Pharmacology and Toxicology of Antidepressants and Antipsychotics

Prof Ian Whyte FRACP, FRCP Edin Hunter New England Toxicology Service

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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)

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Newer Antipsychotics

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Antipsychotics

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Differences among Antipsychotic Drugs

All effective antipsychotic drugs block D2 receptors Chlorpromazine and thioridazine

block 1 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 1 receptors negligible effects on D1 receptors

Pimozide and amisulpride

act almost exclusively on D2 receptors

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Differences among Antipsychotic Drugs

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Differences among Antipsychotic Drugs

Chlorpromazine: 1 = 5-HT2 > D2 > D1 Haloperidol: D2 > D1 = D4 > 1 > 5-HT2 Clozapine: D4 = 1 > 5-HT2 > D2 = D1

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Metabolic effects
Weight gain over 1 year (kg) aripiprazole 1

amisulpride quetiapine risperidone

olanzapine clozapine

1.5 23 23
>6 >6

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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)

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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)

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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)

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Selectivity of antidepressants
1000 Nisoxetine Nomifensine Maprotiline (approx) 100 Ratio NA: 5-HT uptake inhibition NAselective

10

Desipramine Imipramine Nortriptyline Amitriptyline Clomipramine Trazodone Zimelidine

Nonselective

0.1

5-HTselective

0.01 Fluoxetine 0.001 Citalopram (approx)

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

RIMA

NaSSA

NaRI SSRI
NaSSA

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Sternbach criteria
Mental status changes (confusion, hypomania) Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhoea Incoordination Fever
Diarrhoea

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonin receptors

5HT1
subtypes

5HT1A, 5HT1B, 5HT1D, 5HT1E, 5HT1F

5HT2
subtypes

5HT2A, 5HT2B, 5HT2C

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonin receptors

5HT3 5HT4 (rat) 5HT5 (rat)

5HT5A, 5HT5

5HT6 (rat) 5HT7 (rat and human)

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonin receptors

5HT1
subtypes

5HT1A, 5HT1B, 5HT1D, 5 HT1E, 5HT1F

primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin

5HT2
subtypes

5HT2A, 5HT2B, 5HT2C

primarily responsible for the toxic effects of increased intrasynaptic serotonin

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonergic drugs

Serotonin precursors
SadenylLmethionine Ltryptophan 5hydroxytryptophan dopamine

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonergic drugs

Serotonin re-uptake inhibitors

citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine clomipramine, imipramine nefazodone, trazodone chlorpheniramine cocaine, dextromethorphan, pentazocine, pethidine, tramadol

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonergic drugs

Serotonin agonists
fenfluramine, pchloramphetamine bromocriptine, dihydroergotamine, gepirone sumatriptan buspirone, ipsapirone eltoprazin, quipazine

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonergic drugs

Monoamine oxidase inhibitors (MAOIs)

clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine selegiline furazolidone procarbazine

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonergic drugs

Reversible inhibitors of MAO (RIMAs)

brofaramine befloxatone, toloxatone moclobemide

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonergic drugs

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonin excess

Primary neuroexcitation (5HT2A)

mental status

agitation/delirium clonus/myoclonus
inducible/spontaneous/ocular

motor system

tremor/shivering hyperreflexia/hypertonia

autonomic system

diaphoresis/tachycardia/mydriasis

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Serotonin excess

Other responses to neuroexcitation

fever rhabdomyolysis

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Severe serotonin toxicity

Combination therapy
multiple different mechanisms of serotonin elevation

Rapidly rising temperature Respiratory failure

hypertonia/rigidity

Spontaneous clonus

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Treatment options

Supportive care
symptom control control of fever ventilation

5HT2A antagonists
ideal
safe effective available

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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

100 71 233 2.8 62 170 25 260 14 178

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
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Chlorpromazine

5HT2 antagonist
PET scans show avid 5HT2 binding

Oral or parenteral medication

ventilated patients impaired absorption

recent activated charcoal

Sedating and a potent vasodilator

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Therapy

Oral therapy
cyproheptadine 12 mg stat then 48 mg q 46h

Oral therapy unsuitable or fails

chlorpromazine 2550 mg IVI stat then up to 50 mg orally or IVI q6h

Ventilation impaired and/or fever > 39oC

anaesthesia, muscle relaxation active cooling chlorpromazine 100400 mg IMI/IVI over first two hours

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital