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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Pharmacology and Toxicology of Pharmacology and Toxicology of Antidepressants and Antidepressants and
AntipsychoticsAntipsychoticsProf Ian Whyte FRACP, FRCP Edin
Hunter New England Toxicology Service
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Traditional AntipsychoticsTraditional Antipsychotics
Phenothiazines– chlorpromazine (Chlorpromazine Mixture,
Chlorpromazine Mixture Forte, Largactil)– fluphenazine (Anatensol, Modecate)– flupenthixol (Fluanxol)– pericyazine (Neulactil)– pimozide (Orap)– thioridazine (Aldazine)– trifluoperazine (Stelazine)– zuclopenthixol (Clopixol)
Butyrophenones– droperidol (Droleptan Injection)– haloperidol (Haldol, Serenace)
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Newer AntipsychoticsNewer Antipsychotics
Atypical agents– aripiprazole (Abilify)– clozapine (CloSyn, Clopine, Clozaril)– risperidone (Risperdal)– quetiapine (Seroquel)– amisulpride (Solian) – olanzapine (Zyprexa)
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
AntipsychoticsAntipsychotics
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Differences among Differences among Antipsychotic DrugsAntipsychotic Drugs
All effective antipsychotic drugs block D2 receptors Chlorpromazine and thioridazine
– block α1 adrenoceptors more potently than D2 receptors– block serotonin 5-HT2 receptors relatively strongly – affinity for D1 receptors is relatively weak
Haloperidol – acts mainly on D2 receptors– some effect on 5-HT2 and α1 receptors – negligible effects on D1 receptors
Pimozide and amisulpride†
– act almost exclusively on D2 receptors
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Differences among Differences among Antipsychotic DrugsAntipsychotic Drugs
Clozapine – binds more to D4, 5-HT2, α1, and histamine H1
receptors than to either D2 or D1 receptors Risperidone
– about equally potent in blocking D2 and 5-HT2 receptors
Olanzapine– more potent as an antagonist of 5-HT2 receptors– lesser potency at D1, D2, and α1 receptors
Quetiapine– lower-potency compound with relatively similar
antagonism of 5-HT2, D2, α1, and α2 receptors
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Differences among Differences among Antipsychotic DrugsAntipsychotic Drugs
Clozapine, olanzapine and quetiapine– potent inhibitors of H1 histamine
receptors– consistent with their sedative properties
Aripiprazole– partial agonist effects at D2 and 5-HT1A
receptors
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Differences among Differences among Antipsychotic DrugsAntipsychotic Drugs
Chlorpromazine: α1 = 5-HT2 > D2 > D1
Haloperidol: D2 > D1 = D4 > α1 > 5-HT2
Clozapine: D4 = α1 > 5-HT2 > D2 = D1
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Metabolic effectsMetabolic effects
Weight gain over 1 year (kg)
aripiprazole 1
amisulpride 1.5
quetiapine 2 – 3
risperidone 2 – 3
olanzapine > 6
clozapine > 6
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Insulin resistanceInsulin resistance
Prediabetes (impaired fasting glycaemia) has ~ 10% chance / year of converting to Type 2 diabetes
Prediabetes plus olanzapine has a 6-fold increased risk of conversion
If olanzapine is stopped 70% will revert back to prediabetes
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Stroke in the elderlyStroke in the elderly
Risperidone and olanzapine associated with increased risk of stroke when used for behavioural control in dementia
Risperidone 3.3% vs 1.2% for placebo Olanzapine 1.3% vs 0.4% for placebo However, large observational database
studies – Show no increased risk of stroke compared with
typical antipsychotics or untreated dementia patients
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
ConclusionsConclusions Atypical antipsychotics have serotonin
blocking effects as well as dopamine blockade
As a group have less chance of extrapyramidal side effects
