The Serotonin Syndrome

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The Serotonin Syndrome

• Hunter Area Toxicology Service

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Serotonin

• 5hydroxytryptamine or 5HT
• 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 5hydroxy tryptophan by tryptophan
  hydroxylase
• then to 5-HT by a nonspecific decarboxylase
• Specific transport system into cells
• Degradation
• mainly monoamine oxidase (MAOA gt MAOB)
• 5hydroxyindoleacetic 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

• 5HT1
• 7 transmembrane domains
• G protein linked
• cAMP dependant
• anxiolytic and antidepressant
• subtypes
• 5HT1A, 5HT1B, 5HT1D, 5HT1E, 5HT1F

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5HT1

• 5HT1A
• limbic system
• regulation of emotions
• neocortex
• hypothalamus
• substantia gelatinosa
• proprioception
• 5HT1B (rat)

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5HT1

• 5HT1D
• autoreceptors
• inhibitory feedback
• heteroreceptors
• modulate release
• acetylcholine
• glutamate
• antimigraine effect of sumatriptan

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5HT1

• 5HT1E
• ? functional role
• 5HT1F
• ? functional role
• distribution includes CNS, uterus, mesentery
• inhibit cAMP
• high affinity
• sumatriptan, methysergide

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Serotonin receptors

• 5HT2
• 7 transmembrane domains
• G protein linked
• phospholipase C dependant
• hallucinogens
• subtypes
• 5HT2A, 5HT2B, 5HT2C

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5HT2

• 5HT2A
• Periphery
• contraction of vascular/nonvascular 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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5HT2

• 5HT2A
• CNS
• motor behaviour
• head twitch
• wet dog shakes
• sleep regulation
• nociception
• neuroexcitation

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5HT2

• 5HT2B (rat)
• stomach fundus
• 5HT2C
• CSF production
• locomotion
• eating disorders
• anxiety
• migraine

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Serotonin receptors

• 5HT3
• ligand gated cation channels
• 5-HT4 (rat)
• coupled to adenylate cyclase
• 5-HT5 (rat)
• coupled to adenylate cyclase
• subtypes
• 5HT5A, 5HT5B

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5HT3

• 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 5HT 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
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Serotinergic drugs

• Serotonin precursors
• SadenylLmethionine
• Ltryptophan
• 5hydroxytryptophan
• dopamine

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Serotinergic drugs

• Serotonin reuptake 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, pchloramphetamine
• 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)
• 3,4methylenedioxymethamphetamine (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
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Serotinergic drugs taken
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Serotinergic drugs (Odds ratios)
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Sternbach criteria ()
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Frequency of Sternbach criteria
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Other clinical features ()
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Frequency of all clinical features
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Sternbach criteria in HATS ()
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Sternbach criteria (Odds ratio)
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Other clinical features in HATS ()
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Other clinical features (Odds ratio)
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Major features
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Minor features
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Nonfeatures
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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
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Signs suggestive of serotinergic drug overdose
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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 (gt39oC) is an
  indication for urgent intervention
• specific therapy may be very beneficial

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Drugs used to treat serotonin syndrome

• Nonspecific 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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5HT receptors in serotonin syndrome

• Originally thought to be 5HT1 mediated (5HT1A)
• blocked in animals by nonspecific 5HT blockers
• methysergide
• cyproheptadine
• not blocked by ketanserin (5HT2 blocker)
• More recent evidence implicates 5HT2
• failure of propranolol (5HT1A blocker) in
  several cases
• cyproheptadine more potent at 5HT2 than 5HT1

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Antagonist potencies

• Ki values (5HT2)
• chlorprothixene (0.43 nM) gt chlorpromazine gt
  cyproheptadine gt haloperidol (36 nM)
• limited experience suggests haloperidol
  ineffective
• Ki values (5HT1)
• chlorprothixene (230 nM) gt haloperidol gt
  chlorpromazine gt cyproheptadine (3200 nM)

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Therapy

• Moderate
• when oral therapy suitable
• cyproheptadine 8 mg stat then 4 mg q46h
• 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 lt
  39oC
• chlorpromazine 50100 mg IMI/IVI stat then 50100
  mg orally or IMI/IVI q6h
• when symptoms are progressive and fever lt 39oC
• chlorpromazine 100400 mg IMI/IVI over first two
  hours
• when symptoms are progressive and fever gt 39oC
• barbiturate anaesthesia, muscle relaxation
  active cooling
• chlorpromazine 100400 mg IMI/IVI over first two
  hours