Dopamine in the Pathophysiology and Treatment of Schizophrenia: New Findings

Dopamine in the Pathophysiology and Treatment of Schizophrenia New Findings

Dopamine in the Pathophysiology and Treatment of Schizophrenia New Findings Edited by

Shitij Kapur, MD PhD FRCPC Schizophrenia Program and PET Centre Centre for Addiction and Mental Health Toronto Canada Yves Lecrubier, MD PhD INSERM Unite 302, Hopital de la Pitie-Salpetriere Pavillon Clérambault Paris France

LONDON AND NEW YORK

© 2003 Martin Dunitz, an imprint of the Taylor & Francis Group plc First published in the United Kingdom in 2003 by Martin Dunitz, an imprint of the Taylor & Francis Group plc, 11 New Fetter Lane, London EC4P 4EE Tel: +44 (0)20 7583 9855 Fax: +44 (0)20 7842 2298 E-mail: [email protected] Website: http://www.dunitz.co.uk/ This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.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. ISBN 0-203-42734-3 Master e-book ISBN

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Contents Contributors Preface

1. Historical aspects and future directions Arvid Carlsson 2. Evidence from brain imaging studies for dopaminergic alterations in schizophrenia Anissa Abi-Dargham 3. Modulation of dopamine D2 receptors as a basis of antipsychotic effect Shitij Kapur 4. Amisulpride as a model: clinical effects of a pure dopaminergic agent Yves Lecrubier 5. A meta-analysis of studies with the atypical antipsychotic amisulpride Stefan Leucht, Gabi Pitschel-Walz, Werner Kissling and Rolf R Engel 6. Evidence from brain imaging for regional monoaminergic specificity in schizophrenia Jean-Luc Martinot and Marie-Laure Paillère-Martinot 7. Dopamine, the prefrontal cortex, and a genetic mechanism of schizophrenia Daniel Weinberger 8. Models of schizophrenia: from neuroplasticity and dopamine to psychopathology and clinical management Manfred Spitzer 9. Multiple neurotransmitters involved in antipsychotic drug action Herbert Meltzer 10. Dopaminergic and glutamatergic influences in the systems biology of schizophrenia Carol Tamminga and Deborah Medoff 11. Pharmacogenomics of antipsychotic drugs Robert Kerwin, Maria Arranz and Dalu Mancama 12. Key issues and unmet needs in schizophrenia Stephen Stahl Index

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42 57 76 92

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Contributors Anissa Abi-Dargham Departments of Psychiatry and Radiology Columbia University New York State Psychiatric Institute New York USA Maria Arranz Clinical Neuropharmacology Institute of Psychiatry London UK Arvid Carlsson Department of Pharmacology University of Goteborg 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 Marie-Laure Paillère-Martinot ERM Team INSERM—CEA

Frederic Joliot Hospital Orsay France Yves Lecrubier Unite 302, Hopital de la Pitié-Salpêtrière Pavilion Clérambault 47 Boulevard de L’Hôpital 75651 Paris Cedex 13 France Stefan Leucht Clinic for Psychiatry and Psychotherapy Munich University of Technology Klinikum rechts der Isar Munich Germany Jean-Luc Martinot ERM Team INSERM—CEA Frederic Joliot Hospital Orsay France Dalu Mancama Clinical Neuropharmacology Institute of Psychiatry London UK Deborah Medoff Maryland Psychiatric Research Center University of Maryland School of Medicine Department of Psychiatry Baltimore MD USA Herbert Meltzer Dept of Psychiatry and Pharmacology Vanderbilt University School of Medicine Nashville TN USA 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 Dept of Psychiatry, UCSD San Diego 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 book grew, as many good things do, from a casual conversation between the two of us about the state of schizophrenia and antipsychotics, and how things had changed in many ways, whereas in other ways they had remained unchanged. Both of us felt that dopamine was a ‘comeback kid’ of neurotransmitters. With 2002 being the fiftieth anniversary of the introduction of antipsychotics, and with the recent recognition of dopamine researchers as Nobel laureates, we thought this would be a good occasion to get together some of the leaders in the field of dopamine and schizophrenia for a meeting to discuss where we were, and, based on this event, to produce a book aimed at updating current knowledge and theories. We approached Sanofi-Synthelabo and secured from them an unrestricted grant to hold this meeting in Montreal in the summer of 2002. An effort was made to seek a representative spectrum of ideas from across the world. This book serves as a record of the proceedings of that meeting. We begin with a chapter by Professor Arvid Carlsson who has personally watched and shaped much of the history related to dopamine, schizophrenia and antipsychotics. The chapter provides a good historical background and also looks into the future of dopamine therapeutics with the exciting new idea of ‘dopamine stabilizers’. The next chapter by Abi-Dargham provides a broad overview of the dopamine system, including some of the latest concepts about the different dopamine receptors and their specific roles in different brain regions. The chapter reviews findings of Abi-Dargham’s group which has been pivotal in putting dopamine back into the centre stage of the pathophysiology of schizophrenia. This is followed by a chapter by one of us (SK), which highlights the critical role of the action at the dopamine D2 receptor in atypical antipsychotic action and puts forward a psychological mechanism—salience—to tie together pharmacology and phenomenology. The importance of appropriate modulation of dopamine D2-like receptors is uniquely important in the context of amisulpride, as this drug is not known to bind to any other receptor type; the chapter by the other editor (YL) shows how, through action on this one target, the drug is able to affect multiple domains of positive, negative and long-term consequences in schizophrenia. This is further buttressed by the arguments of Leucht et al who, through a meta-analytic approach, show that drugs acting at a single dopamine receptor are able to obtain equivalent clinical effects in multiple domains, compared to drugs that act on multiple receptors. The chapter by Weinberger ties these threads to genetics and shows how a genetic alteration, by virtue of changing dopamine metabolism in the prefrontal cortex, might be a paradigm for schizophrenia and similar illnesses. This idea is picked up by Spitzer who casts this into an even wider context and links together, dopamine, cognition, large-scale networks and how psychological and social influences may all come together in a real world therapeutic intervention. Everything should be made as simple as possible, but not simpler. (Albert Einstein)

While there has been a lot of new evidence, new interest and new ideas regarding dopamine in the context of schizophrenia and antipsychotics even its most ardent supporters would admit that an exclusive focus on it may be myopic. In the very opening chapter Carlsson puts it bluntly; ‘we have moved in the direction of drugs of narrow specificity to treat schizophrenia—I believe that this has taken us in the wrong direction’. While dopamine may have a central role in the expression of some symptoms in schizophrenia, there is still no convincing proof that it is the primary point of aetiology or that it can claim exclusivity with any domain of schizophrenia. This point is meticulously made by Meltzer who shows that, when considering the action of antipsychotics, one cannot ignore the very prominent effects on the serotonergic, adrenergic, cholinergic and other brain transmitter systems—and hints at the possibility of some non-D2 antipsychotics. The point is also made by Tamminga, who suggests that the role of dopamine may be only secondary to alterations in the glutamate system and that it may be this latter neurotransmitter pathway which holds the reins of schizophrenia. This complexity is also underscored in pharmacogenetic studies, as described by Kerwin et al, where a broad range of neurotransmitter gene predict antipsy-chotic response. The book ends with the chapter by Steve Stahl which points out the many areas of unmet needs in schizophrenia and how our patients receive some relief in symptoms but not remission from them, how primary negative symptoms remain largely uncontrolled, and how cognitive symptoms are barely touched. Thus, while this volume attempts to bring under one umbrella some of the recent highlights of dopamine research, it also cautions against a monotheistic view of schizophrenia while anticipating the complex challenges for the next generation of pharmacotherapy. The meeting in Montreal was exciting; the process of editing this book gratifying, and we hope that you, the reader, will find the contents of it to your liking. Shitij Kapur and Yves Lecrubier February 2003

chapter 1 Historical aspects and future directions Arvid Carlsson In 2002 the fiftieth anniversary of chlorpromazine was celebrated. This could also be considered the fiftieth anniversary of modern neuropsychopharmacology. It came about because a French naval surgeon, Henri Laborit, was interested in artificial hibernation to minimize surgical stress. He developed a method of placing his patients in an ice bath while at the same time administering an antihistaminic drug, promethazine. This worked to a certain extent but then Laborit asked the manufacturers to modify the drug to try to broaden its spectrum of action. This led to the synthesis of chlorpromazine, which was found to have a strong sedative effect on the patients. Eventually the psychiatrists, Jean Delay and Pierre Deniker, tested chlorpromazine in psychotic patients with remarkable results (Delay et al, 1952), although initially they also continued with the ice bath treatment. Then, one day when the ice ran out, they found that the drug worked just as well without it. The rest, as they say, is history. However, it is perhaps ironic that such a major discovery was made by trying to broaden drug action when, since then, we have moved in the opposite direction of wanting drugs of narrow specificity to treat schizophrenia. As will be discussed further below, I believe that this has taken us in the wrong direction. The story then moves across the Atlantic to the National Heart Institute in Bethesda, Maryland, to the laboratory of Bernard B Brodie who was interested in the actions of another recently introduced antipsychotic drug, reserpine. Brodie and his colleagues demonstrated that reserpine had a dramatic effect on serotonin stores, causing their virtual depletion in the brain and other tissues (Pletscher et al, 1956a, b). I joined his laboratory around this time and proposed that we should also investigate the effect of reserpine on the catecholamines but Brodie wanted to concentrate on serotonin. However, I thought the idea was worth pursuing and on my return home started to work on the subject, in collaboration with Professor Nils-Åke Hillarp. We found essentially the same results as Brodie’s laboratory had with serotonin, i.e. reserpine depleted catecholamine stores in rabbit adrenal medulla, heart and brain (Carlsson and Hillarp, 1956; Carlsson et al, 1957b). The reserpine-treated animals showed strong sedation and hypokinesis (Figure 1.1). We also found that their sympathetic nerves no longer responded to stimulation following treatment (Carlsson et al, 1957b) and hypothesized that this was due to catecholamine depletion, probably noradrenaline. It should be pointed out that in the mid-fifties dopamine itself was considered to be merely an inactive precursor of noradrenaline, due to its low activity when tested on smooth muscle preparations. Administrating L-DOPA (dihydroxyphenylalanine) to the reserpine-treated rabbits, to replenish what was thought would be the noradrenaline stores, gave spectacular results, as within 10 minutes the animals had made a complete recovery (Figure 1.1) (Carlsson et

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al, 1957a). This remains one of the defining moments of my career and we felt that we had discovered the Rosetta stone of chemical transmission. However, when we analysed brain tissue from these animals, we found, to our initial disappointment, that it was still fully depleted of noradrenaline. Further experiments showed that DOPA itself was not the active agent so we turned our attention to dopamine and demonstrated that (i) it occurs in the brain in slightly higher quantities than noradrenaline with high concentrations in the basal ganglia (Bertler and Rosengren, 1959); (ii) it is indeed depleted by reserpine treatment; and (iii) the anti-reserpine action of L-DOPA is correlated to the restoration of dopamine levels in the brain (Carlsson, 1959).

Figure 1.1 The reversal of the effects of reserpine by DOPA. (a) Rabbits treated with reserpine (5 mg/kg iv) show strong sedation and hypokinesia. (b) The same animals 15 minutes after treatment with D-L-DOPA (200 mg/kg iv). iv, intravenous. (From Carlsson et al, 1957a.) These results led us to suggest that dopamine as well as noradrenaline and serotonin had important mental and motor functions. The proposal initially met with quite a lot of scepticism, especially as the prevailing dogma was that chemical transmission was of little importance in the central nervous system. However, we overcame this resistance by establishing the neuronal localization of the monoamines in both central and peripheral nerves and by showing that there were distinct dopamine, noradrenaline and serotonin pathways in the brain. We also produced a model of a monoaminergic synapse that mapped the sites of action of the major psychotropic drugs (Carlsson, 1966).

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A key experiment, published in 1963, showed that chlorpromazine had a specific action on the catecholamines, enhancing the turnover of both noradrenaline and dopamine (Carlsson and Lindqvist, 1963). 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 we did not particularly emphasize dopamine over noradrenaline or even serotonin. However, as more drugs were analysed 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 daily clinical dose (Creese et al, 1976; Seeman et al, 1976). Later, when it was found that dopamine had several different binding sites the relevant receptor for the antipsychotics was found to be what was then termed the D2 receptor (Kebabian and Calne, 1979). The dopamine hypothesis of schizophrenia has been further strengthened in recent years by imaging studies showing that dopamine function and release are indeed elevated in schizophrenia, at least under some circumstances (Laruelle et al, 1996; Breier et al, 1997; Abi-Dargham et al, 1998, 2000). These notions are discussed further in Chapter 2. To bring us up to the present day two areas of research will now be described, by no means unrelated, that we have been interested in for some time now and which may point the way to the future. Dopamine stabilizers By 1972 a method had been developed to measure catecholamine synthesis in vivo and this led to the discovery of a negative feedback mechanism on dopamine synthesis and release, mediated by dopamine receptors situated on the neurone (Kehr et al, 1972) that was termed ‘autoreceptors’ (Carlsson, 1975), and since shown to be members of the D2 family of dopamine receptors. Presynaptic dopamine autoreceptors are inhibitory on overall dopamine activity and thus in opposition to postsynaptic D2 receptors. This results in a paradoxical antidopaminergic action of dopamine agonists. It was on this basis that several such molecules, such as apomorphine and bromocriptine, were tested as antipsychotic drugs with variable degrees of success. This is further reviewed by Tamminga (2002). The discovery of the dopamine autoreceptors led to a new approach to the treatment of schizophrenia that was termed dopamine stabilization. All currently used antipsychotic drugs are antagonists at the D2 receptor. However the resulting hypodopaminergia limits their utility due to unwanted side effects. Even though there is evidence of elevated dopaminergic activity in schizophrenia this may be limited to psychotic episodes and it is possible that we may be dealing with instability of dopamine release rather than a continuously elevated baseline. It was hypothesized that a way around these problems would be to search for dopamine stabilizers, drugs capable of occupying functionally antagonistic pre- and postsynaptic receptors and regulating their activation in such a way that tonic baseline dopaminergic activation remains essentially unchanged and phasic excessive dopaminergic activity is attenuated. An appropriate way of doing this would be to develop partial agonists at D2 receptors. Further discussion and details of this principle can be found in Carlsson (2002).

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The first molecule from this programme to be tested both in animal models and in the clinic was (-)-3-PPP ((-)3-(3-hydroxyphenyl)-N-n-propylpiperidine), a partial agonist with some selectivity for D2 autoreceptors (Clark et al, 1985). (-)-3-PPP has been found to have antipsychotic properties in schizophrenic patients, although it is not yet clear whether it will find a place in clinical practice (Tamminga et al, 1992; Lahti et al, 1998). Further details of (-)-3-PPP can be found in Tamminga (2002). Another interesting molecule was (-)-OSU6162, ((S)-(-)-3-(3(methylsulfonyl)phenyl)-1-propylpiperidine), a congener of (-)-3-PPP, but modified to have some selectivity as a dopamine autoreceptor antagonist. (-)-OSU6162 has little affinity for dopamine D2 receptors in classical in vitro assays (Sonesson et al, 1994), however, in vivo it increases dopamine synthesis and release in the rat and in a positron emission tomography (PET) study was found to displace the binding of the D2 receptor antagonist raclopride in monkey brain by about 80% (Figure 1.2) (Neu et al, 1997; Ekesbo et al, 1999). (-)-OSU6162 has a unique pharmacological profile that

Figure 1.2 A PET study showing binding of the radiolabelled D2 receptor antagonist, [11C]raclopride, in Rhesus monkey brain before and after continuous infusion of (-)OSU6162 (3 mg/kg/hour). (Reproduced with permission from Ekesbo et al, 1999.)

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suggests that it belongs to a new class of functional modulators of dopaminergic systems (Sonesson et al, 1994; Tedroff et al, 1998; Hadj Tahar et al, 2001). The stabilizing properties of this molecule are illustrated by its action in rats placed in an environment to which they are or are not habituated, where (-)-OSU6162 increases locomotor activity to a modest extent (Figure 1.3), although this stimulation is lower than that obtained with amphetamine. However, (-)-OSU6162 can also reduce the locomotor stimulation evoked by amphetamine in a dose-dependent manner. This demonstrates the stabilizing nature of (-)-OSU6162, and suggests that the molecule can either stimulate or inhibit behaviour depending on the initial behavioural state. This is the principle of stabilization, as regardless of the initial level of activity of the system, treatment with the stabilizer normalizes activity to a defined level.

Figure 1.3 Stabilization of the behavioural state in rats by (-)OSU6162. (-)-OSU6162 increases locomotor activity in rats placed either in a novel or habituated environment. In addition, the same dose of (-)OSU6162 reduces locomotor stimulation evoked by amphetamine. Ctrl, control; hab., habituation; damph, d-amphetamine; res., reserpine. The clinical potential of (-)-OSU6162 has also been investigated in Parkinson’s disease, Huntington’s disease and schizophrenia. In a primate model of Parkinson’s disease, (-)OSU6162, unlike the D2 receptor antagonist raclopride, suppressed L-DOPA-induced

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dyskinesias without interfering with its therapeutic effect (Hadj Tahar et al, 2001) and similar results have been found in initial studies with patients. In Huntington’s disease, a single administration of (-)-OSU6162, suppressed choreiform movement in a patient for several weeks, despite a half-life of only 200 minutes in vivo and no known active metabolite (Tedroff et al, 1999). In a double-blind crossover study against placebo involving three schizophrenic patients, a single oral treatment with 100 mg of (-)-OSU6162 produced the following results: a dramatic drop in positive symptoms measured on the Positive and Negative Symptom Scale (PANSS) scores within a day in the first patient, with no change in negative symptoms; a drop in both positive and negative symptoms in the second patient that appeared after 1 day and lasted for 2 more days; and a reduction in negative symptoms in the third patient who was already taking a depot antipsychotic that had successfully reduced positive symptoms. Placebo had no effect in any of these cases. Finally, in a study of 10 patients, over a 5-day period of daily treatment with 100 mg (-)OSU6162, five patients responded dramatically in 1 day with the response lasting throughout the study period, while the remaining five patients showed little response (Lundberg et al, 2002). Unfortunately, due to patent restrictions we have not been able to proceed further with (-)-OSU6162. However, tests are underway with a similar molecule that has at least the same, if not a better, profile. This compound, ACR 16, has been through phase 1 trials with promising results and we will soon be starting trials in schizophrenic patients. A glutamatergic deficiency model of schizophrenia It has become increasingly clear that several neurotransmitters have to be taken into account in the pathophysiology of schizophrenia and that some, such as glutamate and serotonin, may be at least as important as dopamine (see Chapters 9 and 10). Glutamate, the major excitatory transmitter in the central nervous system, has been implicated in synaptic plasticity, growth, development, learning and memory and modulating motor function (Tamminga, 1999; Chapter 10). The first indications that glutamate might be involved in schizophrenia came with the observations that phencyclidine (PCP), a psychotomimetic that can induce the signs and symptoms of psychosis in normal humans and exacerbate those of schizophrenics (Pearlson, 1981), was an antagonist at N-methylD-aspartate (NMDA) glutamate receptors (Anis et al, 1983). Since then other NMDA receptor antagonists such as ketamine have also been shown to induce experimental psychotic symptoms (Krystal et al, 1994; Tamminga, 1999). We started out with a simple hypothesis, well founded in terms of neuroanatomy, whereby sensory information reaching the cerebral cortex is controlled by inhibitory γamino butyric acid (GABA)ergic projection neurones originating from the striatum and projecting to the thalamus (Carlsson, 1988; Figure 1.4). This constitutes a highly selective filter mechanism that protects the cerebral cortex against overload. If thalamic inhibition is reduced, there will be an overflow of information that could lead to confusion and perhaps psychosis. The output activity of GABAergic neurones in the striatum is modulated by two functionally antagonistic neuronal systems: an inhibitory ascending dopaminergic input from the lower brainstem and an excitatory descending

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Figure 1.4 Hypothetical schematic representation of the cerebral cortex being protected from information overload and hyperarousal by feedback loops involving the striatal complexes and the thalamus. (Reproduced with permission from Carlsson, 1988.) glutamatergic input from the cortex. Both an elevation of dopamine function in the striatum or a decrease in glutamate function therefore would have the same outcome of relieving striatal inhibition of the thalamus and opening up the filter. In addition, the activity of dopamine neurones in the lower brainstem also seems to be controlled by glutamatergic neurones, either directly or via GABAergic interneurones (Figure 1.5). In the former case, glutamate has a stimulatory effect on the dopamine neurones (accelerator) and in the latter case it has an inhibitory effect (brake). Normally there appears to be a balance between the two, with perhaps a slight predominance of the brake effect. Hypoglutamatergia can therefore either increase or decrease dopamine function. As glutamate antagonists can counteract hypomotility in animals, it is possible that the immobility triggered by blocking dopamine receptors is actually an indirect effect of glutamatergic activation due to a change in the balance of striatal output leading to increased glutamatergic tone. If this were true, then blocking the NMDA receptor would reduce glutamatergic tone and the animal would start to move again. This was confirmed experimentally when it was shown that monoamine-depleted mice regained motility when treated with the NMDA receptor antagonists, MK-801 (Carlsson and Carlsson, 1989) and AP-5 (Svensson et al, 1992). Subsequent work revealed a dramatic synergy between a variety of monoaminergic agonists and MK-801 or other NMDA receptor antagonists (Carlsson and Carlsson, 1990; Carlsson and Svensson, 1990; Carlsson, 1995).

