Antipsychotic Drugs and Their Side-Effects

Thomas R.E. Barnes, Peter Jenner

• Publisher: Academic Press
• Year: 2013
• Print ISBN: 9780120790357
• eBook ISBN: 9781483288109
• Topic: Medicine
• Subtopic: Pharmacology

In line with other volumes in the Neuroscience Perspectives Series, this volume covers the background, pharmacology, molecular biology, and biochemistry of antipsychotic drugs, together with an overview assessment of the therapeutic considerations. Over the past 40 years, the effectiveness of conventional neuroleptic agents for psychotic illness has been offset by a wide range of adverse side-effects, including motor side-effects like parkinsonism. Studies show that lowering doses may still produce the antipsychotic effect while lessening the risk of side-effects. As all available antispychotic drugs are able to block dopamine, specifically D2 receptors, doses below the threshold level for producing acute motor disorder can still be therapeutically effective. With the identification and characterization of multiple dopamine receptors, the possibility of more selective drugs with better side-effect potential has arisen. Other novel antipsychotic agents include D1 receptor blockers, partial dopamine agonists and non-dopamine drugs such as 5-HT receptor blockers, sigma receptor antagonists and NMDA receptor agonists. This volume reviews both the basic science of the conventional and atypical neuroleptics and their present and potential therapeutic use.

Part I

Basic science

CHAPTER 1

THE PHARMACOLOGY OF THE PHENOTHIAZINES, BUTYROPHENONES, THIOXANTHINES AND DIPHENYLBUTYLPIPERIDINES

Brian E. Leonard, Department of Pharmacology, University College, Galway, Republic of Ireland

Publisher Summary

The use of the “classical” neuroleptics, as exemplified by the phenothiazines, thioxanthines, butyrophenones and diphenylbutylpiperidines, has been a landmark in the pharmacotherapy of schizophrenia and psychotic disorders. The efficacy of such drugs in the alleviation of the symptoms of schizophrenia is universally accepted. However, it is also evident that they have a spectrum of adverse effects that frequently renders their long-term use problematic. Side-effects such as akathisia, parkinsonism, tardive dyskinesia and the frequent changes in peripheral autonomic activity are largely predictable from the structure of the molecules and the basic animal pharmacology data. Such adverse effects, and the difficulty encountered in reducing their frequency and severity by concurrent medication, has stimulated the development of such “atypical” neuroleptics as the benzamides and clozapine, which might combine efficacy with a reduction in the side effects. Clozapine has received extensive interest in the recent years because of its proven benefit in the treatment of schizophrenia patients who fail to respond adequately to conventional neuroleptic treatment, and has a unique inhibitory profile on dopamine receptors.

Table of Contents

1.1 Introduction

1.2 Effects of Neuroleptics on Dopaminergic and Other Neurotransmitter Systems

1.3 Heterogeneity of Dopaminergic Neurons in the Mesocortical System

1.4 Interaction of Neuroleptics with Non-dopaminergic Receptors

1.5 Action of Neuroleptics on Different Types of Neurotransmitter Receptor

1.6 Structure-Activity Relationships and Pharmacokinetic Aspects

1.7 Behavioural and Pharmacological Properties of the Neuroleptics

1.8 Clinical Pharmacology of the Neuroleptics

1.9 Hormonal Changes Resulting From Neuroleptic Treatment

1.10 Conclusion

1.1 Introduction

Schizophrenia is a group of illnesses of unknown origin that occurs in approximately 1% of the adult population in most countries in which surveys have been conducted. The economic and social costs of schizophrenia are 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; all have consistently shown a risk for the disease in the relatives of schizophrenics that 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 (Kendler, 1987).

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 and bizarre behaviour. So far, there is no known cure and the disease is chronic and generally progressive. Nevertheless, the introduction of the phenothiazine neuroleptic chlorpromazine by Delay and Deniker in France in 1952 initiated the era of pharmacotherapy in psychiatric medicine and has led to the marketing of dozens of clinically diverse antipsychotic drugs that have played a major role in limiting the disintegration of the personality of the schizophrenic patient.

Although the discovery that chlorpromazine and related phenothiazine neuroleptics were effective in the treatment of schizophrenia was 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 by Carlsson & Lindqvist (1963) that chlorpromazine, haloperidol and other related neuroleptics not only antagonized the stimulant action of L-dopa 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 & Lindqvist (1963) helped to lay the basis of the dopamine hypothesis of schizophrenia and the mode of action of neuroleptic drugs. Later studies in Canada and the USA showed that there was a good correlation between the average clinical dose of neuroleptic administered and the affinity of the drug for postsynaptic dopamine receptors (Seeman et al., 1976; Creese & Hess, 1986; Creese et al., 1976). The dopamine hypothesis of schizophrenia, which has been reviewed by Carlsson (1988) amongst others, has reasonably good support from pharmacological studies but the supporting evidence from post mortem material (Crow et al., 1982), and from studies on schizophrenic patients by means of imaging techniques such as positron emission tomography, are more controversial (Wong et al., 1986; Farde et al., 1987). Whatever the final outcome, however, the dopamine hypothesis has had a major impact on drug development. Even though dopamine may not be the only neurotransmitter involved in the illness, the hypothesis 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.

1.2 Effects of neuroleptics on dopaminergic and other neurotransmitter systems

Because of the discovery that all neuroleptics in clinical use are dopamine receptor antagonists, and that an abnormality in the dopaminergic system might underlie the pathology of the condition, the action of neuroleptics on the dopaminergic system has been extensively studied over the past two decades. Four major anatomical divisions of the dopaminergic system have been described:

(1) The nigrostriatal system, in which fibres originate from the A9 region of the pars compacta and project rostrally to become widely distributed in the caudate nucleus and the putamen.

(2) The mesolimbic system, where the dopaminergic projections originate in the ventral tegmental area, the A10 region, and then spread to the amygdala, pyriform cortex, lateral septal nuclei and the nucleus accumbens.

(3) The mesocortical system. In this system the dopaminergic fibres also arise from the A10 region (the ventral tegmental area) and project to the frontal cortex and septo-hippocampal regions.

(4) The tubero-infundibular system, which originates in the arcuate nucleus of the hypothalamus and projects to the median eminence.

Following its release, dopamine produces its physiological effects by activating postsynaptic receptors which have been classified as D₁ or D₂ (Kebabian & Calne, 1979). The D₁ receptors are linked to adenylate cyclase which, when activated, produces cyclic adenosine monophosphate (cAMP) as a secondary messenger (Kebabian et al., 1972). The D₂ receptors are not linked to adenylate cyclase and may owe their physiological effects to their ability to inhibit adenylate cyclase activity (St...

Table of contents

• Cover image
• Title page
• Table of Contents
• NEUROSCIENCE PERSPECTIVES
• Copyright
• Contributors
• Series Preface
• Neuroscience Editorial Advisory Board
• Preface
• Part I: Basic science
• Part II: Clinical issues
• Index