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Pharmacology and Toxicology of Antidepressants and Antipsychotics

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1 Pharmacology and Toxicology of Antidepressants and Antipsychotics
Prof Ian Whyte FRACP, FRCP Edin Hunter New England Toxicology Service


3 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)


5 Newer Antipsychotics Atypical agents aripiprazole (Abilify)
clozapine (CloSyn, Clopine, Clozaril) risperidone (Risperdal) quetiapine (Seroquel) amisulpride (Solian) olanzapine (Zyprexa)

6 Antipsychotics


8 Differences among Antipsychotic 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

9 Differences among Antipsychotic 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

10 Differences among Antipsychotic 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

11 Differences among Antipsychotic Drugs
Chlorpromazine: α1 = 5-HT2 > D2 > D1 Haloperidol: D2 > D1 = D4 > α1 > 5-HT2 Clozapine: D4 = α1 > 5-HT2 > D2 = D1



14 Weight gain over 1 year (kg)
Metabolic effects Weight gain over 1 year (kg) aripiprazole 1 amisulpride 1.5 quetiapine 2 – 3 risperidone olanzapine > 6 clozapine

15 Insulin 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

16 Stroke 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

17 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

18 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) MAOIs (monoamine oxidase inhibitors) Phenelzine (Nardil) Tranylcypromine (Parnate)




22 Newer 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)


24 Newest 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)

25 Selectivity of antidepressants
1000 Nisoxetine Nomifensine Maprotiline (approx) 100 NA- selective 10 Desipramine Imipramine Nortriptyline Amitriptyline Non- selective 1 Ratio NA: 5-HT uptake inhibition Clomipramine Trazodone Zimelidine 0.1 5-HT- selective 0.01 Fluoxetine 0.001 Citalopram (approx)


27 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

28 Sternbach criteria

29 Serotonin receptors 5–HT1 5–HT2 subtypes
5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F 5–HT2 5–HT2A, 5–HT2B, 5–HT2C

30 Serotonin receptors 5–HT3 5–HT4 (rat) 5–HT5 (rat) 5–HT6 (rat)
5–HT5A, 5–HT5 5–HT6 (rat) 5–HT7 (rat and human)

31 Serotonin receptors 5–HT1 5–HT2 subtypes
5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin 5–HT2 5–HT2A, 5–HT2B, 5–HT2C primarily responsible for the toxic effects of increased intrasynaptic serotonin

32 Boyer EW, Shannon M The serotonin syndrome New England Journal of Medicine 2005 Mar 17;352(11): Isbister GK, Buckley NA The Pathophysiology of Serotonin Toxicity in Animals and Humans: Implications for Diagnosis and Treatment Clinical Neuropharmacology 2005;28(5):

33 Serotonergic drugs Serotonin precursors S–adenyl–L–methionine
L–tryptophan 5–hydroxytryptophan dopamine

34 Serotonergic drugs Serotonin re-uptake inhibitors
citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine clomipramine, imipramine nefazodone, trazodone chlorpheniramine cocaine, dextromethorphan, pentazocine, pethidine, tramadol

35 Serotonergic drugs Serotonin agonists fenfluramine, p–chloramphetamine
bromocriptine, dihydroergotamine, gepirone sumatriptan buspirone, ipsapirone eltoprazin, quipazine

36 Serotonergic drugs Monoamine oxidase inhibitors (MAOIs)
clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine selegiline furazolidone procarbazine

37 Serotonergic drugs Reversible inhibitors of MAO (RIMAs) brofaramine
befloxatone, toloxatone moclobemide

38 Serotonergic drugs Miscellaneous/mixed lithium
lysergic acid diethylamide (LSD) 3,4–methylenedioxymethamphetamine (MDMA, ecstasy) methylenedioxyethamphetamine (eve) propranolol, pindolol

39 Serotonin 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

40 Serotonin excess Other responses to neuroexcitation fever



43 Severe serotonin toxicity
Combination therapy multiple different mechanisms of serotonin elevation Rapidly rising temperature Respiratory failure hypertonia/rigidity Spontaneous clonus


45 Treatment options Supportive care 5–HT2A antagonists symptom control
control of fever ventilation 5–HT2A antagonists ideal safe effective available

46 Cyproheptadine Oral preparation Safe
20–30 mg required to achieve 90% blockade of brain 5–HT2 receptors Affinity at 5-HT2 = 10-7 x 1/Kd Kapur, S et al. (1997). Cyproheptadine: a potent in vivo serotonin antagonist. American Journal of Psychiatry, 154, 884

47 Chlorpromazine 5–HT2 antagonist Oral or parenteral medication
PET scans show avid 5–HT2 binding Oral or parenteral medication ventilated patients impaired absorption recent activated charcoal Sedating and a potent vasodilator

48 Therapy Oral therapy Oral therapy unsuitable or fails
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

49 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 5–HT1 Newer agents with little or no risk of serotonin toxicity Reboxetine and mirtazapine

50 Conclusions 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

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