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Figure 1.5 Hypothetical schematic representation of cortical regulation of monoaminergic brainstem neurones by a direct glutamatergic pathway (accelerator) or an indirect glutamatergic/GABAergic pathway (brake). The outcome of glutamatergic failure will partly depend on the balance between the accelerator and the brake. The balance may also be regulated in part by feedback loops, probably involving the thalamus (cf Figs 1.4 and 1.7). Further details can be found in Carlsson et al, 2000. (Reproduced with permission from Carlsson et al, 2000.) However, the neurotransmitter systems that control locomotor activity are not restricted to dopamine and glutamate, and must involve complex regulatory systems. An example is provided by the effect of MDL 100907, a specific 5-HT2A receptor antagonist reported to be an antipsychotic agent. This drug reduced, in a dose-dependent manner, the psychomotor activity induced by MK-801 in mice, while having little intrinsic effect (Figure 1.6; Martin et al, 1997). Of course the situation in vivo is far more complicated than illustrated in Figures 1.4 and 1.5, but observations over the years have allowed us to build up a hypothetical scheme of the interactions between several neurotransmitters to form networks of psychotogenic pathways (Figure 1.7) that may be bringing us closer to

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the true picture. A more complete review of the interactions between monoamines, glutamate, and GABA in schizophrenia can be found in Carlsson et al (2001).

Figure 1.6 Concentration-dependent effect of MDL 100 907 on MK-801stimulated and normal locomotor activity in mice. (Reproduced with permission from Martin et al, 1997.)

Figure 1.7 Schematic representation of potential psychotogenic pathways and sites of action of psychotogenic and antipsychotic agents. Further

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details can be found in Carlsson et al, 2000. Ach, acetylcholine; DA, dopamine; 5-HT, 5hydroxytryptamine; GABA, γ-amino butyric acid; Glu, glutamate; LSD, lysergic acid diethylamide; NA, noradrenaline; NMDA, N-methyl-Daspartate; PCP, phencyclidine; rec, receptor; Str, striatum; SN, substantia nigra; VTA, ventral tegmental area. (Reproduced with permission from Carlsson et al, 2000.) Conclusions For many years now received wisdom has been that the best antipsychotic will be a single drug acting on a single target, although reality speaks very much against this. From our results and those of others it is clear that in schizophrenia many different neurotransmitters can interact to produce the schizophrenic syndrome and to mediate the effects of current and future antipsychotic drugs. We need to look at the system as a whole, as a small change in one component can have far reaching consequences on another. An integrated approach is thus required to increase our understanding of this complex disease. However, better understanding of the system will generate strategies for developing future generations of antipsychotic drugs that will fulfil the needs of patients and psychiatrists more comprehensively than those that exist today. References Abi-Dargham A, Gil R, Krystal J et al. (1998) Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 155:761–7. Abi-Dargham A, Rodenhiser J, Printz D et al. (2000) From the cover: increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 97:8104–9. Anis NA, Berry SC, Burton NR, Lodge D. (1983) The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methylaspartate. Br J Pharmacol 79:565–75. Bertler A, Rosengren E. (1959) Occurence and distribution of dopamine in brain and other tissues. Experientia 15:10. Breier A, Su TP, Saunders R et al. (1997) Schizophrenia is associated with elevated amphetamineinduced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 94:2569–74. Carlsson A. (1959) The occurrence, distribution and physiological role of catecholamines in the central nervous system. Pharmacol Rev 11:490–3.

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Carlsson A. (1966) Physiological and pharmacological release of monoamines in the central nervous system. In: (von Euler US, Resells S, Unvas B, eds.) Mechanisms of Release of Biogenic Amines. (Pergamon Press: Oxford) pp. 331–46. Carlsson A. (1975) Dopaminergic autoreceptors. In: (Almgren O, Carlsson A, Engel J, eds.) Chemical Tools in Catecholamine Research. (North-Holland: Amsterdam) pp. 219–29. Carlsson A. (1988) The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1:179–86. Carlsson A. (2002) Treatment of Parkinson’s with L-DOPA. The early discovery phase, and a comment on current problems. J Neural Transm 109:777–87. Carlsson A, Hillarp N-A. (1956) Release of adrenalin from the adrenal medulla of rabbits produced by reserpine. Kungl Fysiogr Sallsk i Lund Forhandl 26:8. Carlsson A, Lindqvist M. (1963) Effect of chlorpromazine or haloperidol on the formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol 20:140–4. Carlsson A, Lindqvist M, Magnusson T. (1957a) 3,4-Dihydroxyphenylalanine and 5hydroxytryptamine as reserpine antagonists. Nature 180:1200. Carlsson A, Rosengren E, Bertler A, Nilsson J. (1957b) Effect of reserpine on the metabolism of catecholamines. In (Garratini S, Ghetti V, eds.) Psychotropic Drugs. (Elsevier: Amsterdam) p. 363. Carlsson A, Waters N, Waters S, Carlsson ML. (2000) Network interactions in schizophrenia— therapeutic implications. Brain Res Rev 31:342–9. Carlsson A, Waters N, Holm-Waters S et al. (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol 41:237–60. Carlsson M, Carlsson A. (1989) Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulatory effect in monoamine-depleted mice. J Neural Transm 77:65–71. Carlsson M, Carlsson A. (1990) Interactions between glutamatergic and monoaminergic systems within the basal ganglia—implications for schizophrenia and Parkinson’s disease. Trends Neurosci 13:272–6. Carlsson ML. (1995) The selective 5-HT2A receptor antagonist MDL 100,907 counteracts the psychomotor stimulation ensuing manipulations with monoaminergic, glutamatergic or muscarinic neurotransmission in the mouse—implications for psychosis. J Neural Transm (Gen Sect) 100:225–37. Carlsson ML, Svensson A. (1990) Interfering with glutamatergic neurotransmission by means of MK-801 administration discloses the locomotor stimulatory potential of other transmitter systems in rats and mice. Pharmacol Biochem Behav 26:45–50. Clark D, Hjorth S, Carlsson A. (1985) Dopamine-receptor agonists: mechanisms underlying autoreceptor selectivity. I. Review of the evidence. J Neural Transm 62:1–52. Creese I, Burt DR, Snyder SH. (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–3. Delay J, Deniker P, Harl J-M. (1952) Traitments de etats d’excitation et d’agitation par une methode medicamenteuse derivée de l’hibernotherapie. Ann Med Psychol 110: 267–73. Ekesbo A, Torstenson R, Hartvig P et al. (1999) Effects of the substituted (S)-3-phenylpiperidine ()-OSU6162 on PET measurements of [11C]SCH23390 and [11C]raclopride binding in primate brains. Neuropharmacology 38:331–8. Hadj Tahar A, Ekesbo A, Gregoire L et al. (2001) Effects of acute and repeated treatment with a novel dopamine D2 receptor ligand on L-DOPA-induced dyskinesias in MPTP monkeys. Eur J Pharmacol 412:247–54. Kebabian JW, Calne DB. (1979) Multiple receptors for dopamine. Nature 277:93–6. Kehr W, Carlsson A, Lindqvist M, Magnusson T, Atack C. (1972) Evidence for a receptormediated feedback control of striatal tyrosine hydroxylase activity. J Pharm Pharmacol 24:744–7.

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Krystal JH, Karper LP, Seibyl JP et al. (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214. Lahti AC, Weiler MA, Corey PK et al. (1998) Antipsychotic properties of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (preclamol) in schizophrenia. Biol Psychiatry 43:2–11. Laruelle M, Abi-Dargham A, van Dyck CH et al. (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 93:9235–40. Lundberg T, Tedroff J, Waters N et al. (2002) Safety and early clinical experience with (-)OSU6162, a dopamine stabilizer with antipsychotic properties. Nordic J Psychiatry Abst:24. Martin P, Waters N, Waters S, Carlsson A, Carlsson ML. (1997) MK-801-induced hyperlocomotion: differential effects of M100907, SDZ PSD 958 and raclopride. Eur J Pharmacol 335:107–16. Neu H, Hartvig P, Torstenson R et al. (1997) Synthesis of [11C-methyl]-(-)-OSU6162, its regional brain distribution and some pharmacological effects of (-)-OSU6162 on the dopaminergic system studied in the rhesus monkey by positron emission tomography. Nucl Med Biol 24:507– 11. Pearlson GD. (1981) Psychiatric and medical syndromes associated with phencyclidine (PCP) abuse. Johns Hopkins Med J 148:25–33. Pletscher A, Shore PA, Brodie BB. (1956a) Serotonin release as a mediator of reserpine action in brain. J Pharm Exp Ther 116:84–9. Pletscher A, Shore PA, Brodie BB. (1956b) Serotonin release as a possible mechanism of reserpine action. Science 122:374–5. Seeman P, Lee T, Chau-Wong M, Wong K. (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–19. Sonesson C, Lin CH, Hansson L et al. (1994) Substituted (S)-phenylpiperidines and rigid congeners as preferential dopamine autoreceptor antagonists: synthesis and structure-activity relationships. J Med Chem 37:2735–53. Svensson A, Carlsson ML, Carlsson A. (1992) Interaction between glutamatergic and dopaminergic tone in the nucleus accumbens of mice: evidence for a dual glutamatergic function with respect to psychomotor control. J Neural Transm (Gen Sect) 88:235–40. Tamminga C. (1999) Glutamatergic aspects of schizophrenia. Br J Psychiatry Suppl 37: 12–15. Tamminga CA. (2002) Partial dopamine agonists in the treatment of psychosis. J Neural Transm 109:411–20. Tamminga CA, Cascella NG, Lahti RA, Lindberg M, Carlsson A. (1992) Pharmacologic properties of (-)-3PPP (preclamol) in man. J Neural Transm (Gen Sect) 88:165–75. Tedroff J, Torstenson R, Hartvig P et al. (1998) Effects of the substituted (S)-3-phenylpiperidine ()-OSU6162 on PET measurements in subhuman primates: evidence for tone-dependent normalization of striatal dopaminergic activity. Synapse 28:280–7. Tedroff J, Ekesbo A, Sonesson C, Waters N, Carlsson A. (1999) Long-lasting improvement following (-)-OSU6162 in a patient with Huntington’s disease. Neurology 53:1605–6.

chapter 2 Evidence from brain imaging studies for dopaminergic alterations in schizophrenia Anissa Abi-Dargham The ‘classical’ dopamine (DA) hypothesis of schizophrenia proposed that hyperactivity of DA transmission is responsible for the positive symptoms (hallucinations, delusions) observed in this disorder (Carlsson and Lindqvist, 1963). This hypothesis was supported by the correlation between clinical doses of antipsychotic drugs and their potency to block DA D2 receptors (Seeman and Lee, 1975; Creese et al, 1976) and by the psychotogenic effects of DA enhancing drugs (for review see Angrist and van Kammen, 1984; Lieberman et al, 1987). Negative and cognitive symptoms of the illness, on the other hand, are generally resistant to treatment by antipsychotic drugs (Keefe et al, 1999). Impairment in higher cognitive functions such as working memory is one of the most enduring symptoms of schizophrenia and a strong predictor of poor clinical outcome (Green, 1996). Functional brain imaging studies suggested that these symptoms might be associated with a dysfunction of the prefrontal cortex (PFC) (for reviews see Weinberger, 1987; Knable and Weinberger, 1997). Studies in non-human primates demonstrated that deficit in DA transmission in the PFC and lack of stimulation of D1 receptors (the main DA receptor subtype in the PFC) induces cognitive impairments reminiscent of those observed in patients with schizophrenia (Goldman-Rakic and Selemon, 1997). Together, these observations suggest that a deficit in DA transmission at D1 receptors in the PFC might be implicated in the cognitive impairments and negative symptoms presented by these patients. This cortico-subcortical imbalance is referred to as the ‘revised’ dopamine hypothesis of schizophrenia (Weinberger, 1987; Davis et al, 1991): subcortical mesolimbic DA projections might be hyperactive (resulting in hyperstimulation of D2 receptors and positive symptoms) while mesocortical DA projections to the PFC might be hypoactive (resulting in hypostimulation of D1 receptors, negative symptoms and cognitive impairment). Since the seminal work of Pycock et al (1980), many laboratories have described reciprocal and opposite regulations between cortical and subcortical DA systems (for review see Tzschentke, 2001). An abundant literature suggests that prefrontal DA activity exerts an inhibitory influence on subcortical DA activity, for example in conditions of mild stress (Deutch, 1990; Kolachana et al, 1995; Karreman and Moghaddam, 1996; Wilkinson, 1997). From these observations, it has been proposed that, in schizophrenia, both arms of the DA imbalance model might be related, inasmuch as a deficiency in mesocortical DA function might translate into disinhibition of mesolimbic DA activity (Weinberger, 1987; Davis et al, 1991).

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Despite decades of effort to generate experimental data supporting these hypotheses, documentation of abnormalities of DA function in schizophrenia has been difficult. Postmortem studies measuring DA and its metabolites and DA receptors in the brains of schizophrenic patients yielded inconsistent or inconclusive results (for review see Davis et al, 1991). The lack of clear evidence for altered dopaminergic indices in schizophrenia prompted some authors to propose that DA transmission in schizophrenia might be essentially normal and elevated only relative to other systems, such as the glutamatergic or serotonergic systems (Carlsson, 1988; Meltzer, 1989). Under this perspective, the antipsychotic properties of D2 receptor blockade do not derive from correcting a hyperdopaminergic state, but from re-establishing an appropriate balance between DA and other neuronal systems (although at a lower level). Yet, the absence of data supporting the DA hypothesis of schizophrenia might be due to the difficulty in obtaining a direct measurement of DA transmission in the living human brain. Over the past few years, progress in brain imaging methods has enabled direct measurement of DA transmission at D2 receptors, and the application of these techniques to the study of schizophrenia has provided new insights into the nature and the role of DA function dysregulation in schizophrenia. This chapter will review the evidence from imaging studies for alterations in indices of DA transmission in the brain of patients with schizophrenia, and its relevance to positive, negative and cognitive symptoms. The review of the imaging results will be introduced by a brief overview of the anatomy of DA systems followed by an integrative discussion of the imaging findings where it will be proposed that alterations of DA systems in schizophrenia might be secondary to deficits in glutamatergic transmission. Dopaminergic systems in the brain Dopaminergic projections Dopaminergic projections are classically divided into nigrostriatal, mesolimbic and mesocortical systems (Lindvall and Björklund, 1983; Figure 2.1). The nigrostriatal system projects from the substantia nigra (SN) to the dorsal striatum, and has been classically involved in cognitive integration, habituation, sensorimotor coordination and initiation of movement. The mesolimbic system projects from the ventral tegmental area (VTA) to limbic structures such as the ventral striatum (the part of the striatum that is rostral and ventral to the anterior commissure and that includes the nucleus accumbens, shell and core, and the ventral parts of the caudate nucleus and putamen), hippocampus and amygdala. The mesocortical system projects from the VTA to cortical regions, mostly orbitofrontal, medial prefrontal and cingulate cortices, but also to the dorsolateral prefrontal cortex (DLPFC), temporal cortex and parietal cortex. The mesolimbic and mesocortical systems are involved in regulation of motivation, attention and reward (Mogenson et al, 1980).

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Figure 2.1 Schematic representation of dopaminergic pathways in the brain. The three anatomically distinct pathways are shown in green. Cing Cx, cingulate cortex; MPF Cx, medial prefrontal cortex; OFr Cx, orbitofrontal cortex; CN, caudate nucleus; Put, putamen; NA, nucleus accumbens; VS, ventral striatum (ventral parts of the caudate nucleus and putamen); Amy, amygdala; HC, hippocampus; SNpc, substantia nigra pars compacta; VTA, ventraltegmental area; DLPFC, dorsolateral prefrontal cortex. Corticostriatal-thalamocortical loops are important targets of DA modulation. The general scheme of these loops involves projections from the cortex to striatum to the internal segment of the globus pallidum (GPi) or the SN pars reticulata (SNr) to the thalamus and back to the cortex (Figure 2.2). These loops have been classified into ‘limbic’ loops (medial prefrontal and orbitofrontal cortex—ventral striatum—ventral pallidum—mediodorsal thalamic nuclei—cortex); associative loops (DLPFC—head of the caudate—GPi/SNr—ventral anterior thalamic nuclei—cortex); and motor loops (premotor and motorareas—putamen and body of the caudate—GPi/SNr—ventral anterior thalamic nuclei—cortex) (Alexander et al, 1986; Hoover and Strick, 1993; Parent and Hazrati, 1995a; Ferry et al, 2000; Joel and Weiner, 2000). The amygdala and hippocampus provide significant inputs to the ventral striatum, contributing to

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information integration into the limbic loop (Everitt et al, 1991; Kunishio and Haber, 1994; Pennartz et al, 1994; Grace, 2000). Animal studies suggest that the nucleus accumbens is the critical region in which both typical and atypical antipsychotic drugs exert their antipsychotic effects (Chiodo and Bunney, 1983; Deutch et al, 1991, 1992; Robertson et al, 1994). It is important to note that these different corticostriatalthalamocortical loops are not completely segregated parallel loops. While corticostriatalthalamic loops do generally re-enter the cortical area that provides input to the striatal subregions involved in these loops, thus forming closed circuits and serving segregated processes, they also project back to other areas of the cortex, forming open circuits and serving integrative processes (Joel and Weiner, 2000). Within each loop, the striatal output reaches the GPi/SNr via a direct pathway and via an indirect pathway that traverses the external segment of the globus pallidus (GPe) and the subthalamic nuclei (STN), both pathways providing antagonistic inputs to the GPi/SNr (DeLong et al, 1985; Albin et al, 1989; Gerfen, 1992; Joel and Weiner, 2000). Corticostriatal projections are glutamatergic, striatopallidal and pallidothalamic

Figure 2.2 Schematic representation of corticothalamic pathways influencing the function of the basal ganglia. Excitatory glutamatergic pathways are shown in red, inhibitory GABAergic pathways in blue, and the modulatory dopaminergic pathway in green. GP, globus pallidus; STN, subthalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata.

