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Screening of Antipsychotic Drugs Seminar
1. SEMINAR ON
Screening of
Antipsychotic Drugs
Dr Divya Krishnan
Calicut medical college
1
2. Contents
• Introduction
• Clinical features of schizophrenia
• Pathophysiology of schizophrenia
• Classification of antipsychotics
• Screening methods for antipsychotics
• Conclusion
2
3. Introduction
Antipsychotics are drugs having therapeutic
effect in psychoses.
Psychoses
Functional disorders Cognitive disorders
- schizophrenia - delirium , dementia
3
4. Schizophrenia
• Affects 1% of population
• Affects young & old
• Affects men & women equally
• Chronic & disabling disease
• Etiology
- Genetic predisposition (10%)
- Prenatal ( viral infections , maternal drug abuse)
- Perinatal ( trauma to brain , oxygen deprivation
- Postnatal (CNS infections)
- Stress in adolescence & young adulthood
4
5. Clinical features
5
Positive symptoms
-Delusions
-hallucinations
-thought disorders
-stereotyped or at
times aggressiveness
Negative symptoms
-introvert behaviour
-poor socialisation
-emotional blunting
Cognitive deficits
-lack of attention
-loss of memory
8. Classical vs Atypical antipsychotics
Classical Atypical
D2 receptor blockade-antipsychotic
action
5HT2 , D4 & weak D2
blockade-antipsychotic action
Extrapyramidal side effects &
hyperprolactinemia due to
strong D2 blockade – side
effects
Lesser incidence of EPS &
hyperprolactinemia due to
weak D2 blockade
Effective against positive
symptoms
Effective against positive C
&
negative symptoms
Effective in patients refractory
to classical drugs 8
10. Screening tests
• Tests designed to exhibit a drug action
• The specific effect of a test drug is compared to a
reference drug already known to be clinically
effective.
• Screening tests are done in experimental models of
the disease.
10
11. Model
• Experimental preparation developed to study a
particular condition in same or different species
• Typically models are animals that mimic a human
condition.
• Rats & mice behavioural models used for screening
antipsychotics
- small size , easy to handle
- sensitive to small doses of drugs
- easily trained
- sturdy to long periods of experimentation
- easily bred
- cheap
11
12. Characteristics of an ideal model
• Behaviour assessed is relevant to clinical condition
• Behaviour paradigm used to index the action of
antipsychotics can be used in rats/mice & humans
• Model is selective & specific for antipsychotics.
• Model is able to differentiate between typical & atypical
antipsychotics
• Model doesn’t require previous pharmacological
manipulation to manifest the behavioural index of
antipsychotic activity
• Model is able to shed light on the mechanism of action
of antipsychotics
12
13. Are available models ideal???
• Models of psychic disturbances difficult to
produce in animals due to complex
pathogenic mechanisms & clinical course.
• Higher intellect of man makes it difficult to
predict the usefulness of behavioural studies
in animals for treatment in man
• Difficulty in conducting experiments in
schizophrenic patients makes it difficult to
assess the validity of animal experiments.
13
NO
14. Animal models
14
Pharmacological
models
Non pharmacological models
Use antipsychotics in
combination with
propsychotics
Test the effects of
antipsychotics given on their
own.
Reveal only
antipsychotic action
mediated via
neurotransmitter
system affected by the
challenge drug.
Behaviour assessed
sometimes doesn’t mimic
human behaviour.
17. Inhibition of Amphetamine induced
hyperactivity in mice/rats
17
• Principle
-Amphetamine (lower doses) causes increased
activity in rats/mice due to excessive dopamine
activity in limbic system.
-Typical antipsychotics can inhibit this hyperactivity
by blocking D2 receptors.
-Atypical antipsychotics weakly or donot inhibit
this hyperactivity due to weak D2 blockade.
-Hyperactivity studied with help of actophotometer.
18. Actophotometer
• Cage 30cm long & 30 cm deep with wire mesh at the
bottom
• 6 lights & 6photo cells in outer periphery of bottom.1
mouse can block only 1 beam of light.
