Progress in Dopamine Research Schizophrenia: A Guide for Physicians

Progress in Dopamine Research in Schizophrenia A guide for physicians Edited by

Arvid Carlsson, MD, PhD Department of Pharmacology Göteborg University Göteborg, Sweden Yves Lecrubier, MD, PhD INSERM Hôpital Pitié Salpêtrière Paris, France

LONDON AND NEW YORK A MARTIN DUNITZ BOOK

© 2004 Taylor & Francis, an imprint of the Taylor & Francis Group First published in the United Kingdom in 2004 By Taylor & Francis, an imprint of the Taylor & Francis Group, 2 Park Square, Milton Park, Abingdon, Oxfordshire OC14 4RN This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledges collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/.” Tel: +44 (0) 20 7583 9855 Fax: +44 (0) 20 7842 2298 E-mail: [email protected] Website: http://www.dunitz.co.uk/ All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs, and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Data available on application ISBN 0-203-60554-3 (Adobe e-Reader Format) ISBN: 1-84184-459-4 (Print Edition) Composition by Creative, Glasgow, UK

Contents Contributors

iv

Preface

vii

Acknowlegements

viii

1. Introduction

1

2. Genetics of schizophrenia

4

3. Neurotransmitters in schizophrenia

13

4. The role of dopamine in the etiology and pathophysiology of schizophrenia

27

5. The role of dopamine in the phenomenology of schizophrenia

36

6. The role of D2 receptors in the action of antipsychotic drugs

47

7. Amisulpride: a selective dopaminergic agent and atypical antipsychotic

57

8. Conclusions and perspectives

74

Bibliography

79

Index

87

Contributors Anissa Abi-Dargham Departments of Psychiatry and Radiology Columbia University New York State Psychiatric Institute New York, NY USA Maria Arranz Clinical Neuropharmacology Institute of Psychiatry London UK Arvid Carlsson Department of Pharmacology Göteborg University Göteborg Sweden Rolf R Engel Clinic for Psychiatry and Psychotherapy Munich University of Technology Klinikum rechts der Isar Munich Germany Shitij Kapur Schizophrenia Program and PET Centre Centre for Addiction and Mental Health Toronto Canada Robert Kerwin Clinical Neuropharmacology Institute of Psychiatry London UK Werner Kissling Clinic for Psychiatry and Psychotherapy Munich University of Technology Klinikum rechts der Isar Munich Germany Yves Lecrubier INSERM

Hôpital Pitié Salpêtrière Paris France Stefan Leucht Clinic for Psychiatry and Psychotherapy Munich University of Technology Klinikum rechts der Isar Munich Germany Dalu Mancama Clinical Neuropharmacology Institute of Psychiatry London UK Jean-Luc Martinot ERM Team INSERM—CEA Frederic Joliot Hospital Orsay France Deborah Medoff Maryland Psychiatric Research Center University of Maryland School of Medicine Department of Psychiatry Baltimore, MD USA Herbert Meltzer Department of Psychiatry and Pharmacology Vanderbilt University School of Medicine Nashville, TN USA Marie-Laure Paillère-Martinot ERM Team INSERM—CEA Frederic Joliot Hospital Orsay France Gabi Pitschel-Walz Clinic for Psychiatry and Psychotherapy Munich University of Technology Klinikum rechts der Isar Munich Germany Manfred Spitzer Department of Psychiatry University of Ulm

Ulm Germany Stephen M Stahl Neuroscience Education Institute Department of Psychiatry University of California at San Diego San Diego, CA USA Carol Tamminga Maryland Psychiatric Research Center University of Maryland School of Medicine Department of Psychiatry Baltimore, MD USA Daniel Weinberger Clinical Brain Disorders Branch Intramural Research Program National Institute of Mental Health Bethesda, MD USA

Preface This pocketbook has been prepared by the publishers from the recent symposium proceedings entitled Dopamine in the Pathophysiology and Treatment of Schizophrenia, edited by S. Kapur and Y.Lecrubier (Martin Dunitz, 2003). In the opinion of the present editors, whose task has in fact been fairly modest, this book has achieved its goal successfully by focusing on some of the most interesting points made in the original proceedings. Inevitably, a compilation of this kind is not devoid of problems. Not unexpectedly, the different authors of the original symposium chapters have expressed a number of divergent opinions, sometimes regarding quite fundamental issues, such as the most important brain region involved in the schizophrenic psychopathology, or the most relevant neurobiological target(s) of the current antipsychotic agents. It has not been deemed possible to point out and comment upon these divergences more specifically. However, a list of the authors referred to in different sections of the book is included. All the same, in our opinion, this book makes most interesting reading even for those who have read the original proceedings. For example, its comparison between amisulpride and other atypical antipsychotic agents brings more clearly to light what an interesting concept amisulpride presents, given its uniquely high selectivity for dopamine receptors. Arvid Carlsson Yves Lecrubier

Acknowledgements The material in this pocketbook is adapted from Dopamine in the Pathophysiology and Treatment of Schizophrenia: New findings, a multi-contributor volume edited by Shitij Kapur and Yves Lecrubier, and published in the UK in 2003 by Martin Dunitz. The fact that material from more than one author has been collated into the same chapter in the present work should not be taken to indicate that individual authors, or the editors of the pocketbook, necessarily endorse all the material therein. The list below gives details, chapter by chapter, of the original source, to which the interested reader is referred for more extensive coverage of the topics addressed. Chapter 1: Introduction pp 1–2, 3–4 from the original Ch.9, ‘Multiple neurotransmitters involved in antipsychotic drug action’, by Herbert Meltzer pp 2–3 from the original Ch.1, ‘Historical aspects and future directions’, by Arvid Carlsson pp 4–5 from the original Ch.3, ‘Modulation of dopamine D2 receptors as a basis of antipsychotic effect’, by Shitij Kapur Chapter 2: Genetics of schizophrenia pp 7, 11–18 from the original Ch.11, ‘Pharmacogenomics of antipsychotic drugs’, by Robert Kerwin, Maria Arranz and Dalu Mancama pp 8–11 from the original Ch.7, ‘Dopamine, the prefrontal cortex, and a genetic mechanism of schizophrenia’, by Daniel Weinberger Chapter 3: Neurotransmitters in schizophrenia pp 19–20, 31–35 from the original Ch.9, ‘Multiple neurotransmitters involved in antipsychotic drug action’, by Herbert Meltzer pp 20–24 from the original Ch.2, ‘Evidence from brain imaging studies for dopaminergic alterations in schizophrenia’, by Anissa Abi-Dargham pp 25–28, 30 from the original Ch.10, ‘Dopaminergic and glutamatergic influences in the systems biology of schizophrenia’, by Carol Tamminga and Deborah Medoff pp 29, 30–31 from the original Ch.1, ‘Historical aspects and future directions’, by Arvid Carlsson p 34 from the original Ch.6, ‘Evidence from brain imaging for regional monoaminergic specificity in schizophrenia’, by Jean-Luc Martinot and Marie-Laure Paillère-Martinot

Chapter 4: The role of dopamine in the etiology and pathophysiology of schizophrenia pp 37–44 from the original Ch.2, ‘Evidence from brain imaging studies for dopaminergic alterations in schizophrenia’, by Anissa Abi-Dargham pp 44–47 from the original Ch.6, ‘Evidence from brain imaging for regional monoaminergic specificity in schizophrenia’, by Jean-Luc Martinot and MarieLaure Paillère-Martinot Chapter 5: The role of dopamine in the phenomenology of schizophrenia pp 49, 57–60, 61, 63, 64 from the original Ch.8, ‘Models of schizophrenia: from neuroplasticity and dopamine to psychopathology and clinical management’, by Manfred Spitzer pp 49–57 from the original Ch.7, ‘Dopamine, the prefrontal cortex, and a genetic mechanism of schizophrenia’, by Daniel Weinberger pp 61–64 from the original Ch.3, ‘Modulation of dopamine D2 receptors as a basis of antipsychotic effect’, by Shitij Kapur Chapter 6: The role of D2 receptors in the action of antipsychotic drugs pp 65–68 from the original Ch.9, ‘Multiple neurotransmitters involved in antipsychotic drug action’, by Herbert Meltzer pp 68–70, 74–77 from the original Ch.3, ‘Modulation of dopamine D2 receptors as a basis of antipsychotic effect’, by Shitij Kapur pp 70, 72–73, 76 from the original Ch.6, ‘Evidence from brain imaging for regional monoaminergic specificity in schizophrenia’, by Jean-Luc Martinot and Marie-Laure Paillère-Martinot Chapter 7: Amisulpride: a selective dopaminergic agent and atypical antipsychotic pp 79–81, 86, 88–90, 91–98 from the original Ch.4, ‘Amisulpride as a model: clinical effects of a pure dopaminergic agent’, by Yves Lecrubier pp 81–84 from the original Ch.6, ‘Evidence from brain imaging for regional monoaminergic specificity in schizophrenia’, by Jean-Luc Martinot and MarieLaure Paillère-Martinot pp 86–88, 90–91 from the original Ch.5, ‘A meta-analysis of studies with the atypical antipsychotic amisulpride’, by Stefan Leucht, Gabi Pitschel-Walz, Werner Kissling and Rolf R Engel Chapter 8: Conclusions and perspectives pp 99–106 from the original Ch.12, ‘Key issues and unmet needs in schizophrenia’ by Stephen Stahl

1 Introduction Schizophrenia is the most devastating of the major psychoses, affecting approximately 1% of the population, irrespective of culture, social status or gender. The concept of schizophrenia developed out of that of dementia praecox, a diagnostic entity first formulated by Emil Kraepelin, the great German psychiatrist and systematizer, a century ago. It was renamed as schizophrenia by Eugen Bleuler, a leading Swiss psychiatrist, who gave more prominence to the symptoms rather than to the age of onset and course. How long schizophrenia will exist as an entity and what will be its future name or names is difficult to predict. Like melancholia, it seems likely that schizophrenia will cease to have significant medical meaning in the future, as the group of disorders it encompasses is sorted into more specific entities. The current diagnostic concept of schizophrenia developed within the past decade by international consensus of experts lacks a solid biological foundation. It still relies heavily on the Kraepelinian differentiation from manic-depressive illness, even though this is likely to be a flawed concept due to the extensive overlap between these conditions. Schizophrenia as a syndrome is composed of a variety of relatively specific core symptoms. These can be divided into positive and negative symptoms; the former include hallucinations, delusions and disorganization, and the latter anergia, flattening of affect, and poverty of thought content. Disorganization is a third dimension which, over the past few decades, has become recognized as a relatively independent symptom. It includes bizarre thoughts and behavior as well as cognitive disturbances. In addition to these core symptoms, about 85% of patients with schizophrenia show clinically significant disturbances in cognitive function. Many modern theorists see the disturbance in cognition as central to the disorder and the key to the disturbance in work and social function that is characteristic of most patients with schizophrenia. About 25% of patients with schizophrenia exhibit significant depression at any time and about 10% commit suicide. It is important to realize that the extent to which any individual symptom is present in individual patients with schizophrenia may vary considerably. In addition, the importance of specific symptoms may vary over time within the same patient although the negative symptomatology and cognitive disturbances remain relatively stable. The dopamine hypothesis of schizophrenia Since the 1960s, the most robust biological theories of schizophrenia have focused on dysfunction of the neurotransmitter dopamine. The dopamine theory of schizophrenia was based on the ability of drugs that stimulate dopaminergic activity to produce paranoid psychoses in amphetamine abusers and exacerbations of psychosis in schizophrenia and on the ability of antipsychotic drugs such as chlorpromazine and

Progress in dopamine research in schizophrenia

2

haloperidol to block dopaminergic activity. A key experiment, published in 1963, showed that chlorpromazine had a specific action on the catecholamines, enhancing the turnover of both noradrenaline and dopamine. This is often quoted as the origin of the dopamine hypothesis of schizophrenia and antipsychotic action, although this is not quite true, as at that time the relative importance of dopamine over noradrenaline or even serotonin was not clear. However, as more drugs were analyzed it became clear that dopamine was the common denominator in their mechanisms of action and this was confirmed in 1976 by the demonstration that the specific binding of antipsychotic drugs to dopamine receptor sites could be correlated to clinical daily dose. Later, when it was found that dopamine had several different binding sites the relevant receptor for the antipsychotics was found to be the D2 receptor. All antipsychotic drugs increase the turnover and release of dopamine as a consequence of blockade of postsynaptic dopamine receptors in certain regions of the brain. Although direct evidence for a dopaminergic dysfunction in the etiology or symptomatology of schizophrenia has remained elusive, a role for this neurotransmitter in the action of antipsychotic drugs has been clearly established. Recent neuroimaging studies have provided some of the first evidence for increased dopamine release in schizophrenia, and these will be discussed in this book. Antipsychotic drugs In 2002 we celebrated the fiftieth anniversary of chlorpromazine and thereby the fiftieth anniversary of modern neuropsychopharmacology. To some extent, antipsychotics were discovered by accident, as efforts to make better antihistamines for use in artificial hibernation to minimize surgical stress led to the synthesis of chlorpromazine. Since artificial hibernation had also been proposed to be of use in treating psychosis, the French psychiatrists, Jean Delay and Pierre Deniker, eventually tested chlorpromazine in psychotic patients with remarkable results. The rest, as they say, is history. It was the pioneering work of Delay and Deniker which established chlorpromazine’s efficacy as a ‘major tranquilizer’ against psychotic disorders, an effect we now tend to call ‘antipsychotic’. At this time, chlorpromazine was known to present antihistamine properties, although it had been developed from previous antihistamines in an attempt to broaden its profile of action (hence its original trade name of Largactil). In fact, when the first antipsychotic drugs were introduced, a neurotransmitter role for dopamine was not considered likely. The situation changed as a result of experiments showing that neural dopamine stores in reserpine-treated rabbits could be replenished by L-dopa, which concomitantly restored behavioral function. These results led to the suggestion that dopamine as well as noradrenaline and serotonin had important mental and motor functions. Since the 1950s, it has been possible to treat aspects of schizophrenia with pharmacotherapy. Antipsychotic drugs, of which chlorpromazine was the prototype, and haloperidol the most commonly used, treated mainly psychotic symptoms, delusions, hallucinations and disorganization. However, most of the first generation of antipsychotic drugs had modest, if any, beneficial effect on negative symptoms, and did little to improve mood and cognitive function. Moreover, these drugs displayed serious and

Introduction

3

debilitating neurological side effects due to interference with the extrapyramidal motor system. An exception to this was clozapine, which had a more comprehensive impact on the entire schizophrenic syndrome and appeared to produce few extrapyramidal side effects (EPS). For this reason, clozapine was classed as an ‘atypical’ antipsychotic, i.e. an antipsychotic which does not produce clinically significant EPS in most patients at clinically effective doses, not just the minimally effective dose. In the wake of these observations, much effort has been devoted to the development of other atypical antipsychotic drugs that would be devoid of the hematological side effects of clozapine, which has limited its use. Subsequently, clozapine was shown to be efficacious in patients who were resistant to treatment with other antipsychotic agents. The past ten years have seen the introduction of several such novel atypical drugs. These can be divided into two main classes: first the substituted benzamide drugs, such as remoxipride and amisulpride that are specific dopamine receptor antagonists; and, secondly, the mixed serotonin-dopamine receptor antagonists, namely risperidone, olanzapine, quetiapine, ziprasidone, sertindole and aripiprazole. As a class, the currently available ‘atypical’ antipsychotics show a lower level of extrapyramidal symptoms, and require less anticholinergic use, even when controlling for high doses of haloperido1 that have been used conventionally. However, the high selectivity of amisulpride for dopamine D2 and D3 receptors, as compared to drugs such as risperidone and olanzapine that also interact with serotonin receptors, raises interesting questions as to the mechanism of action of the atypical antipsychotics in general. The other most commonly shared feature is that most of the newer atypical antipsychotics show either no, or transient, prolactin elevation. The two notable exceptions in this regard are risperidone and amisulpride, and it is now understood that this exception can largely be explained by the fact that these drugs have a higher peripheral:central distribution ratio, thereby leading to excessive dopamine blockade in the pituitary that lies outside the blood-brain barrier. Several other issues have been raised as central to ‘atypical’ antipsychotic activity— notable amongst them being effects on negative symptoms, mood and affective symptoms as well as efficacy in ‘refractory’ schizophrenia. With regards to negative symptoms there are reasonable data that atypical antipsychotics as a class show greater improvement in negative symptoms, although it remains unclear whether this is just a reflection of milder mental or motor side effects (a more primary property), a consequence of a better effect on positive symptoms or depression, or a primary efficacy against negative symptoms. While there is some suggestion of superior efficacy against positive and affective symptoms, it remains unclear whether this improvement can be sustained beyond the confounds of selection bias and dose inequivalence. It should also be pointed out though that even though two drugs may have roughly equal ‘efficacy’ in a controlled clinical trial, they may have very different ‘effectiveness’ in the real world. Since atypical antipsychotics give rise to less EPS and are generally better tolerated, they may lead to higher compliance and thereby– greater effectiveness.

2 Genetics of schizophrenia Clinical psychiatry can benefit greatly from recent advances in pharmacogenomic research. This methodology can be used to investigate genetic risk factors for the development, clinical course or symptomatic presentation of schizophrenia, and thus help provide a satisfactory biological explanation for the etiology of this condition. In addition, application of pharmacogenomic strategies to antipsychotic treatment will have obvious advantages including matching drug treatment to the genotype of the individual in order to optimize response and limit the risk of adverse reactions. This involves the identification of genetic variants associated with treatment response and with the development of side effects. Recent years have seen a series of reports associating genetic variability and clinical phenotypes. Genetic polymorphisms as risk factors for schizophrenia Much data have been accumulated over the past 50 years concerning the classical genetics of schizophrenia. These have unequivocally demonstrated that hereditary risk factors exist for this condition. However, it is also apparent that the genetics of schizophrenia is complex and it is probable that, in most patients, individual susceptibility alleles are likely to have small biological effects by themselves. All patients with schizophrenia are not likely to have the same risk genes or be exposed to the same environmental factors. Thus, individual genotypes may contribute risk differently across populations, perhaps because of protective or modifying alleles at other loci. Therefore, even strong statistical evidence of association is not likely to be sufficient to validate that a causative gene has been found. For this reason, it is necessary to clarify the biology of candidate alleles and determine how it relates to the biology of the illness. In this respect, one of the most promising candidates for genetic susceptibility to schizophrenia is a polymorphism in the gene encoding catechol-O-methyltrans-ferase (COMT). Prefrontal dopamine signaling, the COMT gene and genetic susceptibility to schizophrenia The interest in COMT polymorphisms arose from studies showing that these affect the efficacy of dopamine (DA) signaling in the prefrontal cortex, which is involved in executive information processing (see Chapter 5) and known to be related to genetic susceptibility for schizophrenia. Prefrontal DA signaling is critically dependent on presynaptic DA biosynthesis and postsynaptic inactivation, which occurs primarily via diffusion and methylation. In contrast with the situation in the striatum, where the synaptic action of DA is terminated primarily by transporter reuptake into presynaptic

Genetics of schizophrenia

5

terminals and recycling into secretory vesicles, DA transporters in the cortex appear to play little if any role in DA reuptake, and are expressed in low abundance, primarily extrasynaptically (Figure 2.1). As a result, methylation via COMT plays an important role in prefrontal DA metabolism in the cortex. This is illustrated by the observation that COMT knockout mice show increases in prefrontal DA levels, but no change in striatum. Thus, changes in COMT activity could affect prefrontal cortical function, as has been demonstrated by the beneficial effects of COMT inhibitors in rats and in humans.

Figure 2.1 Dopamine (DA) synapses in the striatum and the prefrontal cortex. In the striatum, dopamine is removed from the synapse principally by reuptake into the presynaptic nerve terminal by a specific reuptake system. In contrast, in the prefrontal cortex, these transporter proteins are mainly extra-synaptic, and dopamine is eliminated by metabolism by COMT. NE, norepinephrine transporter (Adapted from Sesack et al, 1998.)