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projections are γ-amino-butyric acid (GABA)ergic, and thalamocortical projections are glutamatergic. It follows that activation of striatal neurones of the direct pathway by glutamatergic inputs from the cortex results in decreased activity of the pallidostriatal inhibitory projections to the thalamus, and that the direct pathway is generally considered as stimulatory. Projections from the striatum to the GPe and from the GPe to the STN are GABAergic, and from the STN back to GPe and to GPi/SNr are glutamatergic. Activation of the indirect pathway is generally considered as providing an inhibitory effect on thalamocortical neurones (DeLong et al, 1985). The view of the antagonistic nature of the direct/stimulatory pathway versus the indirect/inhibitory pathway has been criticized as being oversimplistic (Parent and Hazrati, 1995b). Nevertheless, it is important to keep in mind that activation of medium spiny GABAergic neurones in the striatum by corticostriatal glutamatergic afferents can provide both stimulatory and inhibitory influences on thalamocortical projections (Carlsson et al, 1999). DA modulates the flow of information within these loops. In primates, DA cells from the VTA project to the ventral striatum and cortex, the dorsal tier of the SN includes cells that project to all striatal regions and cortex, and the ventral tier of the SN projects widely throughout the dorsal striatum but not to the cortex (for review see Haber and Fudge, 1997). The striatum provides GABA projections back to the VTA and SN. Projections from the ventral striatum to midbrain DA neurones are not restricted to the VTA and dorsal tier of the SN (where DA neurones projecting to the ventral striatum are located), but also terminate in the ventral tier of the SN (where DA neurones projecting to the dorsal striatum are located). Based on these observations, Haber proposed that the DA system provides a bridge by which information circulating in the ventral limbic corticostriatal-thalamocortical loops spirals along nigrostriatal loops and feeds into the cognitive and sensorimotor loops, translating drives into actions (Haber and Fudge, 1997; Haber et al, 2000; Joel and Weiner, 2000). Dopaminergic receptors DA receptors include a D1-like family (D1 and D5 receptors), and a D2-like family (D2, D3 and D4 receptors) based on pharmacological similarities. The advent of molecular biology techniques in the late 1980s enabled the cloning of these receptors (Bunzow et al, 1988; Dearry et al, 1990; Monsma et al, 1990; Sokoloff et al, 1990; Zhou et al, 1990; Sunahara et al, 1991, Tiberi et al, 1991, Van Tol et al, 1991). D1 receptors stimulate adenylate cyclase while the D2 receptors are not coupled to or inhibit this effector (Kebabian and Calne, 1979). D2 receptors are both postsynaptic and presynaptic auto-receptors (for review, see Missale et al, 1998; Palermo-Neto, 1997). DA receptors differ in their regional localization in the human brain (for reviews see Seeman, 1992; Meador-Woodruff et al, 1996; Joyce and MeadorWoodruff, 1997). D1 receptors show a widespread neocortical distribution, including the prefrontal cortex, and are also present in high concentration in the striatum. D5 receptors are concentrated in the hippocampus and entorhinal cortex. D2 receptors are concentrated in the striatum, with low concentration in medial temporal structures (hippocampus, entorhinal cortex, amygdala) and thalamus. The concentration of D2 receptors in the prefrontal cortex is extremely low. D3 receptors are present in the striatum, where their concentration is

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particularly high in the ventral striatum. D4 receptors are present in the prefrontal cortex and hippocampus, but not detected in the striatum. In the striatum, D2 receptors are preferentially found in encephalin-rich GABAergic neurones that participate in the indirect pathways, while D1 receptors are most abundant in dynorphin/substance P GABAergic neurones that contribute to the direct pathways (Le Moine et al, 1990, 1991; Gerfen, 1992; Hersch et al, 1995). The magnitude of the segregation versus co-expression of D1 and D2 receptors in striatal neurones is still a matter of debate (Surmeier et al, 1992, 1996). In the VST, D3 receptors co-localize preferentially on neurones expressing D1 receptors (Schwartz et al, 1998). The segregation of D2 and D1 receptors on different and antagonistic pathways might account for the fact that activation of these receptors is often synergistic at the behavioural level (for example, stimulation of both D1 and D2 receptors stimulates locomotion), while their effects on intracellular signalling (starting with adenylate cyclase activity) are opposite in many regards. For example, stimulation of D1 and D2 receptors increases or decreases DARP32 phosphorylation, induces or blocks c-fos expression and promotes or inhibits Nmethyl-D-aspartate (NMDA) receptor function (Nguyen et al, 1992; Nishi et al, 1997; Konradi, 1998; Leveque et al, 2000; Dunah and Standaert, 2001). Thus, activation of D2 receptors by DA might provide an inhibitory influence to the indirect pathway and activation of D1 receptors by DA might provide a stimulatory influence on the direct pathway. Both effects are expected to result in stimulation of thalamocortical neurones. However, the action of DA on target neurones should not be viewed in terms of simple excitation or inhibition. Unlike classical ‘fast’ transmitters, DA does not directly gate ion channels, but stimulation of the DA G-protein linked receptor induces a cascade of intracellular signalling that results in modifying the response of the cells to other transmitters. DA is neither ‘inhibitory’ or ‘excitatory’, but its action will depend on the state of the neurones at the time of the stimulation (Yang et al, 1999). In the striatum, DA modulates response of GABAergic medium spiny neurones to glutamatergic drive from the cortex. In this structure, it has been proposed that DA is ‘reinforcing’, i.e. it augments the inhibition of neurones that are inhibited and the excitability of those that are excited (Wickens, 2000). In this manner, DA acts to gate glutamatergic inputs by increasing their signal to noise ratio. Moreover, DA input might produce long-term changes in the strength of corticostriatal glutamatergic synapses (long-term depression (LTD) and longterm potentiation (LTP)) (Arbuthnott et al, 2000; Kerr and Wickens, 2001), a process that might underlie DA mediated incentive learning and play a role in the plasticity associated with emergence of positive symptoms upon prolonged DA hyperactivity. In the prefrontal cortex, D1/5 receptors are localized both on pyramidal cells (dendritic spines and shafts) and on axonal terminals of non-dopaminergic neurones (Smiley et al, 1994), while some data suggest that D4 receptors might be localized on GABA interneurones (Mrzljak et al, 1996). DA modulates pyramidal cell excitability, both directly and via GABAergic interneurones (Yang et al, 1999). Recent data suggest that DA differently affects GABAergic activity in the PFC via stimulation of D1-like (D1/5) or D2-like receptors, whereby the former enhances and the latter inhibits GABAergic activity. Here again, it has been proposed that DA increases the signal to noise ratio of glutamatergic afferents (Seamans et al, 2001).

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Imaging studies documenting alterations of DA systems in schizophrenia The majority of imaging studies have focused on striatal DA parameters, since their high density in this region facilitates imaging investigations. Cortical DA parameters became amenable to imaging much more recently, and less information is currently available for these. Results of imaging studies of DA systems in the striatum will be reviewed first. Striatal DA parameters Many aspects of striatal DA transmission have been subject to imaging studies. Historically, postsynaptic markers (D2 and D1 receptors) were studied first, and these investigations resulted in mostly negative results. More recently, attention has shifted towards imaging presynaptic DA activity, and the majority of these studies have provided strong evidence for a dysregulation of presynaptic DA function in schizophrenia. Postsynaptic markers D2 receptors Striatal D2 receptor density in schizophrenia has been extensively studied with positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging. Studies comparing parameters of D2 receptor binding in patients with schizophrenia and healthy controls (Crawley et al, 1986; Wong et al, 1986; Blin et al, 1989; Farde et al, 1990; Martinot et al, 1990, 1991, 1994; Tune et al, 1993; Hietala et al, 1994; Pilowsky et al, 1994; Nordstrom et al, 1995; Laruelle et al, 1996; Breier et al, 1997; Knable et al, 1997; Okubo et al, 1997; Abi-Dargham et al, 1998, 2000) included a total of 245 patients (112 were neuroleptic naive, and 133 were neuroleptic free for variable periods of time). These patients were compared to 231 controls, matched for age and sex. Eleven studies used PET and six studies used SPECT. Radiotracers included butyrophenones ([11C]N-methylspiperone ([11C]NMSP), N=4; and [76Br]bromospiperone; N=3), benzamides ([11C]raclopride, N=3; and [123I]IBZM; N=5) or the ergot derivative [76Br]lisuride, N=2. Only two out of 17 studies detected a significant elevation of D2 receptor density parameters at a probability level of <0.05. However, meta-analysis of the 17 studies reveals a small but significant elevation of D2 receptors in patients with schizophrenia. If D2 receptor density did not differ between patients and controls (null hypothesis), one would expect approximately 50% of the studies to report lower D2 receptor levels in schizophrenics compared to controls. Instead, 13 out of 17 studies reported an increase (although not significant in 11 out of 13 cases), two reported no change, and only two studies reported a decrease in patients compared to controls. This distribution is unlikely (p<0.05, sign test) under the null hypothesis. The average effect size (mean value in schizophrenic group—mean value in control group/SD (standard deviation) in control group) of the 17 studies was 0.51±0.76 (SD), and the probability to yield such effect size under the null hypothesis is again <0.05. The aggregate magnitude of this elevation is thus 51% of the SD of controls. Given an average control SD of 23%, the effect is about 12%. To detect an effect size of 0.50 at 0.05 significance level with a power of 80%, a

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sample of 64 patients and 64 controls would be needed. Clearly, none of the individual studies included enough patients to detect this small effect with appropriate power. No clinical correlate of increased D2 receptor binding parameters has been reliably identified. Thus, the simplest conclusions from these studies are that untreated or never treated patients with schizophrenia show a modest elevation in D2 receptor density parameters (of about 12%) of undetermined clinical significance, that all studies were underpowered, and that positive results occasionally reported (Crawley et al, 1986; Wong et al, 1986) are due to a sampling effect. D1 receptors Imaging studies of D1 receptors consistently failed to detect abnormalities of D1 receptor availability in the striatum of patients with schizophrenia (Okubo et al, 1997; AbiDargham et al, 2002; Karlsson et al, 2002). Presynaptic markers DOPA decarboxylase activity Six studies reported DOPA decarboxylase activity in patients with schizophrenia, using [18F]DOPA (Reith et al, 1994; Hietala et al, 1995; Dao-Castellana et al, 1997; Hietala et al, 1999; Meyer-Lindenberg et al, 2002) or [11C]DOPA (Lindstrom et al, 1999). Five out of six studies reported increased accumulation of DOPA in the striatum of patients with schizophrenia, and the combined analysis yielded an effect size of 0.92±0.45 (p=0.01). Several studies reported high DOPA accumulation in psychotic paranoid patients. While the relationship between DOPA decarboxylase and DA synthesis rate is unclear (DOPA decarboxylase is not the rate-limiting step of DA synthesis), these observations are compatible with higher DA synthesis activity in patients experiencing psychotic symptoms. Interestingly, a recent study observed a relationship between poor prefrontal activation during the Wisconsin Card Sort Task and elevated [18F]DOPA accumulation in the striatum, suggesting a link between alteration of prefrontal function and increased striatal DA activity in schizophrenia (Meyer-Lindenberg et al, 2002). Amphetamine-induced DA release Neuroreceptor imaging studies with PET and SPECT are classically aimed at measuring neuroreceptor parameters in the living human brain. More recently, several groups demonstrated that, under specific conditions, in vivo neuroreceptor binding techniques can also be used to measure acute fluctuations in the concentration of endogenous transmitters in the vicinity of radiolabelled receptors (Dewey et al, 1991; Innis et al, 1992; Carson et al, 1997; Laruelle et al, 1997b). Competition between radiotracers and transmitters for binding to neuroreceptors is the principle underlying this approach, although other mechanisms such as agonist-induced receptor internalization might also play a role (for review see Laruelle, 2000). So far, applications of this new paradigm have been mainly developed to study DA transmission at D2 receptors. The amphetamine-induced reduction in [123I]IBZM or [11C]raclopride BP (binding potential) has been well validated as an indirect measure of the changes in synaptic DA concentration induced by the challenge (Breier et al, 1997; Laruelle et al, 1997b, 1999; Kegeles et al, 1999). Several studies reported that amphetamine-induced DA release is

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Figure 2.3 Effect of amphetamine (0.3 mg/kg) on [123I]IBZM binding in healthy controls and untreated patients with schizophrenia. The y-axis shows the percentage decrease in [123I]IBZM binding potential induced by amphetamine, which is a measure of the increased occupancy of D2 receptors by DA following the challenge. increased in patients with schizophrenia compared to matched healthy controls (Laruelle et al, 1996, 1999; Breier et al, 1997; Abi-Dargham et al, 1998). In the present author’s sample, the amphetamine-induced reduction in [123I]IBZM BP was 7.5±7.1% in control subjects (N=34) and 17.1±13.2% in patients with schizophrenia (N=34, p<0.001; Figure 2.3). A similar finding was reported by Breier et al (1997) using [11C]raclopride, PET and a smaller dose of amphetamine (0.2 mg/kg, iv). Providing that the affinity of D2 receptors for DA is unchanged in this illness (see discussion in Laruelle et al, 1999), these data are consistent with increased amphetamine-induced DA release in schizophrenia. The amphetamine effect on [123I]IBZM BP was similar between chronic/previously treated patients and first episode/neuroleptic naive patients, and both groups were significantly different from controls. In the previously treated group, no association was found between the duration of the neuroleptic free period and the amphetamine-induced

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[123I]IBZM displacement. Together, these data indicated that the exaggerated dopaminergic response to amphetamine exposure was not a prolonged side effect of previous neuroleptic exposure.

Figure 2.4 Relationship between striatal amphetamine-induced dopamine release (y-axis) and amphetamine-induced changes in positive symptoms measured with the positive subscale of the Positive and Negative Symptom Scale (PANSS) in patients with schizophrenia. Stimulation of D2 receptors was associated with emergence of worsening of positive symptoms and accounted for about 30% of the variance in this behavioural response. In patients with schizophrenia, the amphetamine challenge induced a significant increase in positive symptoms. The emergence or worsening of positive symptoms was transient, and patients returned to their baseline symptomatology within a few hours of the challenge. A significant correlation was observed between the increase in positive

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symptoms and the [123I]IBZM displacement (r=0.54, p=0.0009; Figure 2.4). This result provided first direct evidence that exaggerated activation of DA transmission at D2 receptors mediates the expression of psychotic symptoms following amphetamine challenge. Patients who were experiencing an illness exacerbation (identified by the fact that their admission was motivated by clinical reasons) presented a higher amphetamineinduced [123I]IBZM displacement (23.7±13.2%, N=17) than patients who were in remission and recruited as outpatients (10.5±9.7%, N=17, p=0.002). Furthermore, amphetamine-induced [123I]IBZM displacement in remitted patients (10.5±9.7%, N=17) was not statistically different from controls (7.5±7.1%, N=36, P=0.27). This observation suggests that dysregulation of DA release in patients with schizophrenia might be present only during episodes of illness exacerbation. Studying the same patients during exacerbation and remission phases is required to confirm this point. An important question raised by these studies is whether the stress associated with psychiatric hospitalization and/or the scanning procedure might account for the excess DA release measured in patients with schizophrenia, since stress activates DA release (Deutch et al, 1990; Kalivas and Duffy, 1995). To investigate this potential confounding factor, amphetamine-induced DA release in a group of non-psychotic unipolar depressed subjects was recently studied (Parsey et al, 2001). Despite reporting pre-amphetamine anxiety levels higher than schizophrenic patients, patients with depression showed normal amphetamine-induced displacement of [123I]IBZM This finding supports the hypothesis that the increased amphetamine effect observed in patients with schizophrenia is not a non-specific consequence of stressful conditions (although it could represent a specific interaction between stress and schizophrenia). Baseline DA activity A major limitation of the amphetamine studies is that they measured changes in synaptic DA transmission following a non-physiological challenge (i.e. amphetamine) and did not provide any information about ‘baseline’ synaptic DA levels, i.e. synaptic DA levels in the absence of pharmacological interventions. Several laboratories reported that, in rodents and non-human primates, acute depletion of synaptic DA is associated with an acute increase in the in vivo binding of [11C]raclopride or [123I]IBZM to D2 receptors (Van der Werf et al, 1986; Ross and Jackson, 1989; Seeman et al, 1989; Ross, 1991; Young et al, 1991; Dewey et al, 1992; Ginovart et al, 1997). The increased binding was observed in vivo but not in vitro, indicating that it was not due to receptor upregulation (Laruelle et al, 1997a), but to removal of endogenous DA and unmasking of D2 receptors previously occupied by DA. Using this acute depletion strategy, baseline occupancy of striatal D2 receptors by DA was studied in acute patients with schizophrenia (AbiDargham et al, 2000). D2 receptor availability was measured at baseline (i.e. in the absence of any pharmacological intervention) and during acute DA depletion. Acute DA depletion was achieved by administration of high doses of α-methyl-para-tyrosine (αMPT) for two days (Spector et al, 1965; Uden-friend et al, 1965). Comparing D2 receptor availability at baseline and in the depleted state provided an indirect measure of the proportion of D2 receptors occupied by DA in the baseline state. Removal of endogenous DA by α-MPT increased D2 receptor availability by 9±7% in controls (N=18) and by 19±11% in patients with schizophrenia (N=18, p=0.003). The effect of α-MPT on D2

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receptor availability was not statistically different between drug naive (N=8, 17±6%) and previously treated patients (N=10, 20±15%), and both groups were significantly different from controls. Thus, the results of this study suggest that DA occupies a greater proportion of striatal D2 receptors in patients with schizophrenia compared to matched control subjects during first episode of illness and subsequent episodes of illness exacerbation. The significance of this result stems from the fact that the paradigm used here reveals D2 receptor occupancy by DA during the baseline scan, i.e. in the absence of any pharmacological intervention. The result of this study directly supports the classical dopamine hypothesis of schizophrenia, but should be viewed with caution until independently replicated. Since patients were studied during an episode of illness exacerbation, the occupancy of D2 receptors by DA during periods of illness remission remains uncharacterized. The term ‘baseline’ activity used here simply denotes that this study aimed at measuring occupancy of D2 receptors by DA in the absence of pharmacological challenge. The ‘baseline’ DA activity studied by the α-MPT paradigm should not be confused with the tonic release described by Grace (1991, 1993) in his model of DA dysregulation associated with schizophrenia. This model rests on the distinction between tonic and phasic DA release. Tonic release refers to the extracellular extrasynaptic DA release, is impulse-independent and regulated by glutamatergic projections from the PFC to DA terminals in the striatum. In contrast, the phasic release is the impulse-dependent synaptic DA release. Grace (1991, 1993) speculated that schizophrenia might be associated with low tonic DA activity, resulting from a decreased glutamatergic stimulation. This low DA tonic activity would in turn induce increased phasic DA activity, leading to overstimulation of post-synaptic D2 receptors and emergence of positive symptoms. The baseline D2 receptor occupancy by DA measured in the α-MPT study is presumably due to the temporal and spatial integration of phasic release, as several lines of evidence suggest that the effect measured by these imaging techniques is intra- rather than extrasynaptic (for review and discussion see Laruelle, 2000). Thus, results of the α-MPT are consistent with the Grace (1991, 1993) model. Patients included in the α-MPT study completed 6 weeks of antipsychotic medication as inpatients. High synaptic level of DA at baseline, measured by the α-MPT effect on D2 receptor BP, was significantly associated with greater improvement of positive symptoms following 6 weeks of antipsychotic treatment. Thus, the dysregulation of DA transmission revealed by the imaging study was predictive of better response of positive symptoms to antipsychotic treatment. Schizophrenic patients who experienced positive symptoms in the presence of increased DA stimulation of D2 receptors showed a remarkable and rapid decline in these symptoms following treatment with antipsychotic drugs. Subjects who experienced positive symptoms in the presence of apparently normal stimulation of D2 receptors by DA showed little improvement of these symptoms following 6 weeks of antipsychotic treatment. The fact that high levels of synaptic DA at baseline predicted better or faster response to atypical antipsychotic drugs (13 out of 14 patients were treated with atypical drugs) also suggests that the D2 receptor blockade induced by these drugs remains a key component of their initial mode of action. Contrary to widely accepted views, antipsychotic drugs have only partial efficacy against positive symptoms. A substantial proportion of schizophrenic patients, possibly a third, remain actively psychotic despite appropriate and prolonged blockade of D2

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receptors (Huckle and Palia, 1993; Weiden et al, 1996). The data from the α-MPT study suggest that, in some patients, blockade of D2 receptors by antipsychotic drugs fails to significantly alter positive symptoms because these symptoms might not be related to excessive stimulation of these receptors by DA. DA transporters The data reviewed above are consistent with higher DA output in the striatum of patients with schizophrenia. This phenomenon is probably not due to increased density of DA terminals. Striatal DA transporters (DAT) are exclusively localized on DA terminals, and the in vivo binding of the DAT radioligands [123I]β-CIT (Laruelle et al, 2000) or [18F]CFT (Laakso et al, 2000) is unaltered in patients with schizophrenia. These in vivo observations confirmed the post-mortem findings of normal DAT density in the striatum of patients with schizophrenia discussed above. In addition, in vivo measurement of the vesicular monoamine transporter in the caudate, putamen and ventral striatum with [11C]dihydrotetrabenazine is unaltered in patients with schizophrenia (Taylor et al, 2000). Laruelle et al (2002) observed no association between amphetamine-induced DA release and DAT density. Thus, the increased presynaptic output suggested by the amphetamine studies appears to be associated with a functional dysregulation of DA neurones, rather than an increased number of these neurones. Cortical DA parameters So far, imaging parameters of DA transmission in cortical regions in schizophrenia has been restricted to postsynaptic markers. D1 receptors D1 receptors are the predominant dopaminergic receptors in the DLPFC, an area involved in working memory and executive functioning. Prefrontal D1 receptors can be quantified in vivo using PET. [11C]SCH 23390 was the first radiotracer developed to visualize D1 receptors in vivo with PET (Halldin et al, 1986; Farde et al, 1987). Using [11C]SCH 23390, Okubo et al (1997) reported decreased D1 receptor availability in the PFC in patients with schizophrenia compared to controls. This study was, however, limited by the use of a PET camera with limited resolution and by the poor signal to noise ratio associated with [11C]SCH 23390 in the PFC. A more recent study using the same tracer and a better scanner failed to detect any differences between patients and controls in prefrontal [11C]SCH 23 390 binding (Karlsson et al, 2002). [11C]NNC 112 was also introduced recently as a superior PET radiotracer for quantification of D1 receptors in extrastriatal areas (Halldin et al, 1998). The main advantage of [11C]NNC 112 compared to [11C]SCH 23390 is an enhanced specific to nonspecific activity ratio. This property is of special importance in the measurement of D1 receptors in extrastriatal areas such as the neocortex, where the density of these receptors is much lower than in the striatum (De Keyser et al, 1989; Hall et al, 1994). [11C]NNC 112 was used to assess D1 receptors in DLPFC in relationship to working memory performance in patients with schizophrenia compared to controls (Abi-Dargham et al, 2002). DLPFC [11C]NNC 112 BP was higher in patients compared to controls (Figure 2.5). Patients tended to show higher [11C]NNC 112 BP compared to controls in the

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medial prefrontal cortex (p=0.08) and temporal cortex (p=0.08). Other cortical regions (striatal, limbic, paralimbic) and thalamic regions showed no difference between groups. In patients, high DLPFC D1 receptor availability was associated with poor working memory function (Figure 2.6).

