service

19. Serotonin excess
Oates (1960) suggested excess serotonin as the cause of symptoms after MAOIs with tryptophan
Animal work (1980s) attributed MAOI/pethidine interaction to excess serotonin
Insel (1982) often quoted as describing the serotonin syndrome
Sternbach (1991) developed diagnostic criteria for serotonin syndrome
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20. Sternbach criteria
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21. Serotinergic drugs Serotonin precursors S–adenyl–L–methionine
L–tryptophan
5–hydroxytryptophan
dopamine
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22. Serotinergic drugs Serotonin re–uptake inhibitors
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine
clomipramine, imipramine
nefazodone, trazodone
chlorpheniramine
cocaine, dextromethorphan, pentazocine, pethidine
Hunter Area Toxicology Service

23. Serotinergic drugs Serotonin agonists fenfluramine, p–chloramphetamine
bromocriptine, dihydroergotamine, gepirone
sumatriptan
buspirone, ipsapirone
eltoprazin, quipazine
Hunter Area Toxicology Service

24. Serotinergic drugs Monoamine oxidase inhibitors (MAOIs)
clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine
selegiline
furazolidone
procarbazine
Hunter Area Toxicology Service

25. Serotinergic drugs Reversible inhibitors of MAO (RIMAs) brofaramine
befloxatone, toloxatone
moclobemide
Hunter Area Toxicology Service

26. Serotinergic drugs Miscellaneous/mixed lithium
lysergic acid diethylamide (LSD)
3,4–methylenedioxymethamphetamine (MDMA, ecstasy), methylenedioxyethamphetamine (eve)
propranolol, pindolol
Hunter Area Toxicology Service

27. Incidence Over last 10 years
4130 admissions for deliberate self poisoning
267 admissions for serotinergic drug overdose
41 admissions with serotonin syndrome
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28. Incidence
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29. Serotinergic drugs taken
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30. Serotinergic drugs (Odds ratios)
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31. Sternbach criteria (%)
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32. Frequency of Sternbach criteria
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33. Other clinical features (%)
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34. Frequency of all clinical features
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35. Sternbach criteria in HATS (%)
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36. Sternbach criteria (Odds ratio)
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37. Other clinical features in HATS (%)
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38. Other clinical features (Odds ratio)
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39. Major features
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40. Minor features
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41. Non–features
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42. Suggested criteria Agitation/confusion/hypomania
Clonus (inducible/spontaneous/ocular)
Tremor/shivering/myoclonus
Diaphoresis
Fever
Hyperreflexia
Hypertonia/rigidity
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43. Suggested criteria
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44. Signs suggestive of serotinergic drug overdose
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45. Treatment of serotonin syndrome
Depends on severity
Many (if not most) do not require treatment
Many would benefit if a safe effective therapy was available
Hunter Area Toxicology Service

46. Severity of serotonin syndrome
Mild
three symptoms are present but they are not progressive and not significantly affecting the patient
no action is required
Moderate
four or more definite symptoms that between them cause significant impairment of functioning or distress to the patient
specific therapy may be indicated
Hunter Area Toxicology Service

47. Severity of serotonin syndrome
Severe
most symptoms are present and significant impairment of consciousness or functioning is also present
often progression of symptoms, particularly fever
rapidly rising temperature (>39oC) is an indication for urgent intervention
specific therapy may be very beneficial
Hunter Area Toxicology Service

48. Drugs used to treat serotonin syndrome
Non–specific blocking agents
methysergide
cyproheptadine
–blockers
propranolol
pindolol
Hunter Area Toxicology Service

49. Drugs used to treat serotonin syndrome
Benzodiazepines
lorazepam
diazepam
clonazepam
Neuroleptics
chlorprothixene
chlorpromazine
haloperidol
Hunter Area Toxicology Service

50. Drugs used to treat serotonin syndrome
Miscellaneous
chlormethiazole
nitroglycerine
Drugs used for neuroleptic malignant syndrome
dantrolene
bromocriptine
Hunter Area Toxicology Service

51. 5–HT receptors in serotonin syndrome
Originally thought to be 5–HT1 mediated (5–HT1A)
blocked in animals by non–specific 5–HT blockers
methysergide
cyproheptadine
not blocked by ketanserin (5–HT2 blocker)
More recent evidence implicates 5–HT2
failure of propranolol (5–HT1A blocker) in several cases
cyproheptadine more potent at 5–HT2 than 5–HT1
Hunter Area Toxicology Service

52. Antagonist potencies Ki values (5–HT2) Ki values (5–HT1)
chlorprothixene (0.43 nM) > chlorpromazine > cyproheptadine > haloperidol (36 nM)
limited experience suggests haloperidol ineffective
Ki values (5–HT1)
chlorprothixene (230 nM) > haloperidol > chlorpromazine > cyproheptadine (3200 nM)
Hunter Area Toxicology Service

53. Therapy Moderate when oral therapy suitable
cyproheptadine 8 mg stat then 4 mg q4–6h
when oral therapy unsuitable or cyproheptadine fails
chlorpromazine 50 mg IMI/IVI stat then up to 50 mg orally or IMI/IVI q6h
Hunter Area Toxicology Service

54. Therapy Severe when symptoms are not progressive and fever < 39oC
chlorpromazine 50–100 mg IMI/IVI stat then 50–100 mg orally or IMI/IVI q6h
when symptoms are progressive and fever < 39oC
chlorpromazine 100–400 mg IMI/IVI over first two hours
when symptoms are progressive and fever > 39oC
barbiturate anaesthesia, muscle relaxation ± active cooling
Hunter Area Toxicology Service