Progress in dopamine research in schizophrenia

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In humans, the COMT gene contains a common variation in its coding sequence, at position 472 (guanine-to-adenine substitution), which translates into a valine-tomethionine (Val/Met) change in the peptide sequence. This single amino acid substitution dramatically affects the temperature lability of the enzyme; at body temperature the Met allele has one-fourth the enzyme activity of the Val allele. In peripheral blood and in the liver, over 90% of the variance in COMT activity is explained by this genotype, and the alleles are co-dominant. These data suggest that individuals with Val alleles have relatively greater inactivation of prefrontal DA and therefore, relatively poorer prefrontal function. The COMT genotype influences cognitive performance in a number of neuropsychological tests, with the Val allele being associated with relatively poorer performance (i.e. more perseverative errors) and heterozygous subjects performing midway between homozygous Val/Val and Met/Met subjects. These findings have received support from functional magnetic resonance imaging (fMRI) studies evaluating the cortical physiologic response during a working memory task with fMRI, which found a lower signal to noise ratio (i.e. lower efficiency) in individuals with Val/Val genotypes than individuals with Met/Met, with Val/Met individuals being intermediate (Figure 2.2). As the COMT genotype has an impact on prefrontal information processing and mesencephalic DA regulation, and because abnormal prefrontal cortical function is associated with schizophrenia and risk for schizophrenia, it follows that the COMT genotype may be a risk factor for the development of schizophrenia. Although earlier case-control association studies of COMT and schizophrenia were inconclusive, all these studies were underpowered to find weak effect alleles as well as being susceptible to

Figure 2.2 Effect of COMT genotype on fMRI during a memory task. The images represent difference maps in fMRI activation between COMT genotypes during the two-back

Genetics of schizophrenia

7

working memory task, with areas of significant differences indicated in red. Activation was greater in Val/Val (3 patients) than in Met/Val (5 patients), who were in turn more activated than Met/Met patients (3 patients). Note the large red areas in the dorsolateral prefrontal cortex (circled). (From Egan et al, 2001b.) population stratification artifacts. More recent familial association studies using the Transmission Disequilibrium Test in three different samples have found the COMT Val allele (the one associated with abnormal prefrontal cortical function and upregulated mesencephalic DA activity) to be transmitted significantly more frequently to schizophrenic offspring than would be predicted by random assortment. These studies are not, however, free from criticism. For example, they were all relatively underpowered, and the possibility has been raised that the Val allele might not be the causative mutation, but a single nucleotide polymorphism in linkage disequilibrium with the ‘true’ risk polymorphism. However, this possibility is virtually discounted by the strong evidence for a biologically relevant effect of the Val/Met polymorphism on enzymatic activity and cognitive function. Another doubt that has been raised about the COMT genetic association with schizophrenia concerns the weakness of the statistical effect. COMT by itself accounts for a small increased risk for schizophrenia, about a two-fold increase in the general population. The COMT Val allele is certainly not a necessary or sufficient causative factor for schizophrenia, nor is it likely to increase risk only for schizophrenia. Likewise, risk factors other than COMT genotype will probably contribute to prefrontal deficits in schizophrenia However, the convergent evidence of the biological impact of COMT Val inheritance on brain function as it relates to schizophrenia represents the first plausible biological mechanism by which a specific allele increases risk for a mental illness (Box 2.1). Activity of antipsychotic drugs Not all patients with schizophrenia treated with antipsychotic drugs respond with a favorable clinical response. The response rate to any individual antipsychotic drug is generally thought to be around 50–60%. Moreover, different individuals may respond specifically to different drugs. For example, clozapine has staked a place for itself in the treatment of schizophrenia that is resistant to classical phenothiazine and butyrophenone antipsychotic drugs. Understanding, and above all predicting, these differences in treatment response is an important challenge for schizophrenia researchers. The advent of modern molecular genetics has provided new opportunities to unravel this puzzle. The high inter-individual variability in treatment response indicates a complex trait, influenced by a combination of genes with interactive or additive effects, located either in the metabolic pathways and/or the sites of action of psychotropic drugs (Figure 2.3). In

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recent years, attention has turned to the neurotransmitter systems targeted by drugs used in psychiatry since these may play an important part in determining treatment success or failure. Box 2.1 Evidence that COMT Val is a susceptibility allele for schizophrenia ● 22q11 locus near ‘suggestive’ linkage signal from genome scan studies ● Functional polymorphism that markedly affects the activity of an enzyme involved in prefrontal dopamine function ● Predicted adverse effects on executive cognition and prefrontal cortical physiology and on mesencephalic DA regulation that relate to core biologic aspects of schizophrenia ● Positive family association studies (Li et al, 1996; Kunugi et al, 1997; Li et al, 2000; Egan et al, 2001) ● Odds ratio for Val/Val is 1.8 (CI 1.3 to 2.4) ● Population attributable risk in USA=200,000 cases

All antipsychotics interact to a greater or lesser extent with multiple receptors. All current antipsychotic drugs interact with dopamine D2 receptors, and this is believed to underlie their therapeutic efficacy in acute schizophrenic psychosis (see Chapter 6). As well as their high affinity for dopamine receptors, particularly the D2 receptors, typical antipsychotics such as haloperidol and fluphenazine may also target receptors for other monoamine neurotransmitters. Atypical antipsychotics generally have highest affinity for serotonin receptors, in particular 5-HT2A, but may also interact with dopamine, histamine, muscarinic and adrenergic receptors. An exception to this is amisulpride, an atypical antipsychotic that has a high specificity for D2 and D3 receptors. These differences in receptor binding selectivity may contribute to the variability in clinical profiles between different drugs. Efficacy of antipsychotic drugs and polymorphisms in dopamine receptors A number of studies have investigated associations between treatment response and polymorphisms in certain monoamine receptors with which antipsychotic drugs interact. The identification of such associations can be useful for predicting therapeutic responses. Moreover, the identification of such mutations provides evidence for the role of the receptor of interest in the clinical activity of the drug. This validation of drug targets will allow the development of more selective and improved drugs. Several polymorphisms in dopamine receptors have been linked to response to a variety of antipsychotic drugs (Table 2.1). For the D2 receptor, a-141C ins/del in the promoter region of the gene has been associated with response to clozapine as well as the anxiolytic and antidepressant effects of certain antipsychotics. A polymorphism in the 3′ flanking region of the gene, the Taq 1 locus, has been related to early therapeutic response.

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Figure 2.3. A combination of genes, either in the metabolic pathways and/or the sites of action of psychotropic drugs may influence treatment response. Table 2.1. Polymorphisms in dopamine and serotonin receptors associated with response to antipsychotic drugs. bp, base pair; VNTR, variable nucleotide tandem repeat. Receptor

Polymorphism

Associated with

D2

−141C ins/del

Clozapine

D2

Taq I

Nemonapride

D2

Taq I

Haloperidol

D3

Ser9Gly

Clozapine

D3

Ser9Gly

Clozapine

D3

Ser9Gly

Neuroleptics

D4

48bp repeat

Clozapine

D4

48bp repeat

Neuroleptics

Progress in dopamine research in schizophrenia

10

D4

48bp repeat

Neuroleptics

5-HT2A

−1438-G/A

Clozapine

5-HT2A

102-T/C

Clozapine

5-HT2A

102-T/C

Neuroleptics

5-HT2A

His452Tyr

Clozapine

5-HT2C

Cys23Ser

Clozapine

5-HT2C

VNTR

Clozapine

5-HT6

267-C/T

Clozapine

In the dopamine D3 receptor a base pair polymorphism, −205-G/A, leads to an amino acid change of serine to glycine at residue 9 (Ser/9Gly) in the N-terminal extracellular domain of the protein. Some but not all data suggest that the Gly/Gly genotype is more frequent in responders to clozapine (Figure 2.4) than in nonresponders, a finding recently extended to conventional antipsychotics. In addition, this Ser9Gly polymorphism may be relevant to the improvement of positive symptoms.

Figure 2.4. Pooled analysis of genetic variation in D3 and 5-HT2A receptors and clozapine response from available published studies: Blue columns, responders; red columns, nonresponders.

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In the D4 receptor a variable 48 base pair repeat polymorphic locus in the third exon of the gene codes for different length segments in the third intracytoplasmic loop of the protein. The number of repeats, from two to ten, may affect the pharmacological properties of the receptor, and possibly responsiveness to clozapine and residual negative symptomatology. Interestingly, there is considerable ethnic variation in allele distribution. Efficacy of antipsychotic drugs and polymorphisms in serotonin receptors Polymorphisms that affect antipsychotic drug responses have been found in three serotonin receptors namely 5-HT2A, 5-HT2C and 5-HT6 (see Table 2.1). A silent base pair change, 102-T/C, in the 5-HT2A gene has been associated with response to clozapine, as well as poor long-term outcome. A polymorphism in the promoter region of the 5-HT2A gene, −1438-G/A, also associated with clozapine response (the −1438G allele being higher amongst responders than non-responders) is in complete linkage disequilibrium with 102-T/C. It has therefore been proposed that −1438-G/A may influence gene expression, thereby having an influence on clinical response and thus explaining the effect of the silent polymorphism. Another base pair change in the 5-HT2A receptor leads to an amino acid substitution of histidine for tyrosine and several studies have shown that the Tyr452 allele is associated with poor response to clozapine. It is interesting that the Tyr542 variant of 5HT2A has been associated with altered Ca2+ mobilization in vitro. To date, two polymorphisms in the 5-HT2C receptor have been associated with antipsychotic drug response. The first causes a cysteine to serine substitution at position 19 in the N-terminal extracellular domain of the receptor, and the presence of at least one Ser23 allele is more common in patients who respond to clozapine than those who do not. The second, a variable nucleotide tandem repeat (−330-GT/−244-CT), also influences response to clozapine. In the 5-HT6 receptor, the 267-C/T base pair change has been linked to clozapine response, patients with the homozygote 267T/T genotype having a better response than 267T/T homozygotes or 267C/T heterozygotes. In spite of the apparent success of these studies, there has been difficulty in replicating significant findings by independent groups, thus limiting their credibility and possible clinical applications. The reasons for this discrepancy could include insufficient sample size, duration of treatment, method of response assessment and ethnic origin. Several attempts have been made at combining information from several genes to increase their predictive value. In a retrospective study of 200 schizophrenic patients treated with clozapine, it was shown that a combination of six mutations in four different genes could predict response to the antipsychotic clozapine with some accuracy (>78% success, P<0.001). These polymorphisms were in genes coding for three neurotransmitter receptors: 5-HT2A (102-T/C and His452/Tyr); 5-HT2C (330-GT/-244-CT and Cys23Ser) and H2 (−1018-G/A) as well as a mutation in the promoter region of a serotonin transporter protein, 5-HTTLPR. In addition, possession of both the T102/- and His452/His452 phenotypes in the 5-HT2A receptor was associated with good response to clozapine in 80% of the patients. Although only about 50% of the patients showed this

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genotype combination, this could provide a simple method of identifying individuals likely to benefit from clozapine treatment. Response to antipsychotic drugs and polymorphisms in drug metabolizing enzymes Initial investigations in pharmacogenetic research concentrated on mutations in single genes coding for cytochrome P450 (CYP) enzymes that metabolize antipsychotic drugs. There is considerable variability in steady-state plasma concentrations for the same dose of a given drug, which has been attributed, in part, to the numerous polymorphisms that occur in these enzymes. For example, CYP2D6, an enzyme involved in the biotransformation of a large number of antipsychotic drugs such as haloperidol, chlorpromazine and risperidone, exists in different forms, including two variants that confer slow or ultra rapid metabolism. Moreover, individuals with two copies of the slow metabolic CYP2D6 variant are more frequently found among Caucasian (5–7%) than in Asian populations (1%). Population variations in the frequency of mutations in other CYP enzymes involved in the metabolism of antipsychotic drugs have also been reported. These differences may explain in part the variability in treatment response observed between ethnic groups. Drug-induced adverse events and polymorphisms in drug metabolizing enzymes Polymorphisms in drug metabolizing enzymes are also suggested to contribute to the relative risk of emergence of drug side effects. The prescription of these drugs is often limited by such side effects, principally extrapyramidal side effects for classic antipsychotics, weight gain and sedation for atypical antipsychotics, and weight gain and sedation, as well as severe agranulocytosis in % of treated patients with clozapine. For example, polymorphisms in CYP2D6 and CYP1A2, the main metabolizing enzymes for clozapine and olanzapine, have been implicated in susceptibility to antipsychotic-induced movement disorders. Metabolizing enzymes may not be the only source of genetic variation influencing side effect profiles of antipsychotic drugs. For example, significantly less drug-induced weight gain in patients with a −759-T variant of the 5-HT2C gene than in those without this allele has been described. In addition, the glycine allele of the Ser9Gly polymorphism in the D3 receptor has been associated with antipsychotic-induced extrapyramidal effects. Finally, the Taq 1 polymorphism in the D2 receptor has been linked to hyperprolactinemia with nemonapride and bromperidol. Evidence for an influence of genetic mechanisms on clozapine-induced agranulocytosis has also been uncovered, involving variants within the major histocompatibility complex, and to a lesser extent the heat shock protein gene and tumour necrosis factor gene.

3 Neurotransmitters in schizophrenia Schizophrenia is an illness with unknown pathophysiology and etiology and inadequate treatments. However, data have accumulated which are progressively contributing to characterization of the mechanisms of the illness. Schizophrenia is not merely an illness of a single brain region, and probably not of any one single neurotransmitter system. Rather, it appears that, during the manifestation of disease symptoms, an entire neural system, probably the limbic system, behaves abnormally when performing mental tasks, and abnormally influences related neocortical and subcortical brain areas. This chapter discusses the principal neurotransmitters that have been implicated in the syndrome. How they interact to generate the specific behavioral anomalies observed in schizophrenia will be discussed in Chapter 5. Dopamine Historically, interest in the neurobiology of schizophrenia has centered around dopamine (DA). This interest arose from important findings over 40 years ago that antipsychotic drugs were DA receptor antagonists and that pro-dopaminergic agents could produce experimental psychoses in man. Blockade of dopamine D2 receptor-mediated transmission reduces psychosis in schizophrenia. One of the most widely and consistently replicated observations in schizophrenia has been that the antipsychotic potency of these drugs is broadly correlated with its affinity for the D2 receptor. Since direct evidence for dopaminergic dysfunction in the etiology or symptomatology of schizophrenia remained elusive, in the past decade attention shifted to other neurotransmitter systems, particularly glutamate and serotonin. However, recent evidence from neuroimaging studies (see Chapter 4) has rekindled interes in DA biology in schizophrenia. Dopaminergic pathways in the brain. Dopaminergic projections are classically divided in nigrostriatal, mesolimbic and mesocortical systems (Figure 3.1), as well as the tuberoinfundibular pathway. The nigrostriatal system projects from the substantia nigra (SN) to the dorsal striatum, and has been implicated in cognitive integration, habituation, sensorimotor coordination and initiation of movement. The mesolimbic system projects from the ventral tegmental area (VTA) to limbic structures such as the ventral striatum, including the nucleus accumbens, the hippocampus, and the amygdala. The mesocortical system projects from the VTA to cortical regions, mostly orbitofrontal, medial prefrontal and cingulate cortices, but also to the dorsolateral prefrontal cortex (DLPFC), and the temporal and parietal cortices. The

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mesolimbic and mesocortical systems are involved in regulation of motivation, attention and reward.

Figure 3.1. Schematic representation of dopaminergic pathways in the brain. The three anatomically distinct pathways are shown in green. DLPFC, dorsolateral prefrontal cortex; Cing Cx, cingulate cortex; MPF Cx, medial prefrontal cortex; OFr Cx, orbitofrontal cortex; CN, caudate nucleus; Put, putamen; NA, nucleus accumbens; VS, ventral striatum (ventral parts of the caudate nucleus and putamen);Amy, amygdala; HC, hippocampus; SNc, substantia nigra pars compacta; VTA, ventrotegmental area. Corticostriatal-thalamocortical loops are important targets of DA modulation. The general scheme of these loops involves projections from the cortex to the striatum to the internal segment of the globus pallidum (GPi) or the SN pars reticulata (SNr) to the thalamus and back to the cortex (Figure 3.2). These loops have been classified into ‘limbic’ loops (medial prefrontal and orbitofrontal cortex—ventral striatum—ventral

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pallidum—mediodorsal thalamic nuclei—cortex); associative loops (DLPFC—head of the caudate—GPi/SNr—ventral anterior thalamic nuclei—cortex); and motor loops (premotor and motor areas–putamen and body of the caudate—GPi/SNr—ventral anterior thalamic nuclei—cortex). It is important to note that these different corticostriatalthalamocortical loops are not completely segregated parallel loops. While corticostriatalthalamic loops do generally re-enter the cortical area that provides input to the striatal subregions involved in these loops, thus forming closed circuits and serving segregated processes, they also project back to other areas of the cortex, forming open circuits and serving integrative processes.

Figure 3.2. Schematic representation of corticothalamic pathways influencing the function of the basal ganglia. Excitatory glutamatergic pathways are shown in pink, inhibitory GABAergic pathways in blue, and the modulatory dopaminergic pathway in green. GPi, internal segment of the globus pallidus; STN, subthalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata. The amygdala and hippocampus provide significant inputs to the ventral striatum, contributing to information integration into the limbic loop. Animal studies suggest that the nucleus accumbens is the critical region in which both typical and atypical antipsychotic drugs exert their antipsychotic effects.

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Within each loop, the striatal output reaches the GPi/SNR via a direct pathway and via an indirect pathway that traverses the external segment of the globus pallidus (GPe) and the subthalamic nuclei (STN), both pathways providing antagonistic inputs to the GPi/SNr. Corticostriatal projections are glutamatergic, striatopallidal and pallidothalamic projections are GABAergic, and thalamocortical projections are glutamatergic. It follows that activation of striatal neurons of the direct pathway by glutamatergic inputs from the cortex results in decreased activity of the pallidostriatal inhibitory projections to the thalamus, and that the direct pathway is generally considered as stimulatory. Projections from the striatum to the GPe and from the the GPe to the STN are GABAergic, and from the STN back to GPe and to GPi/SNr are glutamatergic. Activation of the indirect pathway is generally considered to provide an inhibitory effect on thalamocortical neurons. DA modulates the flow of information within these loops and it has been proposed that the dopaminergic system provides a bridge by which information circulating in the ventral limbic corticostriatal-thalamocortical loops spirals along nigrostriatal loops and feeds into the cognitive and sensorimotor loops, translating drives into actions. Dopaminergic receptors Based on pharmacological similarities, dopaminergic receptors have been classified into a D1-like family (D1 and D5 receptors), and a D2-like family (D2, D3 and D4 receptors). The various DA receptors differ in their regional localization in the human brain. D1 receptors show a widespread neocortical distribution, including the prefrontal cortex, and are also present in high densities in the striatum. D5 receptors are concentrated in the hippocampus and entorhinal cortex. D2 receptors are concentrated in the striatum, with low densities in medial temporal structures (hippocampus, entorhinal cortex, amygdala) and the thalamus. The density of D2 receptors in the prefrontal cortex is extremely low. D3 receptors are present in the striatum, where their density is particularly high in the ventral part. D4 receptors are present in the prefrontal cortex and hippocampus, but not detected in the striatum. The action of DA on target neurons should not be viewed in terms of simple excitation or inhibition. Unlike classic ‘fast’ transmitters, DA does not directly gate ion channels, but stimulation of DA G-protein linked receptors induces a cascade of intracellular signaling that results in modifying the response of the cells to other transmitters. For example, D1 receptors stimulate adenylate cyclase while the D2 receptors either inhibit this effector or modulate membrane potassium conductance. Thus, DA is neither ‘inhibitory’ nor ‘excitatory’, but its action will depend on the state of the neurons at the time of the stimulation. In the striatum, D2 receptors are preferentially found in enkephalin-rich GABAergic neurons that participate in the indirect pathways, while D1 receptors are most abundant in dynorphin/substance P GABAergic neurons that contribute to the direct pathways. The segregation of D2 and D1 receptors on different and antagonistic pathways might account for the fact that activation of these receptors is often synergistic at the behavioral level (for example, activation of both D1 and D2 receptors stimulate locomotion), while their effect on intracellular signaling (for example, on adenylate cyclase activity) is, in many regards, opposing. Thus, activation of D2 receptors by DA might provide an inhibitory

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influence to the indirect pathway and activation of D1 receptors by DA might provide a stimulatory influence on the direct pathway, both of which would be expected to result in activation of the thalamocortical neurons. Functionally, DA modulates responses of GABAergic medium spiny neurons to the glutamatergic drive from the cortex. It is believed that the effect of DA is ‘reinforcing’, i.e. it facilitates inhibition of neurons that are inhibited and enhances excitability of those that are excited. In this manner, DA acts to gate glutamatergic inputs by increasing their signal to noise ratio. Moreover, DA activity might produce long-term changes in the strength of corticostriatal glutamatergic synapses (long-term depression, LTD, and long-term potentiation, LTP), a process that may underlie DA mediated incentive learning and play a role in the plasticity associated with emergence of positive symptoms upon prolonged DA hyperactivity. In the prefrontal cortex, D1/5 receptors are localized both on pyramidal cells (dendritic spines and shafts) and on axonal terminals of non-dopaminergic neurons while some data suggest that D4 receptors might be localized on GABA interneurons. DA modulates pyramidal cell excitability, both directly and via GABAergic interneurons. Recent data suggest that DA differently affects GABAergic activity in the prefrontal cortex via stimulation of D1-like or D2-like receptors, whereby the former enhances and the latter inhibits GABAergic activity. Here again, it has been proposed that DA increases the signal to noise ratio of glutamatergic afferents. Dopamine and motor function The important modulatory effects of DA in the basal ganglia also have implications for motor function. Either the loss of DA (as in Parkinson’s disease) or a full blockade of D2 dopamine receptors (as with antipsychotic drugs) disinhibits GABAergic medium spiny neurons in the striatum through the loss of inhibitory dopaminergic tone in the striatum. This action, transmitted through the thalamus to the cortical motor executive pathways is responsible for ideopathic or iatrogenic parkinsonian symptoms. However, in the cortex, this information is regulated by other neocortical and limbic systems, which may account for the varying propensities of different antipsychotic drugs to produce extrapyramidal symptoms. In addition, long-term changes in the SNr produced by antipsychotic drugs may underlie the later manifestations of the extrapyramidal syndrome, such as tardive dyskinesia (Figure 3.3). Glutamic acid Glutamate, the major excitatory transmitter in the central nervous system (CNS), may be at least as important as DA in the pathophysiology of schizophrenia. In addition, it has been implicated in synaptic plasticity, growth, development, learning and memory, which may be pertinent for neurodevelopmental aspects of schizophrenia, as well as in modulating motor function. The first indications that glutamate might be involved in schizophrenia came with the observations that certain psychotomimetic agents are glutamate receptor antagonists.