Figure 2.5 Distribution of [11C]NNC 112 BP in DLPFC of healthy controls (N=16, open circles) and patients with schizophrenia (N=16; antipsychotic naive patients, □; patients antipsychotic free since more than 1 year, ●; patients with 2–3 weeks of antipsychotic free interval,▲. Patients with schizophrenia displayed increased D1 receptor availability compared to controls (p=0.02). (AbiDargham et al, 2002.)

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Figure 2.6 Relationship between upregulation of D1 receptors in the DLPFC of untreated patients with schizophrenia and performance at WM task (3-back adjusted hit rate, lower values represent poorer performance). WM, working memory; AHR, adjusted hit rate. (Abi-Dargham et al, 2002.) As chronic DA depletion results in upregulation of prefrontal [11C]NNC 112 binding in rodents (Guo et al, 2001), the imaging results suggest that schizophrenia might be associated with chronic deficiency of prefrontal DA function, leading to an ineffective compensatory upregulation of D1 receptors and poor working memory performance. Results obtained with [11C]NNC 112 contradict the results obtained with [11C]SCH 23 390 (Okubo et al, 1997; Karlsson et al, 2002). The three studies may differ because of differences in patient population, or because of differences in the effect of chronic DA depletion on the in vivo binding of both radiotracers. For example, in rodents, chronic DA depletion leads to upregulation of in vivo [11C]NNC 112 binding, but no change in prefrontal [11C]SCH 23 390 in vivo binding (Guo et al, 2001). Additional studies are needed to resolve this issue, and to understand better the factors affecting the in vivo binding of PET radiotracers. D2 receptors.

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The first generation of D2 receptor ligands ([11C]NMSP, [11C]raclopride, [123I]IBZM enabled imaging D2 receptors only in the striatum. The recent introduction of a new generation of D2 receptor radiotracers allows visualization of extrastriatal D2 receptors. Because of the low density of extrastriatal D2 receptors (Lidow et al, 1989; Joyce et al, 1991; Kessler et al, 1993; Hall et al, 1994; Murray et al, 1994;), radiotracers with very high affinity and/or low non-specific binding are required, such as [11C]FLB 457 (KD=0.018 nM) (Halldin et al, 1995) and [18F]fallypride (KD=0.030 nM) (Mukherjee et al, 1995). In a recent study of drug naive patients with schizophrenia performed with [11C]FLB 457, Suhara et al (2002) observed lower D2 receptor availability in the anterior cingulate cortex in patients compared to controls. A significant negative correlation was observed between low D2 receptor availability in the anterior cingulate cortex and positive symptoms severity. The meaning of this result for the pathophysiology of DA in schizophrenia remains to be established. The recent demonstration that [18F]fallypride binding is vulnerable to acute changes in endogenous DA will enable, in the future, probing of presynaptic DA function in the anterior cingulate (Narendran et al, 2002). Glutamate-DA interactions: relevance to schizophrenia The imaging findings reviewed above are generally consistent with the model that schizophrenia might be associated with a DA imbalance (Weinberger, 1987; Davis et al, 1991), involving an excess of subcortical DA function and a deficit in cortical DA function: subcortical mesolimbic DA projections might be hyperactive (resulting in hyperstimulation of D2 receptors and positive symptoms) while mesocortical DA projections to the PFC might be hypoactive (resulting in hypostimulation of D1 receptors, negative symptoms and cognitive impairment). The mechanism(s) by which such a DA imbalance might emerge in the brain of patients with schizophrenia remains unknown. While it cannot be definitively excluded that the DA dysregulations revealed by these imaging studies may stem from a primary abnormality of DA neurones, it seems more likely that these abnormalities are a consequence of a more general brain pathology. Moreover, given the weight of evidence implicating PFC connectivity as a central deficient node in the schizophrenic brain, it is tempting to speculate that dysregulated DA activity might be due to a failure of the PFC to regulate this process (Weinberger et al, 1986; Grace, 1991; Bertolino et al, 2000). This perspective leads the discussion toward glutamatergic mediated mechanisms that might account for the DA dysregulations observed in schizophrenia. The NMDA hypofunction hypothesis of schizophrenia Several lines of evidence support the hypothesis that schizophrenia might be associated with a persistent dysfunction of glutamate (GLU) transmission involving N-methyl-Daspartate (NMDA) receptors (for reviews see Javitt and Zukin, 1991; Olney and Farber, 1995; Tamminga et al, 1995; Jentsch and Roth, 1999; Goff and Coyle, 2001). Competitive NMDA antagonists such as phencyclidine (PCP) or ketamine induce both

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positive and negative symptoms in healthy and schizophrenic subjects (Krystal et al, 1994; Lahti et al, 1995). Unmedicated patients with schizophrenia are more sensitive than normal volunteers to the effects of NMDA antagonists and do experience worsening of positive, as well as negative, symptoms (Lahti et al, 2001). In addition, adjunctive treatment with NMDA agonists such as glycine (Javitt et al, 1994, 2001; Heresco-Levy et al, 1999), D-cycloserine (Heresco-Levy et al, 1998, 2001, 2002; Goff et al, 1999), and Dserine (Tsai et al, 1998) might provide symptom improvement in schizophrenia. Long-term administration of NMDA antagonists in animal studies shows that sustained disruption of NMDA transmission induces alterations in DA transmission (reduced mesocortical DA activity and excessive subcortical reactivity) that are consistent with the abnormalities postulated by the DA imbalance hypothesis of schizophrenia (for review see Jentsch and Roth, 1999). These observations led to the formulation of the unifying hypothesis that both abnormalities in DA transmission in schizophrenia (mesocortical DA deficit and mesolimbic DA hyperactivity) might be related to a persistent alteration in PFC connectivity, best modelled by a dysfunction in NMDA transmission in the PFC. Furthermore, as discussed above, mesocortical DA deficit might, in addition to its contribution to cognitive and negative symptoms, contribute to the disinhibition of subcortical DA function, to the extent that the mesocortical DA system has an inhibitory effect on subcortical DA function (Deutch et al, 1990). A neuronal circuitry model of GLU-DA interactions GLU and DA systems interact at multiple levels. Both in cortical and subcortical areas, close apposition between DA and GLU terminals on target cells (GABAergic or GLU neurones) suggests that DA modulates the responsivity of target neurones to GLU input (Grace, 1991; Goldman-Rakic and Selemon, 1997). Whether DA opposes or facilitates GLU transmission at this level depends on the type of DA receptors stimulated (D1 versus D2 receptors), and the state of the neurones at the time of the interaction (Konradi, 1998; Yang et al, 1999; Leveque et al, 2000; Wickens, 2000; Dunah and Standaert, 2001). GLU also modulates DA release at the level of DA terminals (see Grace, 1991, and references therein). Finally, the activity of DA neurones is modulated by glutamatergic projections from the PFC and other areas, such as the amygdala. A general model for GLU modulation of DA neurones in the VTA has been introduced recently by Arvid Carlsson (1999) and Kegeles et al (2000) (see Chapter 1). This model provides an anatomical framework relating three fundamental putative neurochemical dysregulations involved in the pathophysiology of schizophrenia: (i) a deficiency in GLU transmission; (ii) a deficit in mesocortical DA transmission; and (iii) a dysregulation of mesolimbic DA transmission. According to this model, the PFC modulates activity of midbrain DA neurones via both an activating pathway (the ‘accelerator’) and an inhibitory pathway (‘the brake’), allowing fine tuning of dopaminergic activity by the PFC (Figure 2.7). The activating pathway is provided by direct and indirect glutamatergic projections onto the dopaminergic cells. A recent electron microscopy study in rodents suggests that direct stimulation of DA neurones by prefrental afferents is restricted to DA neurones that project back to the cortex, while a polysynaptic mechanism, possibly involving the

Dopamine in the pathophysiology and treatment of schizophrenia

Figure 2.7 (a) Proposed model of modulation of DA cells activity by cortical projections. This model, adapted from Carlsson, proposes a bimodal modulation of DA activity in the ventral tegumental area (VTA) by glutamatergic (GLU) tracks originating in the frontal cortex. Stimulation of VTA DA neurones by GLU tracks is represented on the left (‘activating system’). These neurones exert a tonic excitatory influence on DA activity. Evidence in rodents suggests that direct stimulation of DA neurones by GLU afferents from the PFC is restricted to DA neurones that project back to the cortex (mesocortical DA system, MC DA). Stimulation of mesolimbic (ML) DA neurones by GLU afferents from the cortex is probably polysynaptic, maybe involving relay in the pedunculopontine tegmentum. The ‘inhibitory’ system, represented on the right, exerts an inhibitory influence on DA activity via NMDA receptor mediated stimulation of VTA GABAergic interneurones or striatotegmental GABA neurones, and

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comes predominantly into play when DA activity is increased (such as stress). In addition, the brake system regulating ML DA activity is activated by MC DA projection. (b) This model predicts that a deficiency in NMDA transmission in the cortex would result in decreased MC DA activity, and would have unpredictable effects on ML DA activity under ‘baseline’ conditions. Yet, it would result in an increase in stress (or amphetamine)induced ML DA release. (See text for references.) pedunculopontine tegmentum, mediates the prefrontal activation of mesolimbic DA neurones (see discussion and references in Carr and Sesack,2000). The inhibitory pathway is provided by PFC glutamatergic efferents to midbrain GABAergic interneurones and striatomesencephalic GAB A neurones. The model of dual modulation of the mesolimbic DA system by the PFC has been recently confirmed by studies demonstrating that extracellular DA concentration in the accumbens is decreased and increased following low and high frequency PFC stimulation, respectively (Jackson et al, 2001). Furthermore, blockade of glutamate transmission in the VTA increases DA release in the accumbens and decreases DA release in the PFC (Takahata and Moghaddam, 2000). This observation demonstrates a glutamatergic mediated tonic inhibitory regulation of mesoaccumbens neurones and a tonic excitatory regulation of mesoprefrontal DA neurones. From this model, it is speculated that a reduced prefrontal activity, possibly secondary to NMDA transmission deficiency, could, in addition to inducing PFC dysfuntion, result in a reduction of mesocortical DA activity (further worsening prefrontal related cognitive impairment), and, under conditions of stress (such as stimulation of the DA system by the amygdala), failure of the PFC to properly regulate DA activity in subcortical territories. If sustained, this dysregulation of mesolimbic DA might precipitate positive symptoms. We must emphasize that this circuit encompasses only a limited aspect of GLU-DA interaction, leaving out interactions at the level of terminals and at the intracellular level. Nonetheless, it provides a general organizing principle and generates testable hypotheses. Imaging GLU-DA interactions with SPECT and PET The circuits described in Figure 2.7 are mainly derived from rodent experiments. A number of imaging experiments have been performed in healthy subjects to test the relevance of these models to the human brain (Laruelle et al, 1999; Kegeles et al, 2000, 2002; Figure 2.8). The effect of acute disruption of NMDA transmission by ketamine on DA release, under resting and stimulated conditions was investigated.

Dopamine in the pathophysiology and treatment of schizophrenia

Figure 2.8 Summary of imaging studies investigating GLU-DA interactions in the human brain. In the first study (left panel), we did not observe any effects of ketamine alone on D2 receptor availability (changes were within the range of test/retest reproducibility of the method, as measured under no challenge conditions in the same healthy subjects). In the second study, we observed that the addition of ketamine to a small dose of amphetamine (0.25 mg/kg) (middle panel) resulted in a significant increase in the effect of amphetamine compared to the effect of amphetamine alone, measured in the same healthy subjects. The relative increase in the amphetamine effect (2.32-fold) induced by ketamine was similar to the increase (right panel) in amphetamine-induced DA release (0.3 mg/kg) observed in patients with schizophrenia compared to matched

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healthy controls (2.28-fold). Details of the studies can be found in Laruelle et al, 1999 and Kegeles et al, 2000, 2002). Sch, Schizophrenia; ns, not significant. Under resting conditions, no effect of ketamine on [11C]raclopride binding potential was detected, suggesting that ketamine-induced changes in DA release are too small to be measurable with this technique (Kegeles et al, 2002). The results of this study have been recently confirmed (Aalto et al, 2002) and are consistent with a microdialysis study that failed to detect any effect of PCP and ketamine on extracellular striatal DA levels in awake Rhesus monkeys (Adams et al, 2002). Thus, in non-human primates and humans, acute disruption of NMDA transmission has little effect on DA release in the resting state. Since NMDA antagonism impairs both the inhibitory and stimulatory pathways, the results of this study are generally compatible with the Carlsson model. In contrast, it has been observed that acute treatment by ketamine increased amphetamine-induced DA release in healthy volunteers to levels similar to those observed in patients with schizophrenia. In a first study (Kegeles et al, 1999), it was documented that amphetamine-induced DA release measured twice at approximately 2 week intervals in healthy volunteers was stable (no sensitization or tolerance was observed to this effect). A second study (Kegeles et al, 2000) investigated the effects of ketamine on amphetamine-induced DA release in healthy volunteers. Amphetamineinduced DA release was significantly elevated under ketamine conditions compared to control conditions. This result confirmed that, when the DA system is stimulated (such as after amphetamine), i.e. when the inhibitory pathways (the brake) should predominate, impairment of NMDA transmission might result in exaggerated DA release. This study supported the hypothesis that alteration in subcortical DA release observed in patients with schizophrenia after amphetamine might be secondary to impairment of regulatory pathways involving GLU transmission. In addition, a recent study (Kakiuchi et al, 2001) documented that chronic exposure to the NMDA antagonist MK-801 in monkeys results in decreased prefrontal DA and elevated in vivo [11C]NNC 112 binding in the prefrontal cortex. Thus, while more research is needed to validate this model, currently available evidence is compatible with the model that alterations of both subcortical and cortical DA in schizophrenia might be secondary to dysfunction of neuronal connectivity, best modelled by administration of drugs that impair NMDA transmission. It should also be clarified that chronic NMDAreceptor hypofunction is a pharmacological model of schizophrenia supported by extensive preclinical and clinical studies. Yet, unambiguous evidence for NMDA dysfunction is currently not available in schizophrenia. The present author and colleagues thus propose that chronic alteration of NMDA function in schizophrenia is an appropriate and reasonable model of neuronal dysconnectivity associated with this illness, but do not imply that this specific mechanism is the only one that could lead to such neuronal dysconnectivity.

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Conclusions In this chapter, evidence from imaging studies implicating alterations of DA transmission in the pathophysiology of schizophrenia have been reviewed. The most robust set of finding pertains to imaging of presynaptic function in the striatum. The results of these studies have been relatively consistent in showing that schizophrenia, at least during episodes of illness exacerbation, is associated with increased activity of DA neurones, and that this increased presynaptic activity is associated with positive symptoms and good therapeutic response. Studies of cortical DA function are less numerous and less consistent. In the future, technical advances in PET instrumentation and radioligand development should contribute to a clarification of the role of prefrontal DA in cognitive impairment presented by these patients. Finally, a general hypothesis was presented, in which alterations of DA transmission in schizophrenia is a consequence of altered cortico-subcortical connectivity involving deficits in NMDA mediated information flow. Acknowledgements Supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD), and the National Institute of Mental Health. References Aalto SS, Hirvonen J, Kajander J et al. (2002) Ketamine does not decrease striatal dopamine D2 receptor binding in man. Psychopharmacology (Berl) 164:401–6. Abi-Dargham A, Gil R, Krystal J et al. (1998) Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 155:761–7. Abi-Dargham A, Rodenhiser J, Printz D et al. (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 97:8104–9. Abi-Dargham A, Mawlawi O, Lombardo I et al. (2002) Dopamine D1 receptors and working memory in schizophrenia. J Neurosci 22:3708–19. Adams BW, Bradberry CW, Moghaddam B. (2002) NMDA antagonist effects on striatal dopamine release: microdialysis studies in awake monkeys. Synapse 43:12–18. Albin RL, Young AB, Penney JB. (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366–75. Alexander GE, Delong MR, Stick PL. (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci 9:357–81. Angrist B, van Kammen DP. (1984) CNS stimulants as a tool in the study of schizophrenia. Trends Neurosci 7:388–90. Arbuthnott GW, Ingham CA, Wickens JR. (2000) Dopamine and synaptic plasticity in the neostriatum. J Anat 196:587–96. Bertolino A, Breier A, Callicott JH et al. (2000) The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology 22:125–32.

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Chapter 3 Modulation of dopamine D2 receptors as a basis of antipsychotic effect Shitij Kapur Antipsychotics were discovered by accident—as efforts to make better antihistaminics led to the synthesis of chlorpromazine. It was the work of Delay and Deniker (Delay et al, 1952) which established chlorpromazine’s efficacy as a ‘major tranquillizer’ against psychotic disorders, an effect we now tend to call ‘antipsychotic’ (King and Voruganti, 2002). That dopamine may have a critical role in antipsychotics was realized in the 1960s with the work of Carlsson et al (Carlsson and Lindqvist, 1963) and it was finally Seeman et al (1976) who established dopamine D2 blockade as central to antipsychotic efficacy. Over this period, hundreds of compounds with putative antipsychotic activity have been synthesized and dozens have made it to the clinic. The more recent agents have avoided the motor side effects of the earlier antipsychotics and are often called ‘atypical’ antipsychotics. Despite years of research several important questions remain: What is the most critical ingredient in optimal antipsychotic activity? What is the molecular basis of this activity? Why are antipsychotics anti-‘psychotic’? How do psychosis and antipsychotics fit into the larger context of schizophrenia? This chapter will attempt to address some of these questions drawing heavily upon several previous articles by the present author (Kapur and Remington, 2001a, 2000b; Kapur and Seeman, 2001; Kapur 2003). Given the limitations of space it will not be possible to refer to the primary references for each of the following sections—the reader will be referred to appropriate articles for further discussion and references. Atypical antipsychotics—what is really ‘atypical’ about them When antipsychotics were first introduced they were called ‘major tranquillizers’. The trend to call them antipsychotics, thus suggesting specificity for psychosis started sometime in the 1960s. Later the term ‘atypical’ took hold, when it was observed that clozapine was an effective antipsychotic, without causing catalepsy in animal models or extrapyramidal side effects (EPSE) in patients (King and Voruganti, 2002). As a class (Box 3.1), the currently available atypical antipsychotics show a lower level of EPSE, and require less anticholinergic use, even when controlling for high doses of haloperidol that have been used conventionally (Geddes et al, 2000). The second most common shared feature is that most of the newer atypical antipsychotics show 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

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excessive dopamine blockade in the pituitary that lies outside the blood-brain barrier (Kapur et al, 2002). Box 3.1 Atypical antipsychotics Clozapine

Risperidone

Olanzapine

Sertindole†

Quetiapine

Ziprasidone

Amisulpride

Aripiprazole§

Remoxipride* *Remoxiprode has been withdrawn from use in most countries due to the occurrence of severe aplastic anaemia. †The use of sertindole has been restricted due to concerns regarding cardiac arrhythmias. §Aripiprazole has recently (November 2002) been introduced in USA.

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, though it remains unclear whether this is just a reflection of lower EPSE (a more primary property) or a primary efficacy against negative symptoms (Leucht et al, 1999). 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 inequities (Leucht et al, 1999; Geddes et al, 2000). It should also be pointed out 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 EPSE and are generally better tolerated, they may lead to higher compliance and thereby greater effectiveness. Is appropriate modulation of dopamine D2 receptors sufficient for atypical antipsychotic activity? What then is the basis of antipsychotic activity, and more interestingly ‘atypical’ antipsychotic activity. The answer is complicated by the fact that most of the newer atypical antipsychotics act at multiple receptors (Figure 3.1), thereby leading to a multitude of theoretical ideas. One of the most interesting comparisons is provided by the study of multireceptor atypicals such as risperidone, olanzapine and quetiapine, as compared to the specific dopamine D2/3 antagonist, amisulpride (Curran and Perry, 2001; Lewis, 2002). The comparative data on these atypicals have been analysed in a systematic analysis by Leucht et al (1999, 2002) (reviewed in Chapter 5), but the data can be summarized as in Table 3.1. As indicated in Table 3.1, amisulpride has demonstrated as much atypicality as the 5-HT2/D2 drugs, despite being a selective D2/3 antagonist. This

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impression is borne out in recent double-blind studies comparing amisulpride to risperidone and olanzapine which confirm this similarity (Peuskens et al, 1999; Martin et al, 2002). 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. This then raises the question—do all antipsychotics block the dopamine D2/3 receptor in a similar fashion?

