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The Search for Novel Antipsychotic Drugs
Author Paul Kenyon

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Overview :

This lecture builds on the material we explored in a previous lecture on schizophrenia. The main purpose of the lecture is to show you how behavioural techniques can be used to discover more effective drug treatments for schizophrenia. The lecture begins with a brief rationale for the use of drugs to treat schizophrenia, before moving on to consider side effects associated with the use of the largest group of antipsychotic drugs, so-called classic antipsychotics. The location and roles of the nigrostriatal and mesolimbic dopamine system in EPS and symptom control are described. The strengths and weaknesses of the Discriminated Avoidance Inhibition Model as a screening technique are explored before reviewing the Amphetamine-Induced Stereotyped Behaviour Model . The similarities and differences between classic and atypical antipsychotics are presented as a rationale for introducing a new screening technique - the Amphetamine-Induced Stereotyped Locomotion Model . In this model hyperactivity and stereotypy of amphetamine treated rats can be measured separately. Finally the effects of an atypical drug are examined in this new screening technique.


 
Evidence for Biological Basis of Schizophrenia

 incidence of schizophrenia is higher in people who are related to a schizophrenic  

Three lines of evidence suggest that schizophrenia has a biological basis:

  1. A genetic factor would seem to account for the finding that the incidence of schizophrenia is higher in people who are related to a schizophrenic.
  2. Amphetamine-induced psychosis resembles paranoid schizophrenia and involves specific brain transmitter systems
  3. Antipsychotic drugs alleviate some schizophrenic symptoms presumably by interfering with specific chemical transmitter systems
Points to ponder
If schizophrenia is a physical illness, why is diagnosis based on clinical interview rather than a blood or urine test?

Clearly schizophrenia is not inherited in the same way as eye colour. What do you think might be inherited by the children of schizophrenic parents?


 
Diagnosis and Treatment of Schizophrenia

Diagnosing schizophrenia should be carried out by a psychiatrist using criteria set out in a diagnostic manual (e.g. DSM-III-R). In brief, schizophrenics typically suffer from delusions (e.g. paranoia), hallucinations (auditory and visual), disordered thought, inappropriate emotional behaviour, social withdrawal, and apathy. Lickey and Gordon (1991) provide a clear and detailed description of the difficulties and uncertainties involved in diagnosing schizophrenia.

There is no known cure for schizophrenia. Left untreated the disease persists and the symptoms generally get worse. Thankfully, antipsychotic drugs can limit the progressive disintegration of the schizophrenic's personality.

Antipsychotic drugs are also known by the older terms:

  • neuroleptics
  • major tranquillizers

This diagram shows the percentage of patients treated successfully with each of four different treatment methods.

Successful treatment was defined as release from the hospital within one year.

Redrawn from data in May (1968).


Reduced Relapse Rates by Combining Psychological & Drug Therapies

Although antipsychotic drugs alleviate the symptoms of schizophrenia, about 90% of patients eventually relapse (the symptoms return) if they stop taking medication.

Furthermore, about 40% of patients relapse - even if they continue to take an antipsychotic drug.

Reduced relapse rates by combining psychological and drug therapiesOne way of helping these people is to combine a psychological treatment with drug treatment. For example,

  • Social skills training helps the patient develop skills to deal with their family, everyday stress, as well as the practical skills involved in obtaining and holding down a job, managing money, and daily tasks such as managing diet and general health.
  • Family therapy is designed to help families understand schizophrenia, and appreciate that stressors may precipitate the onset and relapse of schizophrenia. This educational element is then followed by sessions in which the family is helped to develop strategies to manage, or avoid, these stressors in the future (Birchwood et al, 1988).

Notice the dramatic reduction in relapse by combining drug with social skills training and family therapy.

Figure drawn from data in Hogarty et al (1986).

Relapse rates under drug and placebo therapy

Figure drawn from data in Hogarty et al (1977).

 


Side Effects of Classic Antipsychotics

If, combining drug and psychological therapies produces low relapse rates you might think that the problem of schizophrenia has been solved . Unfortunately most antipsychotic drugs produce side effects as well as controlling the disease. The most commonly used antipsychotic drugs - typical or classic antipsychotics - cause very unpleasant side effects.

