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Antipsychotic screening- Dr Divya Krishnan

This document summarizes a seminar on screening methods for antipsychotic drugs. It discusses various animal models used to screen antipsychotics, including pharmacological models using dopamine agonists like amphetamine that cause hyperactivity and stereotypy in rats, and glutamatergic models using NMDA antagonists like phencyclidine. Commonly used tests involve measuring a drug's ability to inhibit amphetamine-induced hyperactivity and stereotypy in rats, which can identify drugs with D2 receptor blocking effects. Newer models based on deficits in sensory gating like prepulse inhibition of the startle response are also described. No animal model fully captures the human condition of schizophrenia, but these tests provide methods to screen drugs' antip

Health & Medicine◦
SEMINAR ON Screening of Antipsychotic Drugs Dr Divya Krishnan Calicut medical college 1
Contents • Introduction • Clinical features of schizophrenia • Pathophysiology of schizophrenia • Classification of antipsychotics • Screening methods for antipsychotics • Conclusion 2
Introduction Antipsychotics are drugs having therapeutic effect in psychoses. Psychoses Functional disorders Cognitive disorders - schizophrenia - delirium , dementia 3
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
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
Pathophysiology of schizophrenia o Neurochemical theories : 1. Dopamine theory 2. Serotonin theory 3. Glutamate theory 6
Classification of antipsychotics  Classical antipsychotics  Phenothiazines Aliphatic side chain : Chlorpromazine , Triflupromazine Piperidine side chain : Thioridazine Piperazine side chain : Trifluoperazine , Fluphenazine  Butyrophenones Haloperidol , Trifluridol , Penfluridol  Thioxanthenes Flupenthixol  Other heterocyclics Pimozide , Loxapine  Atypical antipsychotics  Clozapine , Risperidone , Olanzapine , Quetiapine , Aripiprazole , Ziprasidone 7
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
Screening Of antipsychotics 9
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
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
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
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
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.
• Behaviour paradigms assessed in the tests - Locomotor activity (hyperactivity , stereotypy) - Social behaviour - Sensorimotor gating measures (PPI) - Catalepsy - Conditioned responses - Cognition (attention ,memory) 15
Available models Pharmacological models  Dopamine agonist models - Amphetamine/apomorphine induced hyperactivity - ’’ ’’ ’’ stereotypy  Glutamatergic models - Phencyclidine induced hyperactivity/stereotypy - Phencyclidine induced social isolation  Recent models Amphetamine/phencyclidine induced Prepulse inhibition (PPI) disruption models Non pharmacological models catalepsy conditioned avoidance response 16
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.
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
• Requirements Animal : mice/rats Equipments : actophotometer , syringes , needles Drugs : Saline Amphetamine (1.5mg/kg) CPZ (3mg/kg) Test drug (x mg/kg) 19
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
• Observations 21
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
• 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
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
• Requirements Animal : mice/rats Equipment : 250ml clean beakers , syringes , needles Drugs : Saline Amphetamine ( 5mg/kg) CPZ (3mg/kg) Test drug 25
• 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
• 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
• 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
• 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
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
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
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
• 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
Non pharmacological models • Effect on Conditioned avoidance response in rats • Study of cataleptic activity of antipsychotics in rats 34
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 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
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
• 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
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
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
• 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
• 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. 42
Therapeutic efficacy vs adverse effect in typical & atypical antipsychotics 43
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 44
• 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 45
Conclusion • PCP induced disruption of PPI & inhibition of CAR are the 2 screening tests most widely used 46
Antipsychotic screening- Dr Divya Krishnan