Figure 3.1 Receptor selectivity of atypical antipsychotic drugs. Data are represented as receptor-pies to give a pictorial impression of the relative affinities of the drugs at the different targets. While these plots are a good aid to quick visualization, the reader is referred to more authoritative references for precise affinity numbers (Schotte et al, 1996; Scatton et al, 1997). Before we proceed further, a note regarding the precise use of terminology is important here. Dopamine binds to two families of receptors: the D1-family (includes D1 and D5) and the D2-family (includes D2, D3 and D4) of receptors (see Chapter 2). While there are specific pharmacological ligands that clearly distinguish between D2/3 and D4 receptors, the distinction between D2 and D3 is rarely made. Thus, in this chapter when the term D2 is used, it is used in the broad (and mixed) sense of D2/3. However, this term D2 is clearly distinguished to exclude D4 receptors. This does not imply or assume that it is precisely known what the contributions of D2 or D3 are, but, reflects the current state of ambiguity of what these receptors do in the context of antipsychotic action. Dopamine D2 receptor occupancy in patients—similarities and differences

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Table 3.1 Is appropriate modulation of dopamine D2 receptors sufficient for atypical antipsychotic activity? Therapeutic dimension 5-HT2/D4, etc./D2 as compared to high(Risp/Olanz/Quet/Zip) dose haloperidol

D2 antagonist (Remoxipride)

D2 antagonist Amisulpride

Equivalent or better for positive symptoms

Yes

Yes

Yes

Less EPSE

Yes

Yes

Yes

Better for negative symptoms

Yes

Yes

Yes

Efficacy in ‘negative symptom’ schizophrenia

Not tried

Not tried

Yes

Better impact on functional outcome measures

Yes

Yes

Yes

Release prevention with long-term use

Yes

Yes

Yes

Risp, risperidone; Olanz, olanzapine; Quet, quetiapine; Zip, ziprasidone; EPSE; extrapyramidal side effects.

The advent of neuroimaging has made it possible to investigate the receptor occupancy of antipsychotics in patients while they are being treated. The usefulness of this was first demonstrated by Farde et al (1988) who showed that most antipsychotics, with the exception of clozapine, showed high (70% and above) D2 occupancy at usual clinical doses. Further studies have shown the suggestion of a ‘therapeutic window’ for most antipsychotics; 60–65% receptor blockade may be necessary to invoke optimal antipsychotic response with occupancies greater than 80% being associated with EPSE (Farde et al, 1992; Nordstrom et al, 1993; Kapur et al, 2000a). Risperidone becomes an effective antipsychotic at a level of D2 occupancy conventionally seen with typical antipsychotics, i.e. at doses of 2 mg it exhibits 60% or greater D2 occupancy (Kapur et al, 1999). High levels of 5-HT2 occupancy are observed even at these lower doses (Farde et al, 1995; Kapur et al, 1999) but this does not lead to an antipsychotic effect. Olanzapine also shows a preferential blockade of serotonin 5-HT2 as compared to the dopamine D2 receptors (Nyberg et al, 1997; Kapur et al, 1998). However, it also becomes an effective antipsychotic only at doses which gives rise to 60–70% dopamine D2 blockade (around 10 mg per day for most patients) (Kapur et al, 1998; Nordstrom et al, 1998). In the dose range of 10–20 mg/day, its D2 occupancy is within the range of 65–80%. However, at doses of 30 mg/day and above it does tend to give rise to occupancy above 80%, and there is a suggestion of greater prolactin elevation and EPSE in the >30 mg/day range (Kapur et al, 1998). Diminished EPSE with olanzapine, even at higher levels of D2 occupancy, may be related to its high affinity for cholinergic receptors (Schotte et al,

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1996), although in vivo this property seems to be somewhat muted (Zhang and Bymaster, 1999; Raedler et al, 2000). Clozapine is the prototypical atypical antipsychotic, and has now been extensively investigated using PET (positron emission tomography) (Farde and Nordstrom, 1992; Nordstrom et al, 1995a; Kapur et al, 1999). At very low doses (50 mg/day), less than what is routinely required for antipsychotic effect, it shows complete occupancy of the serotonin 5-HT2 system (Kapur et al, 1999), even though it is not as yet an effective antipsychotic. Clozapine’s antipsychotic efficacy, at least in refractory patients, is best seen in the range of 300–400 ng/ml, a dose where its D2 occupancy is in the range of 50– 60% (Nordstrom et al, 1995a; Kapur et al, 1999). While controlled comparative studies are not available, all the published data suggest that clozapine’s D2 occupancy, at least at the time points measured, is lower than that of typical antipsychotics, lower than that of risperidone and olanzapine, and lower than the threshold required for EPSE or prolactin elevation. This low level of D2 occupancy, therefore, is the simplest explanation required to explain why clozapine does not give rise to EPSE and sustained prolactin elevation (Nordstrom et al, 1995; Kapur et al, 1999). Thus, while clozapine’s effects on D2 receptors may quite easily explain a part of atypicality (i.e. low EPSE, low prolactin elevation, fewer secondary negative symptoms and, perhaps, decreased cognitive impairment), it is not as easy to explain its superior efficacy in refractory patients. Quetiapine, like clozapine, risperidone and olanzapine, also exhibits a higher level of 5-HT2 than dopamine D2 occupancy at all clinical doses studied (Gefvert et al, 1998; Kapur et al, 2000b). However, even at doses of 450–600 mg/day its D2 occupancy is in the rather low range, i.e. <30% 12 hours after the last dose. While this finding by itself may challenge the importance of D2 blockade in its antipsychotic efficacy, recent examination of the time course of D2 occupancy with quetiapine shows that it gives rise to a higher D2 occupancy (45–60%) in the time period immediately after administration. It then declines rather rapidly, as predicted by its rapid pharmacokinetics during the interdose interval (Gefvert et al, 1998; Kapur et al, 2000b). Like clozapine, its low level of D2 occupancy may explain its very low risk of EPSE and prolactin elevation. This may also explain why doses of 150–300 mg/day show questionable efficacy (Small et al, 1997). In fact, the dose of quetiapine required to reach 60% occupancy during peak would be 600–800 mg/day or above. Amisulpride, unlike the other atypicals reviewed here, does not have any affinity for the serotonin 5-HT2 receptors (Trichard et al, 1998). Doses of amisulpride between 600– 900mg/day achieve 70–80% D2 occupancy, while doses >1100 mg/day result in >85% D2 occupancy—at these higher levels dose-dependent EPSE can be observed (Martinot et al, 1996). Amisulpride shows an optimal balance between efficacy and diminished EPSE risk in the 400–800 mg/day range (Freeman, 1997), as would be expected from its D2 occupancy. Differential effects at the striatal versus extrastriatal dopamine D2 receptors While most of the above studies focused on ‘striatal’ dopamine D2 receptor blockade, there is an increasing interest in examining the effects of antipsychotics in the

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extrastriatal regions (mainly the thalamus and the cortex). 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 (Bigliani et al, 2000; Xiberas et al, 2001). These reports have been questioned on methodological grounds (Olsson and Farde, 2001), and there are reports to the contrary (Talvik et al, 2001). However, what is of interest is that atypical antipsychotics, regardless of whether they are multireceptorial or D2 specific, share this property. The precise molecular basis for this difference, if indeed this striatalextrastriatal difference is a reliable finding, is not entirely clear. However, it has been suggested that differences in the way that the different antipsychotics interact with the dopamine D2 receptor may be relevant here (Kapur and Seeman, 2002). 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 overall affinity for the dopamine D2 receptor (Kapur and Seeman, 2001). This proposal reconciles one of the findings by Meltzer (1989), i.e. lower affinity at the dopamine D2 receptors is the single biggest discriminator of typical/atypicals even in the face of multireceptor profile and the suggestion by others (Hartvig et al, 1986; Seeman and Tallerico, 1998) that atypicals are distinguished by ‘loose’ binding. This raises the question of how a lower affinity and a faster dissociation at the dopamine D2 receptor may be the most important elements responsible for atypical effects. Drugs with lower affinity and faster dissociation (Table 3.2) are often given at comparably higher doses. 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 behaviour under physiological conditions. Regardless of fast or slow dissociation, all drugs depress tonic dopamine transmission to a degree determined by their overall occupancy (Kapur and Seeman, 2001). However, drugs with a faster dissociation are much more responsive to phasic bursts of dopamine transmission. 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 signalling (Kapur and Seeman, 2001). This may account for the fact that antipsychotics with a faster dissociation from the dopamine D2 receptor may lead to an antipsychotic effect with little or minimal EPSE or prolactin elevation, decreased cognitive impairment, and perhaps greater improvement in secondary negative symptoms.

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Table 3.2 Dissociation rate constants for antipsychotic drugs at the D2 dopamine receptor Antipsychotic

Koff (Per minute)

Dissociation time (t1/2)

Quetiapine

3.013

<30 seconds

Clozapine

1.386

30 seconds

Amisulpride

0.730

<60 seconds

Olanzapine

0.039

17 minutes

Sertindole

0.014

49 minutes

Haloperidol

0.017

42 minutes

Chlorpromazine

0.022

36 minutes

Data from Kapur and Seeman (2001), data for amisulpride from Seeman (2002).

With the fast-off/low affinity explanation, one would not see typical/ atypical as a dichotomy, but as two ends of a continuum—from very high likelihood of EPSE (haloperidol) to very low likelihood of EPSE (clozapine). While it is not possible to measure the koff of all the drugs as it requires the radiolabelling of these drugs, it has been shown that since the kon of the drugs is relatively similar, affinity is a reasonable surrogate of koff—with low affinity being an indicator of fast off (although there are some exceptions). According to this idea, it will be the lower affinity/fast koff which will be a more important predictor of the order of atypicality—rather than an index like the 5HT2/D2 ratio. For example, risperidone has a much higher 5-HT2/D2 ratio (~20) as compared to olanzapine (~8) as compared to quetiapine (~2). However, in terms of atypicality (as seen as the propensity to cause EPSE), there is broad consensus that risperidone gives rise to more EPSE than olanzapine, which in turn has a higher likelihood of EPSE than quetiapine. This is the reverse of what would be predicted by the 5-HT2/D2 ratio, but is in keeping with their low-affinity/fast koff at the D2 receptor which is in the order of quetiapine>olanzapine>risperidone. However, the fast koff hypothesis also has several difficulties. First, it deals mainly with EPSE/prolactin and does not address the issue of refractory schizophrenia or cognitive symptoms directly. Second, given the technical requirement (radiolabelling of ligand) for determination of koff, this has been measured only for a limited number of antipsychotics at the moment. Third, some drugs (e.g. sertindole) do not follow the rule, i.e. they are atypical in clinical practice but have a much slower koff than would be predicted by this hypothesis (Kapur and Seeman, 2001), although subsequent re-analysis of sertindole using different assay conditions leads to a faster koff (~18 minutes) (Seeman 2002). Finally, a drug like aripiprazole acts like an atypical antipsychotic with a very high affinity (and likely very slow koff) for the dopamine D2 receptor. This may be because aripiprazole is a partial agonist and hence the usual considerations that apply to antagonists (typical and atypical) may not apply fully here. Figure 3.2 provides a simple schematic of what leads to a good atypical antipsychotic.

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Figure 3.2 Features of atypical antipsychotic action. Sx, symptoms. Why are antipsychotics anti-‘psychotic’? Most theories regarding antipsychotics, some of which are touched upon above, are largely biological theories. However, psychosis is essentially an experiential phenomenon. How does one bridge the biology of psychosis, the phenomenology of its experience and the pharmacology of its treatment (Kapur, 2003)? This has largely been an unexplored area. The evidence linking an abnormality in dopamine to psychosis is reasonable. Psychostimulant agents that trigger release of dopamine are associated with de novo psychosis and with the worsening of psychosis (Angrist and Gershorn, 1970; Angrist et al, 1974, 1980; Harris and Batki, 2000). Moreover, post-mortem data show abnormalities in dopaminergic indices in schizophrenia, though the interpretation of these data was always confounded by drug effects (Seeman, 1987; Davis et al, 1991). More direct evidence emerges from neuroimaging studies (details reviewed in Laruelle and Abi-Dargham, 1999; Soares and Innis, 1999; Seeman and Kapur, 2000), which show a heightened synthesis of dopamine (Reith et al, 1994; Hietäla et al, 1995; Lindstrom et al, 1999; Meyer-Lindenberg et al, 2002), an exaggerated release of dopamine (Laruelle et al, 1996; Breier et al, 1997; Abi-Dargham et al, 1998), higher than normal levels of dopamine at baseline when psychotic (Abi-Dargham et al, 2000; Gjedde and Wong, 2001) and some conflicting suggestions regarding an increase in receptor number (Wong et al, 1986, 1997; Andreasen et al, 1988; Farde et al, 1990; Nordstrom et al, 1995b). This

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begs the question of how an abnormal release of dopamine, a chemical, can induce the experience of psychosis. There is near universal agreement for a central role of dopamine in ‘reward’ and ‘motivation’, but exactly how this is brought about is not entirely clear. Berridge and Robinson (1998) propose that one of the functional roles of dopamine is to mediate the conversion of an external stimulus from a neutral and cold bit of sensory information into an attractive or aversive entity (Berridge and Robinson, 1998; Berridge, 1999). In particular, the mesolimbic dopamine system is seen as a critical component in the ‘attribution of salience’, a process whereby events and thoughts come to grab attention, drive action and influence goal-directed behaviour due to their assocation with reward or punishment (Berridge and Robinson, 1998; Berridge, 1999). It is proposed that this conceptualization provides the best bridge from abnormal dopamine to the experience of psychosis. Under normal circumstances, it is the stimulus-driven release of dopamine that mediates the acquisition and expression of appropriate motivational saliences in response to the subject’s experiences and predispositions (Heinz, 1999; Berridge and Robinson, 1998; Shizgal, 1997; Berridge, 1999). Dopamine mediates the process of motivational salience—it does not create this process. It is proposed that in psychosis the dysregulated dopamine transmission leads to a stimulus-inappropriate release of dopamine. This neurochemical aberration usurps the normal process of salience attribution and leads to aberrant assignment of salience to external objects and internal representations. Thus dopamine, which under normal conditions is a mediator of contextually-relevant saliences, in the psychotic state becomes a creator of salience, albeit aberrant ones (Figure 3.3). Delusions in this framework are a ‘top-down’ cognitive explanation that the individual imposes upon these aberrant salience experiences in an effort to make sense of them. Since delusions are constructed by the individual they are imbued with the psychodynamic themes relevant to the individual and are embedded in the cultural context of the individual. This explains how the same neurochemical dysregulation leads to variable phenomenological expression: a patient in Africa struggling to make sense of aberrant saliences is much more likely to accord them to the evil ministrations of a Shaman while the patient living in Toronto is more likely to see them as the machinations of the Royal Canadian Mounted Police. Hallucinations in this framework arise from a conceptually similar but a more direct process—the abnormal salience of the internal representations of percepts and memories—as a result of which the individual experiences these internal representations in a manner that is vivid and real, leading them to confuse this experience with that of an external reality. How do the antipsychotics reverse this process? It is proposed that antipsychotics are efficacious in psychosis because by their biological actions (which involve dopamine blockade) they ‘dampen the salience’ of the symptoms. In this scheme antipsychotics only provide a platform of dampened salience, the process of symptomatic improvement requires further psychological and cognitive resolution. The antipsychotics do not change thoughts or ideas primarily, but provide a neurochemical milieu wherein new aberrant saliences are less likely to form, and previously aberrant saliences are more likely to extinguish (Clody and Carlton, 1980; Miller, 1987, 1989). This is consistent with how

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Figure 3.3 Psychosis as a disorder of dysregulated dopamine leading to aberrant salience. A model unifying biology and psychology. DA, dopamine. patients’ experience their improvement. Patients do not immediately abandon the psychotic idea or percept, but, report that the idea or percept ‘doesn’t bother me as much’ (Elkes and Elkes, 1954; Winkelman, 1954). In fact, for many patients this is as good a resolution as antipsychotics can provide. At the same time, since the antipsychotic cannot limit itself only to dampening the salience of symptoms, some normal life saliences may also get dampened leading to the, what is often called, neuroleptic-induced dysphoria or drug-induced negative/depressive symptoms. Qualifications and implications It is important here to comment on the putative implications of antipsychotic binding to receptors other than dopamine D2. Various candidates have been proposed: 5-HT2 (Meltzer, 1989), D4 (Van Tol et al, 1991), glutamate (Olney and Farber, 1994, 1995), alpha adrenergic receptors (Svensson et al, 1995) and others (Gerlach and Casey, 1994) (some of these are discussed elsewhere in the book, in particular, see Chapters 9 and 10). Action on these other receptors has been proposed to enhance efficacy on the psychotic and non-psychotic dimensions as well as reduce side effects. It should, however, be pointed out that the case of amisulpride teaches that it is possible to achieve contemporary atypical antipsychotic activity without action at any of these other receptors. Also, at this moment, action at any of these receptors either by themselves or in combination is not sufficient to achieve antipsychotic activity if an element of dopamine

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D2 receptor blockade is not present. Thus, action at dopamine D2 receptors remains a necessary, and a putatively sufficient criterion, to achieve contemporary levels of atypical antipsychotic effects. However, this focus on dopamine D2 receptors also underscores the relative poverty of therapeutic options. Several unmet therapeutic needs remain (see Chapter 12 for a more comprehensive discussion). First, in a large majority of patients, the improvement of psychosis is incomplete and partial. While clozapine is often seen as an option for these patients, the additional efficacy of clozapine is at best, modest. Second, even the newer antipsychotics have limited efficacy against the negative/deficit dimensions of schizophrenia. Thus, one is often left with a patient whose psychosis is improved, but dysfunction is not. Third, the heightened therapeutic optimism ushered in by the newer antipsychotics has drawn our attention to a major hurdle in restoring function—the primary cognitive dysfunction in schizophrenia. The current antipsychotics address these only partially, and perhaps secondarily. Fourth, while the motor side effects are much diminished by the newer antipsychotics, new side effects have come to the forefront. Weight gain, lipid dysmetabolism and insulin resistance have become new challenges with some of these agents. It is likely that the next generation of treatments will have to move beyond reliance on a single drug, as the sole treatment for the multidimensional disorder of schizophrenia. There is no question that optimal treatment of schizophrenia will require action at more than just the dopamine system. This does not mean that all the different targets need to be bundled into one pill. In fact our current approach of multireceptor atypicals is tantamount to a kind of one-size-fits-all polypharmacy-in-a-pill. In most other branches in medicine, when optimal therapy requires more than one target (as is often the case in cancer, hypertension, arthritis) this is usually achieved by different preparations, each with unique pharmacology and indications. Thus one can look forward to a time where there will be different therapeutic strategies, each uniquely targeted against a different dimension of schizophrenia: psychosis, negative, cognitive and affective. It will then be the physician’s job to titrate these strategies flexibly to match the dimensionality of the illness in each individual patient. References Abi-Dargham A, Gil R, Krystal J et al. (1998) Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 155:761–7. Abi-Dargham A, Rodenhiser J, Printz D et al. (2000) From the cover: increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 97:8104–9. Andreasen NC, Carson R, Diksic M et al. (1988) Workshop on schizophrenia, PET, and dopamine D2 receptors in the human neostriatum. Schizophrenia Bull 14:471–84. Angrist BM, Gershon S. (1970) The phenomenology of experimentally induced amphetamine psychosis—preliminary observations. Biol Psychiatry 2:95–107. Angrist B, Sathananthan G, Wilk S, Gershon S. (1974) Amphetamine psychosis: behavioral and biochemical aspects. J Psychiatr Res 11:13–23. Angrist B, Rotrosen J, Gershon S. (1980) Responses to apomorphine, amphetamine, and neuroleptics in schizophrenic subjects. Psychopharmacology (Berl) 67:31–8.

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Berridge KC. (1999) Pleasure, pain, desire and dread: Hidden core processes of emotion. In (Kahneman D, Diener E, Schwarz N eds.) Well Being: The Foundations of Hedonic Psychology. (Russel Sage Foundation: New York) pp. 525–57. Berridge KC, Robinson TE. (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev 28:309–69. Bigliani V, Mulligan RS, Acton PD et al. (2000) Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123l]epidepride single photon emission tomography (SPET) study. Psychopharmacology (Berl) 150:132–40. Breier A, Su TP, Saunders R et al. (1997) Schizophrenia is associated with elevated amphetamineinduced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 94:2569–74. Carlsson A, Lindqvist M. (1963) Effect of chlorpromazine or haloperidol on the formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 20:140–4. Clody DE, Carlton PL. (1980) Stimulus efficacy, chlorpromazine, and schizophrenia. Psychopharmacology 69:127–31. Curran MP, Perry CM. (2001) Amisulpride: a review of its use in the management of schizophrenia. Drugs 61:2123–50. Davis KL, Kahn RS, Ko G, Davidson M. (1991) Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148:1474–86. Delay J, Deniker P, Harl JM. (1952) Traitement des états d’excitation et d’agitation par une méthode médicamenteuse derivée de l’hibernothérapie. Ann Med Psychol 110: 260–73. Elkes J, Elkes C. (1954) Effect of chlorpromazine on the behaviour of chronically overactive psychotic patients. BMJ 2:560–5. Farde L, Nordstrom AL. (1992) PET analysis indicates atypical central dopamine receptor occupancy in clozapine-treated patients. Br J Psychiatry 160:30–3. Farde L, Wiesel FA, Halldin C, Sedvall G. (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–6. Farde L, Wiesel FA, Stone-Elander S et al. (1990) D2 dopamine receptors in neuroleptic-naive schizophrenic patients. Arch Gen Psychiatry 47:213–19. Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. (1992) Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry 49:538–44. Farde L, Nyberg S, Oxenstierna G, Nakashima Y, Halldin C, Ericsson B. (1995) Positron emission tomography studies on D2 and 5-HT2 receptor binding in risperidonetreated schizophrenic patients. J Clin Psychopharmacol 15:19S–23S. Freeman HL. (1997) Amisulpride compared with standard neuroleptics in acute exacerbations of schizophrenia: three efficacy studies. Int Clin Psychopharmacol 12(Suppl 2):S11–S17. Geddes J, Freemantle N, Harrison P, Bebbington P. (2000) Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 321:1371–6. Gefvert O, Bergstrom M, Langstrom B, Lundberg T, Lindstrom L, Yates R. (1998) Time course of central nervous dopamine-D-2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel®) in patients with schizophrenia. Psychopharmacology 135:119–26. Gerlach J, Casey DE. (1994) Drug treatment of schizophrenia: myths and realities. Curr Opin Psychiatry 7:65–70. Gjedde A, Wong DF. (2001) Quantification of neuroreceptors in living human brain, v. endogenous neurotransmitter inhibition of haloperidol binding in psychosis. J Cereb Blood Flow Metab 21:982–94. Harris D, Batki SL. (2000) Stimulant psychosis: symptom profile and acute clinical course. Am J Addict 9:28–37.