Classic antipsychotics produce a constellation of disordered movements called the extrapyramidal syndrome (EPS) . EPS is thought to be caused by effects of classic antipsychotics on the extrapyramidal system of the brain.
  • EPS occurs in about 40-50% of patients given classic antipsychotics
  • EPS can be controlled by drugs that interfere with the cholinergic system (anticholinergic drugs)
  • EPS is made worse by drugs that facilitate the cholinergic system ( cholinomimetic drugs )
  • Parkinson's disease is known to be associated with a loss of dopamine (DA) in the substantia nigra which is part of the nigrostriatal system
  • Normally the nigrostriatal system inhibits the cholinergic system, therefore
  • DA deficiency in the nigrostriatal system removes an inhibitory influence on pathways that release acetylcholine.

These observations suggest that the EPS may be the result of classic antipsychotic drugs blocking receptors in the nigrostriatal DA system.

Extrapyramidal Side Effects
  • Dystonia - uncontrolled movements of the face, neck, and tongue
  • Oculomotor crisis - uncontrollable eye movements
  • Akathisia - restlessness & agitation
  • Parkinsonian symptoms - slow movement, shuffle, facial tremor
  • Tardive dyskinesia - "late appearing movement disorder", jerky movement of tongue & face, eventually entire body affected.

Source: Diaz (1977).


Dopamine Systems in the Brain

There are a number of collections of nerves in the brain that release dopamine.

Two systems have been implicated in the behavioural effects of antipsychotic drugs.

  1. The nigrostriatal system is thought to be involved in EPS produced by neuroleptics.
  2. An action on the mesolimbic system is thought to alleviation schizophrenic symptoms
  1. the nigrostriatal system projects forward in the brain from the substantia nigra (black mass) to the corpus striatum (striped body) which consists of:
    • caudate
    • putamen
    • globus pallidus
  2. the mesolimbic system - projects from the ventral tegmental area (VTA) to limbic structures :
    • septum
    • olfactory tubercle
    • nucleus accumbens
    • amygdala
    • piriform cortex

The Need for Novel Antipsychotic Drugs

When antipsychotic drugs were first used, some psychiatrists increased the dose of the drug until extrapyramidal side effects (EPS) appeared. They believed that the appearance of side effects indicated that sufficient drug had been given to affect the patient's schizophrenic symptoms (figure redrawn from data in Marsden et al, 1986, table 12.2). However antipsychotic drugs

  • differ in the extent to which they produce extrapyramidal side effects
  • do not vary in their clinical effectiveness

Consequently there is no evidence to support the view that the appearance of EPS is a sign of clinical effectiveness.

This diagram was constructed from data in Marsden et al, (1986, Table 12.2) and shows that the risk of developing extrapyramidal side effects is not the same for all types of antipsychotic drugs. i have included the table of raw data to show how I calculated the statistic 'Cumulative percentage of patients with EPS'. This data will be used later in this lecture when we discuss the link between EPS and discriminated avoidance behaviour.

Percentage of patients exhibiting side effects under placebo and three antipsychotic drugs
Extrapyramidal side effect (EPS) Placebo Thioridazine Chlorpromazine Fluphenazine
Muscle rigidity 8.1 4.4 12.5 24.2
Facial rigidity 5.4 8.8 12.5 14.3
Tremor of hands, arms and face 5.4 13.2 5.7 12.1
Loss of associated movements 2.7 0 3.4 19.8
Akathisia 4.1 3.3 5.7 12.1
Increased salivation 0 3.3 5.7 8.8
Dystonia 0 1.1 4.5 6.6
Oculogyric crisis 0 0 1.1 0
Cumulative percentage with EPS 25.7% 34.1% 51.1% 97.9%

There is clearly a need for new antipsychotic drugs that possess the beneficial effects of classical antipsychotics in treating schizophrenia, but lack the potential to cause extrapyramidal side effects. There is good reason to believe that that it will be possible to develop new drugs with this profile of effects. For example, in an earlier part of your course you learned about atypical antipsychotic drugs. Atypical antipsychotics (e.g. sulpiride and clozapine) are as effective as older classic antipsychotics in controlling the symptoms of schizophrenia, but do not cause EPS.