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NMDA receptor antagonists and experimental psychosis The first psychotomimetic drug to be evaluated was phencyclidine, a drug that can induce the signs and symptoms of psychosis in normal individuals and exacerbate those of schizophrenics. This compound was subsequently demonstrated to be an antagonist at Nmethyl-D-aspartate (NMDA) glutamate receptors. Since then, other NMDA receptor antagonists such as ketamine have also been shown to induce experimental psychotic symptoms in normal subjects and to exacerbate preexisting psychotic symptoms in schizophrenia (Figure 3.4). Unlike other psychotomimetic compounds which produce a uniform standard behavioral repertoire when given to people with schizophrenia, ketamine administration usually exacerbates an individual’s symptom profile. Because ketamine alters neuronal firing in limbic grey matter regions (hippocampus and anterior cingulate), this psychotomimetic characteristic is probably mediated by alterations in the activity of the

Figure 3.3. Basal gangliathalamocortical circuitry in the untreated brain (a) and after chronic administration of haloperidol (b). The different neuronal types are shown in different colors: dark blue (glutamate); light blue (GABA/substance P); orange (dopamine). The ‘+’ symbols indicate excitatory synapses, and the ‘−’ symbols inhibitory synapses. Glu, glutamate; SP, substance P; GP, globus pallidus; DA, dopamine; STN, subthalamic nucleus; SNr, substantia nigra pars reticulata; SNc, substantia nigra pars compacta.

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Figure 3.4. (a–d) Ketamine increases the magnitude of psychotic symptoms in people with schizophrenia and produces a syndrome in normal people which includes psychotic symptoms very similar to those observed in schizophrenia. BPRS, Brief Psychiatric Rating Scale; SZ, schizophrenia; NC, normal controls; pbo, placebo. limbic system. This implies that glutamate may modulate the expression of psychosis at some relevant set of CNS synapses that compose a circuit, and thereby may be involved in generating certain aspects of the symptoms manifested in schizophrenia.

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These findings have stimulated attempts to document the neural substrates and circuits mediating this pharmacological action, a problem that can be addressed in man by assessing regional cerebral blood flow (rCBF). In normal volunteers, ketamine elevates rCBF in the anterior cingulate and inferior frontal cortex and depresses rCBF in the cerebellum (Figure 3.5). In schizophrenia, the elevation of rCBF in the anterior cingulate cortex is elevated compared with normal controls and correlates with the magnitude of the exacerbation of psychosis. In addition, rCBF is also depressed in the hippocampus of patients with schizophrenia. Thus, the psychotomimetic action of ketamine appears to be mediated by NMDA receptor blockade in limbic circuit structures. Glutamatergic pathways involved in schizophrenia The limbic cortex uses glutamate as its major excitatory neurotransmitter and is highly plastic, mediating responses to novel and learned events. Glutamate mediates transmission of information forward from the hippocampus to the anterior cingulate cortex, then on to the frontal neocortex. Moreover, glutamate mediates local and regional feedback systems, which modulate overall system activity (tone) and probably learning systems.

Figure 3.5. Volunteers with schizophrenia who receive ketamine show a significantly greater elevation of rCBF in the cingulate cortex (green line) than normal controls (blue line) when followed for 66 minutes. The grey line corresponds to values obtained in normal controls who received vehicle.

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The glutamatergic pathways implicated in schizophrenia are those involved in the cortiocostriato-thalamic loops discussed above. Sensory information reaching the cerebral cortex is controlled by inhibitory GABAergic projection neurons originating from the striatum and projecting to the thalamus. The output activity of these GABAergic neurons is modulated by two functionally antagonistic neuronal systems: an inhibitory ascending dopaminergic input from the lower brainstem and an excitatory descending glutamatergic input from the cortex. In addition, the activity of dopamine neurons in the lower brainstem also seems to be controlled by glutamatergic neurons, either directly or via GABAergic interneurons (Figure 3.6). In the former case, glutamate has a stimulatory

Figure 3.6. Hypothetical schematic representation of cortical regulation of monoaminergic brainstem neurons by a direct glutamatergic pathway (accelerator) or indirect glutamatergic/GABAergic pathways (brake). The outcome of glutamatergic failure will partly depend on the balance between the accelerator and the brake. The balance may also be regulated in part by feedback loops, probably involving the thalamus. DA,

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dopamine; 5-HT, 5hydroxytryptamine; Glu, glutamate; NA, noradrenalin. Further details can be found in Carlsson et al, 2000, from which this diagram is reproduced, with permission. effect on the dopamine neurons (accelerator) and in the latter case it has an inhibitory effect (brake). Normally there appears to be a balance between the two, with perhaps a slight predominance of the brake effect. A glutamatergic deficiency model of schizophrenia The inhibitory GABAergic projection neurons from the striatum to the thalamus constitute a highly selective filter mechanism that protect the cerebral cortex against overload. A reduction of the thalamic inhibition may cause an overflow of information that could lead to confusion and perhaps psychosis. Since the output activity of the GABAergic is under dopaminergic and glutamatergic control, both an elevation of dopamine function in the striatum or a decrease in glutamate function would lead to relief of striatal inhibition of the thalamus and opening up of the filter. Interactions between glutamic acid and dopamine Even though the initial sites of action of DA receptor antagonists and NMDA glutamate receptor antagonists in the brain are different, substantial functional overlap can occur. Although the initial site of action of the NMDA antagonist is a change in the firing of hippocampal neurons, the influence of the limbic system on related neocortical and subcortical structures is so extensive that neuronal function is altered downstream in the frontal cortex and even in the limbic striatum. Thus, a convergent projection area of both of these systems, the frontal neocortex and limbic cortex, is shared by both dopaminergic and NMDA-glutamatergic transmission. Thus, while DA and glutamate act primarily on distinct neural systems, each delivers their ‘information’ to common brain regions in a highly interactive/overlapping fashion, through well-characterized neuronal circuits. This interaction also has implications for the motor effects of agents affecting these systems. Since glutamate antagonists can counteract hypomotility in experimental animals induced by DA receptor blockade, it is possible that this hypomotility actually corresponds to an indirect effect of glutamatergic activation. This would be due to a change in the balance of striatal output leading to increased glutamatergic tone. If this were true, then blocking the NMDA receptor would reduce glutamatergic tone and restore movement. There is now a substantial amount of work in experimental animals demonstrating both relief by NMDA receptor antagonists of hypomotility induced by monoamine depletion as well as a dramatic synergy between a variety of monoaminergic agonists and NMDA receptor antagonists.

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Serotonin Interest in serotonin has been stimulated largely by the observation that many antipsychotic drugs, in particular the majority of the atypical drugs, also bind with high affinity to certain serotonin receptors (Table 3.1). Serotonin pathways in the central nervous system Central serotonergic neurons arise exclusively in the raphé nucleus in the midbrain and ramify extensively, innervating essentially all of the brain, making contact with a very large number of different postsynaptic neurons. The density of serotonergic synapses in the forebrain is very high and has been estimated as over one million varicosities per mm3 in the hippocampus. This endows the serotonergic system with a modulatory function allowing the activity of large areas of the nervous system to be regulated in a coherent manner by changes in serotonergic tone. The target specificity of the serotonergic system lies not so much in the origin of its neurons but rather in the distribution and activity of over a dozen types of postsynaptic receptor (Table 3.2). For example, the reason why 5-hydroxytryptamine (HT) receptor antagonism may confer atypicity on certain antipsychotic drugs may reside in the ability of 5-HT receptors to modulate the activity of dopaminergic neurons differentially in different parts of the brain. Serotonin receptors in schizophrenia 5-HT2A receptors are present on pyramidal cells in the cerebral cortex; these glutamatergic neurons project rostrally to the substantia nigra and ventrotegmental area

Table 3.1. Affinity of various antipsychotic drugs for dopamine D2 and serotonin 5-HT2A receptors in the rat brain. Drug

D2 receptor

5-HT2A receptor

D2/5-HT2A ratio

Amisulpride

14

5600

0.003

Chlorpromazine

25

19

1.32

Clozapine

150

3.3

45.5

α-Flupenthixol

3.0

13

0.231

Fluphenazine

3.7

25

0.148

Haloperidol

4.4

45

0.098

Olanzapine

17

1.9

8.9

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Pimozide

3.6

25

0.144

Quetiapine

310

120

2.6

Remoxipride

1400

>10,000

<0.140

Risperidone

3.3

0.16

20.6

Sertindole

7.4

0.85

8.7

Spiperone

0.68

0.59

1.15

Sulpiride

130

>10,000

<0,013

Thioridazine

63

16

3.9

Thiothixene

4.5

36

0.125

Trifluoperazine

4.4

24

0.183

Ziprasidone

9.7

0.31

31.3

Data is presented as IO50 concentrations in nM. Antipsychotics in bold type are considered to be atypicals.

which contain the cell bodies of dopaminergic neurons and regulate their firing rate. Exactly how 5-HT2A receptor antagonists modulate dopaminergic activity differentially in the nigrostriatal, mesolimbic and mesocortical systems has been investigated in a series of microdialysis studies with typical and atypical antipsychotic drugs in experimental animals. The results of these studies suggest that concomitant blockade of 5-HT2A and D2 receptors may cause a relative stimulation of the mesocortical dopamine pathway with respect to the nigrostriatal and mesolimbic pathways. If mesocortical dopaminergic activity is important for the antipsychotic action of these drugs, especially with respect to impact on negative symptoms and cognition, this relative activation of the mesocortical systems with respect to the nigrostriatal system may explain why the atypical drugs show incisive antipsychotic effects at doses which do not produce extrapyramidal side effects. The concomitant 5-HT2A/D2 receptor blockade hypothesis also explains satisfactorily why 5-HT2A receptor antagonists without D2 receptor blocking action, such as ritanserin, fananserin or M 100907 do not show prominent antipsychotic activity when administered alone. There is also evidence that antipsychotic drugs acting at 5-HT2A receptors may improve mood. The notion that serotonergic neurotransmission is involved in the control of mood has been popular for a long time, and this is the neurochemical target of many of the most widely used antidepressant drugs. Whether serotonin receptors are down-regulated in schizophrenia, as has been suggested by certain post mortem studies, has been investigated using positron emission tomography (PET) techniques with the radioligand [18F]-setoperone. The density of cortical 5-HT2A serotonin receptors was estimated in 14 untreated schizophrenic patients and compared with 15 healthy subjects, using PET and the radioligand [18F]0-setoperone. No significant difference was observed in the 5-HT2A receptor density index between patients and normal controls (Table 3.3).

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Table 3.2. Subtypes of serotonin receptors and their known distribution in the human central nervous system. Receptor Distribution

Receptor Distribution

5-HT1A

Widespread, particularly hippocampus, septum, amygdala, raphé nucleus

5-HT3

Area postrema, nucleus tractus solidarus, substantia gelatinosa, lower brainstem nuclei

5-HT1B

Basal ganglia, striatum, frontal cortex

5-HT4

Basal ganglia, hippocampus

5-HT1D

Ventral pallidum

5-HT5A

Cortex, hippocampus, cerebellum

5-HT1E

Highest in caudate putamen, also amygdala, frontal cortex, globus pallidus

5-HT5B

No functional protein detected in human tissue

5-HT1F

Trigeminal ganglia

5-HT6

Widespread, particularly striatum, cortex

5-HT2A

Mainly peripheral, also cortex, claustrum, basal ganglia

5-HT7

5-HT2B

Mainly peripheral, low levels in brain

Widespread, particularly caudate putamen, hippocampus, thalamus, raphé nucleus

5-HT2C

Highest in choroid plexus, also cortex, striatum, substantia nigra

Many antipsychotic drugs that bind to 5-HT2A receptors with high affinity also bind to some extent to the structurally related 5-HT2C receptor. This receptor has received relatively little attention in studies of antipsychotic drugs, but may well be important in explaining some of the differences observed between the various antipsychotic drugs, and in pointing the way for future antipsychotic drug development. Messenger RNA for the 5-HT2C receptor is present in both the cell bodies and terminal fields of dopaminergic neurons of the nigrostriatal and mesolimbic systems. They are also located on the soma of ventral tegmental and SN DA neurons, where they play a key role in regulating the tonic activity of these neurons. 5-HT2C receptors exert a tonic and phasic facilitatory control on basal DA efflux in the striatum, whereas in the ventrotegmental area this receptor subtype appears to mediate the tonic inhibitory serotonergic tone on DA neurons. The 5-HT1A receptor is perhaps the best characterized 5-HT receptor subtype from a functional point of view, and plays an important role in controlling the activity of monoaminergic neurons. This receptor subtype can be considered as functionally antagonistic to the 5-HT2A receptor, both at the presynaptic and at the postsynaptic levels. In the cortex, both 5-HT1A and 5-HT2A receptors are localized on the pyramidal output

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Table 3.3. Binding of [18F]-setoperone to 5-HT2A receptors in the cortex of schizophrenic patients and normal controls. Data are presented as [18F]-setoperone binding potential. From Trichard et al (1998a). Schizophrenics (n=14)

Controls (n=15)

Left

Right

Left

Right

Whole cortex

1.29±0.31

1.22±0.30

1.26±0.24

1.16±0.26

Frontal cortex

1.14±0.30

1.22±0.31

1.17±0.24

1.16±0.25

Temporal cortex

1.22±0.48

0.99±0.29

1.21±0.34

1.00±0.24

Parietal cortex

1.40±0.49

1.22±0.30

1.34±0.33

1.15±0.26

Occipital cortex

1.40±0.46

1.27±0.36

1.41±0.46

1.25±0.33

neurons. The former receptor subtype inhibits neuronal output by activation of a hyperpolarizing potassium current, and the latter facilitates output via activation of phospholipase C. Activity at 5-HT1A receptors may contribute to the efficacy of the novel antipsychotic agent aripiprazole, which is a potent partial agonist at this receptor subtype as well as showing some postsynaptic D2 receptor antagonist properties.

4 The role of dopamine in the etiology and pathophysiology of schizophrenia Interest in potential abnormalities of the dopamine (DA) system in the etiology of schizophrenia, or at least in symptom manifestation of acute psychotic states has been a recurrent theme in schizophrenia research for over 40 years. This stemmed first from the key discovery that the common pharmacological effect of antipsychotic drugs was antagonism at DA receptors, and secondly from the observation that drugs that stimulated dopaminergic activity could provoke psychosis. However, until recently there has been relatively little direct evidence for anomalies in brain dopaminergic function in schizophrenia. Earlier reports from post mortem studies of elevated DA receptor density in schizophrenia turned out to be artifacts of long-term antipsychotic treatment. However, recent advances in neuroimaging technology has allowed the question of DA abnormalities in schizophrenia to be reevaluated and have provided exciting evidence that such anomalies may indeed exist. Imaging studies of dopamine abnormalities in schizophrenia The majority of imaging studies have focused on striatal DA parameters, since their high density in this region facilitates imaging investigations. Less information is currently available on cortical DA parameters because these became amenable to imaging much more recently. Striatal dopamine parameters Many aspects of striatal DA transmission have been subjected to imaging studies. Historically, postsynaptic markers (D2 receptors and D1 receptors) were studied first, and these investigations resulted in mostly negative results. More recently, attention has shifted toward imaging presynaptic DA activity, and the majority of studies have provided strong evidence for a dysregulation of presynaptic DA function in schizophrenia. Postsynaptic markers D2 receptors Striatal D2 receptor density in schizophrenia has been extensively studied with positron emission spectrometry (PET) and single photon emission photometry (SPECT) imaging.

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Seventeen studies have compared parameters of D2 receptor binding in patients with schizophrenia and healthy controls, including a total of 245 patients (112 were neuroleptic-naive and 133 were neurolepticfree for variable periods of time) and 231 controls, matched for age and sex. Only two out of 17 studies detected a significant elevation of D2 receptor density parameters at a probability level of <0.05. However, meta-analysis of the 17 studies reveals a small but significant elevation of D2 receptors in patients with schizophrenia. Clearly, none of the individual studies included enough patients to detect this small effect with appropriate power. No clinical correlate of increased D2 receptor binding parameters has been reliably identified. Thus, the simplest conclusion from these studies is that untreated or never treated patients with schizophrenia show a modest elevation in D2 receptor density parameters (of about 12%) of undetermined clinical significance. D1 receptors Imaging studies of D1 receptors have consistently failed to detect abnormalities of D1 receptor availability in the striatum of patients with schizophrenia. Presynaptic markers DOPA decarboxylase activity Six studies reported DOPA decarboxylase activity in patients with schizophrenia, using [18F]DOPA or [11C]DOPA of which five reported increased accumulation of DOPA in the striatum of patients with schizophrenia, particularly in psychotic paranoid patients. While the relationship between DOPA decarboxylase and DA synthesis rate is unclear (DOPA decarboxylase is not the ratelimiting step of DA synthesis), these observations are compatible with higher DA synthesis activity in patients experiencing psychotic symptoms. Interestingly, a recent study observed a relationship between poor prefrontal activation during the Wisconsin Card Sort Task and elevated [18F]DOPA accumulation in the striatum, suggesting a link between alteration of prefrontal function and increased striatal DA activity in schizophrenia. Amphetamine-induced dopamine release Neuroreceptor imaging studies with PET and SPECT are classically aimed at measuring receptor parameters in the living human brain. However, under specific conditions, these techniques can also be used to measure acute fluctuations in the concentration of endogenous transmitters in the vicinity of radiolabeled receptors caused by competition between radiotracers and transmitters for receptor binding. In this context, the amphetamine-induced reduction in [123I]IBZM or [11C]raclopride binding has been well validated as an indirect measure of the changes in synaptic dopamine concentration induced by amphetamine. Several studies reported that amphetamine-induced DA release is increased in patients with schizophrenia compared with matched healthy controls (Figure 4.1). Providing that the affinity of D2 receptors for

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DA is unchanged in this illness, these data are consistent with increased amphetamineinduced DA release in schizophrenia. The amphetamine effect on [123I]IBZM binding was similar between chronic/previously treated patients and first episode/ antipsychotic-naive patients, and both groups were significantly different from controls, suggesting that the exaggerated

Figure 4.1. Effect of amphetamine (0.3mg/kg) on [123I]IBZM binding in healthy controls and untreated patients with schizophrenia. They axis shows the percentage decrease in [123I]IBZM binding potential induced by amphetamine, which is a measure of the increased occupancy of D2 receptors by dopamine following the challenge.