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Hartvig P, Eckernas SA, Lindstrom L et al. (1986) Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET). Psychopharmacology 89:248–52. Heinz A. (1999) [Anhedonia—a general nosology surmounting correlate of a dysfunctional dopaminergic reward system?]. Nervenarzt 70:391–8. Hietäla J, Syvalahti E, Vuorio K et al. (1995) Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 346:1130–1. Kapur S. (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology and pharmacology in schizophrenia. Am J Psychiatry 161:13–21. Kapur S, Remington G. (2001a) Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 50: 873–83. Kapur S, Remington G. (2001b) Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia. Annu Rev Med 52:503–17. Kapur S, Seeman P. (2001) Does fast dissociation from the dopamine D(2) receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 158:360–9. Kapur S, Seeman P. (2002) Atypical antipsychotics, cortical D(2) receptors and sensitivity to endogenous dopamine. Br J Psychiatry 180:465–6. Kapur S, Zipursky RB, Remington G et al. (1998) 5-HT2 and D-2 receptor occupancy of olanzapine in schizophrenia: A PET investigation. Am J Psychiatry 155:921–8. Kapur S, Zipursky RB, Remington G. (1999) Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 156:286–93. Kapur S, Zipursky R, Jones C, Remington G, Houle S. (2000a) Relationship between dopamine D(2) occupancy, clinical response, and side effects: A double-blind PET study of first-episode schizophrenia. Am Psychiatry 157:514–20. Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P. (2000b) A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 57:553–9. Kapur S, Langlois X, Vinken P et al. (2002) The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: a pharmacological analysis in rats. J Pharmacol Exp Therap 302:1129–34. King C, Voruganti LN. (2002) What’s in a name? The evolution of the nomenclature of antipsychotic drugs. J Psychiatry Neurosci 27:168–75. Laruelle M, Abi-Dargham A. (1999) Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J Psychopharmacol 13:358–71. Laruelle M, Abi-Dargham A, van Dyck CH et al. (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 93:9235–40. Leucht S, Pitschel-Walz G, Abraham D, Kissling W. (1999) Efficacy and extrapyramidal sideeffects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophrenia Res 35:51–68. Leucht S, Pitschel-Walz G, Engel RR, Kissling W. (2002) Amisulpride, an unusual ‘atypical’ antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 159:180–90. Lewis DA. (2002) Atypical antipsychotic medications and the treatment of schizophrenia. Am J Psychiatry 159:177–9. Lindstrom LH, Gefvert O, Hagberg G et al. (1999) Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET. Biol Psychiatry 46:681–8.

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Martin S, Lôo H, Peuskens J et al. (2002) A double blind, randomised comparative trial of amisulpride versus olanzapine in the treatment of schizophrenia. Short-term results at two months. Curr Med Res Opin 18:355–62. Martinot JL, Paillere-Martinot ML, Poirier MF, Dao-Castellana MH, Loc’h C, Maziere B. (1996) In vivo characteristics of dopamine D-2 receptor occupancy by amisulpride in schizophrenia. Psychopharmacology 124:154–8. Meltzer HY. (1989) Clinical studies on the mechanism of action of clozapine: the dopamineserotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 99(Suppl):S18–S27. Meyer-Lindenberg A, Miletich RS, Kohn PD et al. (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5:267–71. Miller R. (1987) The time course of neuroleptic therapy for psychosis: role of learning processes and implications for concepts of psychotic illness. Psychopharmacology 92:405–15. Miller R. (1989) Hyperactivity of associations in psychosis. Aust NZ J Psychiatry 23: 241–8. Nordstrom AL, Farde L, Wiesel FA et al. (1993) Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects—a double-blind PET study of schizophrenic patients. Biol Psychiatry 33:227–35. Nordstrom AL, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G. (1995a) D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients [see comments]. Am J Psychiatry 152:1444–9. Nordstrom AL, Farde L, Eriksson L, Halldin C. (1995b) No elevated d-2 dopamine receptors in neuroleptic-naive schizophrenic patients revealed by positron emission tomography and [c11]n-methylspiperone. Psychiatry Res Neuroimaging 61:67–83. Nordstrom AL, Nyberg S, Olsson H, Farde L. (1998) Positron emission tomography finding of a high striatal D-2 receptor occupancy in olanzapine-treated patients. Arch Gen Psychiatry 55:283–4. Nyberg S, Farde L, Halldin C. (1997) A PET study of 5-HT2 and D-2 dopamine receptor occupancy induced by olanzapine in healthy subjects. Neuropsychopharmacology 16:1–7. Olney JW, Farber NB. (1994) Efficacy of clozapine compared with other antipsychotics in preventing NMDA-antagonist neurotoxicity. J Clin Psychiatry 55(Suppl B): 43–6. Olney JW, Farber NB. (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007. Olsson H, Farde L. (2001) Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy—a simulation study based on experimental data. Neuroimage 14:936–45. Peuskens J, Bech P, Moller HJ, Bale R, Fleurot O, Rein W. (1999) Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Amisulpride study group. Psychiatry Res 88:107–17. Raedler TJ, Knable MB, Jones DW et al. (2000) In vivo olanzapine occupancy of muscarinic acetylcholine receptors in patients with schizophrenia. Neuropsychopharmacology 23:56–68. Reith J, Benkelfat C, Sherwin A et al. (1994) Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci USA 91:11651–4. Scatton B, Claustre Y, Cudennec A, Oblin A, Perrault G, Sanger DJ, Schoemaker H. (1997) Amisulpride: from animal pharmacology to therapeutic action. Int Clin Psychopharmacol 12(Suppl 2):S29–S36. Schotte A, Janssen PFM, Gommeren W et al. (1996) Risperidone compared with new and reference antipsychotic drugs: In vitro and in vivo receptor binding. Psychopharmacology 124:57–73. Seeman P. (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–52. Seeman P. (2002) Atypical antipsychotics: mechanism of action. Can J Psychiatry 47: 27–38. Seeman P, Tallerico T. (1998) Antipsychotic drugs which elicit little or no Parkin-sonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 3:123–34.

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Seeman P, Kapur S. (2000) Schizophrenia: more dopamine, more D2 receptors. Proc Natl Acad Sci USA 97:7673–5. Seeman P, Lee T, Chau-Wong M, Wong K. (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–19. Shizgal P. (1997) Neural basis of utility estimation. Curr Opin Neurobiol 7:198–208. Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CG. (1997) Quetiapine in patients with schizophrenia—A high- and low-dose double-blind comparison with placebo. Arch Gen Psychiatry 54:549–57. Scares JC, Innis RB. (1999) Neurochemical brain imaging investigations of schizophrenia. Biol Psychiatry 46:600–15. Svensson TH, Mathe JM, Andersson JL, Nomikos GG, Hildebrand BE, Marcus M. (1995) Mode of action of atypical neuroleptics in relation to the phencyclidine model of schizophrenia: Role of 5-HT2 receptor and alpha(1)-adrenoreceptor antagonism. J Clin Psychopharmacol 15:S11–S18. Talvik M, Nordstrom AL, Nyberg S, Olsson H, Halldin C, Farde L. (2001) No support for regional selectivity in clozapine-treated patients: a PET study with [(11)C]raclopride and [(11)C]FLB 457. Am J Psychiatry 158:926–30. Trichard C, Paillere-Martinot ML, Attar-Levy D, Recassens C, Monnet F, Martinot JL. (1998) Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients. Am J Psychiatry 155:505–8. Van Tol HH, Bunzow JR, Guan HC et al. (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–14. Winkelman NW. (1954) Chlorpromazine in the treament of neuropsychiatric disorders. JAMA 155:18–21. Wong DF, Wagner HN, Jr, Tune L et al. (1986) Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234: 1558–63. Wong DF, Pearlson GD, Tune LE et al. (1997) Quantification of neuroreceptors in the living human brain. IV. Effect of aging and elevations of D-2-like receptors in schizophrenia and bipolar illness. J Cereb Blood Flow Metab 17:331–42. Xiberas X, Martinot JL, Mallet L et al. (2001) Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry 179:503–8. Zhang W, Bymaster FP. (1999) The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D1, D2, D3, 5-HT2A and muscarinic receptors. Psychopharmacology (Berl) 141:267–78.

Chapter 4 Amisulpride as a model: clinical effects of a pure dopaminergic agent Yves Lecrubier Amisulpride is pharmacologically unique because it is a highly selective dopaminergic D2 and D3 dopamine receptor blocker with no other interactions with CNS (central nervous system) receptors (Scatton et al, 1997). 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 (based on IMS data). It was observed very early on that the clinical profile of amisulpride did not fit with the ‘dopaminergic theory’ of antipsychotic drug action. This pure dopaminergic blocker was effective in controlling positive and negative symptoms in the context of a very low prevalence of extrapyramidal symptoms (see below). Such a profile had previously been described for clozapine, which was thus referred to as an ‘atypical’ antipsychotic (Beckmann et al, 1979; Kane et al, 1988). The profile of amisulpride is paradoxical for an antipsychotic whose only action is to block dopamine receptors. Such a drug would be expected to produce prominent extrapyramidal symptoms, but these were not observed. A worsening, or at least a very mild improvement, of negative symptoms would be anticipated from such a mechanism, but, in fact, the opposite was demonstrated in a number of placebo-controlled trials conducted in schizophrenics with a mixed symptomatology (positive and negative symptoms) or with persistent long-term chronic negative symptoms (see below). Low doses of amisulpride are possibly the best current maintenance treatment in this group of chronically negative schizophrenics (see, for example, Lôo et al, 1997). Therefore, amisulpride challenges the theory that an interaction with 5-HT2 receptors is needed to be an atypical antipsychotic. It probably also suggests that if a high level of D2 dopamine receptor blockade is needed to control positive symptoms, the measure in the striatum is not the most appropriate. In addition, a partial blockade may be the best strategy to control patients with chronic, mainly negative, symptoms (Martinot et al, 1996; Xiberas et al, 2001a, b). For these reasons, this chapter will focus on the pharmacological properties of amisulpride before describing the clinical trials in acute schizophrenia and chronic negative schizophrenia, with an emphasis on efficacy and extrapyramidal function. We will not focus on tolerance itself, although this is very good (Coulouvrat and DondeyNouvel, 1999).

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Mechanism of action of amisulpride The pharmacological effects of amisulpride so far identified in the CNS are all related to the blockade of D2 and D3 dopamine receptors (Scatton et al, 1997). These two receptors are the only ones for which amisulpride has been shown to have a relevant affinity (Schoemaker et al, 1997; Figure 4.1). 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 4.1). Amisulpride is an antagonist at both presynaptic and postsynaptic dopamine receptors in the CNS, and its administration in vivo increases dopamine turnover in the brain (Schoemaker et al, 1989). There is some evidence that, in vivo, amisulpride may antagonize presynaptic dopamine receptors at lower doses than those needed to block postsynaptic receptors (Schoemaker et al, 1997). 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 behavioural experiments showing that this drug blocks behaviours mediated by the

Figure 4.1 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.)

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Figure 4.2 Schematic representation of the action of amisulpride on dopaminergic neurotransmission in the frontal cortex (top) and the limbic system (bottom). The yellow bars represent amisulpride which blocks D2 (●) and D3 (■) receptors. Postsynaptic D1 (▲) receptors in the frontal cortex are unaffected by amisulpride. VTA: ventraltegmental area; DA, dopamine. limbic system at doses lower than those required to block extrapyramidal effects, such as amphetamineinduced stereotypies (Perrault et al, 1997). 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 4.2). 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.

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Amisulpride: the paradox We have seen that amisulpride is a very selective antagonist of D2 and D3 dopamine receptors. D2 receptor blockade is thought to be responsible for the classical antipsychotic effects of neuroleptic drugs such as haloperidol or chlorpromazine (Seeman, 1987). In schizophrenia, this D2-related therapeutic effect mainly targets the positive symptoms of the disease, such as delusions and hallucinations. However, blockade of D2 receptormediated dopaminergic neurotransmission in the striatal motor structures will also induce an extrapyramidal parkinsonian syndrome. Mechanistically, this unwanted side effect is thus closely related to the desired antipsychotic effect. It is therefore surprising that amisulpride produces so few extrapyramidal side effects. On the contrary, D2 receptor blockade is not thought to contribute significantly to relief of negative symptoms, where activation of cortical D1 receptors may be more important. Blockade of D3 dopamine receptors, which is a property of certain, but not all, antipsychotics, may help contribute to the unusual clinical properties of amisulpride. It could be that D3 receptor blockade leads to facilitation of dopaminergic transmission in some brain regions and blockade of transmission in others. However, no pure D3 receptor antagonist is available at this point which would enable this hypothesis to be tested. For other atypical antipsychotics, 5-HT receptor blockade has been proposed to account for the atypical clinical properties of these drugs (see Chapter 9). However, such an explanation cannot be put forward for amisulpride, which has no affinity for 5-HT receptors, or indeed any other nondopaminergic receptor studied (see Figure 4.1). The fact that amisulpride interacts exclusively with dopamine receptors, and yet still produces an atypical clinical profile raises two important questions. One is theoretical and has been addressed in other chapters in this book, namely that the generally accepted theory of antipsychotic drug action may be partially wrong. The other question is practical, namely what can be learnt from such a specific mechanism of action. In particular, how does the therapeutic profile of amisulpride resemble or differ from that of other so-called atypical antipsychotics. This chapter will focus on this second question. 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 1–3 months. Amisulpride has been compared with several typical and atypical antipsychotic drugs. These studies have included both patients with acute exacerbation of psychosis, and patients with predominant negative symptomatology and have evaluated both short-term and long-term benefits. In addition, a study has been performed in recent onset, treatment-naive patients (Paillère-Martinot et al, 1995). Effects on psychosis and general psychopathology 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 4.1). Placebo groups being inappropriate for such patients, who

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require rapid symptom control, these studies have compared amisulpride with other antipsychotics, namely haloperidol, α-flupenthixol, risperidone and olanzapine. Comparisons with conventional antipsychotic drugs A dose ranging study comparing four amisulpride doses (100, 400, 800 and 1200 mg/day) to haloperidol (16 mg/day) was reported by Puech et al (1998). In terms of efficacy on the Brief Psychiatric Rating Scale (BPRS), a bell-shaped dose-response curve was observed, with the dose of 800 mg/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. Later studies of amisulpride have generally used doses consistent with these, and French consensus guidelines for the use of amisulpride in acute psychotic episodes recommend an initial dose of 800 mg/day in patients with severe or recurrent psychosis, and of 400 mg/day in mild or moderate episodes, particularly in an outpatient setting (Lecrubier et al, 2001). Amisulpride 800 mg was compared to haloperidol 20 mg in a 6-week double-blind controlled trial in 188 patients (94 by group) by Möller et al (1997). These patients were recently hospitalized for acute psychotic episodes, which is why this dose of haloperidol was chosen. The positive score of the PANSS (Positive and Negative Symptom Scale) improved 53% with amisulpride and 45% with haloperidol (intention-to-treat (ITT)

Table 4.1 Studies evaluating the short-term efficcy of amisulpride in the treatment of acute psychotic treatment of schizophrenia Study

N

Comparator

Efficacy

Safety

Möller et al, 1997

191 6

800

Haloperidol 20 mg

AMI≥HALO

AMI>HALO

Wetzel et al, 1998

132 6

1000

Flupenthixol 25 AMI≥FPT mg

AMI>HALO

Puech et al, 1998

319 4

100– 1200

Haloperidol 15 mg

≥400 AMI=HALO

AMI>HALO

Peuskens et al, 1999

228 8

800

Risperidone 8 mg

AMI=RIS

AMI≥RIS**

Martin et al, 2002

377 8

200– 800*

Olanzapine 5– 20 mg

AMI=OLZ

AMI>OLZ**

*

Duration(weeks) Dose (mg)

These were flexible dose studies, where the daily dose could be titrated between the indicated limits. AMI, amisulpride; HALO, haloperiodol; FPT, flupenthixol; RIS, risperidone; OLZ, olanzapine. ** Amisulpride is associated with significantly less weight gain than risperidone and olanzapine.

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analysis). The total score of the BPRS was improved by 48% for amisulpride versus 38% for haloperidol. For the CGI (Clinical Global Impression), the figures were 62% and 44%. The advantage of amisulpride was a trend for the PANSS and the BPRS and significant for the CGI (p=0.014) (Figure 4.3a). Extrapyramidal symptoms were measured by the Simpson-Angus Scale (SAS), the Barnes Akathisia scale (BAS) and the Abnormal Involuntary Movement Scale (AIMS). As shown in Figure 4.3b, the exrapyramidal tolerance of amisulpride was much better than that of haloperidol, for a similar, if not better level of efficacy. A pronounced reduction in psychotic symptoms following treatment with amisulpride (1000 mg) has also been demonstrated in a 6-week comparative trial with flupenthixol 15–25 mg/day. There was a significant advantage towards amisulpride on the scale for the assessment of positive symptoms (SAPS) when baseline scores were introduced in the ANOVA and a trend (p=0.059) on the global score of the BPRS. Again, the incidence of extrapyramidal symptoms was lower in the amisulpride group (Wetzel et al, 1998). Comparison with atypical antipsychotic drugs Two double-blind studies have compared amisulpride to atypical antipsychotics in shortterm treatment of acute schizophrenic episodes, one using risperidone (Peuskens et al, 1999) and the other olanzapine (Martin et al, 2002). In the first trial, risperidone (8 mg; N=115) was compared to amisulpride (800 mg/day; N=113). The PANSS positive score improved by 52% and 48% respectively and the BPRS global score by 47% and 42% respectively (Figure 4.4). The advantage observed with amisulpride was not significant. The extrapyramidal tolerance was similar for both drugs with a very low incidence of parkinsonian symptoms (<15% of patients). In the comparative study with olanzapine, a comparable amelioration of the BPRS and the PANSS scores was observed in both groups after 2 months of treatment. Improvement was noted on all the subscores of the BPRS. There was no evidence for the mergence of extrapyramidal side effects over the course of the study. Effects on negative symptoms In the population of acutely ill schizophrenics, amisulpride also reduces negative symptoms. This effect is better for amisulpride than for haloperidol (37% versus 24%) (Möller et al, 1997) and similar to that of risperidone (39% versus 31%) (Peuskens et al, 1999). In this population, the effect on negative symptoms could be secondary to an improvement of positive symptoms, although other studies have shown that only a limited part of the variance in negative symptoms could be so explained (Tollefson and Sanger, 1997; Peralta et al, 2000).

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Figure 4.3 Comparison of amisulpride (800 mg) and haloperidol (20 mg/day) in the treatment of acute psychotic episodes. (a) Evolution of the mean score on the BPRS between baseline and study end (6 weeks). (b) Evolution of the mean score on the SAS for extrapyramidal symptoms between baseline and study end. Yellow columns, amisulpride; orange columns, haloperidol. (From Möller et al, 1997.)

