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 Hunter Area Toxicology Service

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

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

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

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

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

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

5–HT1 5–HT1A 5–HT1B (rat) limbic system neocortex hypothalamus regulation of emotions neocortex hypothalamus substantia gelatinosa proprioception 5–HT1B (rat) Hunter Area Toxicology Service

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

5–HT1 5–HT1E 5–HT1F ? functional role distribution includes CNS, uterus, mesentery inhibit cAMP high affinity sumatriptan, methysergide Hunter Area Toxicology Service

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

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

5–HT2 5–HT2A CNS motor behaviour head twitch wet dog shakes sleep regulation nociception neuroexcitation Hunter Area Toxicology Service

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

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

5–HT3 Peripheral Central 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

Serotonin receptors 5-HT6 (rat) 5-HT7 (rat and human) coupled to adenylate cyclase significance unknown Hunter Area Toxicology Service

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

Sternbach criteria Hunter Area Toxicology Service

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

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

Serotinergic drugs Serotonin agonists fenfluramine, p–chloramphetamine bromocriptine, dihydroergotamine, gepirone sumatriptan buspirone, ipsapirone eltoprazin, quipazine Hunter Area Toxicology Service

Serotinergic drugs Monoamine oxidase inhibitors (MAOIs) clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine selegiline furazolidone procarbazine Hunter Area Toxicology Service

Serotinergic drugs Reversible inhibitors of MAO (RIMAs) brofaramine befloxatone, toloxatone moclobemide Hunter Area Toxicology Service

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

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

Incidence Hunter Area Toxicology Service

Serotinergic drugs taken Hunter Area Toxicology Service

Serotinergic drugs (Odds ratios) Hunter Area Toxicology Service

Sternbach criteria (%) Hunter Area Toxicology Service

Frequency of Sternbach criteria Hunter Area Toxicology Service

Other clinical features (%) Hunter Area Toxicology Service

Frequency of all clinical features Hunter Area Toxicology Service

Sternbach criteria in HATS (%) Hunter Area Toxicology Service

Sternbach criteria (Odds ratio) Hunter Area Toxicology Service

Other clinical features in HATS (%) Hunter Area Toxicology Service

Other clinical features (Odds ratio) Hunter Area Toxicology Service

Major features Hunter Area Toxicology Service

Minor features Hunter Area Toxicology Service

Non–features Hunter Area Toxicology Service

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

Suggested criteria Hunter Area Toxicology Service

Signs suggestive of serotinergic drug overdose Hunter Area Toxicology Service

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

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

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

Drugs used to treat serotonin syndrome Non–specific blocking agents methysergide cyproheptadine –blockers propranolol pindolol Hunter Area Toxicology Service

Drugs used to treat serotonin syndrome Benzodiazepines lorazepam diazepam clonazepam Neuroleptics chlorprothixene chlorpromazine haloperidol Hunter Area Toxicology Service

Drugs used to treat serotonin syndrome Miscellaneous chlormethiazole nitroglycerine Drugs used for neuroleptic malignant syndrome dantrolene bromocriptine Hunter Area Toxicology Service

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 Hunter Area Toxicology Service

Antagonist potencies Ki values (5–HT2) Ki values (5–HT1) 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

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

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 Hunter Area Toxicology Service