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dopaminergic response was not due to previous antipsychotic treatment. In patients with schizophrenia, the amphetamine challenge induced a transient increase in positive symptoms. This increase in positive symptoms was significantly correlated with the degree of [123I]IBZM displacement. This result provided the first direct evidence that exaggerated activation of DA transmission at D2 receptors mediates the expression of psychotic symptoms following amphetamine challenge. The size of the amphetamine effect on [123I]IBZM binding was also more pronounced in patients experiencing an illness exacerbation than in those who were in remission. This observation suggests that dysregulation of DA release in patients with schizophrenia might be present only during episodes of illness exacerbation. Studying the same patients during exacerbation and remission phases is required to confirm this point. Baseline dopamine activity A major limitation of the amphetamine studies is that they measured changes in synaptic DA transmission following a nonphysiological challenge (i.e. amphetamine) and did not provide any information about ‘baseline’ synaptic DA levels in the absence of pharmacological interventions. This can be addressed using acute depletion of synaptic DA with α-methyl-p-tyrosine, which leads to a transient increase in the in vivo binding of [11C]raclopride or [123I]IBZM to D2 receptors as these are unmasked by removal of endogenous dopamine. Comparing D2 receptor availability at baseline and in the depleted state provides an indirect measure of the proportion of D2 receptors occupied by DA in the baseline state. Dopamine depletion increases D2 receptor availability by 9±7% in controls and by 19±11% in patients with schizophrenia. These results suggest that DA occupies a greater proportion of striatal D2 receptors in patients with schizophrenia and thus directly support the classic DA hypothesis of schizophrenia. Interestingly, a high synaptic level of DA at baseline, measured in the depletion experiment, was significantly associated with greater improvement of positive symptoms following six weeks of antipsychotic treatment. Thus, the dysregulation of DA transmission revealed by the imaging study was predictive of a better response of positive symptoms to antipsychotic treatment. This finding is consistent with the notion that the D2 receptor blockade induced by these drugs remains a key component of their initial mode of action, even for the atypical antipsychotic drugs. Dopamine transporters The data reviewed above are consistent with higher DA output in the striatum of patients with schizophrenia. This phenomenon is probably not due to increased density of DA terminals, since the binding of radiotracers for striatal DA transporters, which are exclusively localized on DA terminals, is unaltered in patients with schizophrenia. Thus, the increased presynaptic output suggested by the amphetamine studies appears to be associated with a functional dysregulation of DA neurons, rather than an increased number of these neurons.

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Cortical dopamine parameters So far, imaging parameters of DA transmission in cortical regions in schizophrenia has been restricted to postsynaptic markers and only a limited number of studies have been performed. D1 receptors D1 receptors are the predominant dopaminergic receptors in the dorsolateral prefrontal cortex, an area involved in working memory and executive functioning. Prefrontal D1 receptors can be quantified in vivo using PET with [11C]SCH23390 or [11C]NNC 112, the latter being a more sensitive marker. Studies of D1 receptor density in the prefrontal cortex have yielded conflicting results with both decreased receptor density and no change being reported when using [11C]SCH 23390. In contrast, increased receptor density specific to the dorsolateral prefrontal cortex was reported in a single study with [11C]NNC 112 (Figure 4.2), and this was associated with impaired working memory performance. D2 receptors The first generation of D2 receptor ligands enabled imaging of D2 receptors only in the striatum. Because of the low density of extrastriatal D2 receptors, radiotracers with very high affinity and/or low nonspecific binding are required, and two such tracers have recently been introduced [11C]FLB457 and [18F]fallypride. In a recent study of drug-naive patients with schizophrenia performed with [11C]FLB 457, lower D2 receptor availability was observed in the anterior cingulate cortex in patients compared with controls. A significant negative correlation was observed between low D2 receptor availability in the anterior cingulate cortex and positive symptoms severity. The meaning of this result for the role of DA in the pathophysiology of schizophrenia remains to be established. Glutamate—dopamine interactions: relevance to schizophrenia The imaging findings reviewed above are generally consistent with the hypothesis that schizophrenia might be associated with a DA imbalance, involving an excess of subcortical DA function and a deficit in cortical DA function. The mechanism(s) by which such a DA imbalance might emerge in the brain of patients with schizophrenia remains unknown. While it cannot be definitively excluded that the DA dysregulations revealed by these imaging studies may stem from a primary abnormality of DA neurons, it seems more likely that these abnormalities are a consequence of a more general brain pathology involving impaired gating of excitatory neurotransmission in the prefrontal cortex (see Chapter 5). This perspective has stimulated investigation of glutamatedopamine interactions in schizophrenia using neuroimaging techniques.

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Figure 4.2. Distribution of [11C]NNC 112 BP in the dorsolateral prefrontal cortex of healthy controls (n=16) and patients with schizophrenia (n=16; ▀; antipsychotic-naive patients; ●, patients antipsychotic-free since more than one year; ▲, patients with two to three weeks of antipsychotic-free interval). Patients with schizophrenia displayed increased D1 receptor availability compared with controls (P=0.02). The effect of acute disruption of N-methyl-D-aspartate (NMDA) transmission by ketamine on DA release has been investigated under different conditions in healthy volunteers. Under resting conditions, ketamine does not affect [11C]raclopride binding to D2 receptors, suggesting that ketamine-induced changes in DA release are too small to be measurable with this technique and that acute disruption of NMDA receptor-mediated

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transmission has little effect on DA release in the resting state. In contrast, acute treatment by ketamine increased amphetamine-induced DA release in healthy volunteers to levels similar to those observed in patients with schizophrenia. At present, no data are available on the effects of ketamine on D2 receptor binding properties in schizophrenic patients and, unambiguous evidence for NMDA dysfunction is currently not available in schizophrenia. However, the data currently available are consistent with the hypothesis that alteration in subcortical DA release observed in patients with schizophrenia after amphetamine might be secondary to impairment of regulatory pathways involving glutamatergic neurotransmission. Syndromal specificity of dopamine abnormalities in schizophrenia In any etiological model of schizophrenia, it is important to take into account heterogeneity in disease presentation. In particular, the primary negative symptoms of schizophrenia, present from the onset of the disease, have been considered a syndrome dimension constituting the ‘hard core’ of schizophrenia, and are considered to be particularly refractory to antipsychotic medications. It has been proposed that this core syndrome may have a different physiopathological basis from the episodic productive symptomatology including hallucinations and delusions. Although the latter symptoms may reflect some form of dopaminergic hyperactivity, the core syndrome may be associated with abnormal neural connectivity in the cortex and decreased dopaminergic activity. The development of functional brain imaging techniques has allowed the relationship between dopamine D2 receptor properties and symptomatology to be assessed directly in patients with schizophrenia. The density of D2 receptors in the striatum has been evaluated by PET in ten young patients untreated with antipsychotic agents, presenting with hebephrenic schizophrenia characterized, from the onset of the disease by a large degree of negative symptomatology. Compared with healthy control subjects, patients did not show a marked difference in the estimated density of D2 receptors. Nevertheless, a strong negative correlation existed between the D2 receptor density index and the negative dimension measured by the total score on the Scale for Assessment of Negative Symptoms (SANS), in particular the dimension of the scale that corresponds to psychomotor poverty, as well as other measures of psychomotor retardation (Figure 4.3). In contrast, no correlation was observed with the other two dimensions obtained from factorial analysis of the SANS, namely avolition-anhedonia and disorganization. These results suggest a close relationship between the negative dimension, in particular blunting of affect, and a decrease in dopaminergic transmission in the striatum. This notion is supported by imaging studies in healthy volunteers showing an analogous inverse relationship between emotional expressiveness and D2 striatal receptors or activity of the dopamine transporter. Exactly how striatal D2 receptors participate in modulating these clinical dimensions (psychomotor retardation, psychomotor expressiveness), and how the latter are linked to changes in these receptors is not clear. Moreover, these findings need to be interpreted in the context of changes in the activity of other brain structures, such as the cortex, which are likely to modulate dopamine

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release in the striatum and whose dopaminergic innervation may be abnormal in schizophrenia.

Figure 4.3. Correlation between binding of [76Br]-bromolisuride to striatal D2 receptors, and psychomotor expressiveness. (Data are reproduced from Martinot et al, 1994, with permission.) A PET method has also been used to investigate whether changes in DOPA metabolism may differentiate patients with different clinical presentations of schizophrenia. Six male patients with different subtypes of schizophrenia according to the DSM III-R classification (two undifferentiated subtypes, two disorganized, one schizoaffective and one catatonic subtype) were evaluated. They were compared with seven healthy male control subjects of comparable mean age. Even though the mean uptake of [18F]-fluoro-DOPA was not significantly different between the patients and controls, a higher variance was observed in the patients. The two patients with ‘undifferentiated’ type disorder (the most productive symptom) were located 2 standard deviations (SD) above the controls, whereas patients with catatonic schizophrenia, whose clinical presentation was marked by negative symptoms and motor deficits, had the lowest values, 2 SD below the control group. This difference was noted both for the caudate nucleus and the putamen. Thus, clinical variables more precise than the overall

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diagnosis, appear to be relevant factors to consider in exploring the biology of schizophrenia. These observations are not unique to schizophrenia and a decrease in [18F]-fluoroDOPA uptake in the caudate nucleus (as well as in the nucleus accumbens and hippocampus) was also observed to be associated with the extent of psychomotor retardation. The abnormalities in DA metabolism observed thus may be related more to the clinical presentation than to the diagnosis of schizophrenia. These studies emphasize the value of considering clinical presentation, rather than ‘categorical’ diagnosis, in order to understand better the underlying pathophysiological processes of psychiatric disease.

5 The role of dopamine in the phenomenology of schizophrenia The concept of schizophrenia was developed a century ago by Kraepelin and Bleuler based on clinical description, and 60 years later linked to the neurobiology of the dopamine (DA) system via the discovery of antipsychotic drugs. For several decades, this state of affairs left psychiatry in a highly unsatisfactory situation regarding one of its most prominent disorders. On the one hand, the disorder is characterized by profound changes in the way a person relates to the environment and experiences self, other people and the world. On the other hand, it is treated with substances that act upon a pathway within the brain whose function was hardly known for decades, except for its roles in motor and neuroendocrine function, which are related to the side effects, but not to the therapeutic effects of the drugs. Recent discoveries regarding the function of the prefrontal cortex and the mesocortical and mesolimbic dopaminergic pathways provide a thread to relate these findings to the psychopathology of schizophrenia. Models of neuronal functioning at the systems level have reached a degree of sophistication such that, for the first time, they have clinical implications for the treatment of schizophrenia. The dopamine hypothesis of schizophrenia Dopamine has been the centerpiece of schizophrenia research for over three decades. Evidence that antipsychotic drugs stimulate presynaptic DA metabolism, that they block dopamine receptors, and that dopamimetic drugs are psychotogenic led to the classic DA hypothesis of schizophrenia. In its earliest version, the DA hypothesis proposed that DA levels were increased in patients with schizophrenia. The initial tests of this hypothesis involved assays of DA and metabolites in peripheral fluids (e.g. blood, urine and cerebrospinal fluid (CSF)) and directly in post mortem brain tissue. In the main, these efforts were not confirmatory of increased DA levels, turnover or metabolism. A variation on the DA theme soon emerged, suggesting that while DA metabolism might not be abnormal, there might be increased numbers of DA receptors in the striatum, primarily D2 receptors, the targets of antipsychotic drugs. While some studies of D2 receptor ligand binding both in post mortem tissue and in vivo with positron emission tomography (PET) scanning found evidence of increased abundance of D2 receptors (Bmax), the majority of studies were negative, particularly if the effects of prior treatment with antipsychotic drugs were excluded. As novel DA receptor proteins were identified, investigators attempted to demonstrate increases in their abundance, again, with largely negative results.

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Another variation on the DA hypothesis deals with the possibility that DA neuronal activity might be abnormal as a ‘downstream’ effect of a primary cortical abnormality. This formulation appeared to reconcile much of the old and the new evidence implicating DA as playing a role in the pathophysiology of schizophrenia. In support of this latest version of the DA hypothesis is the evidence, discussed in Chapter 4, for increased responsiveness of DA terminals to amphetamine administration and for increased uptake of the DA precursor, DOPA and the finding that both of these DA abnormalities are predicted in patients by measures of prefrontal cortical neuronal function. A further elaboration of this version of the hypothesis implicates DA signaling at the prefrontal cortical level as a possible factor in the abnormal prefrontal function associated with schizophrenia. Evidence of diminished prefrontal cortical DA activity has been found in imaging studies of living subjects and decreased prefrontal DA innervation has been observed in post mortem tissue. To make the elements of the story even more convergent, animal studies show that diminished prefrontal DA signaling is one of the factors that leads to a downstream upregulation of striatal DA activity. Prefrontal cortical dysfunction as a primary deficit in schizophrenia The evidence for abnormal prefrontal cortical function in patients with schizophrenia is overwhelming. It includes data from many studies of neuropsychological and cognitive function, from neuroimaging, from studies of eye movements and from electrophysiological studies. An example of such a functional magnetic resonance imaging (fMRI) study is presented in Figure 5.1. The presence of most of these abnormalities is not predicted by chronicity of illness or by the length of treatment. However, there is considerable variation, especially in the physiological data, depending on clinical state and on the nature of the experimental paradigm.

Figure 5.1. Hypofrontality in schizophrenia. The images represent

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difference maps in fMRI activation between controls (n=13) and schizophrenics (n=18), with areas of significant differences indicated in red. In schizophrenics activation was markedly reduced in the dorsolateral prefrontal cortex (circled). (From Calicott et al, 2000.) The earlier literature suggested the frontal abnormality in schizophrenia to be one of underactivation (i.e. ‘hypofrontality’). Since the landmark report in 1974 of reduced frontal lobe regional cerebral blood flow (rCBF), many studies have reported reduced prefrontal physiological activity in patients with schizophrenia. This result has been especially consistent during so-called executive cognition and working memory tasks, which are thought to depend on prefrontal activation. Whether such underactivation is necessarily an abnormal response, however, has been questioned by the finding that, in most of these studies patients have tended to perform less accurately than normal subjects. This raises the possibility that underactivation may reflect underperformance. Studies of normal subjects pushed beyond their working memory capacities have suggested that the underactivation observed in the patients is not pathological, per se, though the diminished capacity of patients to perform prefrontal type tasks appears to be. Another approach to characterize the prefrontal physiological abnormality in schizophrenia is to study patients whose working memory performance is at or near normal. Several recent fMRI studies of such patients have appeared and the results are surprisingly consistent in not showing hypofrontality. Indeed, when patients are able to keep up with the information processing demands, their prefrontal response also tends to be abnormal, but in a surprisingly different manner. Under these circumstances, they overactivate their dorsolateral prefrontal cortex. In other words, when they can keep up with the demand, they process information less efficiently for a given level of performance accuracy. The neuronal circuitry involved in handling the information appears to have a poorer signal to noise (STN) response, and has more difficulty honing the most efficient or automatic neural strategy. This is analogous to the recruitment of extraneous neural activity that occurs in the early phases of a variety of learning paradigms; neural activation becomes more focused once a strategy for processing the information has become more automatic and efficient. Thus, patients with schizophrenia have abnormal prefrontal cortical function during performance of prefrontal cognitive tasks, regardless of their level of performance, but the ‘flavour’ of the abnormality does vary depending on how they are managing the demands of the task. They have diminished capacity to stay on task, which is represented as hypofrontality, and they have diminished STN within the prefrontal cortex when they are able to keep up with the task, which is seen in functional neuroimaging studies as hyperfrontality. The degree to which a patient or patient group will manifest either or both of these abnormalities will likely depend on the capacities of the patients and the characteristics of the task paradigm. The evidence from functional neuroimaging studies is supported by data from another imaging technique, proton magnetic resonance spectroscopy (MRS). Proton MRS has

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been used to measure N-acetyl aspartate (NAA), an intracellular neuronal marker that indirectly reflects the relative abundance of neuronal processes and synapses, which vary as a function of the connectivity, integrity and ‘health’ of neurons. Most studies of NAA concentrations in the brains of patients with schizophrenia have found reductions in the dorsolateral prefrontal cortex as well as some other regions, especially the hippocampal formation. Again, the results are not dependent on stage of illness, chronicity or treatment history. The NAA data are consistent with a number of findings in the post mortem literature implicating structural abnormalities of neuronal connectivity in the prefrontal cortex. The relationship of changes in NAA in various brain regions with performance on executive cognition tasks has revealed that in patients who manifested the ‘hypofrontality’ response, activation of the distributed working memory cortical network was predicted directly by NAA concentrations in the dorsolateral prefrontal cortex. Similar observations have been made in patients who showed the abnormal prefrontal overactivation response. In both cases, the lower the dorsolateral prefrontal cortex NAA concentration, the more abnormal was the physiological response. These data implicate a population of neurons in the dorsolateral prefrontal cortex as being specific ‘effectors’ of the abnormal physiological activity of the working memory cortical network in schizophrenia, both its diminished capacity and its diminished efficiency, and as such, this distributed deficit in cortical function may be an emergent property of abnormal information processing in prefrontal neuronal circuitry. In addition to the foregoing data implicating abnormal prefrontal cortical information processing and cellular architecture as primary aspects of schizophrenia, considerable evidence also points to abnormal function of prefrontal cortex as a phenotypic expression of genetic risk for schizophrenia. In studies of monozygotic twins discordant for schizophrenia, deficits in executive cognition/working memory are observed in the unaffected twins, suggesting that shared genes accounted for these deficits, even though not accounting for the presence of illness, per se. Comparisons of monozygotic and dizygotic twins have also suggested such working memory deficits to be heritable, whereas working memory/executive function deficits are four times more frequent in siblings of patients with schizophrenia than they are in the general population. Furthermore, evidence for inefficient prefrontal function using neuroimaging paradigms has revealed that such anomalies are also found in healthy siblings of patients with schizophrenia who have no deficits in task performance. These various findings demonstrate that abnormal prefrontal cortical information processing is associated not just with schizophrenia, but also with increased genetic risk for schizophrenia and, thus, may be a reflection of the biological effects of susceptibility genes. Dopamine and prefrontal cortical function For many years, the importance of dopaminergic projections to the prefrontal cortex was overlooked. The relatively high density of dopaminergic innervation of the striatum and the relatively sparse projections to the prefrontal cortex encouraged many DA researchers to focus on the striatal DA system. Some investigators interpreted the low concentrations of prefrontal DA to mean that DA played little if any role in the cortex. However, a

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landmark study in 1979 showed that depleting the prefrontal cortex of dopamine in the primate produced deficits on tasks involving working memory and executive cognition that were analogous to those seen after surgical ablations, demonstrating the important role played by the DA innervation of the prefrontal cortex in prefrontal cortical function. Over the following decades, studies of cortical DA function have confirmed that it is critically important for modulating aspects of local prefrontal cortical circuitry, particularly the signal to noise of information processing during working memory and other so-called executive cognitive functions. Dopamine modulates prefrontal activity by affecting the excitability of pyramidal (glutamatergic) and local circuit (γ-aminobutyric acid, GABA) neurons. DA afferents to pyramidal neurons synapse on dendritic spines in close proximity to glutamate inputs from other cortical neurons, particularly inputs from hippocampal formation. Dopamine inputs to the dendritic shafts of local circuit neurons also appear to be in close proximity to glutamate terminals. These anatomic observations suggest that DA gates the excitatory impact of associative cortical information mediated by intracortically projecting glutamate neurons and by locally recurrent collaterals of pyramidal neurons. The results of electrophysiological experiments in behaving rats and monkeys support this notion, showing that DA neurons improve the signal to noise response characteristics of pyramidal neurons in a variety of behavioral contexts, including stress, reward, working memory, and various learning paradigms. Imaging studies in humans also have shown that pharmacological manipulation of DA activity improves prefrontal physiological STN during executive cognition and working memory tasks. The mechanisms by which DA modulates STN in local prefrontal information processing circuits have been studied with patchclamp electrochemical techniques and with computational modeling. These investigations reveal specific effects of D1 receptor activation on neuronal conductances gated by glutamate receptors as well as on voltagedependent ion channels on pyramidal neurons. This modifies the responsiveness of these neurons to excitatory and inhibitory inputs in such a way as to potentiate responses related to coincident associations and reduce responses to less relevant stimuli (i.e. distractions), as might be optimum during working memory. This is critical for shaping the selectivity (i.e. signal to noise ratio) of neural activity in these circuits. Dopamine also may enhance STN by increasing excitation of GABAergic interneurons and effective local surround inhibition. Taken together with the direct modulation of pyramidal neuron excitability, this might serve to stabilize a contextually critical set of strongly active representations and diminish the probability of a response to additional inputs and noise (Figure 5.2). At the same time, weakly active representations of stimuli would be suppressed. These various experimental and computational models of the effects of dopamine signaling in prefrontal cortex indicate that an abnormality in DA signaling could be a factor in the abnormal prefrontal STN found in schizophrenia and in association with genetic susceptibility for the illness (Box 5.1). In fact, there is direct evidence that DA signaling in prefrontal cortex is abnormal and diminished in schizophrenia. The first direct link between abnormal prefrontal cortical function in schizophrenia and prefrontal DA signaling came from a study of cortical rCBF during an executive cognition task. This showed that CSF homovanillic acid (HVA) levels strongly predicted activation of the dorsolateral prefrontal cortex during an

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executive cognition task, with no correlation during a task in which prefrontal DA function was not known to be critical (Figure 5.3). Post mortem studies have also

Figure 5.2. Dopamine signaling in the prefrontal cortex (PFC): a cellular substrate of the signal to noise ratio? Dopamine biases pyramidal neurons to respond to sustained or consistent (i.e. salient) inputs and not to transient inputs. In this way, dopamine focuses and stabilizes the response network. The D1 receptor is the relevant receptor subtype here. When D1 receptor function is suboptimal as in (a), salient signals are not recognized and the signal to noise ratio increases. (b) Optimal D1 receptor signaling. (Adapted from Seamans et al, 2001.) Box 5.1. Some cellular effects of dopamine signaling in prefrontal cortex Enhanced physiological signal to noise ‘Tuning’ of pyramidal neuronal responses during working memory Enhanced NMDA currents in pyramidal neurons Reduced non-NMDA currents in pyramidal neurons Enhanced GABA neuron excitability

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revealed decreased expression of tyrosine hydroxylase in patients with schizophrenia, thus providing an anatomical basis for the apparent functional deficiency in prefrontal DA signaling. It is interesting to note that diminished DA innervation in animals is associated with reduced spine density and dendritic arborization of target neurons, both of which are findings reported in post-mortem schizophrenic brain. Information processing in the prefrontal cortex There has been more than a century of debate on the functions of the prefrontal cortex. As this is the part of the human brain that diverges the most from the brains of other primates, direct experimental evidence is limited. Inferences have to be made from small regions of the monkey brain to homologous, but much larger, regions of the human brain. In addition, while low level vision, touch, audition and motor behavior can be studied with well-controlled tasks and settings, the functions of will, context dependency, planning, decision making, motivation, emotion and rule detection do not easily lend themselves to simple experimental paradigms.