Figure 4.4 Comparison of amisulpride (800 mg) and risperidone (8 mg/day) in the treatment of acute psychotic episodes. Evolution of the mean score on the BPRS between baseline and

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study end (8 weeks). Yellow columns, amisulpride; green columns, risperidone. (From Peuskens et al, 1999.) Effects on primary negative symptoms Although most antipsychotics do improve negative symptoms in acute exacerbations of schizophrenia (Leucht et al, 1999), this effect is small and possibly secondary to changes in other psychopathological features, including improvement of positive symptoms, relief of depression, diminished extrapyramidal side effects, in particular akinesia (when switching to atypicals), or deinstitutionalization. Even clozapine has failed to show a consistent effect on negative symptoms (Buchanan et al, 1998). For olanzapine and risperidone, although the effects are relatively small, path analysis suggested that about 50% of the effect observed was not secondary, but directly the consequence of drug treatment (Möller et al, 1995; Tollefson and Sanger, 1997). A subsequent meta-analysis suggested that this could be the case for most atypicals (Leucht et al, 1999; Chakos et al, 2001). However, to demonstrate unequivocally a specific effect on negative symptoms, studies including mainly negative schizophrenics are needed. Amisulpride is one of the most researched antipsychotics with a full devel-opment in schizophrenics with mainly negative symptomatology in placebo-controlled trials. The different amisulpride trials provided very important quantitative and qualitative information in this resistant population concerning the size of the effect, the most effective dosage and the duration and stability of the effect. Moreover, these trials controlled for most of the causalities proposed to be at the origin of a non-specific improvement (e.g. secondary to improvement in positive symptoms). Three short-term studies have evaluated the effect of amisulpride on patients with primary negative symptomatology (Table 4.2). Since primary negative symptoms do not respond well to classical antipsychotics, and since the patients do not have significant florid positive symptomatology that would benefit from these treatments, it is considered ethically acceptable to perform placebo-controlled trials in such patients. Both these studies demonstrated good efficacy of low doses of amisulpride on negative symptoms measured with the SANS (Scale for the Assessment of Negative Symptoms) scale compared to placebo. The first of these trials compared 6 weeks of treatment with amisulpride 50–100 mg to placebo in young patients at the onset of the disorder (Paillère-Martinot et al, 1995). These patients had never been institutionalized or treated with antipsychotic drugs, they had almost no positive symptoms and their depression score on the Montgomery Åsberg depression rating scale (MADRS) at inclusion was low. A significant advantage with respect to placebo was observed in amisulpride-treated patients on the SANS (Figure 4.5). This treatment effect was secondary neither to the withdrawal of previous antipsychotic treatment, since the patients were previously untreated, nor to a decrease in positive symptoms, since these were insignificant and did not change with treatment. The study also ruled out institutionalization and depression as confounding factors in the treatment response.

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A second 6-week trial (Boyer et al, 1995) compared treatment with amisulpride 100 mg, amisulpride 300 mg and placebo in chronic schizophrenics with mainly negative symptoms using the diagnostic criteria proposed by Andreasen and Olsen (1982). Because almost no positive symptoms were present, it was possible to perform a 6-week

Table 4.2 Studies evaluating the short-term efficacy of amisulpride in the treatment of primary negative symptoms of schizophrenia Study Boyer et al, 1995 Paillère-Martinot et al, 1995

N

Duration (weeks)

Dose (mg)

Comparator

Efficacy

104

6 100, 300

placebo

AMI>Pbo

20

6 50–100*

Placebo

AMI>Pbo

Danion et al, 1999

242

12 50, 100

Placebo

AMI>Pbo

Lôo et al, 1997

141

26 100

Placebo

AMI>Pbo

*This was a flexible dose study, where the daily dose could be titrated between the indicated limits. The study the Lôo et al is described in the text. AMI, amisulpride; Pbo, placebo.

Figure 4.5 Evolution of SANS negative symptoms scale in treatment-naive patients with primary negative schizophrenia treated with placebo or

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amisulpride for 6 months. Data represent SANS scores at inclusion (open columns) and at study end (filled columns). (From Paillère-Martinot et al, 1995.)

Figure 4.6 Evolution of SANS negative symptoms scale in patients with primary negative schizophrenia treated with placebo or amisulpride (Ami) for 6 months. Data represent SANS scores at inclusion (open columns) and at study end (filled columns). (From Boyer et al, 1995.) wash-out before starting the active treatment, and thus control for the withdrawal of previous antipsychotic treatment. Both dosages were effective, showing a substantial improvement of scores on the SANS scale and all its subscales (~40%) as compared to placebo (~23%) (Figure 4.6). Again, the results obtained could not be explained by an indirect effect due to a decrease of positive symptoms. The long wash-out period also excluded the risk of an ‘artefactual’ improvement due to resolution of extrapyramidal side effects after withdrawal of conventional antipsychotics. A third double-blind, 3-month trial explored the efficacy of two very low doses (50 and 100 mg) of amisulpride compared to placebo. Beneficial effects were found for both active treatment groups (Danion et al, 1999). In this study, the incidence of extrapyramidal side effects remained extremely low with no increase over time.

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Amisulpride for maintenance therapy of schizophrenia Long-term studies have been performed to verify the stability of the initial treatment response and to assess the utility of amisulpride in maintenance therapy of schizophrenia. These studies range from 4 to 12 months, and include two comparative studies against haloperidol, and a comparative study against risperidone (Table 4.3). In addition, a 12month placebo-controlled study had been performed in patients with chronic negative symptomatology (Lôo et al, 1997). Effects on psychosis Comparison with conventional antipsychotic drugs Two studies have compared long-term treatment with amisulpride and haloperidol. The first (Carrière et al, 2000) was a double-blind study comparing 4 months treatment with amisulpride (400–1200 mg/day; N=370) to haloperidol (10–33 mg/day; N=118). Equivalent efficacy on symptoms measured with the BPRS and the PANSS positive symptom scale was found, whereas amisulpride was superior in terms of improvement of the PANSS negative symptom scale. A significantly greater proportion of patients withdrew prematurely from the study in the haloperidol group, principally for adverse events, than in the amisulpride group (Figure 4.7). The second long-term study with haloperidol was an open-label randomized design, comparing treatment with amisulpride (200–800 mg/day; N=370) with haloperidol (5–20 mg/day; N=118) over 1 year (Colonna et al, 2000). Although patients in both arms of the study improved over the treatment period, those receiving amisulpride responded better than did those on haloperidol, both in terms of the evolution of scores on the BPRS

Table 4.3 Studies evaluating the long-term efficacy of amisulpride in patients with schizophrenia Study

N

Carrière et al, 2000

Duration (weeks)

Dose (mg)

Comparator

Efficacy

Safety

199 16

400– 1200*

Haloperidol 10–30 AMI≥HALO AMI>HALO mg

Colonna et al, 2000

488 52

200– 800*

Haloperidol 5–20 mg

AMI≥HALO AMI>HALO

Sechter et al, 2002

309 24

400– 1000*

Risperidone 4–10 mg

AMI>RIS

AMI>RIS**

*These were flexible dose studies, where the daily dose could be titrated between the indicated limits. AMI, amisulpride; HALO, haloperidol; RIS, risperidone. **Amisulpride is associated with significantly less weight gain than risperidone and olanzapine.

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Figure 4.7 Comparison of rates of premature treatment withdrawals in patients treated with amisulpride (400–1200 mg; yellow column) and haloperidol (10–30 mg/day; orange column) in maintenance therapy of chronic schizophrenia. (From Carrière et al, 2000.) (Figure 4.8) and on the PANSS negative symptoms scale. Improvement in the PANSS positive symptom scale was similar in the two groups. As in the short-term trials, the incidence of extrapyramidal symptoms in the amisulpride-treated patients was low compared to those treated with haloperidol. The length of this study permitted a relevant assessment of the risk of tardive dyskinesia, measured with the AIMS. There was a significant difference between the two treatment groups, with scores on this scale improved some-what for the patients treated with amisulpride (mean change=0.6), whereas they deteriorated in those taking haloperidol (mean change=−0.2). Comparison with atypical antipsychotic drugs Amisulpride (400–1000 mg/day) has also been compared to risperidone (4–10 mg/day) treatment. This was a randomized, double-blind, parallel group non-inferiority trial. It included 309 schizophrenics of the paranoid, disorganized, undifferentiated or residual type with at least 2 years duration of the disorder, who were followed for 6 months. They had to show a recent deterioration and a minimal score of 60 on the PANSS (those with predominant negative symptoms were excluded). Determination of the comparative efficacy of the two treatments was the principal objective of this trial, which was planned as a non-inferiority trial.

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Figure 4.8 Comparison of amisulpride and risperidone in maintenance therapy of chronic schizophrenia. Top: Evolution of the total PANSS score during the study in patients treated with amisulpride (400–1000 mg/day; n=121; yellow symbols) or risperidone (4–10 mg/day; N=123; green symbols). Bottom: Proportion of responders at study end (6 months) among patients treated with amisulpride (yellow columns) or risperidone (green columns). Data are presented for the PANSS, the BPRS, and the CGI-2. M, month. (From Sechter et al, 2000.)

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The trial demonstrated that amisulpride was not inferior to risperidone on the PANSS or the BPRS (Figure 4.8). The treatment effect was maintained in a stable fashion throughout the treatment period. Amisulpride had a significant therapeutic advantage over risperidone in terms of responders: 65% versus 52% when a 50% improvement definition was used (p=0.036) and 77% versus 65% when selecting those much and very much improved on the CGI (p=0.042). The incidence of extrapyramidal symptoms was low in both treatment groups. Effects on chronic negative symptomatology The long-term efficacy of amisulpride in chronic negative schizophrenia has been assessed in a 6-month double-blind study of amisulpride (100 mg) versus placebo, reported by Lôo et al (1997). This trial had two objectives, firstly to assess whether the effect observed was maintained, decreased or increased with time. If the treatment response was stable over time, it was also then possible to explore whether the whole range of negative symptoms was improved or whether some of them were resistant to treatment. The study included 141 patients with mainly negative symptoms (SANS total >60; SAPS total <50). Patients improved 20% with placebo and 42% with amisulpride

Figure 4.9 Evolution of SANS negative symptoms subscores in patients with primary negative schizophrenia treated with placebo (grey columns) or amisulpride (100 mg; yellow columns) for 6 months. Data represent the difference in scores between inclusion and study end. (From Lôo et al, 1997.)

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(p=0.0002). Positive symptoms were very low both at inclusion (SAPS=19 and 22 respectively) and after treatment (SAPS=19 and 21 respectively). As shown in Figure 4.9, all the dimensions of the SANS improved, including anhedonia and asociality. These two symptoms may need more time to improve because it takes time to create new relationships even when one is much 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 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 fulfilment, with quality of life measures, and, most importantly, with patient-reported outcome measures. Data on functional status were collected in the comparative studies with haloperidol reported by Colonna et al (2000) and by Carrière et al (2000), and in an open-label naturalistic study described by Robert et al (1987). As could be expected, amisulpride was shown 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 (QLS; Heinrichs et al, 1984). 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 longer haloperidol, but rather another atypical antipsychotic. Functional outcome was assessed in both of the risperidone studies (Peuskens et al, 1999; Sechter et al, 2002) using the Social and Functional Assessment Scale (SOFAS; American Psychiatric Association, 1994). In the short-term (8 weeks) study a similar degree of improvement in SOFAS score was observed for both treatments. However, in the long-term (180 weeks) study, a higher proportion of patients improving in the amisulpride group than in the risperidone group (Figure 4.10). Moreover, significantly (p=0.015) more patients in the former group (93%) expressed a positive subjective response to treatment at study end than did those in the latter group (83%). In primary negative schizophrenia, changes in functional outcome determined with the Global Assessment of Functioning Scale (GAF; American Psychiatric Association, 1994) in patients treated with amisulpride have also been demonstrated (Lôo et al, 1997). Treated patients improved by 12% over the 12-month study period, compared with only 5% in patients given placebo.

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Figure 4.10 Comparison of amisulpride and risperidone on functional outcome in maintenance therapy of chronic schizophrenia. Data represent the percentage of responders (i.e.>30% improvement in score) on the SOFAS (a) and the percentage of patients reporting significant improvement (b) at study end (6 months) in patients treated with amisulpride (400–1000 mg/day; N=152; yellow columns) or risperidone (4–10 mg/day; N=158; green columns). (From Sechter et al, 2000.) Conclusions Amisulpride is a selective D2/D3 receptor antagonist which blocks dopaminergic neurotransmission in the limbic system. This action is believed to underlie the antipsychotic action of the drug. Amisulpride appears to have some selectivity for dopaminergic synapses in the limbic system compared to the striatum, thus explaining the low incidence of extrapyramidal side effects observed with standard antipsychotic doses. Blockade by amisulpride of presynaptic D2/D3 receptors controlling dopamine release may account for the beneficial effects observed on negative symptomatology.

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Given the pharmacological specificity of amisulpride for monoamine receptors in the CNS, its clinical spectrum of action poses an important theoretical problem. Although the atypical clinical profile of amisulpride is not entirely unexpected from a pharmacological point of view (see Chapter 3), it is nonetheless paradoxical for a specific D2 receptor antagonist. First, this implies an involvement of dopaminergic structures in relation to the entire therapeutic effect of amisulpride, and raises the question of how dopamine receptor blockade can produce these different functional effects, and why they differ between antipsychotic drugs. Second, it challenges the hypothesis that atypicity can be explained satisfactorily by blockade of 5-HT2 receptors alone. Like all other atypical antipsychotics, amisulpride displays a robust efficacy in controlling the acute positive symptoms of schizophrenia. The therapeutic effect of amisulpride against positive symptoms and on the general psychopathology of patients is at least as incisive as that of other conventional and atypical antipsychotic agents. Compared with conventional drugs, amisulpride, like other atypical antipsychotics, has a very low propensity to induce extrapyramidal side effects. The overall tolerance of amisulpride is good, with no unexpected safety issues having been observed with this drug (Coulouvrat and Dondey-Nouvel, 1999). Moreover, amisulpride also has an important tolerability advantage over the atypical agents with which it has been compared in producing significantly less weight gain (Peuskens et al, 1999; Martin et al, 2002). Even atypical antipsychotics with mixed D2/5-HT2 receptor antagonist properties have never proved to be very effective in improving negative symptoms, and some have argued that even the mild improvement observed is secondary to amelioration of positive symptoms, of previous extrapyramidal side effects or of depressive symptoms. Amisulpride, in contrast, has proved to be effective in different populations of schizophrenics with mainly negative symptoms using study designs that allow an indirect effect to be excluded. Moreover, all dimensions of negative symptomatology, including the core symptoms are improved. The relevance of these data has been confirmed in the long-term studies, where a stable therapeutic response on both positive and negative symptomatology is observed without the emergence of significant tardive dyskinesia. On measures of functional outcome, quality of life and patient-reported well-being, amisulpride provides clear benefit. A significant treatment advantage for amisulpride was demonstrated with respect to both a conventional (haloperidol) and an atypical (risperidone) antipsychotic drug. These data illustrate the utility of amisulpride for the routine maintenance therapy of patients with schizophrenia. Since no other drug shares both the pharmacological specificity of amisulpride and its clinical spectrum of action, this makes amisulpride, on the one hand, a reference for clinical practice, and on the other, a fascinating model with which to explore the biological basis of antipsychotic drug action related to dopamine. References American Psychiatric Association. (1994) Diagnostic and Statistical Manual of Mental Disorders (4th Edn). (American Psychiatric Association:Washington DC, USA). Andreason NC, Olsen S. (1982) Negative vs positive schizophrenia: definition and validation. Arch Gen Psychiatry 39:789–94.

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Beckmann B, Hippius H, Ruther E. (1979) Treatment of schizophrenia. Prog Neuropsychopharmacol 3:47–52. Boyer P, Lecrubier Y, Puech AJ, Dewailly J, Aubin F. (1995) Treatment of negative symptoms in schizophrenia with amisulpride. Br J Psychiatry 166:68–72. Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT Jr. (1998) Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J Psychiatry 155:751–60. Carrière P, Bonhomme D, Lampérière T. (2000) Amisulpride has a superior benefit/risk profile to haloperidol in schizophrenia: results of a multicentre, double-blind study (the Amisulpride Study Group). Eur Psychiatry 15:321–9. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. (2001) Effectiveness of secondgeneration antipsychotics in patients with treatment-resistant schizophrenia: a review and metaanalysis of randomized trials. Am J Psychiatry 158: 518–26. Colonna L, Saleem P, Dondey-Nouvel L, Rein W and Amisulpride Study Group. (2000) Long-term safety and efficacy of amisulpride in subchronic or chronic schizophrenia. Int Clin Psychopharmacol 15:13–22. Coulouvrat C, Dondey-Nouvel L. (1999) Safety of amisulpride (Solian): a review of 11 clinical studies. Int Clin Psychopharmacol 14:209–18. Curran MP, Perry CM. (2001) Amisulpride: a review of its use in the management of schizophrenia. Drugs 61:2123–50. Danion JM, Rein W, Fleurot O. (1999) Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Amisulpride Study Group. Am J Psychiatry 156:610–6. Duncan GE, Zorn S, Lieberman JA. (1999) Mechanism of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Mol Psychiatry 4:418–28. Heinrichs SW, Hanlon TE, Carpenter WT. (1984) The quality of life scale: an instrument for rating the schizophrenic deficit syndrome. Schizophrenia Bull 10: 388–96. Kane J, Honigfeld G, Singer J, Meltzer H. (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789– 96. Lecrubier Y, Azorin M, Bottai T et al. (2001) Consensus on the practical use of amisulpride, an atypical antipsychotic, in the treatment of schizophrenia. Neuropsychobiology 44:41–6. Leucht S, Pitschel-Walz G, Abraham D, Kissling W. (1999) Efficacy and extrapyramidal sideeffects of the new atypical antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A metaanalysis of randomized controlled trials. Schizophrenia Res 35:51–68. Lôo H, Poirier-Littré MF, Theron M, Rein W, Fleurot O. (1997) Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. Br J Psychiatry 170:18–22. Martin S, Lôo H, Peuskens J, Thirumalai S, Giudicelli A, Fleurot O, Rein W and SOLIANOL Study Group. (2002) A double-blind randomised comparative trial of amisulpride versus olanzapine in the treatment of schizophrenia: short-term results at two months. Curr Med Res Opin 18:355–62. Martinot JL, Paillére-Martinot ML, Poirier MF, Dao-Castellana MH, Loc’h C, Maziere B. (1996) In vivo characteristics of dopamine D2 receptor occupancy by amisulpride in schizophrenia. Psychopharmacology (Berl) 124:154–8. Meltzer HY. (1999) Clinical studies on the mechanism of action of clozapine: the dopamineserotonin hypothesis of schizophrenia. Psychopharmacology 99(Suppl): S18–S27. Möller HJ, Müller H, Borison RL, Schooler NR, Chouinard G. (1995) A path-analytic approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients: a re-evaluation of the North American risperidone study. Eur Clin Psychiatry Clin Neurosci 245:45–9.

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Möller HJ, Boyer P, Fleurot O, Rein W. (1997) Improvement of acute exacerbations of schizophrenia with amisulpride: a comparison with haloperidol, PROD-ASLP Study Group. Psychopharmacology 132:396–401. Paillére-Martinot ML, Lecrubier Y, Martinot JL, Aubin F. (1995) Improvement of some schizophrenic deficit symptoms with low doses of amisulpride. Am J Psychiatry 152:130–4. Peralta V, Cuesta MJ, Martinez-Larrea A, Serrano JF. (2000) Differentiating primary from secondary negative symptoms in schizophrenia: a study of neuroleptic-naive patients before and after treatment. Am J Psychiatry 157:1461–6. Perrault GH, Depoortere R, Morel E, Sanger DJ, Scatton B. (1997) Psychopharmacological profile of amisulpride, an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity. J Pharmacol Exp Therap 280:73–82. Peuskens J, Bech P, Möller HJ, Bale R, Fleurot O, Rein W. (1999) Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Amisulpride study group. Psychiatry Res 88:107–17. Puech A, Fleurot O, Rein W. (1998) Amisulpride, and atypical antipsychotic, in the treatment of acute episodes of schizophrenia: a dose-ranging study vs. haloperidol. The Amisulpride Study Group. Acta Psychiatr Scand 98:65–72. Robert P, Braccini T, Vitali P, Darcourt G. (1987) Psychosocial aptitude rating scale (PARS): presentation and validation. Psychol Med 19:1761–5. Scatton B, Claustre Y, Cudennec A et al. (1997) Amisulpride: from animal pharmacology to therapeutic action. Int Clin Psychopharmacol 12(Suppl 2):S29–S36. Schoemaker H, Claustre Y, Fage D et al. (1997) Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Therap 280:83–97. Sechter D, Peuskens J, Fleurot O, Rein W, Lecrubier Y. (2002) Amisulpride vs. risperidone in chronic schizophrenia: results of a 6-month, double-blind study. Neuropsychopharmacology 27:1071–81. Seeman P. (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–52. Tollefson GD, Sanger TM. (1997) Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiatry 154:466–74. Wetzel H, Gründer G, Hillert A et al. (1998) Amisulpride versus flupenthixol in schizophrenia with predominantly positive symptomatology—a double-blind controlled study comparing a selective D2-like antagonist to a mixed D1/D2-like antagonist. Psychopharmacology 1137:223– 32. Xiberas X, Martinot JL, Mallet L et al. (2001a) In vivo extrastriatal and striatal D2 dopamine receptor blockade by amisulpride in schizophrenia. J Clin Psychopharmacol 21:207–14 Xiberas X, Martinot JL, Mallet L et al. (2001b) Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry 179:503–8.

chapter 5 A meta-analysis of studies with the atypical antipsychotic amisulpride Stefan Leucht, Gabi Pitschel-Walz, Werner Kissling and Rolf R Engel Since the discovery that clozapine induces less extrapyramidal side effects (EPSE) and is more effective than conventional antipsychotics for the treatment of schizophrenia (Kane et al, 1988; Wahlbeck et al, 1999), psychopharmacological research has for a long time focused on the development of drugs which have higher affinity for 5-HT2 receptors than for D2 receptors. It has been postulated that the ‘atypical’ profile of the new antipsychotic drugs olanzapine, quetiapine, risperidone and ziprasidone has mainly been linked to a combined antagonism of central serotonin (5HT2) and dopamine (D2) receptors (Roth and Meltzer, 1995; Buckley, 1997). However, the ‘dopamine alone’ hypothesis of antipsychotic drug action has recently seen a renaissance, to which the work of many authors of this book has contributed. In this context, the clinical data obtained with amisulpride have been very important. This drug, which has been used as an antipsychotic in France for more than 10 years, does not block serotonin receptors at all, but shows high affinity and selectivity for dopamine D3/D2 receptors, at which it is an antagonist. The pivotal clinical trials performed with amisulpride have demonstrated a lower risk of EPSE and a higher efficacy against negative symptoms compared to conventional antipsychotics. The present authors therefore performed a meta-analysis to compare indirectly the clinical effects of amisulpride with those of the 5-HT2/D2 antagonists. Meta-analytic methodology The meta-analytic method described by Rosenthal (1991) was used. A previous metaanalysis had already evaluated the mixed 5-HT2/D2 antagonists (Leucht et al, 1999); these results have been updated by including newly published studies. For this update, only the effect sizes derived from the new studies and the resulting mean effect sizes will be presented in the figures, More details can be found in Leucht et al (1999). Randomized controlled trials which compared amisulpride, olanzapine, quetiapine, risperidone or sertindole with conventional antipsychotics and/or placebo in the treatment of schizophrenia and schizophrenia-like psychoses were identified first by a Medline search (1966–April 2000) and a Current Contents (1997–April 2000) search, and second by cross-referencing of reviews and included studies. Finally, the pharmaceutical company which produces amisulpride (Sanofi-Synthélabo) was contacted to obtain data from unpublished trials.

