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Prof Ian Whyte FRACP, FRCP Edin Hunter New England Toxicology Service
Traditional 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)
Newer Antipsychotics
Atypical agents
aripiprazole (Abilify) clozapine (CloSyn, Clopine, Clozaril) risperidone (Risperdal) quetiapine (Seroquel) amisulpride (Solian) olanzapine (Zyprexa)
Antipsychotics
Haloperidol
acts mainly on D2 receptors some effect on 5-HT2 and 1 receptors negligible effects on D1 receptors
Clozapine
binds more to D4, 5-HT2, 1, 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 1 receptors
Quetiapine
lower-potency compound with relatively similar antagonism of 5-HT2, D2, 1, and 2 receptors
Aripiprazole
partial agonist effects at D2 and 5-HT1A receptors
Chlorpromazine: 1 = 5-HT2 > D2 > D1 Haloperidol: D2 > D1 = D4 > 1 > 5-HT2 Clozapine: D4 = 1 > 5-HT2 > D2 = D1
Metabolic effects
Weight gain over 1 year (kg) aripiprazole 1
1.5 23 23
>6 >6
Insulin resistance
Prediabetes (impaired fasting glycaemia) has ~ 10% chance / year of converting to Type 2 diabetes Prediabetes plus olanzapine has a 6fold increased risk of conversion If olanzapine is stopped 70% will revert back to prediabetes
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
Conclusions
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
Traditional 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)
Newer antidepressants
Newest antidepressants
Selectivity of antidepressants
1000 Nisoxetine Nomifensine Maprotiline (approx) 100 Ratio NA: 5-HT uptake inhibition NAselective
10
Nonselective
0.1
5-HTselective
RIMA
NaSSA
NaRI SSRI
NaSSA
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
Mental status changes (confusion, hypomania) Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhoea Incoordination Fever
Diarrhoea
Serotonin receptors
5HT1
subtypes
5HT2
subtypes
Serotonin receptors
5HT5A, 5HT5
Serotonin receptors
5HT1
subtypes
primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin
5HT2
subtypes
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
Serotonergic drugs
Serotonin precursors
SadenylLmethionine Ltryptophan 5hydroxytryptophan dopamine
Serotonergic drugs
Serotonergic drugs
Serotonin agonists
fenfluramine, pchloramphetamine bromocriptine, dihydroergotamine, gepirone sumatriptan buspirone, ipsapirone eltoprazin, quipazine
Serotonergic drugs
Serotonergic drugs
Serotonergic drugs
Miscellaneous/mixed
lithium lysergic acid diethylamide (LSD) 3,4methylenedioxymethamphetamine (MDMA, ecstasy) methylenedioxyethamphetamine (eve) propranolol, pindolol
Serotonin excess
agitation/delirium clonus/myoclonus
inducible/spontaneous/ocular
motor system
tremor/shivering hyperreflexia/hypertonia
autonomic system
diaphoresis/tachycardia/mydriasis
Serotonin excess
Combination therapy
multiple different mechanisms of serotonin elevation
Spontaneous clonus
Treatment options
Supportive care
symptom control control of fever ventilation
5HT2A antagonists
ideal
safe effective available
Cyproheptadine
Oral preparation Safe 2030 mg required to achieve 90% blockade of brain 5HT2 receptors
Cyproheptadine Chlorpromazine Chlorprothixene Haloperidol Clozapine Risperidone Olanzapine Sertindole Methysergide Ketanserin
Kapur, S et al. (1997). Cyproheptadine: a potent in vivo serotonin antagonist. American Journal of Psychiatry, 154, 884
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Chlorpromazine
5HT2 antagonist
PET scans show avid 5HT2 binding
Therapy
Oral therapy
cyproheptadine 12 mg stat then 48 mg q 46h
Conclusions
Serotonin toxicity is a spectrum disorder not a discrete syndrome The clinical manifestations of toxicity are 5 HT2 mediated while the therapeutic effect is 5HT1 Newer agents with little or no risk of serotonin toxicity
Reboxetine and mirtazapine
Conclusions
First line of treatment is to remove the offending agent(s) Specific inhibitors of 5HT2 have a role but paralysis and ventilation may be needed