Unfortunately these drugs have other side effects (e.g. clozapine causes agranulocytosis ), and therefore the search continues for an effective treatment for schizophrenia.

The rest of this lecture is concerned with behavioural screening tests that have been employed to detect novel antipsychotic drugs.


Discriminated Avoidance Inhibition Model

Carlton (1983) describes an important behavioural technique that could be used to detect antipsychotic drugs. Rats are first trained to avoid or escape shock on a discriminated avoidance schedule.

In this situation the animal:

When rats - that have successfully learnt to avoid shock - are injected with antipsychotic drugs they:

The diagram (redrawn from Cook & Sepinwall, 1975) shows that chlorpromazine disrupts avoidance behaviour, but has no effect on escape behaviour. Avoidance disruption is dose dependant. Higher doses cause more disruption. But even at the highest dose, escape behaviour remains unaffected. I have magnified the bottom part of the graph to emphasize this important difference between the effect of the antipsychotic on avoidance and escape behaviours.


These findings are encouraging. The next step is to investigate a large number of antipsychotic drugs to confirm that they all exert this differential effect on avoidance-escape behaviours, and examine their relative potencies.

In common with all types of drugs, antipsychotics differ in their clinical potencies. Some drugs must be administered in large doses to control schizophrenic symptoms. Others are more potent, the patient can be given a smaller dose to produce the desired clinical effect. Drugs also differ in their ability to affect animal behaviour. ED50 avoidance is the dose of the drug that - when injected - disrupts avoidance behaviour by 50%. The ED50 value is calculated from the drugs dose response curve. Therefore it is an Estimated Dose.

These results confirm the impression that antipsychotics disrupt avoidance behaviour. Furthermore, there is high correlation between the amount of drug needed to disrupt avoidance in the rat, and the dose used to treat schizophrenia. Nevertheless, there is an important ' outlier ' value.


This table includes the raw data I used to construct the figure. I have included this information because there is considerable clustering of drugs with ED50 values <1 mg/kg. Source: Carlton ( op cit ). In addition, the table suggests that there may be a correlation between a drug's effect on avoidance behaviour in rats and tendency to produce EPS in humans

Drug  ED50-Avoidance Median daily dose Cumulative percentage with EPS
promazine 24.7 2085
clozapine 7.2 1538
mesoridazine 6.5 412
thioridazine 5 788 34.1%
molindone 2.5 122
chlorproyhixene 1.9 330
thiothixene 1.9 38
chlorpromazine 1.8 750 51.1%
triflupromazine 0.87 285
prochlorperazine 0.44 105
fluphenazine 0.37 8 97.9%
trifluoperazine 0.3 22
perphenazine 0.24 68
pimozide 0.23 8
haloperidol 0.16 8

These results suggest that:

In essence I am suggesting that the strong correlation between a drugs potency in the animal test and the clinic may be linked to the tendency for some drugs to affect the extrapyramidal motor system. This is a plausible connection because any drug which interfered with an animl's motor function would be expected to disrupt performance on the discriminated avoidance task.

Point to ponder:
Could the differential effect of classic antipsychotic drugs on avoidance and escape behaviours be explained in terms of drug effects on the extrapyramidal system?

 


Does Discriminated Avoidance Inhibition Predict EPS?

We now know that antipsychotic drugs produce two effects in patients:

  1. clinical improvement
  2. unwanted extrapyramidal side effects (EPS)

We need to be certain that a screening test for improved antipsychotic drugs predicts clinical improvement. Clearly there is little value in a screening technique that is based on a drugs ability to produce unwanted side effects in patients, (unless that is the primary purpose of the test). There is further evidence that disruption of discriminated avoidance responding is an indication that the drug will produce EPS in patients. For example, consider the following profile of action shown by drugs that effect the cholinergic system.