Figure 5.3. Prefrontal dopamine function predicts prefrontocortical function in schizophrenics. Relationship between prefrontal cerebral blood flow (rCBF) and levels of homovanillic acid (HVA) in the cerebrospinal fluid (CSF) in schizophrenics during control performance (a), and while carrying

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out an executive task (b). (Adapted with permission from Weinberger et al, 1988.) Nonetheless, progress has been made, notably from neural network modeling of cognitive control, suggesting that the various parts of the prefrontal cortex subserve similar functions (i.e. context updating, inhibition of reflexive drive directed behavior, and planning) applied to different aspects of high-level information processing. For example, in the dorsolateral prefrontal cortex, abstract rules of language and visuospatial thinking are processed and represented, whereas the orbitofrontal cortex deals with the output of systems related to reward and motivation, and hence, comes to represent goals, emotive experiences and values. From the many neuroimaging studies of prefrontal cortical functioning, one recent study on the automatic perception of rules appears to be of particular relevance for understanding a particular aspect of schizophrenic psychopathology, namely the tendency of the patients to form delusional perceptions and delusions. This used fMRI to identify parts of the brain involved in the formation of rules, when in fact there were no such rules in the stimuli. Normal subjects were shown a completely random succession of circles and squares on a screen for two seconds each. Subjects were told explicitly that the sequence was random, and that they simply had to watch the stimuli and to press one of two buttons, one whenever they saw the square and the other when they saw the circle. Any random sequence contains short strands of subsequent stimuli that appear to be in a specific order and subjects recognize and respond to this apparent order. For example, if four squares appeared in a row, automatic mental processes produced the expectation of yet another square. This can be seen by merely looking at the subjects’ reaction times, which decreased with the number of previous repetitions. Whenever a small bit of apparent order appeared within the random sequence, automatic processes registered this order, and this led to a decrease in response time for the next stimulus that appeared to follow the rule governing the order. It also led to an increase in response time if the stimulus did not follow the rule. The study showed that the reason for this is that the human brain cannot help but detect rules, even if there are none and the subject is told exactly that, and even if the subject does not look for any rules. This was a convincing demonstration that rule detection happens automatically in the brain. Analysis of the subjects’ fMRI scans showed regions in the frontal lobe to be a part of the brain where rule detection takes place. These zones were activated when orders were violated, and that this activation was parametrically dependent upon how well the order had been established beforehand. In other words, activated regions of the brain had increased their activity in a predictable manner. Evidence from studies in which single cell recordings were combined with rule learning paradigms in monkeys further clarified the role of the prefrontal cortex in rule based behavior. Two monkeys were trained to behave according to two different rules. They had to choose one of two pictures after they had been shown one of the pictures together with another stimulus that indicated the rule they had to follow: the rule was either to choose the same stimulus as previously shown (same rule) or to choose the stimulus that was different to the previously shown stimulus (different rule). The monkeys were given a cue that signified the rule they had to follow. Recordings from 492

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neurons located in the dorsolateral prefrontal, the ventrolateral, and the orbitofrontal cortices clearly demonstrated that the abstract rule (‘choose the same stimulus’ versus ‘choose the stimulus that is different’) was represented in the monkey’s prefrontal cortex by 41% of the neurons. However, there was no specific prefrontal area that represented the rule. This implies that the prefrontal cortex contains representations of general rules and relations rather than properties of single stimuli. These rules are constantly sought for in the stream of experience, derived from it, and, if frequently encountered, stored as synaptic weight changes in the very cortical areas that perform the processing. Thus, general rules governing the events in the environment become part of the internal representations of an organism processing these events. One of the functions of the frontal lobes is thus to find regularities in whatever input patterns arrive from lower level cortical areas. However, if something unexpected happens, it may be dangerous (negative) or rewarding (positive). These two types of evaluations are performed—not exclusively but to a large extent—by different brain systems. Negative aspects of incoming information are quickly relayed to the amygdala, where they are associated with fear and anxiety and where behavioral programs dealing with fight, flight, and fright are set into action. Whenever something happens that is better than predicted the dopaminergic reward system becomes activated. Dopamine, reward and salience Whenever something positive happens, the mesolimbic and the mesocortical dopamine systems, which constitute an important component of the brain’s reward system, become active. This has been extensively demonstrated in neuroimaging studies, originally using a very strong ‘positive stimulus’, such as the reintroduction of intravenous cocaine to cocaine addicts in prolonged withdrawal. More recent investigations have shown that the same system is activated in normal human beings upon eating chocolate, hearing nice music, winning a game and even looking at an attractive face or car. These dopaminergic neurons signal the importance of a stimulus, regardless of its nature. As mentioned above, all organisms are bombarded with a large number of stimuli and have to sort out the few that are important from the many that are unimportant. The DA system is thus the signal that becomes attached to the stimuli when the ‘sorting out’ function is applied. One of the roles of the DA system is thus to mediate the conversion of an external stimulus from a neutral and cold bit of sensory information into an attractive or aversive entity. In particular, the mesolimbic DA system is seen as a critical component in the ‘attribution of salience,’ a process whereby events and thoughts come to grab attention, drive action and influence goal-directed behavior due to their association with reward or punishment. Under normal circumstances, it is the stimulus-driven release of DA that mediates acquisition and expression of appropriate motivational salience in response to the subject’s experiences and predispositions. Although DA mediates the process of motivational salience, it does not create this process. It is proposed that in psychosis the dysregulated DA transmission leads to a stimulus-inappropriate release of DA. This neurochemical aberration usurps the normal process of salience attribution and leads to aberrant assignment of salience to external objects and internal representations. Thus DA,

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which under normal conditions is a mediator of contextually relevant salience, in the psychotic state becomes a creator of salience, albeit aberrant ones (Figure 5.4). Salience and dopamine in the psychopathology of schizophrenia In schizophrenia, the DA system is dysfunctional in that it is no longer appropriately fine tuned, becoming either hyperactive in the acute phase of the illness or hypoactive during more chronic states. Within this framework of neurobiological function of the mesolimbic and mesocortical DA systems, some aspects of the psychopathology of schizophrenia become plausible.

Figure 5.4. Psychosis as a disorder of dysregulated dopamine leading to aberrant salience. A model unifying biology and psychology. DA, dopamine. Delusions in this framework are a ‘top-down’ cognitive explanation that the individual imposes upon aberrant salience experiences in an effort to make sense of them. Since delusions are constructed by the individual they are imbued with the psychodynamic themes relevant to the individual and are embedded in the cultural context of the individual. This explains how the same neurochemical dysregulation leads to variable phenomenological expression, for example in the object of paranoid delusions. Hallucinations arise from a conceptually similar but a more direct process—the abnormal salience of the internal representations of percepts and memories. As a result of which the individual experiences these internal representations in a manner that is vivid and real— leading them to confuse this experience with that of an external reality

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Just as important as the psychopathological consequences of an overly active DA system are the symptoms that result from too little dopaminergic activity in this system. A hypoactive dopamine system no longer produces much (or any) meaningful experience. Even stimuli which are normally automatically considered meaningful and worth further consideration, such as social interactions, become uninteresting and boring and hence do not capture cognitive resources for elaborate processing. This process could be the biological correlate of certain of the core negative symptoms of schizophrenia, such as blunted affect and social withdrawal. Why are antipsychotics anti-‘psychotic’? Re-attribution of salience The above paradigm provides a realistic hypothesis for why antipsychotics are efficacious in psychosis. This is because, by their biological actions with respect to blocking dopaminergic neurotransmission, they ‘dampen the salience’ of the symptoms. In this scheme, antipsychotics only provide a platform of dampened salience, however, the process of symptomatic improvement requires further psychological and cognitive resolution. The antipsychotics do not change thoughts or ideas primarily, but provide a neurochemical milieu wherein new aberrant saliences are less likely to form, and previously aberrant saliences are more likely to extinguish. This is consistent with how patients’ experience their improvement. Patients do not immediately abandon the psychotic idea or percept, but report that the idea or percept ‘doesn’t bother me as much’—in fact for many patients this is as good a resolution as antipsychotics can provide. At the same time, since the antipsychotic cannot limit itself only to dampening the salience of symptoms, some normal life saliences may also get dampened leading to the what is often called neuroleptic-induced dysphoria or drug-induced negative/depressive symptoms. In the long term, it should also be clear that treatment of schizophrenia can and should enable re-learning and re-building of salience. If patients are to re-learn during treatment, then medications that make them drowsy or, even worse, interfere with their motivation and emotion should be avoided. However, it should be stressed that this is precisely what many conventional antipsychotic medications, such as chlorpromazine and haloperidol, can do, especially when used in high doses to maintain sedation and behavioral control. Therefore, schizophrenic patients should be treated with atypical antipsychotic medications, as studies have shown that these drugs can decrease negative symptoms by presumably bringing back the DA system to a normal range of function. The newer, atypical antipsychotic medications are currently administered because they cause fewer acute motor side effects and possibly fewer long-term motor side effects (tardive dyskinesia). Within the framework outlined here, these medications, in addition, should be administered because they enable the patients to experience the world more normally, that is to say, more meaningfully.

6 The role of D2 receptors in the action of antipsychotic drugs It has been clear since the discovery of the antidopaminergic properties of chlorpromazine by Carlsson in the early 1960s that this pharmacological activity, and more specifically blockade of dopamine D2 receptors, is shared by all known antipsychotic drugs. Indeed there is a clear correlation between clinically active plasma concentrations of these drugs and their affinity for the D2 receptor. More recently, antipsychotics have been developed that combine D2 receptor antagonist activity with other pharmacological activities, notably 5-HT2 receptor antagonism, with the aim of generating a broader spectrum of antipsychotic activity or a better side effect profile compared with conventional antipsychotic drugs. This strategy was inspired by clinical experience with clozapine, an atypical antipsychotic agent with a rather broad specificity toward a number of monoamine receptors, and led to the introduction of risperidone, olanzapine, quetiapine and others. On the other hand, other drugs that share the atypical clinical profile of clozapine, such as amisulpride and remoxipride, are very specific D2 receptor antagonists. Interaction of antipsychotics with dopamine D2 receptors Historically, the D2 receptor has received the most attention as the biological target of antipsychotic drugs. The advent of radioligand binding studies in the 1970s demonstrated unequivocally that all the principal classes of antipsychotic drugs available at that time bound to this receptor. This was true of phenothiazines, butyrophenones, benzamides, clozapine and other structurally unrelated drugs such as α-flupenthixol and pimozide. In addition, it was demonstrated that clinical dosage correlated with affinity at the D2 receptor for many of these drugs, although it should be pointed out that, in some cases, the clinical dosages chosen were based on doses which produced extrapyramidal symptoms (EPS), rather than on equivalent efficacy to treat psychosis in comparable clinical populations. Although many of the early antipsychotic drugs bind to a wide variety of monoamine receptors, certain drugs are highly specific for D2 (and D3) receptors. This is particularly true for the substituted benzamide class, including amisulpride, raclopride and remoxipride. Interaction with the D2 and possibly D3 receptor may thus well be sufficient to explain the therapeutic effects of the substituted benzamide class. On the other hand, the action of certain drugs, such as clozapine, which have a more complex and extensive therapeutic action, may not be adequately explained by interaction with D2 receptors alone.

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It seems clear that blockade of D2 receptors can adequately explain the beneficial effects of typical antipsychotic drugs on the positive symptoms that manifest themselves in acute psychotic episodes. Blockade of D2 receptors also contributes to the antipsychotic effect of the serotonin-dopamine receptor antagonists, although it is probably not the only mechanism responsible for their benefits, even for this component of schizophrenia. This is clearly the case for the ability of clozapine to improve positive symptoms in many patients with neuroleptic-resistant delusions and hallucinations. In addition, the EPS and prolactin elevations produced by antipsychotic drugs can be satisfactorily accounted for by antagonism of dopaminergic neurotransmission mediated by D2 receptors in the striatum (which is part of the extrapyramidal nervous system) for the extrapyramidal symptoms and in the tuberoinfundibular system of the hypothalamus for the neuroendocrine side effects. On the other hand, it is not possible to explain the beneficial effects of atypical antipsychotics on the negative symptoms of schizophrenia as well as on mood and cognition, by D2 receptor blockade alone, since such properties are not shared by potent D2 receptor antagonists such as the butyrophenones. Interaction of antipsychotics with other dopamine receptor subtypes The central nervous system contains four subtypes of dopamine receptor other than the D2 receptor (Box 6.1), and it is conceivable that these may be involved in the clinical action of current antipsychotic drugs, or may be potential targets for future ones. At the moment, however, the data supporting this idea are not encouraging, with the possible exception of the D3 receptor. The other principal class of dopamine receptor is the D1 receptor, which is positively coupled to (i.e. activates) the enzyme adenylate cyclase. D1 receptors are blocked by phenothiazines and related antipsychotics, as well as clozapine, but not by butyrophenones such as haloperidol. Specific D1 receptor antagonists have been developed and evaluated in the treatment of schizophrenia, but no clear evidence of beneficial therapeutic activity was obtained in pilot studies. The D5 receptor has very similar properties to the D1 receptor, and it too can probably be rejected as a potential target for antipsychotic drugs. The identification of the D4 receptor provoked much interest in the possibility that this was a key mechanism in the action of atypical antipsychotic drugs. This idea originated from early observations that clozapine possessed higher affinity for the D4 receptor than Box 6.1. Subtypes of dopamine receptor D1 receptor family

D2 receptor family

D1

D2

D5

D3 D4

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for the D2 receptor, that the D4 receptor density may be elevated in the schizophrenic brain, and that transmission of polymorphisms in the D4 receptor gene may a risk factor for schizophrenia. However, these initial findings of potential D4 receptor abnormalities in schizophrenia were not confirmed in more extensive studies. In addition, certain substituted benzamide antipsychotic agents such as amisulpride and remoxipride have little or no affinity for the D4 receptor. Interest in the D4 receptor as a target for antipsychotic drugs has waned after the completion of large randomized clinical trials with selective D4 receptor antagonists that failed to demonstrate any useful antipsychotic activity. The D3 receptor has many similarities with the D2 receptor in terms of distribution, sequence and recognition properties. Some highly selective D3 antagonists have been identified in recent years. Judging from data obtained in preclinical studies, these appear promising candidates for antipsychotic drugs, and clinical trials with several of these agents are underway or imminent. However, all currently available antipsychotic drugs have similar efficacy at D3 and at D2 receptors, rendering difficult any attempt to attribute specific physiological or clinical properties to one or other of these two receptors. Occupancy of dopamine D2 receptors in patients The advent of neuroimaging has made it possible to investigate the receptor occupancy of antipsychotics in patients while they are being treated. The usefulness of this was first demonstrated by Farde and colleagues in the 1980s who showed that most antipsychotics, with the exception of clozapine, showed high (70% and above) D2 occupancy at usual clinical doses. Further studies have suggested a ‘therapeutic window’ for most antipsychotics with 60–65% receptor blockade that may be necessary to invoke optimal antipsychotic response, and occupancies greater than 80% being associated with EPS. Risperidone becomes an effective antipsychotic at a level of D2 occupancy conventionally seen with typical antipsychotics i.e. at doses of 2mg it exhibits 60% or greater D2 occupancy. High levels of 5-HT2 occupancy are observed even at lower doses but this does not lead to an antipsychotic effect. Olanzapine also shows a preferential blockade of serotonin 5-HT2 as compared with the dopamine D2 receptors. However, antipsychotic effects are typically observed in the dose range of 10–20mg per day, where its D2 occupancy is within the range of 65–80%. However, at doses of 30mg per day and above, where there is a suggestion of greater prolactin elevation and EPS, occupancy may rise to above 80%. Clozapine is the prototypical atypical antipsychotic, and has now been extensively investigated using positron emission spectrometry (PET). At very low doses (50mg/day), less than what is routinely required for antipsychotic effect, it shows complete occupancy of the serotonin 5-HT2 system, even though it is not as yet an effective antipsychotic. Clozapine’s antipsychotic efficacy, at least in refractory patients, is best seen over a dose range of 300–400ng/ml, where its D2 receptor occupancy is in the range of 50–60%. While controlled comparative studies are not available, all the published data suggest that D2 receptor occupancy with clozapine, at least at the time points measured, is lower than that of typical antipsychotics, lower than that of risperidone and olanzapine, and lower than the threshold required for EPS or prolactin elevation. This low level of D2

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occupancy, therefore, is the simplest explanation required to explain why clozapine does not give rise to EPS and sustained prolactin elevation, although it is less easy to explain its superior efficacy in refractory patients. The binding profile of quetiapine in PET studies is quite similar to that of clozapine. Amisulpride, unlike the other atypical antipsychotics discussed above, does not have any affinity for the serotonin 5-HT2 receptors. Doses of amisulpride between 600 and 900mg/day achieve 70–80% D2 occupancy, while doses >1100mg/day result in >85% D2 occupancy, and at these higher levels dose-dependent EPS can be observed. Amisulpride shows an optimal balance between efficacy and diminished EPS risk in the 400– 800mg/day range, as would be expected from its D2 occupancy. Activity of dopamine D2 receptors and atypical antipsychotic activity As all antipsychotics, be they typical or atypical, bind to dopamine D2 receptors, it is legitimate to enquire what endows certain drugs with ‘atypical’ antipsychotic activity. The answer is complicated by the fact that most of the newer atypical antipsychotics act at several receptors (Table 6.1), thereby leading to a multitude of possible explanations. One of the most interesting insights is provided by the comparison of nonspecific atypical antipsychotics such as risperidone, olanzapine and quetiapine, to the specific dopamine D2/3 antagonist, amisulpride, and related drugs such as remoxipride. The comparative data on these atypicals are summarized in Table 6.2, and show amisulpride to have demonstrated as much atypicality as the mixed 5-HT2/D2 antagonists, despite being a selective D2/3 antagonist. Although less information is available since these drugs have since been withdrawn due to hematological side effects, similar conclusions can be reached for the selective benzamide drugs remoxipride and raclopride. The main conclusion that one can draw is that action at the dopamine D2/3 receptors, is by itself, sufficient to provide the contemporary kind of atypical antipsychotic activity. The role of serotonin receptor occupancy in atypical antipsychotic action As described above, PET studies of atypical antipsychotics have shown extensive occupation of 5-HT2A receptors in the cerebral cortex with clozapine, olanzapine, risperidone and quetiapine, but not with amisulpride. However, virtually complete receptor occupancy is observed at doses inferior to those required for antipsychotic effects. This separation between receptor-occupying and clinically active doses calls into question an effect on 5-HT2A receptors as the unique neurochemical determinant of atypicity. The serotonin hypothesis has also been evaluated in a more elaborate PET study in which concomitant occupancy of striatal D2 dopamine and cortical 5-HT2A serotonin receptors was evaluated in parallel groups of patients with schizophrenia treated with either chlorpromazine, clozapine or amisulpride displaced binding to 5-HT2A receptors (Figure 6.1). Thus, at therapeutic doses, clozapine is not unique in binding to 5-HT2A receptors, and affinity for this receptor does not seem using [18F]-setoperone.

