The Serotonin Syndrome Hunter Area Toxicology Service

The Serotonin SyndromeThe Serotonin Syndrome

Hunter Area Toxicology Service


SerotoninSerotonin

5–hydroxytryptamine or 5–HT Discovered in 1948 Major role in multiple states

– aggression, pain, sleep, appetite– anxiety, depression– migraine, emesis


Serotonin metabolismSerotonin 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


Serotonin actionsSerotonin 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


Serotonin actionsSerotonin actions

– increased gastrointestinal motility direct excitation of smooth muscle and indirect action via

enteric neurons

– contraction of other smooth muscle eg bronchi, uterus


Serotonin rolesSerotonin roles

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


Serotonin rolesSerotonin roles

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


Serotonin receptorsSerotonin 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


5–HT5–HT11

5–HT1A

– limbic system regulation of emotions

– neocortex– hypothalamus– substantia gelatinosa

proprioception

5–HT1B (rat)


5–HT5–HT11

5–HT1D

– autoreceptors inhibitory feedback

– heteroreceptors modulate release

– acetylcholine

– glutamate

– anti–migraine effect of sumatriptan


5–HT5–HT11

5–HT1E

– ? functional role

5–HT1F

– ? functional role– distribution includes CNS, uterus, mesentery– inhibit cAMP– high affinity

sumatriptan, methysergide



5–HT2

– 7 trans–membrane domains– G protein linked– phospholipase C dependant – hallucinogens– subtypes

5–HT2A, 5–HT2B, 5–HT2C


5–HT5–HT22

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


5–HT5–HT22

5–HT2A

– CNS motor behaviour head twitch wet dog shakes sleep regulation nociception neuroexcitation


5–HT5–HT22

5–HT2B (rat)

– stomach fundus

5–HT2C

– CSF production– locomotion– eating disorders– anxiety– migraine


Serotonin receptorsSerotonin 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


5–HT5–HT33

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



5-HT6 (rat)

5-HT7 (rat and human)

– coupled to adenylate cyclase– significance unknown


Serotonin excessSerotonin 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


Sternbach criteriaSternbach criteriaMental status changes (confusion, hypomania)AgitationMyoclonusHyperreflexiaDiaphoresisShiveringTremorDiarrhoeaIncoordinationFever

Diarrhoea


Serotinergic drugsSerotinergic drugs

Serotonin precursors– S–adenyl–L–methionine– L–tryptophan– 5–hydroxytryptophan– dopamine



Serotonin re–uptake inhibitors– citalopram, fluoxetine, fluvoxamine, paroxetine,

sertraline, venlafaxine– clomipramine, imipramine– nefazodone, trazodone– chlorpheniramine– cocaine, dextromethorphan, pentazocine, pethidine



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



Monoamine oxidase inhibitors (MAOIs)– clorgyline, isocarboxazid, nialamide, pargyline,

phenelzine, tranylcypromine– selegiline– furazolidone– procarbazine



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



Miscellaneous/mixed– lithium– lysergic acid diethylamide (LSD)– 3,4–methylenedioxymethamphetamine (MDMA,

ecstasy), methylenedioxyethamphetamine (eve)– propranolol, pindolol


IncidenceIncidence

Over last 10 years 4130 admissions for deliberate self poisoning 267 admissions for serotinergic drug overdose 41 admissions with serotonin syndrome


IncidenceIncidence

0

5

10

15

20

Perc

en

t

87 88 89 90 91 92 93 94 95 96 97

Serotinergic drug Serotonin syndrome


Serotinergic drugs takenSerotinergic drugs takenAll serotinergic drugs

(n=267)Serotonin syndrome

(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%)


Serotinergic drugs (Odds ratios)Serotinergic drugs (Odds ratios)

Single serotinergicdrug

Serotoninsyndrome (n=41)

No serotoninsyndrome (n=226)

Odds ratio(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%) –


Sternbach criteria (%)Sternbach criteria (%)

Sternbach (n=38) Sporer (n=79) HATS (n=41)

Confusion/hypomania 42 45 42Agitation 45 NR 76Myoclonus 34 43 12Hyperreflexia 29 47 81Diaphoresis 26 31 10Shivering 26 21 15Tremor 26 NR 44Diarrhoea 16 10 15Ataxia/incoordination 13 38 15Fever NR 28 44


Frequency of Sternbach criteriaFrequency of Sternbach criteria

05

1015202530354045

Pati

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ts (

%)

)

