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.

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

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).

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

One 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).

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

• 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).

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

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.

• 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

• 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

• 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)

• 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

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).

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

• 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.

• 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 ...

• 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

• 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. 

• The Psychiatric Times is a rich source of articles on mental illness.

• 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.