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
Hunter Area Toxicology Service

6. Serotonin roles
 Peripheral
–
–
–
–
–
–
peristalsis
vomiting
platelet aggregation and haemostasis
inflammatory mediator
sensitisation of nociceptors
microvascular control
Hunter Area Toxicology Service

7. Serotonin roles
 Central
–
–
–
–
–
–
–
control of appetite
sleep
mood
hallucinations
stereotyped behaviour
pain perception
vomiting
Hunter Area Toxicology Service

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

10. 5–HT1
 5–HT1D
– autoreceptors
inhibitory feedback
– heteroreceptors
modulate release
– acetylcholine
– glutamate
– anti–migraine effect of sumatriptan
Hunter Area Toxicology Service

11. 5–HT1
 5–HT1E
– ? functional role
 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
Hunter Area Toxicology Service

15. 5–HT2
 5–HT2B (rat)
– stomach fundus
 5–HT2C
–
–
–
–
–
CSF production
locomotion
eating disorders
anxiety
migraine
Hunter Area Toxicology Service

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

17. 5–HT3
 Peripheral
– 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
Hunter Area Toxicology Service

20. Sternbach criteria
Mental status changes (confusion, hypomania)
Agitation
Myoclonus
Hyperreflexia
Diaphoresis
Shivering
Tremor
Diarrhoea
Incoordination
Fever
Hunter Area Toxicology Service
Diar
rhoea

21. Serotinergic drugs
 Serotonin precursors
–
–
–
–
S–adenyl–L–methionine
L–tryptophan
5–hydroxytryptophan
dopamine
Hunter Area Toxicology Service

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
Hunter Area Toxicology Service

28. Incidence
Serotinergic drug
Serotonin syndrome
20
Percent
15
10
5
0
87
88
Hunter Area Toxicology Service
89
90
91
92
93
94
95
96
97

29. Serotinergic drugs taken
All serotinergic drugs
(n=267)
Paroxetine
Moclobemide
Sertraline
Fluoxetine
Clomipramine
Phenelzine
Lithium
Tranylcypromine
Imipramine
Hunter Area Toxicology Service
Serotonin syndrome
(n=41)
58 (22%)
56 (21%)
51 (19%)
43 (16%)
41 (15%)
14 (5%)
11 (4%)
7 (3%)
2 (1%)
11 (27%)
10 (24%)
15 (37%)
3 (7%)
1 (2%)
3 (7%)
1 (2%)
3 (7%)
2 (5%)

30. Serotinergic drugs (Odds ratios)
Single serotinergic
drug
Serotonin
syndrome (n=41)
No serotonin
syndrome (n=226)
Odds ratio
(95% CI)
Sertraline
Paroxetine
Moclobemide
Fluoxetine
Phenelzine
Tranylcypromine
Lithium
Clomipramine
Imipramine
11 (26.8%)
9 (22.0%)
6 (14.6%)
2 (4.9%)
2 (4.9%)
1 (2.4%)
1 (2.4%)
0
0
33 (14.6%)
44 (19.5%)
43 (19.0%)
38 (16.8%)
9 (4.0%)
3 (1.3%)
1 (0.4%)
39 (17.3%)
0
2.2 (0.98–4.7)
1.2 (0.5–2.6)
0.7 (0.3–1.9)
0.3 (0.1–1.1)
1.2 (0.3–6.0)
1.9 (0.2–18.4)
5.7 (0.3–92.2)
0.0 (0.0–0.4)
Undefined
Total
32 (78.0%)
210 (92.9%)
–
Hunter Area Toxicology Service

31. Sternbach criteria (%)
Sternbach (n=38)
Confusion/hypomania
Agitation
Myoclonus
Hyperreflexia
Diaphoresis
Shivering
Tremor
Diarrhoea
Ataxia/incoordination
Fever
Hunter Area Toxicology Service
42
45
34
29
26
26
26
16
13
NR
Sporer (n=79)
45
NR
43
47
31
21
NR
10
38
28
HATS (n=41)
42
76
12
81
10
15
44
15
15
44

32. Frequency of Sternbach criteria
Patients (%) )
Serotinergic drug overdose with signs
45
40
35
30
25
20
15
10
5
0
0
1
Hunter Area Toxicology Service
2
3
4
5
6
7
8
9
10

33. Other clinical features (%)
Inducible clonus
Tachycardia
Mydriasis
Spontaneous clonus
Hypertonia/rigidity
Coma
Ocular clonus/oscillations
Nystagmus
Rhabdomyolysis
Akathisia
Seizures
Lacrimation
Oculogyric crisis
Opisthotonus
Hunter Area Toxicology Service
56
51
39
29
24
20
20
12
5
2
2
0
0
0

34. Frequency of all clinical features
Serotinergic drug overdose with signs
Patients (%) )
30
25
20
15
10
Hunter Area Toxicology Service
24
22
20
18
16
14
12
10
8
6
4
2
0
0
5

35. Sternbach criteria in HATS (%)
Serotonin
syndrome (n=41)
Hyperreflexia
Agitation
Fever
Tremor
Confusion/hypomania
Diarrhoea
Ataxia/incoordination
Shivering
Myoclonus
Diaphoresis
Hunter Area Toxicology Service
80.5
75.6
43.9
43.9
41.5
14.6
14.6
14.6
12.2
9.8
Serotinergic drug, Other drug
no SS (n=226)
(n=3863)
28.3
5.3
5.3
2.2
1.8
10.2
3.5
0.9
0.4
0.4
8.3
na
3.0
na
5.5
na
na
na
0.6
na