Effect on cholinergic system Effect on EPS in humans Effect on discriminated avoidance in rats
Interfere with the cholinergic system (anticholinergic ) Reduce EPS Reduce effect of antipsychotics
Facilitate the cholinergic system ( cholinomimetic ) Increase EPS Disrupt avoidance behaviour

The effects of cholinergic drugs on discriminated avoidance behaviour suggests that

  1. The ability to disrupt avoidance is not a unique property of antipsychotics: Cholinomimetics share this ability
  2. The cholinergic system is involved in the effects of antipsychotics on avoidance: Cholinomimetics reverse the effects of antipsychotics on avoidance.

These findings are consistent with the notion that neuroleptic disruption of avoidance predicts EPS potential, rather than antipsychotic potential.


Amphetamine-Induced Stereotyped Behaviour Model

We have seen that the Discriminated Avoidance Inhibition Model may have limited usefulness in detecting the antipsychotic potential of new drugs. But there are other ways of discovering new safer drugs that could be used to treat schizophrenia.

A well established screening test for novel antipsychotic drugs involves examining their ability to antagonize the effects of amphetamine on animal behaviours. We have studied this model in detail in a previous lecture . Here is a brief overview.

Injecting animals, usually rats, with amphetamine produces:
  • an increase in locomotion at low and intermediate doses
  • an increase in stereotyped behaviours at higher doses

A behaviour is said to be stereotyped when it is is repeated in an apparently meaningless fashion.
The cardinal features of stereotypy are:

  • repetition of the behaviour
  • invariance - the behaviour is the same each time it is emitted
  • the apparent purposeless nature of the behaviour
Relationship between Stereotypy Scores and amphetamine dose
  • Stereotypy rating scales express the degree of stereotypy as a single number.
  • Stereotypy scores increase with increasing dose of amphetamine.

cartoon showing stereotyped behaviour

Amphetamine-induced increases in locomotion are particularly marked at relatively low doses (less than 4 mg/kg) of the drug.

As we saw in an earlier lecture , classic antipsychotic drugs (e.g. pimozide)

  1. Block the effect of amphetamine on locomotion,
  2. Block the effect of amphetamine on stereotyped behaviours

However, atypical antipsychotics (e.g. clozapine)

  1. Block the effect of amphetamine on locomotion, but
  2. Do not antagonize the effects of amphetamine that are measured on stereotypy rating scales

Importantly both atypical and classic antipsychotics antagonize amphetamine-induced hyperactivity.


Amphetamine-Induced Stereotyped Locomotion

It is now time to pull together a number of things discussed in this lecture to see if we can construct a new model of antipsychotic potential

Some relevant observations from previous research:
  • In humans both classic and atypical antipsychotics are clinically effective
  • In rats both types of drug reduce amphetamine induced increases activity
  • In humans only classic antipsychotics produce severe extrapyramidal side effects
  • In rats only classic antipsychotics reduce amphetamine induced stereotyped behaviour .

Here is a table setting out these findings

The effects of drugs in schizophrenics and rats treated with amphetamine
  Antipsychotic Reduce locomotion EPS side effects Reduce stereotypy
  in humans in rats in humans in rats
Classic
Atypical
This analysis suggests that:
  • antagonism of amphetamine induced hyperactivity may predict antipsychotic potential
  • antagonism of amphetamine induced stereotyped behaviour may reflect a drug's extrapyramidal side effect potential

We began a series of experiments to test this hypothesis see: Kenyon, Moore & Hampson, ( Current Psychology: Research & Reviews , 11, 241-253, 1992)

 

Point to ponder
What would be the advantages of having an animal model of schizophrenia that distinguished between classic and atypical antipsychotic drugs?

Measuring Amphetamine-Induced Stereotyped Locomotion

In order to classify a response as stereotyped it should be exhibited in a repetitive and invariant fashion. Several years ago Schiorring (1979) pointed out that locomotion under amphetamine exhibits stereotyped properties.

This means that we can use one behaviour (locomotion) to study the effects of antipsychotic drugs on both amphetamine-induced hyperactivity and stereotyped behaviour.

Schematic of the open fieldAn open-field is a large box with lines drawn on the floor that divide the floor into four quadrants. The rat is put on the floor, and its movement between quadrants is recorded. Mueller et al.(1989) introduced a way to measure stereotyped locomotion in the open-field test.


