The Serotonin Syndrome

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 Serotonin
 5–hydroxytryptamine or 5–HT
 Discovered in 1948
 Major role in multiple states
– aggression, pain, sleep, appetite
– anxiety, depression
– migraine, emesis

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 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
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 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

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 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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 Serotonin roles
 Peripheral
– peristalsis
– vomiting
– platelet aggregation and haemostasis
– inflammatory mediator
– sensitisation of nociceptors
– microvascular control

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 Serotonin roles
 Central
– control of appetite
– sleep
– mood
– hallucinations
– stereotyped behaviour
– pain perception
– vomiting
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 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

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 5–HT1
 5–HT1A
– limbic system
 regulation of emotions
– neocortex
– hypothalamus
– substantia gelatinosa
 proprioception
 5–HT1B (rat)
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 5–HT1
 5–HT1D
– autoreceptors
 inhibitory feedback
– heteroreceptors
 modulate release
– acetylcholine
– glutamate
– anti–migraine effect of sumatriptan

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 5–HT1
 5–HT1E
– ? functional role
 5–HT1F
– ? functional role
– distribution includes CNS, uterus, mesentery
– inhibit cAMP
– high affinity
 sumatriptan, methysergide
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 Serotonin receptors
 5–HT2
– 7 trans–membrane domains
– G protein linked
– phospholipase C dependant
– hallucinogens
– subtypes
 5–HT2A, 5–HT2B, 5–HT2C

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 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

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 5–HT2
 5–HT2A
– CNS
 motor behaviour
 head twitch

 wet dog shakes

 sleep regulation

 nociception

 neuroexcitation

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 5–HT2
 5–HT2B (rat)
– stomach fundus
 5–HT2C
– CSF production
– locomotion
– eating disorders
– anxiety
– migraine
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 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
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 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
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 Serotonin receptors
 5-HT6 (rat)
 5-HT7 (rat and human)
– coupled to adenylate cyclase
– significance unknown

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 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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 Sternbach criteria
Mental status changes (confusion, hypomania)
Agitation
Myoclonus
Hyperreflexia
Diaphoresis
Shivering
Tremor
Diarrhoea
Incoordination
Fever
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Diarrhoea
 Serotinergic drugs
 Serotonin precursors
– S–adenyl–L–methionine
– L–tryptophan
– 5–hydroxytryptophan
– dopamine

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 Serotinergic drugs
 Serotonin re–uptake inhibitors
– citalopram, fluoxetine, fluvoxamine, paroxetine,
sertraline, venlafaxine
– clomipramine, imipramine
– nefazodone, trazodone
– chlorpheniramine
– cocaine, dextromethorphan, pentazocine, pethidine

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 Serotinergic drugs
 Serotonin agonists
– fenfluramine, p–chloramphetamine
– bromocriptine, dihydroergotamine, gepirone
– sumatriptan
– buspirone, ipsapirone
– eltoprazin, quipazine

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 Serotinergic drugs
 Monoamine oxidase inhibitors (MAOIs)
– clorgyline, isocarboxazid, nialamide, pargyline,
phenelzine, tranylcypromine
– selegiline
– furazolidone
– procarbazine

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 Serotinergic drugs
 Reversible inhibitors of MAO (RIMAs)
– brofaramine
– befloxatone, toloxatone
– moclobemide

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 Serotinergic drugs
 Miscellaneous/mixed
– lithium
– lysergic acid diethylamide (LSD)
– 3,4–methylenedioxymethamphetamine (MDMA,
ecstasy), methylenedioxyethamphetamine (eve)
– propranolol, pindolol

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 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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 Incidence
Serotinergic drug Serotonin syndrome

20

15
Percent

10

0
87 88 89 90 91 92 93 94 95 96 97

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 Serotinergic drugs taken
All serotinergic drugs Serotonin syndrome
(n=267) (n=41)

Paroxetine 58 (22%) 11 (27%)

Moclobemide 56 (21%) 10 (24%)
Sertraline 51 (19%) 15 (37%)
Fluoxetine 43 (16%) 3 (7%)
Clomipramine 41 (15%) 1 (2%)
Phenelzine 14 (5%) 3 (7%)
Lithium 11 (4%) 1 (2%)
Tranylcypromine 7 (3%) 3 (7%)
Imipramine 2 (1%) 2 (5%)
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 Serotinergic drugs (Odds ratios)
Single serotinergic Serotonin No serotonin Odds ratio
drug syndrome (n=41) syndrome (n=226) (95% CI)

Sertraline 11 (26.8%) 33 (14.6%) 2.2 (0.98–4.7)

Paroxetine 9 (22.0%) 44 (19.5%) 1.2 (0.5–2.6)
Moclobemide 6 (14.6%) 43 (19.0%) 0.7 (0.3–1.9)
Fluoxetine 2 (4.9%) 38 (16.8%) 0.3 (0.1–1.1)
Phenelzine 2 (4.9%) 9 (4.0%) 1.2 (0.3–6.0)
Tranylcypromine 1 (2.4%) 3 (1.3%) 1.9 (0.2–18.4)
Lithium 1 (2.4%) 1 (0.4%) 5.7 (0.3–92.2)
Clomipramine 0 39 (17.3%) 0.0 (0.0–0.4)
Imipramine 0 0 Undefined