• Photo cell activated when rays of light falling on it
blocked by mice crossing the beam of light.
• Photo cells connected to electronic counter that
counts the number of ‘cut offs’
18
20. Procedure
• Weigh animals & divide into 3 groups of 3
each
• Inject saline into 1 group (control) , CPZ into
2nd group & test drug into 3rd group.(i.p
route)
• After 30 mins ,inject Amphetamine into all
groups.(i.p. route)
• Place each group of animals in
actophotometer seperately & no. of cut off
recorded for 10 mins at the interval of 30
mins.
20
22. Inference
-Counts are decreased in CPZ treated group
compared to the control
-Test drug has antipsychotic property due to D2
blockade if it decreases the counts compared to
the control.
22
23. • Drawbacks
- Hyperactivity is not seen in schizophrenic
patients…the model doesn’t mimic human
disease (however dopamine overactivity in
limbic system is similar in both…hence the
model is predictive for antipsychotic activity)
- Screens only antipsychotic activity due to D2
blockade . Atypical antipsychotics not
screened in this model.
23
24. Inhibition of amphetamine induced
stereotypy
• Principle
-High doses of amphetamine induces stereotypy in
rats/mice (rearing,sniffing,licking ) similar to
behavioural disorder in schizophrenics.
-Stereotypy occurs due to increased dopamine activity
in the limbic system
-Typical antipsychotics can block stereotypy
24
26. • Procedure
- Weigh animals & divide into 3 groups with 3 in each
group
- Inject saline to 1st group(control) , CPZ to 2nd group
& test drug to 3rd group.
- After 30 mins , inject amphetamine into all animals &
place them into separate beakers
- Observe the intensity of stereotypy at 15,30,60mins
after amphetamine inj.
- Score the responses as below:-
1-presence of response
2-moderate response
3-severe response
26
27. • Observation
27
Group Anim
al
No.
Response scores
Rearing
15’ 30’ 60’
sniffing
15’ 30’ 60’
Licking
15’ 30’ 60’
total
Saline +
amphetamine
1
2
3
Mean
CPZ +
Amphetamine
1
2
3
Mean
Test drug +
amphetamine
1
2
3
Mean
28. • Inference
- Stereotypy induced by amphetamine is
blocked by pretreatment with CPZ as
evidenced by decreased scores in this group.
- Test drug has antipsychotic activity due to D2
blockade if scores are decreased compared
to control.
28
29. • Drawbacks
- Similar to previous experiment
- Recent evidence suggests that stereotypy is
mediated through dopamine over activity in
nigro-striatal pathways . Hence inhibition of
stereotypy is more predictive of propensity to
produce EPS than the antipsychotic activity.
29
30. Dopamine agonist models
2 major drawbacks :-
30
Not a model of full
syndrome.Doesnt
cover negative
symptoms or
cognitive deficits
Doesn’t screen
atypical
antipsychotics
31. Glutamatergic models
Overcomes the 2 drawbacks of dopamine agonist models
Eg :-
- Phencyclidine induced hyperactivity/stereotypy
- Phencyclidine induced social withdrawal
Phencyclidine (NMDA antagonist) produces behavioural
syndrome (positive , negative , cognitive ) in healthy men
and in rats that mimics schizophrenia
Inhibition of PCP induced positive symptoms
(hyperactivity , stereotypy) & negative symptoms (social
withdrawal) can be evaluated by separate tests.
PCP induced positive & negative symptoms are reversed
by atypical antipsychotics—important screening models
for atypical & novel antipychotics.
31
32. Newer models based on deficits in sensory gating
Eg : Disruption of Prepulse inhibition of startle response
Prepulse inhibition of startle response
Loud sound causes normal
startle response
Quieter sound just prior to
loud noise reduces startle
response
32
33. • PPI model merits
Reflex occurs in all mammals
Reflex can be measured easily
PPI can be disrupted by D2 agonists/NMDA antagonists
in animals to mimic PPI disruption in schizophrenia.
