Antipsychotics

History of anti-psychotics

• Chlorpromazine (A phenothiazine) was the first - discovered in

the 1950’s - it had a calming effect in patients.
• 1963 - Carlsson & Linquist demonstrated a link between
inhibition of dopamine receptor function and the therapeutic
effects of phenothiazines.
• 1970’s - It was shown that anti-psychotic action was correlated
with affinity to block dopamine receptors in vitro.
• 1979 - Dopamine receptors classified into 2 types D1 & D2 and
there was a correlation between the anti-psychotic action of
phenothiazines and haloperidol and their affinity for D2 receptors.
 •Reserpine - isolated from the snake plant in the 1950’ -
monoamine depleting agent.
•Phenothiazines - Chlorpromazine the first drug of this class -
still the most widely used worldwide.
•Thioxanthines - Chlorprothixine, clopenthixol, flupenthixol
•Butyrophenones - Haloperidol
•Diphenylbutylpiperidines - Pimozide
•Benzamides - Sulpiride, remoxipride and raclopride.
•Atypicals - Clozapine, olanzapine, quetiapine, risperidone,
sertindole and ziprasidone.

Block dopamine, acetylcholine, noradrenaline, histamine and

serotonin receptors – all are dopamine antagonists
Extent of blockade varies – varied side effect profiles
 Classification of anti-psychotics

• Divided into those with a low potency

(chlorpromazine) and those with a high potency
(haloperidol).

• Therapeutic potency related to affinity for D2

receptors,

• The greater the potency the more likely to cause EPS

and less likely to cause autonomic effects.
 Chlorpromazine
• Representative of least potent anti-psychotics.

• the most sedative with anti-cholinergic, anti-histaminergic

and anti-adrenergic properties.

• Others is this class include Thioridazine

 Phenothiazines
• Aliphatic side chain - Least potent anti-psychotics. They are the
most sedative with anti-cholinergic, anti-histaminergic and anti-
adrenergic properties. Chlorpromazine

• Piperidine side chain - similar to aliphatic phenothiazines but are

more sedative. Have a reduced ability to cause EPR’s - due to their
potent anti-cholinergic effects. Thioridazine

• Piperazine side chain - Most potent anti-psychotics. Lack anti-

cholinergic, anti-histamine and anti-adrenergic actions. But more
likely to cause EPR’s. Fluphenazine.

• Thioxanthines closely related e.g. chlorprothixine and flupenthixol

Structural features pre-dispose to side effects

•Anti-histamine effects
Weight gain

•Muscarinic cholinergic receptor blocking properties

Dry mouth, blurred vision and constipation.

•Alpha-adrenergic blocking properties

Dizziness, hypotension
 Butyrophenones &
diphenylbutylpiperidines
• Non-tricyclic in structure. Haloperidol

• Lack anti-cholinergic, anti-histamine and anti-adrenergic

effects.
• Are non-sedative in therapeutic doses.

• Potent anti-dopaminergic activity - renders them likely to

cause EPR’s.

• diphenylbutylpiperidines - related to the butyrophenones and

have similar properties. Pimozide
Haloperidol
 Benzamides

• The benzamides were the first true anti-psychotics with respect

to side effects. Sulpiride.

• Benzamides have less propensity to produce EPR’s while still

showing good anti-psychotic properties.

• Display selectivity for the mesolimbic (D3/D4) over the

nigrostriatal dopamine system.

• Remoxipride was introduced as an antipsychotic and then

withdrawn due to reports of aplastic anemia.
 Motor side effects of anti-psychotics

• All typical antipsychotics are capable of producing extrapyramidal

reactions (EPR’s) and tardive dyskinesia

- both due to the D2 receptor blockade in the nigrostriatal

dopamine pathway.

• Therefor D2 receptor antagonism mediates side effects as well as

therapeutic effects.
 Dopamine/acetylcholine balance and EPR’s

• Dopamine neurons in the nigrostriatal dopamine pathway make

postsynaptic connections with cholinergic neurons.

• Dopamine has a tonic inhibitory effect on acetylcholine release

from nigrostriatal cholinergic neurons.

• When dopamine receptors are blocked acetylcholine becomes

over active.
•Anti-psychotics with weak anti-cholinergic properties display more
EPR’s than anti-psychotics with potent anti-cholinergic effects.

•Thus anti-cholinergics are often given to patients on anti-psychotics

to reduce EPR’s. Biperiden

•Concurrent anti-cholinergic drug administration leads to possible

worsening of Tardive Dyskinesia (TD).
 Tardive dyskinesia

• Long-term blockade of dopamine receptors in the nigrostriatal

dopamine pathway by anti-psychotic drugs may cause them to up-
regulate.

• The clinical consequence of dopamine receptor up-regulation may be

the hyperkinetic movement disorder known as tardive dyskinesia.