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Table 6.1. Binding affinities (nM) of haloperidol and several atypical antipsychotic drugs for monoamine neurotransmitter receptors. Drug

Receptor D1

D2 D3

D4

555HT1A HT2A HT2C

Halo peridol

120

1.3 3.2

2.3

>1000

78

Cloza pine

141

83 200

20

6.5

2.5

8.6

Risperi done

75

3.1 9.6

7.0

488

0.2

25.8

Olanza pine

31

11

50

27

>1000

5.0

11.3

Ziprasi done

130

3.1 7.2

32

2.5

0.4

0.7

Quetia pine

455

160 940 2200 >1000

295

5HT3

5HT6

M1

H1

>1000 >1000 6000 >1000 >1000 95

11

α2

46

360

23

1.9

3.9

11.6

155

>1000

2.0

3.0

10

7.0

1.9

19

228

76

47

5100

13

310

11

120

7.0

87

>1000 2000 57

α1

>1000 >1000 4100

Amisul >1000 2.8 3.2 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 pride

Table 6.2. Is appropriate modulation of dopamine D2 receptors sufficient for atypical antipsychotic activity? Risperidone, Quetiapine, Olanzapine, Ziprasidone

Remoxipride

Amisulpride

5HT2/D1/D4/D2

Specific D2/D3

Specific D2/D3

Equivalent or better for positive symptoms

Yes

Yes

Yes

Less extrapyramidal side effects

Yes

Yes

Yes

Better for negative symptoms

Yes

Yes

Yes

Receptor specificity Therapeutic dimension compared with highdose haloperidol

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Not tried

Not tried

Yes

Better impact on functional/ outcome measures

Yes

Yes

Yes

Relapse prevention with long-term use

Yes

Yes

Yes

Whereas all three drugs displaced the radiotracer binding to striatal dopamine receptors, only clozapine and chlorpromazine, but not amisulpride, to be a prerequisite for atypical antipsychotic activity, since it is shared by the conventional antipsychotic chlorpromazine but not by the atypical amisulpride.

Figure 6.1. Binding of antipsychotic drugs to D2 receptors in the striatum and to 5-HT2A receptors in the cortex in schizophrenia. [18F]-Setoperone has nanomolar affinity for both dopamine D2 receptors, which predominate in the striatum, and serotonin 5-HT2A receptors, which predominate in the cortex. The same ligand can thus be used to identify both receptors

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simultaneously in the same individual. (a) binding of [18F]-setoperone to D2 receptors in the striatum. (b) binding of [18F]-setoperone to 5-HT2A receptors in the cortex. The color code refers to the percentage of injected radioactivity per liter of tissue (% I.A./I.). Striatum: compare an antipsychotic-free schizophrenic patient (top left), and patients treated with 600mg/d of chlorpromazine (top right), 500mg/day of clozapine (bottom right) or 600mg/day of amisulpride (bottom left). Cortex: note the comparable displacement of [18F]setoperone by chlorpromazine and clozapine in the cortex, whereas the displacement in the striatum of the patient treated by clozapine is less marked. Amisulpride binds only to dopamine D2 receptors; therefore, the cortical [18F]-setoperone appears high in cortex and low in the striatum that are not visible. Both clozapine and chlorpromazine bind to 5-HT2A and to dopamine D2 receptors. The visibility of striatal regions in the clozapinetreated patient could therefore be explained by the lower affinity of clozapine for dopamine D2 receptors than that of chlorpromazine. (Reproduced from Trichard et al, 1998a, with permission.) Antipsychotic interactions with the D2 receptor—affinity and koff considerations It has recently been proposed that the hypothesis that can best account for atypicality is the faster dissociation rate (koff) from the dopamine D2 receptor, which results in a lower

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overall affinity for the dopamine D2 receptor. Drugs with lower affinity and faster dissociation are often given at comparably higher doses (Table 6.3). Thus, faster dissociation by itself does not mean a lesser effect on the dopamine D2 system. One could, in principle, give a proportionally higher dose of a fast koff drug and obtain exactly the same (or even higher) level of equilibrium occupancy. However, even under circumstances of equivalent equilibrium occupancy, drugs with a faster dissociation show different behavior under physiological conditions. Regardless of fast or slow dissociation, all drugs depress tonic dopamine transmission to a degree determined by their overall occupancy. However, drugs with a faster dissociation block phasic bursts of DA transmission less effectively than drugs that bind more tightly. Since phasic transmission is essential for dopamine to exert its physiological effects, drugs with a faster dissociation should attenuate dopamine transmission with lesser distortion of phasic physiological signaling. This may account for the fact that antipsychotics with a faster dissociation from the dopamine D2 receptor may lead to antipsychotic effect with little or minimal EPS or prolactin elevation, decreased cognitive impairment, and perhaps greater improvement in secondary negative symptoms.

Table 6.3. Dissociation rate constants for antipsychotic drugs at the 74 dopamine receptor. Data are taken from Kapur and Seeman, 1002. koff (min−1)

Dissociation time (t1/2)

Quetiapine

3.013

<30 sec

Clozapine

1.386

30 sec

Amisulpride

0.730

<60 sec

Olanzapine

0.039

17 min

Sertindole

0.014

49 min

Haloperidol

0.017

42 min

Chlorpromazine

0.022

36 min

Antipsychotic

Data for amisulpride from Seeman, 2002.

In the light of this hypothesis, one would not see typical/atypical as a dichotomy, but as two ends of a continuum—from very high likelihood of EPS (haloperidol) to very low likelihood of EPS (clozapine). The lower affinity/fast koff will be a more important predictor of the order of atypicality than a specificity index like the 5-HT2/D2 ratio. For example, risperidone has a much higher 5-HT2/D2 ratio (~20) as compared to olanzapine (~8) as compared to quetiapine (~2). However, in terms of atypicality (as seen as the propensity to cause EPS), there is broad consensus that risperidone gives rise to more EPS than olanzapine, which in turn has a higher likelihood of EPS than quetiapine. This is the reverse of what would be predicted by the 5-HT2/D2 ratio, but, is in keeping with their low-affinity/fast koff at the D2 receptor which is in the order of quetiapine>olanzapine>risperidone.

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However, the fast koff hypothesis also has several difficulties. First, it deals mainly with EPS/prolactin and does not address the issue of refractory schizophrenia or cognitive symptoms directly. Secondly, given the technical requirement (radiolabeling of ligand) for determination of koff, this has been measured only for a limited number of antipsychotics at the moment. Thirdly, certain drugs, including sertindole and aripiprazole, which are clearly atypical in clinical practice, do not follow the rule but have a much slower koff than would be predicted by this hypothesis. Evidence for regional specificity in the binding of typical and atypical antipsychotic drugs While most of the above PET studies have focused on ‘striatal’ dopamine D2 receptor blockade, there is an increasing interest in examining the effects of antipsychotics in extrastriatal regions (mainly the thalamus and the cortex) which may be more pertinent for the antipsychotic action of these drugs. There are some reports that suggest that atypical antipsychotics (clozapine, olanzapine, sertindole, risperidone and amisulpride) show a preferential blockade of the cortical dopamine D2 receptors as opposed to striatal dopamine D2 receptors, whereas haloperidol shows equal occupancy in the two regions. Due to the low density of D2 receptors in the cortex compared with the striatum, these studies have necessitated the development of new radiotracers with very high affinity for the D2 receptor, such as [76Br]-FLB-457. A comparison of occupancy of striatal, thalamic and cortical D2 receptors was undertaken using this ligand in the brains of patients with schizophrenia treated with standard doses of the typical antipsychotic agent haloperidol, and of four atypical antipsychotic agents, amisulpride, risperidone, clozapine and olanzapine. All the antipsychotics, both typical and atypical, bound to D2 receptors in the temporal cortex to a comparable extent, occupying between 72 and 97% of receptors. On the other hand, the binding of the atypical compounds in the striatum and thalamus was significantly lower than that of haloperidol (Figure 6.2). In addition, for amisulpride, the dose-response relationship was also investigated. A curvilinear relationship was observed between the binding of the radioligand to D2 receptors and plasma concentrations of amisulpride. The estimated occupancy of extrastriatal D2 receptors in the temporal cortex ranged from 50 to 60%, even for very low doses such as 50mg/day (corresponding to plasma concentrations between 30 and 61 ng/l), which have proved effective in the treatment of the negative symptoms of schizophrenia. These doses did not result in pronounced binding to D2 striatal receptors. At higher doses of amisulpride (above 100ng/l plasma concentration), at which EPS may frequently appear, the estimated occupancy was 80–95% in the temporal lobe, with concomitant striatal binding of 35–60%. What is of interest in these studies is that atypical antipsychotics, regardless of whether they are multi-receptorial or D2 specific, share this relative selectivity for cortical receptors. The results suggest that antipsychotic effects of these drugs, both toward positive and negative symptoms, are probably mediated to a large extent by an action on dopamine receptors in cortical and corticolimbic areas. Although more drugs obviously need to be tested, this is the only neurochemical parameter in the brain identified to date that adequately classifies antipsychotic drugs as atypical. The precise molecular basis for

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this difference, if indeed this striatal-extrastriatal difference is a reliable finding, is not entirely clear, and will no doubt be an important research axis in coming years.

Figure 6.2. Binding of haloperidol and three atypical antipsychotics to dopamine D2 receptors in the striatum and temporal cortex. Data are presented as percent binding index measured by positron emission tomography with [76Br]-FLB-457 following administration of standard doses of haloperidol (3–60mg/day) and atypical antipsychotic agents (risperidone, 6–12mg/day; clozapine, 200–400 mg/day; amisulpride, 400– 1200mg/day; olanzapine, 5– 20mg/day). (Data are reproduced from Xiberas et al, 2001b, with permission.)

7 Amisulpride: a selective dopaminergic agent and atypical antipsychotic Amisulpride is an atypical antipsychotic drug which differs pharmacologically from other atypical agents by virtue of its high selectivity for dopamine D2 and D3 receptors. The drug was first introduced into clinical practice as an antipsychotic in 1987 and has since been used extensively, with over 600 million patient treatment days recorded. Clinically, amisulpride is characterized by a low prevalence of extrapyramidal symptoms (EPS) and efficacy in relieving positive and negative symptoms of schizophrenia. As well as being a highly effective first-line treatment for acute psychotic episodes, amisulpride, when used at low doses, is possibly the best current maintenance treatment for chronically negative schizophrenic subjects. Mechanism of action of amisulpride The pharmacological effects of amisulpride so far identified in the central nervous system are all related to the blockade of dopamine D2 and D3 receptors. These two receptors are the only ones for which amisulpride has been shown to have relevant affinity. In this respect, amisulpride differs from the majority of conventional and atypical antipsychotic drugs, which have some affinity for other dopamine or other monoamine receptors (Figure 7.1). Amisulpride is an antagonist at both presynaptic and postsynaptic dopamine receptors in the central nervous system, and its administration in vivo increases dopamine turnover in the brain. There is good evidence that, in vivo, amisulpride can antagonize presynaptic dopamine receptors at lower doses than those needed to block postsynaptic receptors. These presynaptic receptors control neurotransmitter release from dopamine nerve terminals, and their blockade by amisulpride will lead to an increase in dopamine release. At a systems level, amisulpride appears to be a more potent blocker of dopaminergic neurotransmission in the limbic system than in the striatum. This conclusion is supported by behavioral experiments showing that this drug blocks behaviors mediated by the limbic system at doses lower than those required to block extrapyramidal effects, such as amphetamine-induced stereotypies. In the cortex, amisulpride may actually increase dopaminergic activity. This is because postsynaptic receptors are predominantly of the D1 receptor family, which are not blocked by amisulpride. Thus the major effect of the drug in this brain region is to block presynaptic D2/D3 dopamine receptors, leading to a rise in extracellular dopamine concentrations, and thus to increased D1 receptor activation (Figure 7.2). However the potential role of striatothalamic feedback loops in this action of amisulpride is not known.

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Figure 7.1. Receptor binding profiles of amisulpride and other antipsychotics. Data are presented as pKi values (the longer the bar, the higher the affinity) for amisulpride (AMI), haloperidol (HALO), clozapine (CLOZ), risperidone (RIS), olanzapine (OLZ) and quetiapine (QUET). (From Schoemaker et al, 1997 and Duncan et al, 1999.) These regional differences in the effects of amisulpride on dopaminergic transmission, which are probably due to differences in the relative importance of presynaptic and postsynaptic D2/D3 receptors in different brain regions, are thought to underlie the atypical clinical profile of amisulpride. Interaction of amisulpride with dopamine D2 receptors in man Brain imaging technology has been used to evaluate the interaction of amisulpride with dopamine D2 receptors in the brains of patients with schizophrenia treated with this drug. For example, a comparison was made of D2 receptor occupancy between seven drugnaive young patients with predominantly negative symptomatology treated with a low dose of amisulpride (50–100mg/day) and four patients receiving a higher dose for the treatment of productive symptomatology. Both groups of patients responded clinically to amisulpride treatment.

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Figure 7.2. Schematic representation of the action of amisuipride on dopaminergic neurotransmission in the frontal cortex (top) and the limbic system (bottom). The orange bars represent amisulpride which biocks D2 (●) and D3 (■) receptors. Postsynaptic D1 ( ) receptors in the frontal cortex are unaffected by amisulpride. VTA, ventrotegmental area; DA, dopamine. The patients with negative symptoms, treated with low doses, presented a D2 receptor occupancy in the striatum ranging between 4 and 26% (Figure 7.3). These results may suggest that the therapeutic effect on negative symptomatology demonstrated at these low doses of amisulpride was not necessarily mediated via striatal D2 receptors, but possibly involved dopamine receptors located in other brain structures, such as D3 receptors in the limbic system, for which amisulpride shows high selectivity. Receptor occupancy in the patients presenting positive symptoms was between 40 and 76%.

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Figure 7.3. Evaluation of striatal dopamine D2 receptor blockade by variable doses of amisulpride, using positron emission tomography (PET). [76Br]-bromolisuride PET was used to determine receptor occupancy. The arrows show the range of optimal doses (between 630 and 910mg/day) and the dose for which the risk of adverse events is higher (approximately 1100mg/day). (Data are reproduced from Martinot et al, 1996, with permission.) From these data, it was possible to construct a dose/receptor occupancy curve for amisulpride across the therapeutic dose range. This demonstrated a curvilinear relationship between striatal D2 receptor occupancy and the therapeutic dose administered. By comparison with the axiom that optimum binding to striatal D2 receptors for an antipsychotic effect without undesirable extrapyramidal side effects (EPS) should be 70–80% (see Chapter 6), the data with amisulpride would suggest that a dose of 600–900 mg/day would provide optimal management of productive symptomatology. Higher doses may be associated with high levels of EPS. Binding of amisulpride to extrastriatal receptors in the temporal cortex has also been investigated using [76Br]-FLB-457 and the technology described in Chapter 6. The binding of amisulpride was evaluated in eight schizophrenic patients treated with amisulpride at doses ranging from 50 to 1200mg/day for at least 5 half-lives of the

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medication. A curvilinear relationship was observed between the binding of the radioligand to D2 receptors and plasma concentrations of amisulpride. The estimated occupancy of extrastriatal D2 receptors in the temporal cortex ranged from 50 to 60%, even for very low doses such as 50mg/day (corresponding to plasma concentrations between 30 and 61ng/l), which did not result in pronounced binding to D2 striatal receptors. At higher doses of amisulpride (above 100ng/l plasma concentration), at which EPS may frequently appear, the estimated occupancy was 80–95% in the temporal lobe, with concomitant striatal binding of 35–60% (Figure 7.4) As discussed in Chapter 6, amisulpride does not occupy 5-HT2A receptors in the human brain right across its dose range. Clinical studies with amisulpride Amisulpride has been examined in 18 randomized controlled trials including 2214 patients. Study duration ranged between three weeks to one year. Eleven trials examined the effectiveness of amisulpride in acutely ill patients. In most of these studies, amisulpride was compared with haloperidol, but there was also a comparison with flupenthixol and one with perazine. The patients had moderate to severe schizophrenic symptoms at baseline and they were on average in their mid-thirties. Seven other studies examined low-dose amisulpride (50–300mg/day) for patients with predominant persistent

Figure 7.4. Binding of amisulpride to corticolimbic and striatal dopamine receptors. The PET images were obtained using [76Br]-FLB-457. The color scale represents normalized concentrations of the radioligand in different regions. An elevated radioactivity represents low blockade

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of D2 receptors and vice versa. Left hand panels: images from an untreated subject; center panels: images from a patient with a low plasma concentration of amisulpride (61 ng/ml); right hand panels: images from a patient with elevated concentrations of amisulpride (390ng/ml). Upper panels: the striatum is visible in red. Lower panels: a quantifiable signal is detected in the temporal cortex, the internal temporal regions and the thalamus in the control subject Blockade of the corticolimbic D2/D3 sites was detected in the patient with low plasma concentrations of amisulpride, whereas receptors in the striatum were not In the patient with high plasma concentrations, binding of the radioligand to both striatal and extrastriatal D2/D3 sites was blocked. The regional specificity of D2 receptor blockade thus appears to be dose– dependent with this medication. Images are taken from Xiberas et al, 2001a, with permission. negative symptoms and compared amisulpride with placebo or conventional antipsychotics. These studies are especially important, because they allow a much better assessment of the efficacy against negative symptoms. Such studies with the mixed dopamine-serotonin receptor antagonists have not yet been published. Finally, three large studies have compared amisulpride and two other atypical antipsychotics, namely risperidone and olanzapine. Amisulpride in the short-term management of acutely ill schizophrenic patients The acute antipsychotic activity of amisulpride has been studied in an extensive series of trials lasting from one to three months. Amisulpride has been compared with several typical and atypical antipsychotic drugs. These studies have included both patients with

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acute exacerbation of psychosis and patients with predominant negative symptomatology; both previously treated and drugnaive patients have been included. Effect on acute psychotic symptoms These studies have determined the impact of amisulpride on the acute psychotic manifestations of the disease, essentially corresponding to the positive symptomatology of schizophrenia (Table 7.1). Placebo groups being inappropriate for such patients, who require rapid symptom control, these studies have compared amisulpride with other antipsychotics, namely haloperidol, α-flupenthixol, risperidone and olanzapine. One study compared several doses of amisulpride (100, 400, 800 and 1200mg/day) to haloperidol (16 mg/day). In terms of efficacy on the Brief Psychiatric Rating Scale (BPRS), a bell-shaped dose-response curve was observed, with the dose of 800mg/day being the most effective, although 400 mg could also be recommended. The incidence of extrapyramidal symptoms increased as a function of dose, although in all cases, this was significantly lower than in the haloperidol-treated group. Individual comparisons of amisulpride (600–1000 mg/day) with conventional antipsychotic drugs have generally speaking demonstrated comparable control of psychotic symptoms measured with the BPRS or the Positive And Negative Syndrome Scale (PANSS). In certain trials, there was a significant advantage towards amisulpride.

Table 7.1 Studies evaluating the short-term efficacy of amisulpride in the treatment of acute psychotic treatment of schizophrenia. Study

n

Duration Dose (mg) Comparator

Efficacy

Tolerance

AMI-48% HALO-38%

MI>HALO

Möller et al, 1997

191

6 wks

800

HALO 20 mg

Wetzel et al, 1998

132

6 wks

1000

FLU 25 mg

AMI-42% AMI>HALO HALO-33%

Puech et al, 1998*

319

4 wks

100–1200

HALO 15mg

AMI-59% AMI>HALO HALO-45%

Peuskens et al 1999 228

8 wks

800

RIS 8mg

AMI-7% RIS-42%

AMI≥RIS

Martin et al, 2002

8 wks

200-800†

OLZ 5–20 mg

AMI-31% OLZ-30%

AMI >OLZ

377

Efficacy outcome is presented as percentage improvement on the BPRS. *Response rates are presented for the 800 mg dose of amisulpride. †This was a flexible dose study, where the daily dose could be titrated between the indicated limits. AMI, amisulpride; HALO, haloperidol; RIS, risperidone; FLU, flupenthixol; OLZ, olanzapine.