PPI disrupted by D2 agonists reinstated by both typical &
atypical antipsychotics but that disrupted by
phencyclidine reinstated by atypical antipsychotics only .
Hence PPI disruption can be important screening model
for antipsychotics.
33
34. Non pharmacological models
• Effect on Conditioned avoidance response in
rats
• Study of cataleptic activity of antipsychotics
in rats
34
35. Aim
To study the effect of antipsychotics on condition avoidance
response
Principle
In classical conditioning method , animals trained to act in a
certain way (climbing a pole) in response to a signal (buzzer)
to avoid a noxious stimulus .
Response to the signal is conditioned response while
response to noxious stimulus is unconditioned response
Antipsychotics block CR but do not block UR.
CAR is highly predictive of antipsychotic efficacy
35
Conditioned avoidance response (CAR)
36. 36
Apparatus
Cook’s pole climbing apparatus :
Transparent chamber with electrified
floor & a lid which is attached to the
pole . Whole chamber surrounded by
a wooden box.
Drugs
Saline (0.4ml/kg)
CPZ (3mg/kg)
Clozapine(1mg/kg)
Animals
Rats
37. Procedure
• Rats are trained to climb a pole within 30 sec
when shock is given.
• The shock is then preceded by a buzzer for
15 sec .This is done for 2-3 times a day for 8
days till rats are trained to climb the pole at
the sound of the buzzer.
• Trained animals are treated with the drugs
and CR & UR observed
37
38. • Observations
• Inference
CAR is a specific screening test for antipsychotics
38
Rat no drug CR UR
1 saline Present Present
2 CPZ Absent Present
3 Clozapine Absent Present
39. Study of Catalepsy in rats
• Aim
To study cataleptic activity of Haloperidol &
Clozapine in rats.
• Principle
Catalepsy is the long term maintenance of an
animal in abnormal posture.
Catalepsy is used as a model to study EPS
associated with antipsychotic usage in man.
39
40. Requirements
Animal – Rats (150-200g)
Drugs – Haloperidol & Clozapine(1mg/kg)[dose
at which they block amphetamine induced
hyperactivity)
Equipments - 3cm & 9cm high wooden blocks
Procedure
• Weigh & number the rats.
• Divide the rats into 2 groups with 5 animals
in each group.
• Inject Haloperidol into one group &
Clozapine into second group.
40
41. • Observe severity of catalepsy at different time
intervals in the 2 groups as follows:-
- Stage Ι : Rat moves normally when placed on
table (score = 0)
- Stage II : Rat moves only when pushed (score =
0.5)
- Stage III : Rat placed on the table with front
paws set on a 3cm high block fails to correct
the posture in 10 secs.(score 0.5 for each
paw)
- Stage ΙV : Rat fails to remove its front paws when
placed on a 9cm block.(score = 1 for each
paw)
41
42. • Observe the onset & severity of catalepsy at
5,15,30,45,60,90 ,120 mins.
Observation
Catalepsy is observed in haloperidol group at
the dose that inhibits amphetamine induced
hyperactivity but is absent in clozapine group
at the dose that inhibits hyperactivity.
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44. Future prospects
• PCP induced models of cognitive deficits in
rats
- Delayed matching or non matching to sample
indicates deficits in memory
- Maze based strategy shift task used to depict deficits
in behaviour flexibility , strategy shifting
- 5 choice serial reaction time task to show deficits in
attention
Reversal of these deficits has been demonstrated by
some of the atypical antipsychotics
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45. • Developmental models
- Systemic administration of L-nitroarginine to rat
neonates produces morphological & post pubertal
behavioural changes similar to schizophrenia.
• Transgenic mice
- Chakragati mouse : insertional
transgenic mouse that has
morphological and behavioural
abnormalities mimicking
schizophrenia.
Can become effective screening
models for antipsychotic drugs
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46. Conclusion
• PCP induced disruption of PPI & inhibition of
CAR are the 2 screening tests most widely
used
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