Here is a tracing of a rat's movement
in the open-field apparatus

rat's movement in the open-field apparatus
In the tracing the rat makes 6 trips
in the following sequence of trip lengths:
  • Length 1 ( red )
  • Length 2 ( yellow )
  • Length 3 ( green )
  • Length 4 ( blue )
  • Length 1 ( red )
  • Length 1 ( red )

This sequence of various trip lengths contains:

  • 4 Change trips
  • 1 Repeat trip

Line colour Trip Length looks like ..
Red line length 1
Yellow line length 2 .
Green line length 3 .
Blue line length 4

Mueller developed a statistic - called gamma - to measured the repetitiveness in locomotion.

The number of repeat and change trips are entered into a formula to calculate the gamma statistic.

Gamma = (Repeat trips)/(Repeat trips + Change trips)

In this example Gamma = (1)/(1+4)=0.20


Computer Based System for Recording Locomotion
system for recording locomotion The diagram shows the apparatus Kenyon et al (1992) used to record the effects of amphetamine on locomotion. The open-field test apparatus is a simple open topped box with 1 metre sides painted black to provide contrast with the white rat.

A videocamera is suspended directly over the centre of the open-field. The image from the camera is fed into a digitizer which locates the position of the white rat against the black background of the apparatus. The position of the rat is translated into a stream of X,Y co-ordinates which represent the position of the rat as it moves around the open-field. This data stream is fed into a computer which displays the position of the rat on a screen and stores the X,Y values.

After the test session the data stream is analysed and the locomotion of the rat is broken down into distance moved per minute and the number of trips of various lengths (1 through 4 see above for definition of Trip Lengths)

Point to ponder
What properties of stereotyped locomotion are not measured by this apparatus?



Distance Moved Under Amphetamine & Sulpiride

Distance moved under amphetamine and sulpiride The diagram shows the mean distance moved by four independent groups of rats:
  • Vehicle+Saline: rats treated with vehicle + saline
  • Sulpiride+Saline: rats treated with 20 mg/kg sulpiride + saline
  • Vehicle+Amphetamine: rats treated with vehicle + 3.5 mg/kg amphetamine.
  • Sulpiride+Amphetamine: rats treated with 20 mg/kg sulpiride + 3.5 mg/kg amphetamine

Results:

  • amphetamine increased locomotion dramatically
  • pretreatment with sulpiride significantly reduced this effect of amphetamine


Increase in Length 4 Trips Under Amphetamine

We also found that amphetamine produced an increase in repetitive (stereotyped?) walking around the sides of the apparatus. This was reflected by an increase in the number of Length 4 trips under amphetamine.

The diagram shows the number of complete trips around the perimeter of the apparatus ( Length 4 trips) per 5 min during the 105 min test period.

Sulpiride significantly reduced the number of length 4 trips in amphetamine treated rats (compare the behaviour of the Sulpiride+amphetamine group with the Vehicle+amphetamine group).

Point to ponder:
Is this result surprising in view of the effect of sulpiride on distance moved in amphetamine treated rats?

 

Increase in Length 4 trips under amphetamine

Lack of Effect of Sulpiride on the Proportion of Length 4 Trips Under Amphetamine

Pre-treatment with sulpiride reduces the amphetamine-induced increase in Length 4 trips. This might lead you to conclude that sulpiride reduces the stereotyped locomotion produced by amphetamine but, as we have already seen, rats injected with sulpiride + amphetamine show less activity than rats injected with just amphetamine (Vehicle+Amphetamine group). Therefore the reduction in Length 4 trips might just be the result of the animal moving around less in the open-field.

This led us to focus on the proportions of Length 4 trips in the Vehicle+Amphetamine and Sulpiride+amphetamine groups.

effect of sulpiride on the proportion of Length 4 trips under amphetamine The diagram shows the effect of sulpiride pretreatment on the proportion of Length 4 trips under amphetamine:
  • Only rats treated with amphetamine ( Vehicle+amphetamine and Sulpiride+amphetamine groups) show any significant number of Length 4 trips.
  • 30-40% of trips are Length 4 at the time of peak drug effect i.e. 45 minutes after amphetamine injection.
  • Pre-treatment with sulpiride ( Sulpiride+amphetamine ) has little impact on the proportion of Length 4 trips during the period of greatest activity (the first 45-60 minutes after amphetamine).