• Treatment: reduce dose, change to atypical antipsychotic with

lower risk of EPS
 Treatment of akathisia

Biperiden IV or oral – acute dystonia

Later manifestations – beta blockers, benzodiazepines or
sedative antidepressants
 Neuroleptic Malignant Syndrome

• Characterized by hyperthermia, rigidity, confusion, diaphoresis,

autonomic in-stability, elevated creatine phosphokinase (CPK), and
leukocytosis.

• Rare, (<3% of patients)

• Potentially fatal adverse effect of neuroleptic treatment.

• Associated with high dose neuroleptics

• Immediately discontinue anti-psychotic medication.

• Immediate hospitalization will allow administration of IV fluids to
promote rehydration and cooling.
 Anti-psychotics and prolactin

• Dopamine is an endogenous inhibitor of prolactin release.

• Inhibition of D2 receptors in the tuberoinfundibular dopamine

pathway increases prolactin release.

• Increased prolactin release can cause

– Galactorrhoea
– Amenorrhoea
 Main side effects of typical neuroleptics

Side effect Possible cause

Parkinsonism, dystonias, akathisia Dopamine blockade of basal ganglia

ALL POTENT TYPICAL NEUROLEPTICS

Hypotension Due to α1 receptor blockade

ALL LESS POTENT NEUROLEPTICS

Sedation Due to histamine1 blockade

ALL LESS POTENT NEUROLEPTICS

Tachycardia & other anticholinergic Due to muscarinic receptor blockade

effects ALL LESS POTENT NEUROLEPTICS

Seizures ?Due to muscarinic receptor blockade

MOST NEUROLEPTICS
Side effect Possible cause

Agranulocytosis, skin rashes Allergic reactions

Skin pigmentation
Jaundice
Cardiac conduction defects
MANY NEUROLEPTICS; CLOZAPINE
Dopamine-melanin conversion
ALL LESS POTENT NEUROLEPTICS
Bile duct obstruction?
CHLORPROMAZINE
Muscarinic blockade, Na+ channel blockade
THIORIDAZINE, CHLORPROMAZINE,
SERTINDOLE ?

Galactorrhoea D2 blockade in hypothalamus

 Pharmacokinetics I

• High inter-individual variation in serum concentrations of typical

neuroleptics

• Variation in concentration can arise due to concurrent

administration of drugs which affect absorption/metabolism
e.g. TCAs

• Presence of active metabolites with different pharmacokinetic

profiles to parent drug.
 Pharmacokinetics II

• Relationship between plasma anti-psychotic concentrations

and therapeutic outcome ?

• No evidence that higher doses of typical neuroleptics

accelerate response, increase response or are effective in
treatment resistance

• Results in cardiotoxicity, parkinsonism and akathisia

 Depot preparations

• Developed to over come the lack of compliance with

medication in outpatients.

• Slow release preparations which produce fairly predictable

and constant plasma drug concentration.
e.g. Fluphenazine decanoate and haloperidol decanoate.

• One injection every 4-6 weeks according to response and

severity of condition

• Drugs are not metabolised by the GIT or liver before

reaching the brain.

• EPR’s and relapse is similar to oral administration.

 Advantages and limitations of
traditional anti-psychotic drugs

Advantages
• Positive symptom efficacy
• Available in a range of formulations

Limitations
• High prevalence of acute EPS (≈60%)
( 60%)
• Incidence of TD ≈5% per year
• Poor effects on negative symptoms
• High non-compliance rates
• Frequent relapses and re-hospitalizations
• Lack ability to improve cognitive dysfunction
 The search for new anti-psychotic drugs

• Discovery of the newer atypical anti-psychotic drugs.

• Strategy: selectively target mesolimbic dopamine pathway.

• Classical anti-psychotics do not treat the negative symptoms

of schizophrenia - an unmet need !

• Not all schizophrenics respond to typical anti-psychotics.

 Desirable features of a new anti-psychotic

• Improve positive symptoms in partial and non-responders

• Benefit negative symptoms

• Reduce relapse rates

• Few/No EPS

• Few adverse effects

• Patient acceptability
 Atypical anti-psychotics - Clozapine

• Effective anti-psychotic, in treatment resistant schizophrenia,

negative symptoms, specific cognitive deficits, aggressive and
suicidal behavior

• Effective against L-DOPA associated psychosis, in patients with

Parkinson’s disease

• Few EPRs
• X tardive dyskinesia
• X prolactin

• Desmethylclozapine - metabolite

• Problem: Clozapine produces a life threatening condition called

agranulocytosis (1% of patients). - Restricted use and blood
monitoring.
 Clozapine - tolerability

