Pharmacology and Toxicology of Antidepressants and Antipsychotics

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. Metabolic effects

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

26. RIMA NaSSA SSRI NaRI NaSSA

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 • subtypes • 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F • 5–HT2 • subtypes • 5–HT2A, 5–HT2B, 5–HT2C

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

31. Serotonin 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

32. 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

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 • rhabdomyolysis

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 • 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 • 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 • 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