The Serotonin Syndrome Hunter Area Toxicology Service

The Serotonin Syndrome

• Hunter Area Toxicology Service

Serotonin

• 5–hydroxytryptamine or 5–HT

• Discovered in 1948

• Major role in multiple states

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

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

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

Serotonin actions

• increased gastrointestinal motility
• direct excitation of smooth muscle and indirect action via enteric neurons
• contraction of other smooth muscle eg bronchi, uterus

Serotonin roles

• Peripheral

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

Serotonin roles

• Central

• control of appetite
• sleep
• mood
• hallucinations
• stereotyped behaviour
• pain perception
• vomiting

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

5–HT1

• 5–HT1A

• limbic system
• regulation of emotions
• neocortex
• hypothalamus
• substantia gelatinosa
• proprioception

• 5–HT1B (rat)

5–HT1

• 5–HT1D

• autoreceptors
• inhibitory feedback
• heteroreceptors
• modulate release
• acetylcholine
• glutamate
• anti–migraine effect of sumatriptan

5–HT1

• 5–HT1E

• ? functional role

• 5–HT1F

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

Serotonin receptors

• 5–HT2

• 7 trans–membrane domains
• G protein linked
• phospholipase C dependant
• hallucinogens
• subtypes
• 5–HT2A, 5–HT2B, 5–HT2C

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

5–HT2

• 5–HT2A

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

5–HT2

• 5–HT2B (rat)

• stomach fundus

• 5–HT2C

• CSF production
• locomotion
• eating disorders
• anxiety
• migraine

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

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

Serotonin receptors

• 5-HT6 (rat)

• 5-HT7 (rat and human)

• coupled to adenylate cyclase
• significance unknown

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

Sternbach criteria

Serotinergic drugs

• Serotonin precursors

• S–adenyl–L–methionine
• L–tryptophan
• 5–hydroxytryptophan
• dopamine

Serotinergic drugs

• Serotonin re–uptake inhibitors

• citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine
• clomipramine, imipramine
• nefazodone, trazodone
• chlorpheniramine
• cocaine, dextromethorphan, pentazocine, pethidine

Serotinergic drugs

• Serotonin agonists

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

Serotinergic drugs

• Monoamine oxidase inhibitors (MAOIs)

• clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine
• selegiline
• furazolidone
• procarbazine

Serotinergic drugs

• Reversible inhibitors of MAO (RIMAs)

• brofaramine
• befloxatone, toloxatone
• moclobemide

Serotinergic drugs

• Miscellaneous/mixed

• lithium
• lysergic acid diethylamide (LSD)
• 3,4–methylenedioxymethamphetamine (MDMA, ecstasy), methylenedioxyethamphetamine (eve)
• propranolol, pindolol

Incidence

• Over last 10 years

• 4130 admissions for deliberate self poisoning

• 267 admissions for serotinergic drug overdose

• 41 admissions with serotonin syndrome

Incidence

Serotinergic drugs taken

Serotinergic drugs (Odds ratios)

Sternbach criteria (%)

Frequency of Sternbach criteria

Other clinical features (%)

Frequency of all clinical features

Sternbach criteria in HATS (%)

Sternbach criteria (Odds ratio)

Other clinical features in HATS (%)

Other clinical features (Odds ratio)

Major features

Minor features

Non–features

Suggested criteria

• Agitation/confusion/hypomania

• Clonus (inducible/spontaneous/ocular)

• Tremor/shivering/myoclonus

• Diaphoresis

• Fever

• Hyperreflexia

• Hypertonia/rigidity

Suggested criteria

Signs suggestive of serotinergic drug overdose

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

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

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

Drugs used to treat serotonin syndrome

• Non–specific blocking agents

• methysergide
• cyproheptadine

• –blockers

• propranolol
• pindolol

Drugs used to treat serotonin syndrome

• Benzodiazepines

• lorazepam
• diazepam
• clonazepam

• Neuroleptics

• chlorprothixene
• chlorpromazine
• haloperidol

Drugs used to treat serotonin syndrome

• Miscellaneous

• chlormethiazole
• nitroglycerine

• Drugs used for neuroleptic malignant syndrome

• dantrolene
• bromocriptine

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

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)

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

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