Risk of agranulocytosis in patients exposed to the drug for

at least 6 months - reserved for treatment resistant cases

– Much sedation and hypotension; dose titration required

– Minimal risk of acute and tardive EPS or prolactin

increase

– Seizures, confusion and sexual dysfunction:

dose- or plasma-level dependent

– High risk of weight gain

– Dose related Tachycardia

Atypical antipsychotics
 Anti-psychotic drugs: in vitro receptor binding
(Affinity values Ki in nmol)

Hal Cloz Risp Olanz Quet Zip

D1 210 85 430 31 460 525
D2 1 160 2 44 580 4
D3 2 170 10 50 940 7
D4 3 50 10 50 1900 32
5HT1A 1100 200 210 >10000 720 3
5HT1D >10000 1900 170 800 6200 2
5HT2A 45 16 0.5 5 300 0.4
5HT2C >10000 10 25 11 5100 1
5HT6 9600 14 2200 10 33 130
5HT7 1200 100 2 150 130 23
5HT reuptake 1700 5000 1300 - - 50
NA reuptake 4700 500 >1000 - - 50
NAα1 6 7 1 19 7 10
NAα2 360 8 1 230 90 200
H1 440 1 20 3 1 50
Muscarinic 5500 2 >1000 2 >1000 >1000

The lower the number, the stronger the affinity for the specific neuroreceptor.
Ki, inhibitory constant; NA, noradrenaline.
 Atypical anti-psychotics

• bind with high affinity to 5-HT2A, D2, 5-HT1A, 5-HT2C, 5-HT1D, D1 and
α-adrenergic receptors.

• Olanzepine - structurally similar to clozapine, similar therapeutic

efficacy and side effect profile (no agranulocytosis).
• Quetiapine - similar to olanzapine but has less anti-cholinergic and
anti-adrenergic side effects.
• Resperidone - similar to olanzepine but has no anti-cholinergic
effects.
• Sertindole - has no anti-muscarinic or anti-cholinergic effects but it
prolongs the Q-T interval which can lead to cardiac arrhythmia's.
• Ziprasidone – less weight gain
• Zotepine - Effective against negative symptoms – NA re-uptake
inhibitor)
 Aripiprazole

• High affinity antagonist at 5-HT2A receptors

• High affinity D2 receptor partial agonist.

can act as an agonist or antagonist depending on the strength of

endogenous dopamine neurotransmission

- agonist in low dopamine states

- antagonist in hyperdopaminergic states

Low EPS liability and does not elevate prolactin

Antidepressant used in treatment of bipolar disorder and for

irritability in persons with autism
 Serotonin-dopamine interactions
- relationship to EPR’s
• Serotonin (5-HT2A) inhibits dopamine function in the striatum.
• This type of serotonin input seems to be lacking in the mesolimbic
dopamine system.

• When D2 receptors are blocked in the mesolimbic dopamine pathway

they reduce psychosis.
• When atypical anti-psychotics block D2 receptors in the
nigrostriatal dopamine pathway they also block 5-HT2 receptors. 5-
HT2 blockade tends to reverse the D2 blockade.
• May explain why the atypical anti-psychotics induce less EPR’s.

• 5-HT2 antagonist properties of the atypical antipsychotics plays an

important role in their ability to reduce negative symptoms of
schizophrenia.
 Atypicals: Benefits
+ symptoms

- symptoms Therapy
Atypicals resistance

Concurrent Cognitive
depression function

•A growing sense that the second-generation anti-psychotics should be:

–Available as first-line treatments in schizophrenia
–Preferentially used in first-episode patients
 Weight Gain
The weight gain is the only major disadvantage over traditional
neuroleptics
•Differential risk profiles for weight gain
–clozapine and olanzapine at upper end of weight gain scale;
ziprasidone at lower end
•Disturbances of carbohydrate and lipid metabolism
–risk for new onset diabetes
–unclear whether effects secondary to weight gain
–beware: associated health risks (eg, cardiovascular morbidity)

•Raised triglycerides and low density lipoproteins reported to occur

occasionally after olanzapine but not risperidone.

•No difference reported to occur in glucose and insulin concentrations

after olanzapine
 Other limitations

• Many new agents appear to be less sedative than traditional

agents, which may give rise to:
– problems for treatment of highly agitated/aggressive
patients
– advantages in long-term treatment

• Little known about sexual disturbances

– many are prolactin-independent
– clozapine similar to haloperidol

• Lack of parenteral formulations

(Risperdal Consta now available)
• Cost
• Relatively limited experience and evidence base
 Other properties

In addition to their anti-psychotic properties, neuroleptics have a

number of clinically important properties:

• Treatment resistant bipolar disorder

• Suicide prevention
• Anti-emetic and anti-nauseant effects
• Anti-histamine effects
• Used in intensive care, sedating
• For pain relief, shingles, phantom limb syndrome
• Ability to potentiate the actions of analgesics and anaesthetics