Pharmacology and Toxicology of Antidepressants and Antipsychotics

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

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

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

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

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

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

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

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

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

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)
 MAOIs (monoamine oxidase inhibitors)
– Phenelzine (Nardil)
– Tranylcypromine (Parnate)

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)

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)

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

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
Diarrh oea
Fever
Serotonin receptors
 5–HT1
– subtypes
 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F
 5–HT2
– subtypes
 5–HT2A, 5–HT2B, 5–HT2C

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

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

 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

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

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

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

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

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

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

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

Serotonin excess
 Other responses to neuroexcitation
– fever
– rhabdomyolysis

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

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

Cyproheptadine
 Oral preparation Cyproheptadine 100
Chlorpromazine 71
 Safe Chlorprothixene 233
Haloperidol 2.8
 20–30 mg required to Clozapine 62
achieve 90% blockade Risperidone 170
Olanzapine 25
of brain 5–HT2 receptors Sertindole 260
Methysergide 14
Ketanserin 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
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

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
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

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

Pharmacology and Toxicology of Antidepressants and Antipsychotics

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Pharmacology and Toxicology of

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

 Haloperidol: D2 > D1 = D4 > α1 > 5-HT2

 Clozapine: D4 = α1 > 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

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

0.001 Citalopram (approx)

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

 Isbister GK, Buckley NA

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

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

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

 Kapur, S et al. (1997). Cyproheptadine: a potent in vivo

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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