Introduction

Schizophrenia is a group of illnesses of unknown origin that occur in approximately 1% of the adult population in most countries in which surveys have been conducted. The economic and social cost is considerable, as approximately 40% of all hospitalized psychiatric patients in most industrialized countries suffer from schizophrenia and related disorders. At least 25 major family studies have been published in the last three decades that have consistently shown that the risk for the disease in the relatives of schizophrenics is substantially greater than that expected in the general population. While most of these studies have been criticized on methodological grounds, it is generally accepted that schizophrenia does have a genetic basis.

Schizophrenia usually begins during adolescence or young adulthood and is characterized by a spectrum of symptoms that typically include disordered thought, social withdrawal, hallucinations (both aural and visual), delusions of persecution (paranoia) and bizarre behaviour. These symptoms are sometimes categorized as ''positive'' (e.g. hallucinations) and ''negative'' (e.g. social withdrawal and apathy) (Figure 11.1). So far, there is no known cure and the disease is chronic and generally progressive. Nevertheless the introduction of the phenothiazine neuroleptic chlorpro-mazine by Delay and Denecker in France in 1952 initiated the era of pharmacotherapy in psychiatric medicine and has led to the marketing of many dozens of chemically diverse antipsychotic drugs that have played a major role in limiting the disintegration of the personality of the schizophrenic patient. Drugs used to treat psychotic disorders such as schizophrenia are called neuroleptics, antipsychotics or major tranquillizers.

Although the discovery that chlorpromazine and related phenothiazine neuroleptics were effective in the treatment of schizophrenia was

Fundamentals of Psychopharmacology. Third Edition. By Brian E. Leonard 2003 John Wiley & Sons, Ltd. ISBN 0 471 52178 7

I. "Positive" Psychotic Symptoms:

Delusions Hallucinations

II. Disorganized Symptoms: III. Negative-Deficit Symptoms:

Contused thinking Disorganized speech Disorganized behaviour Disorganized perceptions

Emotional flattening Alogia - limited speech Avolitian - lack ot motivation Anhedonia- lack of interest & pleasure

Catatonia Agitation

Social/Occupational Dysfunction

Interpersonal relationships Self-care

IV. Cognitive Symptoms; 4- Attention I Memory

4- Executive functions (e.g. abstraction)

V. Mood Symptoms:

Dysphoria Suicidal ity Hopslesslsss

Figure 11.1. Schizophrenia's core symptom clusters.

serendipitous, investigators soon attempted to define the mechanism of action of this group of drugs that had begun to revolutionize psychiatric treatment. It was hoped that the elucidation of the mechanism of action of such neuroleptics would not only enable more selective and potent drugs to be discovered, but also give some insight into the pathology of schizophrenia.

A major advance came with the discovery that chlorpromazine, haloperidol and other related neuroleptics not only antagonized the stimulant action of L-dopa (levodopa) in animals but also enhanced the accumulation of the main metabolites of dopamine and noradrenaline in rat brain. These findings led to the suggestion that the neuroleptics must be blocking the postsynaptic receptors for dopamine, and to some extent noradrenaline, thereby leading to a stimulation of the presynaptic nerve terminal through a feedback mechanism. The seminal paper by Carlsson and Lindqvist in 1963 helped to lay the basis for the dopamine hypothesis for schizophrenia and the mode of action of neuroleptic drugs. Later studies in Canada and the United States of America showed that there is a good correlation between the average clinical dose of neuroleptic administered and the affinity of the drug for postsynaptic dopamine receptors. The dopamine hypothesis of schizophrenia has reasonably good support from pharmacological studies, but the supporting evidence from post-mortem material, and from studies on schizophrenic patients using techniques such as positron emission tomography (PET), are more controversial. Whatever the final outcome, however, the dopamine hypothesis has had a major impact on drug development and, even though dopamine may not be the only neurotransmitter involved in the illness, it is leading to an investigation of the interconnection between dopamine and other transmitters which may be more directly involved in the pathology of the illness.

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