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

6

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

Progress in dopamine research in schizophrenia

8

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.

Genetics of schizophrenia

9

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.

Genetics of schizophrenia

11

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, P10,000

10,000

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.

The role of D2 receptors in the action of antipsychotic drugs

51

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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Efficacy in ‘negative symptom’ schizophrenia

52

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

The role of D2 receptors in the action of antipsychotic drugs

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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

risperidone.

The role of D2 receptors in the action of antipsychotic drugs

55

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.

Amisulpride: a selective dopaminergic agent

59

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

Amisulpride: a selective dopaminergic agent

61

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

Amisulpride: a selective dopaminergic agent

63

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.

Amisulpride: a selective dopaminergic agent

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, PAM

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

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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

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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

Index

88

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

Index

89

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