0 1 2 3 4 5 6 7 8 9 10

Serotinergic drug overdose with signs


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


Frequency of all clinical featuresFrequency of all clinical features

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12

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22

24

Serotinergic drug overdose with signs


Sternbach criteria in HATS (%)Sternbach criteria in HATS (%)

Serotoninsyndrome (n=41)

Serotinergic drug,no SS (n=226)

Other drug(n=3863)

Hyperreflexia 80.5 28.3 8.3Agitation 75.6 5.3 naFever 43.9 5.3 3.0Tremor 43.9 2.2 naConfusion/hypomania 41.5 1.8 5.5Diarrhoea 14.6 10.2 naAtaxia/incoordination 14.6 3.5 naShivering 14.6 0.9 naMyoclonus 12.2 0.4 0.6Diaphoresis 9.8 0.4 na


Sternbach criteria (Odds ratio)Sternbach criteria (Odds ratio)Serotonin

syndrome vs no SSSerotinergic drug

vs other drug

Hyperreflexia 10.4 (4.6–23.8) 6.2 (4.7–8.2)Agitation 55.3 (22.0–138.7) naFever 14.0 (6.0–32.6) 2.9 (1.8–4.7)Tremor 34.6 (11.7–101.9) naConfusion/hypomania 39.3 (12.2–126.4) 1.5 (0.9–2.3)Diarrhoea 1.5 (0.6–4.2) naAtaxia/incoordination 4.7 (1.5–14.3) naShivering 19.2 (3.7–99.0) naMyoclonus 31.3 (3.5–275.4) 3.8 (1.5–9.5)Diaphoresis 28.8 (3.1–264.4) na


Other clinical features in HATS (%)Other clinical features in HATS (%)Serotonin syndrome

(n=41)Serotinergic drug,

no SS (n=226)Other drug(n=3863)

Inducible clonus 56.1 3.1 naTachycardia 51.2 23.9 30.8Mydriasis 39.0 29.2 13.9Spontaneous clonus 29.3 2.7 naHypertonia/rigidity 24.4 3.1 1.8Coma 19.5 8.4 9.5Ocular clonus/oscillations 19.5 1.8 naNystagmus 12.2 3.5 6.6Rhabdomyolysis 4.9 0 1.1Akathisia 2.4 0.4 naSeizures 2.4 1.4 2.3Lacrimation 0 0 naOculogyric crisis 0 0.4 naOpisthotonus 0 0 na


Other clinical features (Odds ratio)Other clinical features (Odds ratio)Serotonin syndrome

vs no SSSerotinergic drug

vs other drug

Inducible clonus 40.0 (25.1–105.8) naTachycardia 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) naHypertonia/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) naNystagmus 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) naSeizures 1.9 (0.2–18.3) 0.7 (0.2–1.8)Lacrimation – naOculogyric crisis – naOpisthotonus – na


Major featuresMajor featuresAgitation 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)


Minor featuresMinor 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–)


Non–featuresNon–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 –


Suggested criteriaSuggested criteria

Agitation/confusion/hypomania Clonus (inducible/spontaneous/ocular) Tremor/shivering/myoclonus Diaphoresis Fever Hyperreflexia Hypertonia/rigidity


Suggested criteria Suggested criteria

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0 1 2 3 4 5 6 7

Serotinergic drug with serotonin syndrome

Serotinergic drug without serotonin syndrome


Signs suggestive of serotinergic Signs suggestive of serotinergic drug overdosedrug 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)


Treatment of serotonin syndromeTreatment of serotonin syndrome

Depends on severity Many (if not most) do not require treatment Many would benefit if a safe effective therapy

was available


Severity of serotonin syndromeSeverity 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


Severity of serotonin syndromeSeverity 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


Drugs used to treat serotonin Drugs used to treat serotonin syndromesyndrome

Non–specific blocking agents– methysergide– cyproheptadine

–blockers– propranolol– pindolol



Benzodiazepines– lorazepam– diazepam– clonazepam

Neuroleptics– chlorprothixene– chlorpromazine– haloperidol



Miscellaneous– chlormethiazole– nitroglycerine

Drugs used for neuroleptic malignant syndrome– dantrolene– bromocriptine


5–HT receptors in serotonin 5–HT receptors in serotonin syndromesyndrome

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


Antagonist potenciesAntagonist 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)


TherapyTherapy

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


TherapyTherapy 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

Documents

The Serotonin Syndrome Hunter Area Toxicology Service