A meta-analysis was performed of outcome in all randomized controlled trials which compared amisulpride with conventional antipsychotics and/or placebo in the treatment of schizophrenia and schizophrenia-like psychoses. This analysis allowed comparison of

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treatment effect sizes with those of other atypical antipsychotic agents, namely amisulpride, olanzapine, quetiapine, risperidone or sertindole. Different endpoints were evaluated, principally the mean change from baseline to endpoint of the BPRS total score as a measure of global schizophrenic symptoms, the Scale for the Assessment of Negative Symptoms (SANS) for negative symptoms and emergence of extrapyramidal symptoms assessed by analyzing the number of patients requiring antiparkinsonian medication during the studies. In the 11 studies with acutely ill patients, amisulpride was significantly superior compared to conventional antipsychotics in terms of the mean reduction in BPRS score from inclusion to endpoint. The mean effect size (r) of 0.11 roughly indicates an 11% superiority of amisulpride over conventional antipsychotics. In all but one of these studies (Klein et al, 1985), there was at least a trend in favor of amisulpride (Figure 7.5). Such a statistically significant superiority has not been shown by all new drugs which are considered to be atypical antipsychotic drugs.

Figure 7.5. Mean BPRS change—new versus conventional antipsychotics.

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65

The dotted lines are the mean effect sizes and their confidence intervals using a fixed effects model in all figures. 1

Endpoint analysis, not used for mean effect size. 2

r=0.11, CI 0.06 to 0.16, z=4.4, P<0.0001, n=1654. 3

r=0.04, CI −0.05 to 0.13, z=0.86, P=0.39, n=2994.

4

r=−0.05, CI −0.11 to 0.01, z=−1.5, P=0.13, n=953. 5

r=0.08, CI 0.03 to 0.12, z=3.08, P=0.002, n=3362. 6

r=−0.03, CI −0.08 to 0.03, z=−0.90, P=0.37, n=1218. In addition, two double-blind studies have compared amisulpride with atypical antipsychotics in short-term treatment of acute schizophrenic episodes, one using risperidone and the other olanzapine. In the first trial, risperidone (8mg; n=115) was compared with amisulpride (800mg/day; n=113). The PANSS positive score improved by 52% and 48%, respectively, and the BPRS global score by 47% and 42%, respectively (Figure 7.6). The advantage observed with amisulpride was not significant. In the comparative study with olanzapine, a comparable amelioration of the BPRS score and the PANSS score was observed in both groups after two months of treatment. Improvement was noted on all the subscores of the BPRS. There was no evidence for the emergence of EPS during either of these studies in either treatment arm. Effects on negative symptoms In the population of acutely ill schizophrenics, amisulpride also reduces negative symptoms. This effect is more pronounced for amisulpride than for haloperidol and similar to that of risperidone. In this population, the effect on negative symptoms could be secondary to an improvement of positive symptoms. To address this possibility, studies have been carried out in patients with primary negative symptomatology who were essentially devoid of positive symptomatology. Three such short-term studies were performed comparing amisulpride with placebo.

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Figure 7.6. Comparison of amisulpride (800mg/day) and risperidone (8mg/day) in the treatment of acute psychotic episodes. Evolution of the mean score on the Brief Psychiatric Rating Scale (BPRS) between baseline and study end (eight weeks). Yellow columns, amisulpride; green columns, risperidone. The dotted lines are the mean effect sizes and their confidence intervals using a fixed effects model. (From Peuskens et al, 1999.) Since primary negative symptoms do not respond well to classic antipsychotics, and since the patients do not have significant florid positive symptomatology that would benefit from these treatments, it is considered ethically acceptable to perform placebocontrolled trials in such patients. All these studies demonstrated substantial improvement of negative symptoms measured with the SANS scale with low doses (50–300 mg) of amisulpride compared with placebo. One of the studies included exclusively drug-naive young patients, and thus allowed a treatment effect secondary to the withdrawal of previous conventional antipsychotic treatment to be ruled out. In these studies, the incidence of EPS remained extremely low. Again, meta-analysis confirms the superiority of amisulpride over placebo in these studies (P<0.001; Figure 7.7).

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Figure 7.7. Mean change of negative symptoms—antipsychotics versus placebo. Note that all amisulpride versus placebo studies have been performed in patients with predominantly negative symptoms, whereas all other atypical antipsychotics were studied only in acutely ill patients. 1

This study was not included in the mean effect size because the data was not normally distributed. 2

r=0.26, CI 0.19 to 0.34, z=6.59, P<0.0001, n=624. 3

r=0.21, CI 0.13 to 0.28, z=5.02, P<0.0001, n=582. 4

r=0.19, CI 0.07 to 0.30, z=3.09, P=0.002, n=823.

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5

r=0.20, CI 0.13 to 0.27, z=5.31, P<0.0001, n=686. 6

r=0.19, CI 0.09 to 0.28, z=3.69, P=0.0002, n=392. Amisulpride is the only antipsychotic with a full development in schizophrenics with mainly negative symptomatology in placebocontrolled trials. The different amisulpride trials provided very important quantitative and qualitative information concerning the size of the effect in this resistant population, the most effective dosage and the duration and stability of the effect. Moreover, these trials controlled for most of the causalities proposed to be at the origin of a nonspecific improvement (e.g. secondary to improvement in positive symptoms). Although the effects of mixed dopamine/serotonin receptor antagonists on negative symptoms has been evaluated, and also found to be significantly better than placebo (see Figure 7.7), all of these studies had been performed in acutely ill patients so that it is not clear whether the observed superiority was in terms of primary negative symptoms or secondary negative symptoms. The utility of other atypical antipsychotics in patients with primary negative symptomatology thus remains unclear. Amisulpride for maintenance therapy of schizophrenia Long-term studies have been performed in order to verify the stability of the initial treatment response and to assess the utility of amisulpride in maintenance therapy of schizophrenia (Table 7.2). These studies range in length from four to 12 months, and include two comparative studies against haloperidol, a comparative study against risperidone and one study against olanzapine (in fact this is the six-month outcome data from the same study for which two-month data was described above). In addition, a 12month placebo-controlled study had been performed in patients with chronic negative symptomatology. Two studies have compared long-term treatment with amisulpride and haloperidol in patients with predominantly positive symptomatology. One of these was a double-blind study (four-month duration) and the other an open-label randomized design (one-year duration). The former study demonstrated equivalent efficacy on symptoms measured with the BPRS, whereas the latter demonstrated superiority for amisulpride at study end. In both studies, similar efficacy on the PANSS positive symptoms scale was found, whereas amisulpride was superior in terms of improvement on the PANSS negative symptom scale. As in the short-term trials, the incidence of extrapyramidal symptoms in the amisulpride-treated patients was low compared with those treated with haloperidol. The long-term efficacy of amisulpride has also been confirmed in direct comparisons with risperidone and olanzapine. The trials were designed as non-inferiority trials and the non-inferiority of amisulpride was indeed observed at six months. The treatment effects on both positive and negative symptoms were maintained in a stable fashion throughout the treatment period. In addition, in the six-month comparative study with risperidone,

Amisulpride: a selective dopaminergic agent

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Table 7.2. Studies evaluating the long-term efficacy of amisulpride in patients with schizophrenia. Study

n

Duration

Dose (mg/day)

Comparator

Efficacy

Safety

Carrière et al, 2000

199

16wks

400–1200*

HALO 10–30mg/day

AMI-42% HALO-33%

AMI>HALO

Colonna et al, 2000

488

52wks

200–800*

HALO 5–20mg/day

AMI-45% HALO-34%

AMI>HALO

Sechter et al, 2002

309

24wks

400–1000*

RIS 4–10mg/day

RIS AMI20% RIS-0%

AMI>RIS

Mortimer et al, 377 2004

24 wks

200–800*

OLZ 5–20 mg/day

AMI-33% OLZ-33%

AMI >OLAN

Löo et al, 1997†

24 wks

100

Placebo

AMI-41%‡ Placebo20%

Pbo>AM

141

Efficacy outcome is presented as percentage improvement on the BPRS. *These were flexible dose studies, where the daily dose could be titrated between the indicated limits. †This study investigated patients with primary negative symptomatology. ‡Efficacy was determined as the percentage improvement in scores on the Scale for the Assessment of Negative Symptoms (SANS). Pbo, placebo. For other abbreviations see Table 7.1.

there was a greater proportion of responders with amisulpride than with risperidone (Figures 7.8 and 7.9). The incidence of extrapyramidal symptoms was low in all treatment groups. The long-term efficacy of amisulpride in chronic negative schizophrenia has also been assessed in a six-month double-blind study of amisulpride versus placebo. This trial demonstrated a sustained decrease in negative symptoms measured on the SANS. An item analysis was performed to explore whether the whole range of negative symptoms was improved or whether some of them were resistant to treatment. All the dimensions of the SANS improved over the study period, including anhedonia and asociality, even though these two symptoms may need more time to improve because it takes time to create new relationships even when other intrinsic symptomatology had improved. Amisulpride, social functioning and patient well-being Although the rating scales used in these studies (principally the BPRS and the PANSS) provide essential information on the effectiveness of treatments on clinical outcome, it is also important to address functional outcome. This is particularly important in

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schizophrenia, where poor social and occupational integration characterize the long-term prognosis of patients, and make an important contribution to the economic burden of the disease. Functional outcome can be measured with physician-completed questionnaires concerning social adaptation, psychosocial function or role fulfillment, with quality of life measures, and, most importantly, with patient-reported outcome measures.

Figure 7.8. Comparison of amisulpride and risperidone in maintenance therapy of chronic schizophrenia. Top: Evolution of the total PANSS score during the study in

Amisulpride: a selective dopaminergic agent

71

patients treated with amisulpride (400–1000mg/day; n=121; yellow diamonds) or risperidone (4– 10mg/day; n=123; green squares). Bottom: Proportion of responders at study end (six months) among patients treated with amisulpride (yellow columns) or haloperidol (green columns). Data are presented for the Positive and Negative Syndrome Scale (PANSS), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global lmpression-2 scale (CGI-2). (From Sechter et al, 2000.)

Figure 7.9. Comparison of amisulpride and risperidone on functional outcome in maintenance therapy of chronic schizophrenia. Data represent (a) the percentage of responders (i.e. >30% improvement in score) on the Social and Functional Assessment Scale (SOFAS) and (b) the percentage of patients reporting significant improvement at study end

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(six months) in patients treated with amisulpride (400–1000mg/day; n=152; yellow columns) or risperidone (4–10mg/day; n=158; green columns). (From Sechter et al, 2000.) Preliminary data on functional status from one short-term randomized comparative study with haloperidol, and from two open-label studies, again comparing with haloperidol was evaluated. These studies found amisulpride to be superior to haloperidol on various measures of social functioning as well as on quality of life using the disease-specific Quality of Life Scale measure. However, owing to the open label nature of two of these studies, and the relatively short duration of the other, replication in a controlled long-term study was needed. In addition, the appropriate reference antipsychotic for such studies is no more haloperidol, but rather another ‘atypical’ antipsychotic. For this reason, functional status and quality of life were evaluated in large comparative studies with risperidone and olanzapine. In the short-term (eight weeks) study a similar degree of improvement in Social and Functional Assessment Scale (SOFAS) score was observed for both treat-ments, whereas in the long-term (180 weeks) study, a higher proportion of patients improved in the amisulpride group than in the risperidone group (see Figure 7.9). In the olanzapine study, both treatment groups showed a similar degree of improvement of around 30%. In primary negative schizophrenia, changes in functional outcome determined with the Global Assessment of Functioning Scale in patients treated with amisulpride have also been demonstrated. Extrapyramidal symptoms, prolactin and weight gain The main concern with amisulpride, like risperidone, is the induction of prolactin increase, although it is unclear whether this leads to higher rates of adverse endocrine events than with other antipsychotics. In all other respects the tolerability of amisulpride is good. A meta-analysis of data from placebo-controlled trials has shown that the risk of emergence of EPS in amisulpride-treated patients was close to that observed in placebotreated patients (mean effect size: 0.01, (95% CI −0.08 to 0.1). In this respect, amisulpride resembles other atypical antipsychotic drugs with the exception of risperidone. A satisfactory global tolerability of amisulpride was also shown by significantly fewer patients leaving the studies prematurely due to side effects than with conventional drugs. In addition, the comparative trials of amisulpride with risperidone and olanzapine all monitored body weight, and reported significantly greater weight gain with the two mixed antagonists than with amisulpride. Data from the olanzapine study is presented in Figure 7.10. Meta-analysis of published trials has identified a mean weight gain under treatment with olanzapine, risperidone and sertindole of 3.5kg, 2.0kg, and 2.5kg within 10 weeks. In contrast, weight gain associated with amisulpride is low, approximately

Amisulpride: a selective dopaminergic agent

73

0.7±3.1kg in the short-term trials (4–12 weeks) and 1.2± 6.5kg in the long-term trials (6– 12 months).

Figure 7.10. Evolution of body weight over six months in the comparative study of amisulpride and olanzapine. Data are presented as mean body weight (kg) in patients with acute schizophrenia treated with amisulpride ( ) or olanzapine ( ). (Taken from Mortimer et al, 2004.)

8 Conclusions and perspectives Progress in understanding the pathophysiology of schizophrenia The dopamine hypothesis of schizophrenia, which originally emerged in the 1960s, postulated an overactivity of the dopamine systems of the midbrain as the neurobiological anomaly in schizophrenia. In spite of much research effort over more than 30 years, direct evidence for changes in brain dopamine concentrations or in dopamine receptor densities remained frustratingly intangible. However, in recent years a new lease of life has been given to this hypothesis. This has come about first through a paradigm shift in how the dopamine hypothesis is postulated and, secondly, through technical advances allowing the dynamics of dopaminergic neuro-transmission to be assessed in a more sophisticated fashion. Rather than seeing dopamine hyperactivity as a primary source of pathology in schizophrenia, we now see this rather as a vector of a more complex primary etiology, which allows the expression of psychotic symptomatology. In this model, the primary deficit would lie in inappropriate information processing in the prefrontal cortex, perhaps through structural anomalies in synaptic organization during development, perhaps due to plastic changes in connectivity involving anomalies in glutamatergic transmission. In addition, the abnormalities in dopaminergic neurotransmission may be better considered as dysregulation rather than hyperactivity, with certain symptoms, particularly cognitive ones being related to insufficient dopaminergic activity in the cortex. Technological advances in imaging technology have allowed subtle and transient changes in dopaminergic transmission to be visualized in the living brain of patients with schizophrenia. These changes represent activation of dopaminergic neurons in the midbrain, with increased transmitter release during the manifestation of psychotic symptoms. Such dynamic changes would have been impossible to detect in the post mortem studies that were the mainstay of such research before the advent of modern imaging technologies. Although these findings are quite recent, they provide a starting point to unravel the complex series of events underlying symptom expression in schizophrenia. Challenges for understanding the pathophysiology of schizophrenia If the primary defect in schizophrenia lies in abnormal information processing in the prefrontal cortex, this begs the question of why this processing is abnormal. Understanding this phenomenon will be crucial in establishing a holistic and coherent hypothesis for explaining the pathophysiology of this disease. Promising research axes may be exploring the role of neurodevelopmental changes or neurodegeneration in schizophrenia.

Conclusions and perspectives

75

The neurodevelopmental theory suggests a problem in the formation of synapses and neuronal migration during the prenatal and early childhood stages. Neurons that fail to migrate to the correct parts of the brain and form appropriate connections might break down when used by the individual in adolescence and early adulthood. Cell death by apoptosis during normal neurodevelopment eliminates unwanted neurons. Inappropriate apoptosis at this time might select the wrong neurons with the consequence that the wrong connections are made. Alternatively or additionally, a degenerative process may be turned on at the beginning of the course of schizophrenia leading to cell death by necrosis or apoptosis. A degenerative model would explain satisfactorily the natural history of the disorder, which generally shows a irreversible downhill course. A current hypothe-sis is that this may be caused by excitotoxicity mediated by excess glutamate. The excitotoxic mechanism would begin with a pathologic process that triggers excessive glutamate release, leading to overactivation of postsynaptic neurons and their ensuing death. The therapeutic implications of this hypothesis are important and will need to be adequately explored. Progress in antipsychotic drug development The discovery of the dopamine D2 receptor antagonists in the 1950s led to an emphasis on the positive symptoms of the disease, which these drugs, now known as conventional or typical antipsychotics, can so dramatically reduce. However, conventional antipsychotics show little propensity for alleviating the other symptom dimensions of schizophrenia, and in addition cause side effects such as extrapyramidal side effects (EPS), tardive dyskinesia and hyperprolactinemia. The more recently introduced atypical antipsychotics have changed this scenario considerably. These drugs, including clozapine, risperidone, amisulpride and olanzapine, show comparable efficacy to the conventional antipsychotics for positive symptoms, but are superior to conventional agents for treating negative and cognitive symptoms. In addition, they are much less likely to cause EPS or hyperprolactinemia. Atypical antipsychotic drugs are now considered the most suitable first-line treatment for schizophrenia, a notion enshrined in consensus prescription guidelines in many countries. Challenges for understanding antipsychotic drug action The benefit of atypical antipsychotic drugs in terms of a lower risk of EPS has now been clearly established. For certain atypical agents, efficacy benefits have also been established compared with conventional antipsychotic drugs. These include the use of clozapine in resistant schizophrenia and of amisulpride in patients with primary negative symptomatology. However, the pharmacologic mechanisms that endow certain antipsychotic drugs with these atypical clinical properties remain obscure. Proposed hypotheses include ancillary antagonist activity at serotonin receptors, rate of dissociation from the dopamine D2 receptor and selectivity for limbic over striatal dopamine receptors. A possible preferential action of amisulpride on presynaptic dopamine receptors over postsynaptic

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receptors may also help explain the mechanism of action of this atypical drug. Presynaptic receptors control dopamine release from nerve terminals and their blockade by amisulpride will therefore lead to an increase in release of the neurotransmitter. However, none of these explanations is entirely satisfactory. Elucidating these mechanisms is an important challenge for neuropharmacologists, and will be critical for the development of future generations of improved antipsychotic drugs. New therapeutic avenues Improved understanding of the pathophysiology of schizophrenia suggests new avenues of research for the development of new potential antipsychotic agents that may have different therapeutic profiles to the current generation of D2 dopamine receptor antagonists. Dopamine receptor stabilizers One promising avenue involves the development of stabilizing or normalizing drugs that act on the dopaminergic system. This is based on the idea that a molecule with partial agonist properties can have different effects in different neuronal pathways depending on the level of background tone. A partial agonist will activate dopamine receptors at synapses with a low dopaminergic tone, but attenuate receptor activation in areas with high intrinsic tone. Such a dopamine stabilizer may produce enough conformational changes in the receptor to allow sufficient receptor blockade to reduce positive symptoms in the mesolimbic system, whereas dopaminergic hypoactivity may be enhanced in the prefrontal cortex with beneficial effects on negative and cognitive symptoms. A first example of such a drug is the recently introduced aripiprazole. The place this drug will find in the day-to-day management of schizophrenia is important to establish. In addition, partial dopamine receptor antagonists have been found which lack intrinsic stimulating activity on dopamine receptors and yet exhibit the dopamine stabilizer profile. Like amisulpride, these agents exert a preferential action on presynaptic dopamine receptors (or ‘autoreceptors’). In fact, amisulpride can be said to share certain features of the dopamine receptor stabilizers. Drugs acting on glutamate systems Increasing evidence for a primary glutamatergic dysfunction in the prefrontal cortex in schizophrenia has increased interest in therapies targeting this neurotransmitter system. However, given the ubiquitous role of glutamate in excitatory neurotransmission in the central nervous system, and the potential excitotoxic effects of glutamate receptor agonists, compounds need to be identified that can modulate glutamatergic transmission specifically in brain regions where it is dysregulated. One possibility is to develop drugs that act as partial agonists at the glycine regulatory site on the N-methyl-D-aspartate (NMDA) glutamate receptor. Such agents exist, and pilot studies have been performed in schizophrenia with two of these, D-serine and D-cycloserine. Developments in this field will be followed with interest, as they may lead to the first antipsychotic drugs that act

Conclusions and perspectives

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elsewhere than on the dopaminergic system, which could conceivably be used in combination with current D2 receptor antagonist antipsychotic drugs to produce a more incisive therapeutic effect. Challenges for treatment There remain many unmet medical needs in the treatment of schizophrenia, and these should be addressed either by the development of appropriate novel treatments or the design of optimized treatment regimens with those existing antipsychotic drugs that have the best risk–benefit ratios. Faster acting drugs for cognitive symptoms One of the major problems of schizophrenia is that although positive symptoms respond well to available treatments, cognitive symptoms do not. In particular, impairments in verbal fluency, serial learning and executive functioning are debilitating to the patient and unresponsive to treatment. What is observed repeatedly in clinical trials is that, although positive symptoms may be reduced in a 4–12 week trial, it can take months to see improvements in cognitive symptoms. Better efficacy Even with regard to positive symptoms, which are the most responsive to current antipsychotic drugs, treatment response is unsatisfactory. Most patients will only experience a partial response, with a 20–50% drop in total Brief Psychiatric Rating Scale (BPRS) scores. Responses of greater than 50%, although occurring occasionally are rare and are an unrealistic goal of treatment. Most clinical trials define response in the 20– 30% range, but the clinical relevance of this in the day-to-day management of schizophrenia is questionable. A 20–30% reduction in symptoms may not be very dramatic for the patients and may be considered unsatisfactory by the physician who may be tempted to initiate polytherapy. Onset of treatment response Even when a response is adequate, the time required to see a significant response is long. In many patients, positive symptoms may not significantly improve after 4–12 weeks of treatment. Only 35% of patients on risperidone reach a 30% clinical improvement, as measured by Positive And Negative Syndrome Scale (PANSS) scores, by four months, although this rises to 55% at 12 months. For a 60% clinical improvement,only 10% of the patients have achieved this target at four months, rising to 20 % after 1 year. Similar observations have been made for most atypical antipsychotics. It is not clear whether this delay is due to a limit on the progression possible, to a lag-time for full efficacy, or to something else. Longer clinical trials than those customarily performed may provide important information on this point.