Most have weight gain and insulin resistance as a side effect (except perhaps aripiprazole and maybe amisulpride)
May be associated with stroke when used for behavioural control in dementia
Many have idiosyncratic toxicities
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Traditional AntidepressantsTraditional Antidepressants
Tricyclic antidepressants– amitriptylline (Endep, Tryptanol)– clomipramine (Anafranil, Chem mart Clomipramine, GenRx
Clomipramine, Placil, Terry White Chemists Clomipramine)– doxepin (Deptran, Sinequan)– dothiepin (Dothep, Prothiaden)– imipramine (Tofranil)– nortriptylline (Allegron)– trimipramine (Surmontil)
Tetracyclic antidepressants– Mianserin (Lumin, Tolvon)
MAOIs (monoamine oxidase inhibitors)– Phenelzine (Nardil)– Tranylcypromine (Parnate)
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Newer antidepressantsNewer antidepressants SSRIs (specific serotonin reuptake inhibitors)
– citalopram (Celapram, Chem mart Citalopram, Ciazil, Cipramil, GenRx Citalopram, Talam, Talohexal, Terry White Chemists Citalopram)
– escitalopram (Lexapro)– fluoxetine (Auscap 20 mg Capsules, Chem mart Fluoxetine,
Fluohexal, Fluoxebell, Fluoxetine-DP, GenRx Fluoxetine, Lovan, Prozac, Terry White Chemists Fluoxetine, Zactin)
– fluvoxamine (Faverin, Luvox, Movox, Voxam)– paroxetine (Aropax, Chem mart Paroxetine, GenRx Paroxetine,
Oxetine, Paxtine, Terry White Chemists Paroxetine)– sertraline (Chem mart Sertraline, Concorz, Eleva, GenRx
Sertraline, Sertraline-DP, Terry White Chemists Sertraline, Xydep, Zoloft)
RIMA (reversible inhibitor of monoamine oxidase A)– moclobemide (Arima, Aurorix, Chem mart Moclobemide,
Clobemix, GenRx Moclobemide, Maosig, Mohexal 150 mg, Terry White Chemists Moclobemide)
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Newest antidepressantsNewest antidepressants
SNRI (serotonin noradrenergic reuptake inhibitors)– venlafaxine (Efexor-XR)
NaSSA (noradrenergic and specific serotonergic antidepressant)– mirtazapine (Avanza, Avanza SolTab, Axit,
Mirtazon, Remeron) NaRI (selective noradrenaline reuptake
inhibitor )– reboxetine (Edronax)
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Selectivity of Selectivity of antidepressantsantidepressants
0.001
0.01
0.1
1
10
100
1000 Nisoxetine
NomifensineMaprotiline (approx)
Desipramine
Imipramine Nortriptyline Amitriptyline
Clomipramine Trazodone Zimelidine
Fluoxetine
Citalopram (approx)
NA-selective
Non-selective
5-HT-selective R
atio
NA
: 5-
HT
upt
ake
inhi
biti
on
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
SSRINaRI
RIMA
NaSSA
NaSSA
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Sternbach criteriaSternbach criteriaMental status changes (confusion, hypomania) Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhoea Incoordination Fever
Diarrhoea
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonin receptorsSerotonin receptors
5–HT1
– subtypes 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F
5–HT2
– subtypes 5–HT2A, 5–HT2B, 5–HT2C
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonin receptorsSerotonin receptors
5–HT3
5–HT4 (rat)
5–HT5 (rat) 5–HT5A, 5–HT5
5–HT6 (rat)
5–HT7 (rat and human)
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonin receptorsSerotonin receptors
5–HT1
– subtypes 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E,
5–HT1F
– primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin
5–HT2
– subtypes 5–HT2A, 5–HT2B, 5–HT2C
– primarily responsible for the toxic effects of increased intrasynaptic serotonin
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Boyer EW, Shannon M
The serotonin syndrome
New England Journal of Medicine
2005 Mar 17;352(11):1112-20
Isbister GK, Buckley NA
The Pathophysiology of Serotonin Toxicity in Animals and Humans: Implications for Diagnosis and Treatment
Clinical Neuropharmacology 2005;28(5):205-214
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonergic drugsSerotonergic drugs