Total 32 (78.0%) 210 (92.9%) –

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

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 Frequency of Sternbach criteria
Serotinergic drug overdose with signs

45
40
35
Patients (%) )

30
25
20
15
10
5
0
0 1 2 3 4 5 6 7 8 9 10

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 Other clinical features (%)
Inducible clonus 56
Tachycardia 51
Mydriasis 39
Spontaneous clonus 29
Hypertonia/rigidity 24
Coma 20
Ocular clonus/oscillations 20
Nystagmus 12
Rhabdomyolysis 5
Akathisia 2
Seizures 2
Lacrimation 0
Oculogyric crisis 0
Opisthotonus 0
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 Frequency of all clinical features
Serotinergic drug overdose with signs

30

25
Patients (%) )

20

15

10

0
10

12

14

16

18

20

22

24
0

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

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

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Other clinical features in HATS (%)
Serotonin syndrome Serotinergic drug, Other drug
(n=41) no SS (n=226) (n=3863)

Inducible clonus 56.1 3.1 na

Tachycardia 51.2 23.9 30.8
Mydriasis 39.0 29.2 13.9
Spontaneous clonus 29.3 2.7 na
Hypertonia/rigidity 24.4 3.1 1.8
Coma 19.5 8.4 9.5
Ocular clonus/oscillations 19.5 1.8 na
Nystagmus 12.2 3.5 6.6
Rhabdomyolysis 4.9 0 1.1
Akathisia 2.4 0.4 na
Seizures 2.4 1.4 2.3
Lacrimation 0 0 na
Oculogyric crisis 0 0.4 na
Opisthotonus 0 0 na

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Other clinical features (Odds ratio)
Serotonin syndrome Serotinergic drug
vs no SS vs other drug

Inducible clonus 40.0 (25.1–105.8) na

Tachycardia 3.3 (1.7–6.6) 0.9 (0.7–1.2)
Mydriasis 1.6 (0.8–3.1) 2.7 (2.1–3.6)
Spontaneous clonus 15.7 (5.3–43.5) na
Hypertonia/rigidity 10.1 (3.6–28.5) 3.8 (2.2–6.6)
Coma 2.6 (1.1–6.5) 1.1 (0.7–1.6)
Ocular clonus/oscillations 13.5 (3.8–47.2) na
Nystagmus 3.8 (1.2–12.2) 0.7 (0.4–1.3)
Rhabdomyolysis  (1.6–) 0.7 (0.2–2.7)
Akathisia 5.6 (0.3–91.8) na
Seizures 1.9 (0.2–18.3) 0.7 (0.2–1.8)
Lacrimation – na
Oculogyric crisis – na
Opisthotonus – na
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 Major features
Agitation 55.3 (22.0–138.7)
Inducible clonus 40.0 (25.1–105.8)
Confusion/hypomania 39.3 (12.2–126.4)
Tremor 34.6 (11.7–101.9)
Myoclonus 31.3 (3.5–275.4)
Diaphoresis 28.8 (3.1–264.4)
Shivering 19.2 (3.7–99.0)
Spontaneous clonus 15.7 (5.3–43.5)
Fever 14.0 (6.0–32.6)
Ocular clonus/oscillations 13.5 (3.8–47.2)
Hyperreflexia 10.4 (4.6–23.8)
Hypertonia/rigidity 10.1 (3.6–28.5)
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 Minor features

Ataxia/incoordination 4.7 (1.5–14.3)

Nystagmus 3.8 (1.2–12.2)
Tachycardia 3.3 (1.7–6.6)
Coma 2.6 (1.1–6.5)
Rhabdomyolysis  (1.6–)

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 Non–features
Akathisia 5.6 (0.3–91.8)
Seizures 1.9 (0.2–18.3)
Diarrhoea 1.5 (0.6–4.2)
Mydriasis 1.6 (0.8–3.1)
Lacrimation –
Oculogyric crisis –
Opisthotonus –
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 Suggested criteria
 Agitation/confusion/hypomania
 Clonus (inducible/spontaneous/ocular)
 Tremor/shivering/myoclonus
 Diaphoresis
 Fever
 Hyperreflexia
 Hypertonia/rigidity
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 Suggested criteria
Serotinergic drug with serotonin syndrome
Serotinergic drug without serotonin syndrome

60
50
Patients (%) )

40
30
20
10
0
0 1 2 3 4 5 6 7

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

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 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

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 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
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 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

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 Drugs used to treat serotonin
syndrome
 Non–specific blocking agents
– methysergide
– cyproheptadine
 –blockers
– propranolol
– pindolol

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 Drugs used to treat serotonin
syndrome
 Benzodiazepines
– lorazepam
– diazepam
– clonazepam
 Neuroleptics
– chlorprothixene
– chlorpromazine
– haloperidol
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 Drugs used to treat serotonin
syndrome
 Miscellaneous
– chlormethiazole
– nitroglycerine
 Drugs used for neuroleptic malignant syndrome
– dantrolene
– bromocriptine

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 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
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 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)

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 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

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 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

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