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)

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 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
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 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