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Non-responders A significant minority of schizophrenic patients fail to respond to first-line monotherapy with even a 30% response. At the moment, there is a tendency to treat non-responders with cocktails of antipsychotic drugs, perhaps combining a drug with a long receptor occupancy time with a drug with a short occupancy time. However, resorting to antipsychotic combination therapy is probably neither the most efficient nor the cheapest way to improve response. In addition, it exposes the patient to a potentially wider range of side effects than would the use of a single antipsychotic drug. Other alternatives may be the use of augmentation strategies with other classes of drug, such as mood stabilizers and cognitive enhancers. Preventing or managing recurrence Another problem with current treatments for schizophrenia is that the number of psychotic episodes that a patient experiences may affect the time to remission. It has been demonstrated in natural history studies that the mean time to remission is linearly related to the number of previous acute episodes. It is important to understand why the drugs no longer work as well as before, whether this involves the natural progression of the illness or the development of tolerance. This also raises questions about the nature of the underlying pathophysiology of schizophrenia. From a pragmatic point of view, strategies aimed at preventing recurrence need to be developed. Side effects Although the modern atypical antipsychotics produce less EPS and, in part, also less neuroendocrine side effects at antipsychotic doses than do earlier generations of drugs, they are not entirely free of side effects. Of growing concern is the increase in incidence of a metabolic syndrome in patients treated with the mixed dopamine-serotonin receptor antagonists. This syndrome is characterized by rapid and significant weight gain, accompanied by atherogenic dyslipidemia, insulin resistance and hypertension. The mechanism of action of these drugs in producing this metabolic syndrome is unknown, but may involve a serotonergic mechanism. The awareness of this risk among treating physicians remains sub-optimal.

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Index Note: Page numbers in italics refer to figures/tables. As the subjects of this title is schizophrenia, index entries ‘schizophrenia’ have been avoided. Readers are advised to seek more specific entries.

N-acetyl aspartate (NAA) 53 amisulpride 4, 79–98 actions in cortex vs limbic system 81, 82 clinical studies/trials 84 D2/D3 receptor specificity 4, 12, 66, 70, 79, 80 D2 receptor binding in striatum 69, 83–4, 85 D2 receptor binding in temporal cortex 83–4, 85 D2 receptor interaction 81–4 D2 receptor occupancy 69 dose/receptor occupancy curve 83 extrapyramidal side effects and dose 83 haloperidol vs 84, 86 maintenance therapy 92–4, 93, 95, 96 mechanism of action 4–5, 79–81, 82 negative symptoms control 88–92 no affinity for 5-HT2 receptor 69, 72, 73 no affinity for D4 receptor 68 positive symptom control 86, 87, 88, 89, 90 pre-/postsynaptic dopamine receptors 79, 81, 102 receptor binding affinities 12, 71 regional specificity of D2 receptor binding 76–7, 77 risperidone vs 88, 90, 94, 95, 96 short-term management in acute schizophrenia 85–92, 87, 89, 90 social function and patient well-being 94–7 striatal 5-HT2A and D2 receptor binding study 72 tolerability 97, 98 weight gain 97, 98 amphetamine-induced dopamine release 39–41, 40, 50 study limitations 41 amygdala 22, 60 antihistamines 3 antipsychotic drugs 3–5 adverse effects see side effects of antipsychotic drugs atypical see atypical antipsychotic drugs challenges 103–6 discovery 3

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dopamine receptor interactions see dopamine receptors drug development progress 101 efficacy and response rate 11–18 inter-individual variability 11–12 mechanism of action challenges 101–2 optimal response 68 re-attribution of salience and 63–4 ‘therapeutic window’ 68 typical 3–4 apoptosis 100 aripiprazole 4, 35, 103 atypical antipsychotic drugs 4–5, 101 classes and drug types 4 D2 receptor activity and 70, 71, 72 mechanism of action 4–5 negative symptoms improved 5, 66 receptor binding affinities 12, 71 regional specificity of D2 receptor binding 75–7 role of D2 receptors 65–79 side effects reduced 64 see also serotonin-dopamine receptor antagonists; specific drugs ‘autoreceptors’ 103 basal ganglia 24, 26 benzamide drugs 4 see also amisulpride; remoxipride Bleuler, Eugen 1 blunting of effect 45 Brief Psychiatric Rating Scale (BPRS) 86, 104 bromperidol 18 catatonic schizophrenia 46–7 catechol-o-methyltransferase (COMT) see COMT; COMT gene cerebral blood flow, regional (rCBF) ketamine effect 27–8, 28 reduced in frontal lobe 52 cerebral cortex, overload (information) protection 30 chlorpromazine 2, 3, 65 sedation 64 striatal 5-HT2A and D2 receptor binding 70, 72, 73 cingulate cortex, rCBF increase 28 clozapine 4 D2 and 5-HT2 receptor occupancy 69 D3 and 5-HT2A receptor polymorphisms 15 D4 receptor affinity 67 extrapyramidal side effects 4, 75 receptor binding affinities 67, 71 in refractory schizophrenia 11

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striatal 5-HT2A and D2 receptor binding 72, 73 cognitive function disturbances 2, 104 cognitive performance, COMT gene role 9–10, 10 compliance, atypical antipsychotics 5 COMT (catechol-o-methyltransferase) 8 COMT gene cognitive performance 9–10, 10 genotype and effect on memory 9–10, 10 COMT gene polymorphisms, schizophrenia susceptibility 8–11 criticisms 11 evidence 10–11, 12 Val/Met variant 8, 10 COMT knockout mice 8 corticostriatal-thalamocortical loops 21, 21–2, 22, 29 D-cycloserine 103 cytochrome P450 and polymorphisms 17 D1 receptors 67, 81 activation, signal to noise and 55–6 antagonists 67 distribution 23 prefrontal cortex 42 stimulatory influence, GABAergic neurons 23–4 striatal, imaging 38 D2 receptor (s) 2, 19, 65–79 activity and atypical antipsychotic property 70, 71 amisulpride interaction 81–4 amisulpride specificity 4, 12, 70, 79, 80 antipsychotic drug action, role 65–79 antipsychotic drug affinity 19, 32, 66, 74, 74–5 antipsychotic drug interactions 12, 65–7, 70, 72 atypical antipsychotic regional binding 75–7 availability increased by dopamine depletion 41 distribution 23, 75–7 extrastriatal, imaging 42–3 fast dissociation rate (Koff) of antipsychotics 74, 74–5, 102 fast Koff hypothesis 74, 74–5 5-HT2A receptor blockade with 34, 70, 72 inhibitory influence, GABAergic neurons 23–4 ketamine effect on binding 44 occupancy in schizophrenia 68–9, 82 polymorphisms 13, 14, 18 serotonin hypothesis 70, 72 striatal, GABAergic neurons 23 striatal, imaging 38 striatal density 45, 50, 54, 76 striatal occupancy and negative symptoms 82 symptomatology link 45 D2 receptor blockade/antagonists 66 see also amisulpride; atypical antipsychotic drugs

Index

90

D3 receptors 68 amisulpride specificity 4, 12, 70, 79, 80 antagonists 68 antipsychotic drug specificity 66 distribution 23 limbic system 82 polymorphisms 14, 14, 18 D4 receptors 67–8 clozapine affinity 67 distribution 23, 24 polymorphisms 14, 14–15, 68 D5 receptors 67 distribution 23 degenerative process 100 delusions, abnormal salience and 61, 62, 63 dementia praecox 1 depression 2 disorganization, in schizophrenia 1 dissociation rates (Koff) 102 D2 receptor-antipsychotic interactions 74, 74–5 L-dopa 3 DOPA decarboxylase 39 DOPA metabolism, changes 46 dopamine, levels baseline synaptic levels 41 increased in schizophrenia 50 dopamine abnormalities 99 “downstream” effect of cortical abnormality 50 dysregulation 41–2, 44, 99 glutamate-dopamine interactions 29, 30–1, 43–4 imaging see imaging of dopamine abnormalities role in schizophrenia etiology 37–47 syndromal specificity 44–7 dopamine actions 19–25 gating of excitatory neurotransmission 24, 44, 55 glutamic acid interactions 29, 30–1, 43–4 information flow in corticostriatal-thalamocortical loops 22 motor function and 24 as neither inhibitory nor excitatory 23 prefrontal cortex function 54–7 ‘reinforcing’ actions 24 signal to noise modulation 24, 55–6 dopamine biosynthesis postsynaptic inactivation in prefrontal cortex 8, 9 psychotic symptoms and 39 dopamine depletion, effect on memory 54 dopamine dysregulation 41–2, 44, 99 dopamine hypothesis 2, 49–51, 99–100 background to 2, 49 early evidence 49–50 variant hypotheses 50–1 dopamine imbalance 41–2, 44, 99

Index

91

dopamine receptors 2, 23–4 antagonists see antipsychotic drugs; serotonin-dopamine receptor antagonists antipsychotic drug affinity 32, 80 antipsychotic drug interactions 12, 65–7, 67, 67–8 D1-/D2-like family 23, 67 distribution 23, 24, 54 partial antagonists 102, 103 polymorphisms affecting drug efficacy 13–15, 14 subtypes 23, 67, 67 see also individual receptors (e.g. D2 receptors) dopamine receptor stabilizers 102–3 dopaminergic neurons 99 activity increased by amisulpride (cortex) 81 glutamate effect on 29–30 hypoactive, negative symptoms 63 importance of stimulus signaled by 61 overactivity, delusions and 61, 63 dopaminergic pathways 20, 20–2, 34, 99 amisulpride blocking 81 GABAergic neuron output modulation 29, 30 dopaminergic reward system 60–1 dopamine signaling, in prefrontal cortex 56 abnormal/reduced in schizophrenia 50, 56–7 cellular effects 56, 57 COMT gene polymorphisms 8–11 dopamine hypothesis variant 50 dopamine synapses, striatum vs prefrontal cortex 8, 9 dopamine transmission decrease and negative symptoms 45 striatal see striatum dopamine transporters 8, 41–2 dorsolateral prefrontal cortex 21, 58 activation, homovanillic acid levels 57, 58 NAA reductions 53 overactivation 52–3 drug metabolizing enzyme polymorphisms antipsychotic drug efficacy 17 antipsychotic drug side effects 17–18 etiology of schizophrenia, dopamine see dopamine abnormalities excitotoxicity, excess glutamate 25, 101, 103 experimental psychosis 25, 27–8 extrapyramidal side effects (EPS) 4, 66, 105 amisulpride dose effect 83 continuum of antipsychotic effects 75 D2 receptor role 66, 69 drug metabolizing enzyme polymorphisms 17–18 [18F]fallypride 42 fananserin 34

Index

92

fast Koff hypothesis 74–5, 102 [11C]FLB457 42, 83 [18F]-fluoro-DOPA 46, 47 flupenthixol 84 fluphenazine 12 frontal cortex, amisulpride action 81, 82 functional MRI (fMRI) abnormal prefrontal cortex function 51, 51–2, 58 COMT gene and cognitive performance 9–10, 10 rule learning and prefrontal cortex 58–9 GABAergic neurons 23, 24, 29, 55 excitation, signal to noise increased 56 output modulation 29, 30 prefrontal cortex 24 protection of cortex from overload 30 genetics, schizophrenia 7–18 polymorphisms as risk factors 7–11 prefrontal cortex abnormalities (twins) 54 globus pallidum, internal segment (Gpi) 21, 22 glutamergic pathways 22, 28–30, 55, 99 deficiency model of schizophrenia 30 direct/indirect 29, 29 drugs acting on 103 glutamic acid 25–31 actions 28, 29–30, 101 dopamine interactions 29, 30–1, 43–4 excess, excitotoxicity 25, 101, 103 receptor antagonists see NMDA receptor antagonists hallucinations, abnormal salience 63 haloperidol 4 amisulpride comparison 84, 86, 92, 96 basal ganglia-thalamocortical circuitry 25, 26 receptor binding affinities 71 regional specificity of D2 receptor binding 76, 77 sedation 64 heat shock protein genes 18 hebephrenic schizophrenia 45 hippocampus 22, 28 homovanillic acid 57, 58 5-HT see entries beginning serotonin; serotonin hyperprolactinemia 18 hypofrontality 51, 51–2, 53 hypomotility, glutamate antagonists reducing 30 [123I]IBZM 39, 40, 41 imaging of dopamine abnormalities 37–44 cortical 42–3 striatal 38–42

Index

93

information processing, in prefrontal cortex 57–60, 100 overactive dorsolateral cortex 52–3, 99 ketamine effect on D2 receptor binding 44 experimental psychosis 25, 27–8 NMDA transmission disruption 44 regional cerebral blood flow increase 27–8, 28 symptom exacerbation 25, 27, 27 Koff (fast dissociation rate) and D2 receptors 74, 74–5, 102 Kraepelin, Emil 1 limbic cortex, glutamate action 28–30 ‘limbic’ loops 21 limbic system amisulpride action 81, 82 D3 receptor 82 NMDA receptor antagonist action 30 M100907 34 memory COMT genotype effect 9–10, 10 dopamine depletion effect 54 prefrontal cortex abnormalities 52–3 mesocortical system 20, 20–1, 34, 60 mesolimbic system 20, 20 salience and dopamine 60, 61 metabolic syndrome 105 methylation, dopamine 8, 9 a-methyl-p-tyrosine 41 mood, improvement 34 motor function, dopamine role 24 motor loops 21–2 N-acetyl aspartate (NAA) 53 negative symptoms 1, 45 amisulpride treatment 82–3, 83, 88–92 atypical antipsychotics effect 5, 66 DOPA metabolism changes 46–7 dopamine abnormalities 45–7 serotonin-dopamine receptor antagonist action 92 typical antipsychotics effect 4 nemonapride 18 neurodevelopmental theory 100 neurotransmitters 19–35 excitatory 25, 101 see also dopamine; glutamic acid; serotonin nigrostriatal system 20, 20, 34

Index

94

NMDA, ketamine effect on transmission 44 NMDA receptor antagonists 25, 27–8 action on limbic system 30 hypomotility reduction 30–1 partial 103 see also ketamine [11C]NNC112 42, 43 non-responders 105 noradrenaline 2 nucleus accumbens 22 olanzapine 4 amisulpride comparison 88, 94 extrapyramidal side effects 75 5-HT2 blockade 69 receptor binding affinities 71 weight gain 97, 98 onset of drug response 104 orbitofrontal cortex 58 parkinsonian symptoms 24 perazine 84 phenomenology of schizophrenia, dopamine role 49–64 information processing see information processing, in prefrontal cortex prefrontal cortical dysfunction see prefrontal cortex reward system 60–1 salience see salience and dopamine signal to noise modulation 24, 55–6 phenycyclidine 25 Positive and Negative Syndrome Scale (PANSS) 86, 104 positive symptoms 1 abnormal salience and 61, 62, 63 amisulpride comparative studies 86–8, 87, 89, 90 new drug requirements 104 positron emission tomography (PET) 38, 46, 69, 70 postsynaptic markers, dopamine transmission (striatal) 38 postsynaptic receptors, amisulpride action 79, 81 prefrontal cortex abnormal dopamine signaling 50, 56–7 cerebral blood flow reduction 52 D1 receptors 42 dopamine receptors 24, 54 dopamine signaling see dopamine signaling dopamine synapses and inactivation 8, 9 dorsolateral 21, 58 see dorsolateral prefrontal cortex dysfunction, genetic risk and 54 dysfunction as primary schizophrenia deficit 51, 51–4 function and dopamine role 50, 54–7, 58 GABAergic neurons 24, 55 impaired gating of excitatory neurotransmission 44, 55 information processing see information processing, in prefrontal cortex

Index

95

rule learning 58–60 signal to noise 24, 53, 55–6 presynaptic markers, dopamine transmission (striatal) 39–42 presynaptic receptors 103 amisulpride action 79, 81, 102 prevalence, of schizophrenia 1 prolactin elevation 4, 66 D2 receptor role 66, 69 proton magnetic resonance spectroscopy (MRS) 53 quetiapine 4 extrapyramidal side effects 75 receptor binding affinities 71 raclopride 39, 41, 44, 66 recurrence of schizophrenia, therapy 105 refractory schizophrenia, atypical antipsychotics effect 5, 11 remoxipride 4, 65, 66, 68 reward system 60–1 risk factors, for schizophrenia 7–11 risperidone 4 amisulpride comparison 88, 90, 94, 95, 96, 97 D2 receptor occupancy level 68–9 extrapyramidal side effects 75 mechanism of action 4–5 receptor binding affinities 71 weight gain 97 ritanserin 34 rules, automatic perception and learning 58–60 salience and dopamine 61, 63 abnormal 61, 62, 63 antipsychotic action 63–4 ‘attribution of,’ mesolimbic system 61 re-attribution 63–4 Scale for Assessment of Negative Symptoms (SANS) 45, 46, 86, 94 [11C]SCH23390 42 sensory information 28 D-serine 103 serotonergic synapses, density 31 serotonin 2, 31–5 receptors see serotonin receptor serotonin-dopamine receptor antagonists 4, 66 effect on negative symptoms 92 metabolic syndrome due to 105 see also olanzapine; risperidone serotonin hypothesis 70, 72 serotonin pathways 31 serotonin receptor (5-HT1A), distribution and action 35 serotonin receptor (5-HT2A)

Index

96

antipsychotic drug affinity 12, 32, 34 blockade with D2 receptor blockade 34 density index 34, 35 distribution 31–2, 35 dopaminergic activity modulation 32, 34 occupancy and atypical antipsychotic action 70 polymorphisms 14, 15, 15–16, 16 serotonin receptor (5-HT2C) actions in striatum 35 antipsychotic drug affinity 34 distribution 34–5 occupancy level and antipsychotic action 69 polymorphisms 14, 16 weight gain and 14, 16 serotonin receptor (5-HT6), polymorphisms 14, 16 serotonin receptor(s) 31–2, 34 antipsychotic drug aifinity 12, 32, 34 distribution 31–2, 34–5 down-regulation 34 occupancy and atypical antipsychotic action 69, 70, 72 polymorphisms 15–17 sertindole 4 [18F]-setoperone 34, 35, 72, 73 side effects of antipsychotic drugs 105–6 drug metabolizing enzyme polymorphisms 17–18 see also extrapyramidal side effects (EPS); weight gain signal to noise modulation by dopamine 24, 55–6 reduced in prefrontal cortex 53 single photon emission photometry (SPECT) 38 striatum 20 D2 and 5-HT2A receptor binding 70, 72, 73 D2 and 5-HT2A receptor occupancy 70, 72 D2 receptor density 23, 45, 50, 54, 76 dopamine synapses and recycling 8, 9 dopamine transmission 38–42 increased dopamine output 41–2 output pathways 22 postsynaptic markers 38 presynaptic markers 39–42 substantia nigra 20, 21, 22 long-term changes by antipsychotics 25, 26 symptoms, schizophrenia dopamine role 49–64 exacerbation by ketamine 25, 27, 27 see also negative symptoms; positive symptoms Taq 1 locus 13, 18 tardive dyskinesia 25, 26

Index

temporal cortex, D2 receptors 76, 77 amisulpride binding 83–4 thalamus, D2 receptor density 76 Transmission Disequilibrium Test 10 twin studies 54 tyrosine hydroxylase 57 weight gain 5-HT2C polymorphisms 14, 16 amisulpride comparisons 97, 98 ziprasidone 4, 71

97