Serotonin precursors– S–adenyl–L–methionine– L–tryptophan– 5–hydroxytryptophan– dopamine
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonergic drugsSerotonergic drugs
Serotonin re-uptake inhibitors– citalopram, fluoxetine, fluvoxamine,
paroxetine, sertraline, venlafaxine– clomipramine, imipramine– nefazodone, trazodone– chlorpheniramine– cocaine, dextromethorphan, pentazocine,
pethidine, tramadol
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonergic drugsSerotonergic drugs
Serotonin agonists– fenfluramine, p–chloramphetamine– bromocriptine, dihydroergotamine,
gepirone– sumatriptan– buspirone, ipsapirone– eltoprazin, quipazine
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonergic drugsSerotonergic drugs
Monoamine oxidase inhibitors (MAOIs)– clorgyline, isocarboxazid, nialamide,
pargyline, phenelzine, tranylcypromine– selegiline– furazolidone– procarbazine
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonergic drugsSerotonergic drugs
Reversible inhibitors of MAO (RIMAs)– brofaramine– befloxatone, toloxatone– moclobemide
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonergic drugsSerotonergic drugs
Miscellaneous/mixed– lithium– lysergic acid diethylamide (LSD)– 3,4–methylenedioxymethamphetamine
(MDMA, ecstasy)– methylenedioxyethamphetamine (eve)– propranolol, pindolol
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonin excessSerotonin excess Primary neuroexcitation (5–HT2A)
– mental status agitation/delirium
– motor system clonus/myoclonus
– inducible/spontaneous/ocular
tremor/shivering hyperreflexia/hypertonia
– autonomic system diaphoresis/tachycardia/mydriasis
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonin excessSerotonin excess
Other responses to neuroexcitation– fever– rhabdomyolysis
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Severe serotonin toxicitySevere serotonin toxicity
Combination therapy – multiple different mechanisms of serotonin
elevation Rapidly rising temperature Respiratory failure
– hypertonia/rigidity Spontaneous clonus
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Treatment optionsTreatment options
Supportive care– symptom control– control of fever– ventilation
5–HT2A antagonists
– ideal safe effective available
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Kapur, S et al. (1997). Cyproheptadine: a potent in vivo serotonin antagonist. American Journal of Psychiatry, 154, 884
CyproheptadineCyproheptadine
Oral preparation Safe 20–30 mg required to
achieve 90% blockade of brain 5–HT2 receptors
Cyproheptadine 100Chlorpromazine 71Chlorprothixene 233Haloperidol 2.8Clozapine 62Risperidone 170Olanzapine 25Sertindole 260Methysergide 14Ketanserin 178
Affinity at 5-HT2 = 10-7 x 1/Kd
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
ChlorpromazineChlorpromazine
5–HT2 antagonist
– PET scans show avid 5–HT2 binding
Oral or parenteral medication– ventilated patients– impaired absorption
recent activated charcoal
Sedating and a potent vasodilator
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
TherapyTherapy
Oral therapy– cyproheptadine 12 mg stat then 4–8 mg q 4–6h
Oral therapy unsuitable or fails– chlorpromazine 25–50 mg IVI stat then up to 50
mg orally or IVI q6h Ventilation impaired and/or fever > 39oC
– anaesthesia, muscle relaxation ± active cooling– chlorpromazine 100–400 mg IMI/IVI over first
two hours
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
ConclusionsConclusions
Serotonin toxicity is a spectrum disorder not a discrete syndrome
The clinical manifestations of toxicity are 5–HT2 mediated while the therapeutic effect is 5–HT1
Newer agents with little or no risk of serotonin toxicity– Reboxetine and mirtazapine
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
ConclusionsConclusions
First line of treatment is to remove the offending agent(s)
Specific inhibitors of 5–HT2 have a role but paralysis and ventilation may be needed