Conclusion:

  • the atypical antipsychotic sulpiride reduces amphetamine-induced hyperactivity,
  • sulpiride does not reduce the proportion of stereotyped (length 4 trips) locomotion produced by the drug.


Gamma Scores Under Amphetamine & Sulpiride

Kenyon et al's (1992) results provoke a series of questions:
  • Can the results be replicated by an independent group of scientists?
  • Do typical antipsychotic drugs reduce amphetamine-induced hyperactivity and stereotyped locomotion?
  • Do other atypiocal antipsychotics reduce amphetamine-induced hyperactivity but leave stereotyped locomotion intact?

The first question is the most important. It gives any scientist greater confidence if their results can be replicated by an independent laboratory. Fritts, Mueller and Morris (19970 have found that sulpiride (25mg/kg) does not reduce amphetamine-induced stereotyped locomotion. They used Mueller's gamma statistic which is a measure of the sameness in the rat's trips around an open-field.

This result confirms our impression that sulpiride exerts a differential effect on amphetamine-induced behaviours. Locomotion is reduced, but the stereotyped nature of locomotion under amphetamine is not abolished by atypical antipsychotic drugs.

But that still leaves two unanswered questions ...

Direct comparison of classic and atypical antipsychotic drugs on stereotyped locomtion

Points to ponder
What would you expect classic antipsychotic drugs to do to the proportion of Length 4 trips?
How would you improve this experiment to include the properties of stereotyped locomotion that were not measured in this study?
Moore & Kenyon (1994) examined the effects the classic antipsychotic haloperidol, and two atypical antipsychotics - sulpiride and clozapine for their ability to antagonize
  • amphetamine-induced hyperactivity and
  • amphetamine-induced stereotyped locomotion

The results presented below indicate that

  • Both classic and atypical antipsychotics reduce amphetamine induced hyperactivity
  • atypical antipsychotics do not disrupt stereotyped locomotion
  • the classic drug - haloperidol reduces stereotyped locomotion
  • These results suggest that differential antagonism of the effects of amphetamine on locomotion may be a fruitful screening technique to detect putative atypical antipsychotic
Type of drug Effect on amphetamine induced hyperactivity Effect on amphetamine induced stereotyped locomotion
Classic antipsychotic Reduction Reduction
Atypical antipsychotic Reduction No change


References


Supplementary Material
  • Here is an extremely useful guide from the National Institute of Mental Health which sets out to answer several important questions about schizophrenia:
    • What is it?
    • What causes schizophrenia?
    • How is it treated?
    • How can other people help?
    • What is the outlook?
  • Warning: The National Institute of Mental Health (NIMH) Page does not contain fancy graphics and not too much user friendly links. Actually, it is a plain text about the basic concepts of schizophrenia. Probably the best thing is to print the document because it gives a valuable introduction to schizophrenia that covers all the basic facts. Despite the old-fashioned outline of the page, it is a source to be considered because in the US the NIMH exerts significant influence on research and treatment decisions.
  • The Internet Mental Health Pages about Schizophrenia provide descriptions, treatment approaches as well as current research projects. All information is clearly structured and easy to access. Regular updates seem to be common. In addition, there is the possibility y to look beyond schizophrenia because Internet Mental Health covers most of the current mental health issues. 
  • Pies (2000) The Role of Psychosocial Treatments in Schizophrenia. Psychiatric Times  March 2000   Vol. XVII  Issue 3
    After reading this article, you will be familiar with:
    • When is exploratory, insight-oriented psychotherapy indicated for patients with schizophrenia?
    • Helpful modifications to prevent counter-therapeutic factors during individual therapy with these patients.
    • Which approach in family educational intervention is most helpful.
    • The appropriate use of vocational rehabilitation for patients with schizophrenia.
Copyright Dr. C.A.P. Kenyon 1994-2006