36. Sternbach criteria (Odds ratio)
Serotonin
syndrome vs no SS
Hyperreflexia
Agitation
Fever
Tremor
Confusion/hypomania
Diarrhoea
Ataxia/incoordination
Shivering
Myoclonus
Diaphoresis
Hunter Area Toxicology Service
Serotinergic drug
vs other drug
10.4 (4.6–23.8)
55.3 (22.0–138.7)
14.0 (6.0–32.6)
34.6 (11.7–101.9)
39.3 (12.2–126.4)
1.5 (0.6–4.2)
4.7 (1.5–14.3)
19.2 (3.7–99.0)
31.3 (3.5–275.4)
28.8 (3.1–264.4)
6.2 (4.7–8.2)
na
2.9 (1.8–4.7)
na
1.5 (0.9–2.3)
na
na
na
3.8 (1.5–9.5)
na

37. Other clinical features in HATS (%)
Serotonin syndrome
(n=41)
Inducible clonus
Tachycardia
Mydriasis
Spontaneous clonus
Hypertonia/rigidity
Coma
Ocular clonus/oscillations
Nystagmus
Rhabdomyolysis
Akathisia
Seizures
Lacrimation
Oculogyric crisis
Opisthotonus
Hunter Area Toxicology Service
Serotinergic drug,
no SS (n=226)
Other drug
(n=3863)
56.1
51.2
39.0
29.3
24.4
19.5
19.5
12.2
4.9
2.4
2.4
0
0
0
3.1
23.9
29.2
2.7
3.1
8.4
1.8
3.5
0
0.4
1.4
0
0.4
0
na
30.8
13.9
na
1.8
9.5
na
6.6
1.1
na
2.3
na
na
na

38. Other clinical features (Odds ratio)
Serotonin syndrome
vs no SS
Inducible clonus
Tachycardia
Mydriasis
Spontaneous clonus
Hypertonia/rigidity
Coma
Ocular clonus/oscillations
Nystagmus
Rhabdomyolysis
Akathisia
Seizures
Lacrimation
Oculogyric crisis
Opisthotonus
Hunter Area Toxicology Service
Serotinergic drug
vs other drug
40.0 (25.1–105.8)
3.3 (1.7–6.6)
1.6 (0.8–3.1)
15.7 (5.3–43.5)
10.1 (3.6–28.5)
2.6 (1.1–6.5)
13.5 (3.8–47.2)
3.8 (1.2–12.2)
)
∞(1.6–∞
5.6 (0.3–91.8)
1.9 (0.2–18.3)
–
–
–
na
0.9 (0.7–1.2)
2.7 (2.1–3.6)
na
3.8 (2.2–6.6)
1.1 (0.7–1.6)
na
0.7 (0.4–1.3)
0.7 (0.2–2.7)
na
0.7 (0.2–1.8)
na
na
na

39. Major features
Agitation
Inducible clonus
Confusion/hypomania
Tremor
Myoclonus
Diaphoresis
Shivering
Spontaneous clonus
Fever
Ocular clonus/oscillations
Hyperreflexia
Hypertonia/rigidity
Hunter Area Toxicology Service
55.3 (22.0–138.7)
40.0 (25.1–105.8)
39.3 (12.2–126.4)
34.6 (11.7–101.9)
31.3 (3.5–275.4)
28.8 (3.1–264.4)
19.2 (3.7–99.0)
15.7 (5.3–43.5)
14.0 (6.0–32.6)
13.5 (3.8–47.2)
10.4 (4.6–23.8)
10.1 (3.6–28.5)

40. Minor features
Ataxia/incoordination
Nystagmus
Tachycardia
Coma
Rhabdomyolysis
Hunter Area Toxicology Service
4.7 (1.5–14.3)
3.8 (1.2–12.2)
3.3 (1.7–6.6)
2.6 (1.1–6.5)
(1.6–∞
)
∞

41. Non–features
Akathisia
Seizures
Diarrhoea
Mydriasis
Lacrimation
Oculogyric crisis
Opisthotonus
Hunter Area Toxicology Service
5.6 (0.3–91.8)
1.9 (0.2–18.3)
1.5 (0.6–4.2)
1.6 (0.8–3.1)
–
–
–

42. Suggested criteria
 Agitation/confusion/hypomania
 Clonus (inducible/spontaneous/ocular)
 Tremor/shivering/myoclonus
 Diaphoresis
 Fever
 Hyperreflexia
 Hypertonia/rigidity
Hunter Area Toxicology Service

43. Suggested criteria
Serotinergic drug with serotonin syndrome
Serotinergic drug without serotonin syndrome
Patients (%) )
60
50
40
30
20
10
0
0
Hunter Area Toxicology Service
1
2
3
4
5
6
7

44. Signs suggestive of serotinergic
drug overdose
Hyperreflexia
Hypertonia/rigidity
Myoclonus
Fever
Mydriasis
Hunter Area Toxicology Service
6.2 (4.7–8.2)
3.8 (2.2–6.6)
3.8 (1.5–9.5)
2.9 (1.8–4.7)
2.7 (2.1–3.6)

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
 β–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–HT 2
– 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)
– 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
chlorpromazine 100–400 mg IMI/IVI over first two hours
Hunter Area Toxicology Service