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The following parameters were analysed: the mean change from baseline to endpoint of the Brief Psychiatric Rating Scale (BPRS) total score (Overall and Gorham, 1962) as a measure of global schizophrenic symptoms and the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1989) for negative symptoms. EPSE were assessed by analysing the number of patients requiring at least one dose of antiparkinsonian medication during the studies. Scale-derived data on EPSE were not used, because these were often not normally distributed. Finally, dropout rates were analysed (global; due to treatment failure; and due to adverse events). Intent-to-treat, last-observation-carriedforward data sets were used whenever available. Various methods for the calculation of effect sizes are available, which generally do not yield greatly different results (Rosenthal, 1991). In this meta-analysis all effect sizes were presented as Pearson’s correlation coefficients (r) according to the method described by Rosenthal (1991), because r can be calculated from both continuous and dichotomous data and is easy to interpret. As a rough estimate, r corresponds to the mean percentage difference in treatment effects between the intervention and the control group (Rosenthal, 1991). For continuous variables r was calculated using the formula r=√(t2/(t2+df)), where df=n1+n2−2, n1 and n2=the number of patients included in the control and in the intervention group, and t=the result of a t-test. For dichotomous data, Phi which corresponds to Pearson’s correlation coefficient for continuous data, was The effect sizes were then transformed calculated according to the formula into Fisher’s zr values and the mean effect size was calculated from r, i.e. the weighted mean of the zr values. For studies which compared several doses of amisulpride with a control group, the different dose groups of amisulpride were pooled, i.e. for continuous data, the mean effect size achieved by the different doses was used and for dichotomous data, all patients treated with amisulpride were considered as a single group. For all outcome parameters the degree of homogeneity of the effect sizes among the studies included for each drug was assessed using a chi-square test. The possibility of a publication bias, i.e. that studies with negative results have not been published, was examined using the ‘funnel-plot’ method preferred by the Cochrane Collaboration (Mulrow and Oxman, 1996). Furthermore, the number (x) of unretrieved studies averaging null results required to bring the new overall p to the level just where k=the significant at p=0.05 was calculated by: number of studies combined and obtained for the k studies (Rosenthal, 1991). Two sensitivity analyses were performed. In the first one, only the optimum doses of amisulpride were examined, and in the second, old studies which did not use lastobservation-carried-forward data analysis were excluded. Studies with amisulpride Amisulpride has been examined in a large number (18) of randomized controlled trials (RCTs) including 2214 patients (Table 5.1). Study durations ranged from 3 weeks to 1 year.

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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-30s. The other seven studies examined low-dose amisulpride (50–300 mg/day) for patients with predominant persistent 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 have not yet been published about the 5-HT2/D2 antagonists, to the best of our knowledge. The details of most studies on the 5-HT2/D2 antagonists have been summarized in an earlier publication (Leucht et al, 1999).

Table 5.1 Randomized controlled studies comparing amisulpride with conventional antipsychotics or placebo Study

Antipsychotic drugs and daily dose (mg)

Sample size Selected entry criteria

Mean illness duration (years)

Study duration (weeks)

Acute studies Möller et AMI 800 al, HAL 20 (1997)

95

Wetzel et AMI 1000/600† al, FLU 25/15† (1998)

70

Puech et al, (1998)

AMI (100;400;800;1200)

Colonna et al, (2002)‡

AMI 200–800

370

HAL 5–20

118

AMI 400–1200

94

HAL 10–30

105

Carrière et al, (2000)

HAL 16

DSM-III-R, chronic or 10 subchronic, residual schizophrenia excluded

6

DSM-III-R, paranoid or undifferentiated schizophrenia with predominant positive symptoms

NI

6

(61;64;65;65) DSM-III-R, paranoid, disorganized or undifferentiated 64 schizophrenia with acute exacerbation

10

4

DSM-III-R, (sub-) chronic schizophrenia with acute exacerbation

12

12 months

DSM-IV, paranoid schizophrenia or schizophreniform disorder

n.i.

4 months

96

62

A meta-analysis of studies

Delker et AMI 490–1000 al, HAL 5–40 (1990)

21

Costa e Silva (1989)

AMI 800–1200

20

HAL 20–30

20

Klein et al, (1985)

AMI 10 mg/kg

9

bodyweight

10

79

ICD-9, schizophrenia

~16

6

20 ICD-9, ‘acute NI psychotic states’ (11 with organic psychotic states)

3

NI

4

ICD-9, schizophrenia ~6 and delusional disorder

4

ICD-9, acute schizophrenia, schizophreniform and schizoaffective disorder

NI

4

Schizophrenia, schizoaffective or schizophreniform disorder

NI

6

ICD-9, acute schizophrenia

HAL 0.5 mg/kg bodyweight Ziegler (1989)

AMI 300–750

20

HAL 2.5–22.5

20

Rüther and Blancke (1998)

AMI 400–1000

15

perazin 400–1000

15

Pichot and Boyer (1988)

AMI 800–1200

19

HAL 20–30

20

Patients with predominant and persistent negative symptoms—placebo-controlled studies Danion et al, (1986)

AMI (50; 100)

(84;75)

PBO

83

Lôo et al, (1997)

AMI 100

69

PBO

72

Boyer et AMI (100;300) al, PBO (1995)

Pallière- AMI 50 Martinot PBO et al, (1995)

(34;36) 34

14 13

DSM-III-R, residual type schizopherina with predominant negative symptoms

~10

12

DSM-III-R, residual or 10 disorganized schizophrenia with predominant negative symptoms

6 months

DSM-III-R residual, disorganized, undifferentiated type fulfilling Andreasen’s criteria for negative schizophrenia

11

6

DSM-III-R, schizophrenia and schizotypal disorder with important negative symptoms

3

6

Dopamine in the pathophysiology and treatment of schizophrenia

Study

Antipsychotic drugs and daily dose (mg)

Sample Selected entry size criteria

80

Mean illness duration (years)

Study duration (weeks)

Patients with predominant and persistent negative symptoms—comparisons with conventional antipsychotics Speller et AMI ‘low-dose’ al, (1997) HAL ‘low-dose’

29

Saletu et AMI 100 al, (1994) FLUPH 4

19

Pichot and Boyer (1989)

31

21

AMI 50–300

34

FLUPH 2–12

28

DSM-III-R, schizophrenia with moderate to severe negative symptoms

37

12 months

ICD-9, ‘unproductive’ schizophrenia

8

6

Min 20 DSM-III, fulfilling Andreasen’s criteria for negative schizophrenia years

6

AMI, amisulpride; HAL, haloperidol; PBO, placebo; FLU, flupentixol; FLUPH, fluphenazine; NI, not indicated; min, minimum; Average BPRS values. †All patients were started on the higher dose which could then be reduced. ‡ The study was only randomized, not double-bind. Furthermore, results at 4 weeks were used to allow a comparison with the other short-term trails. In these studies with patients suffering predominantly from negative symptoms the SANS total score is indicated.

It should be noted that three large comparisons between amisulpride and risperidone (Peuskens et al, 1999; Sechter et al, 2002) and olanzapine (Martin et al, 2002) have also been performed, but these were not in the scope of this meta-analysis. Overall antipsychotic efficacy In the eleven 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 ( ) 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 favour of amisulpride (Figure 5.1). Effects on negative symptoms Concerning the reduction of negative symptoms in the acute studies, there was again a highly statistically significant superiority of amisulpride over conventional antipsychotics (Figure 5.2). A problem with these studies with acutely ill patients, however, is that they do not permit a conclusion to be reached as to whether the superiority refers to primary negative symptoms or merely to secondary negative symptoms. Studies on patients suffering predominantly from persistent negative symptoms are more appropriate for this.

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No such studies have been performed up to now with the mixed dopamine/serotonin antagonists to our best knowledge, but seven studies have been carried out with amisulpride (see Table 5.1). In four placebo-controlled studies in these patients, amisulpride was significantly superior (p<0.001; Figure 5.3). Moreover, all mixed dopamine/serotonin receptor antagonists were also significantly better than placebo for the treatment of negative symptoms (Figure 5.3). However, all of these studies had been

Figure 5.1 Mean BPRS change—new versus conventional antipsychotics. The dotted lines are the mean effect sizes and their confidence intervals using a fixed effects model. *

Endpoint analysis, not used for mean effect size.

Dopamine in the pathophysiology and treatment of schizophrenia †

r=0.11; CI 0.06–0.16; z=4.4; p<0.0001; N=1654. ‡

r=0.04; CI−0.05–0.13; z=0.86; p=0.39; N=2994.

§

r=−0.05; CI−0.11–0.01; z=−1.5; p=0.13; N=953.

#

r=0.08; CI 0.03–0.12; z=3.08; p=0.002; N=3362. q

r=20.03; CI−0.08–0.03; z=−0.90; p=0.37, N=1218.

Figure 5.2 Mean change of negative symptoms—new versus conventional

82

A meta-analysis of studies

83

antipsychotics. Studies in chronic patients and studies in patients with acute exacerbations. The dotted lines are the mean effect sizes and their confidence intervals using a fixed effects model. *

r=0.08; CI−0.12–0.26; z=0.77; p=0.44; N=130 (only endpoint values could be used for the calculation of this effect size).

†

r=0.14; CI 0.08–0.19; z=4.53; p<0.0001; N=1563 (Six early studies did not use scales to assess negative symptoms and could therefore not be included). ‡

r=0.08; CI 0.05–0.12; z=4.63; p<0.0001; N=2993. §

r=−0.05; CI−0.20–0.11; z=−0.62; p=0.53; N=685.

#

r=0.06; CI 0.01–0.12; z=2.29; p=0.02; N=3340. q

r=−0.01; CI−0.07–0.05; z=−0.23; p=0.81; N=1125.

Dopamine in the pathophysiology and treatment of schizophrenia

Figure 5.3 Mean change of negative symptoms—antipsychotics versus placebo. Note that all amisulpride versus placebo studies were performed with patients suffering predominantly from negative symptoms, whereas all other atypical antipsychotics were studied only in acutely ill patients. The dotted lines are the mean effect sizes and their confidence intervals using a fixed effects model. *

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

r=0.26; CI 0.19–0.34; z=6.59; p<0.0001; N=624. ‡

r=0.21; CI 0.13–0.28; z=5.02; p<0.0001; N=582.

84

A meta-analysis of studies

85

§

r=0.19; CI 0.07–0.30; z=3.09; p=0.002; N=823. #

r=0.20; CI 0.13–0.27; z=5.31; p<0.0001; N=686. q

r=0.19; CI 0.09–0.28; z=3.69; p=0.0002; N=392. performed in acutely ill patients so that it is not clear whether there was a superiority in terms of primary negative symptoms or secondary negative symptoms. Finally, there were also three studies which compared amisulpride with haloperidol or fluphenazine in patients with predominantly negative symptoms. There was no significant difference between amisulpride and conventional drugs (see Figure 5.2), possibly because of a lack of statistical power, since all together only 130 patients were included in these trials. Extrapyramidal side effects The use of antiparkinsonian medication was used as a measure of EPSE, because this parameter is indicated quite consistently in recent trials of new antipsychotic drugs.

Figure 5.4 Use of antiparkinsonian medication—antipsychotics versus placebo. The dotted lines are the mean

Dopamine in the pathophysiology and treatment of schizophrenia

86

effect sizes and their confidence intervals using a fixed effects model. *

r=0.01; CI −0.08–0.1; z=0.22; p=0.82; N=507.

†

r=0.02; CI −0.12–0.08; z=0.03; p=0.90; N=418.

‡

r=0.06; CI−0.02–0.08; z=1.50; p=0.13; N=716.

§

r=0.09; CI −0.18–0.00; z=−1.87; p=0.06; N=436.

#

r=0.07; CI −0.02–0.15; z=1.47; p=0.14; N=494.

q

r=0.36; CI −0.42–(−)0.29; z=−5.04; p<0.0001; N=696 (this effect size was calculated from the haloperidol versus placebo comparisons in studies on olanzapine, quetiapine and sertindole).

According to this measure, amisulpride did not lead to more EPSE than placebo (Figure 5.4). In all placebo comparisons, only low doses of amisulpride (50–300 mg/day) were used, because these were studies on patients with predominant negative symptoms in whom amisulpride is thought to be most effective at low doses. Comparisons of higher doses of amisulpride with placebo have not been carried out. Compared to conventional antipsychotics, amisulpride clearly induced less EPSE, as did the mixed dopamine/serotonin antagonists (Figure 5.5). Dropout rates Taken together, there was a significantly lower dropout rate in the acute studies among the patients treated with amisulpride than in those with patients treated with classical drugs (11 studies, r=0.17; CI 0.08–0.26; z=3.68, p=0.0002). This superiority could be attributed to significantly fewer dropouts due to adverse events (r=0.15; CI 0.07–0.25; z=3.02; p=0.003), whereas no difference in dropouts due to inefficacy of treatment was found (r=0.01; CI−0.04–0.06; z=0.34, p=0.37). Metrical validation When the analysis was restricted to the optimum doses of amisulpride (400–800 mg/day for acutely ill patients and 50–300 mg/day for patients suffering from predominant

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87

persistent negative symptoms), the findings were essentially identical. With the exception of dropouts due to adverse events, all effect sizes increased slightly in favour of amisulpride: BPRS change r=0.12; CI 0.06–0.17; negative symptoms change r=0.15; CI 0.09–0.20; antiparkinsonian medication r=0.27; CI 0.17–0.37; global dropouts r=0.21; CI 0.12–0.30; adverse events dropouts r=0.15; CI 0.06–0.26; inefficacy dropouts r=0.02 CI −0.03–0.08. Since all the studies in patients with predominantly negative symptoms used only doses within the optimum range (50–300 mg/day), a similar sensitivity analysis was not necessary. The second sensitivity analysis, in which the small older studies which did not present an intent-to-treat dataset were excluded and this did not lead to any important changes in the results of the meta-analysis. No substantial changes in the amisulpride results were obtained when a fixed instead of a random effects model was used (cf. Figures 5.1–5.5). Contrary to the fixed effects model, in the random effects model the differences between olanzapine and conventional antipsychotics in terms of BPRS change, and the borderline difference between quetiapine and conventional antipsychotics in terms of negative symptoms were no longer statistically significant. The reason for the substantially broader confidence intervals of the effect size for olanzapine in the random effects model was a significant heterogeneity among studies (χ2=9.84, df=2, p=0.007). This disappeared when subtherapeutic doses below 7.5 mg/day were excluded (r=0.10; CI 0.06–0.14; z=5.03; p<0.0001). A funnel plot of the main outcome parameter (mean BPRS) revealed a relationship between sample size and effect size, suggesting a potential publication bias. However, according to the manufacturers, no further unpublished studies on amisulpride have been undertaken. The reason for the asymmetrical funnel-plot may be a chance finding attributable to the low number of studies. Another argument against a real publication bias is that according to Rosenthal’s method (1991), 62 unpublished studies would be necessary to reverse statistical significance. Comparison of amisulpride with other atypical antipsychotics This meta-analysis allowed the effects obtained in the pivotal clinical trials with amisulpride to be compared with those obtained with the mixed 5-HT2/D2 receptor antagonists. Amisulpride showed a significantly greater efficacy than comparators (usually haloperidol), both in terms of general schizophrenic symptoms as measured by the BPRS and in terms of global negative symptoms in the studies in acutely ill patients. Such a statistically significant superiority has not been shown by all new drugs which are considered to be atypical antipsychotic drugs. Similar to the mixed 5-HT2/D2 receptor antagonists, amisulpride was associated with fewer EPSE than conventional antipsychotics. These results are important for our understanding of the mechanisms which make an antipsychotic drug ‘atypical’, because for many years the combined blockade of central dopamine and serotonin receptors was considered as the main reason why some antipsychotic drugs lead to fewer EPSE and are somewhat better for the treatment of negative symptoms than conventional antipsychotics. This meta-analysis showed that a highly selective dopamine antagonist

Dopamine in the pathophysiology and treatment of schizophrenia

Figure 5.5 Use of antiparkinsonian medication—new versus conventional antipsychotics. The dotted lines are the mean effect sizes and their confidence intervals using a fixed effects model. *

r=0.25; CI 0. 7–0.32; z=6.53; p<0.0001; N=1599 (Two studies did not measure this outcome). †

r=0.39; CI 0.30–0.48; z=7.56; p<0.0001; N=2694.

88

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89

‡

r=0.38; CI 0.32–0.44; z=10.90; p<0.0001; N=757. §

r=0.14; CI 0.08–0.21; z=4.29; p<0.0001; N=2421. #

r=0.34; CI 0.25–0.42; z=7.27; p<0.0001; N=424. with no direct effects on serotonergic neurotransmission also possesses atypical properties. The most likely explanation for this effect is that amisulpride selectively blocks dopamine receptors in the mesolimbic pathway, but not in the striatum. Thus, it is an effective antipsychotic for the positive symptoms of schizophrenia without important EPSE. Concerning its effectiveness for the negative symptoms amisulpride is thought to block presynaptic auto-receptors in the frontal lobes, which in turn leads to an enhancement of dopamine transmission in these areas and thus an improvement of negative symptoms. From a methodological point of view, the efficacy of amisulpride on negative symptoms has been studied more extensively than that of the 5-HT2/D2 receptor antagonists, because the latter have only been examined in studies on acutely ill patients (Leucht et al, 1999). Such studies do not allow a conclusion to be drawn as to whether the superiority refers only to secondary or also to primary negative symptoms. In four studies in patients with predominant negative symptoms, amisulpride turned out to be clearly more effective than placebo. However, three small comparisons with typical drugs in studies which had insufficient sample sizes failed to show a significant superiority of amisulpride in such patients. More large randomized controlled trials are necessary to clarify whether the atypical antipsychotics are really more effective for the treatment of primary negative symptoms. The atypical profile of amisulpride has meanwhile also been confirmed in direct comparisons with risperidone and olanzapine. In a large multicentre study, risperidone 8 mg daily and amisulpride 800 mg daily showed similar efficacy for positive and negative symptoms and a similar occurrence of EPSE (Peuskens et al, 1999). Two further large studies which compared amisulpride with risperidone (Sechter et al, 2002) and olanzapine (Martin et al, 2002) generally confirmed these results. However, in the 6month comparative study with risperidone, there was a greater proportion of responders with amisulpride than with risperidone. A better global tolerability of amisulpride was also shown by significantly fewer patients leaving the studies prematurely due to side effects than with conventional drugs. 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 (Coulouvrat and Dondey-Nouvel, 1999). In daily practice, this problem must be balanced with weight gain which is a problem of some 5HT2/D2 antagonists. A mean weight gain under treatment with olanzapine, risperidone and sertindole of 3.5 kg, 2.0 kg, and 2.5 kg within 10 weeks was estimated in a metaanalysis by Allison et al (1999). The weight gain associated with amisulpride was low. It was approximately 0.7±3.1 kg in the short-term trials (4–12 weeks) and 1.2±6.5 kg in the long-term trials (6–12 months, Sanofi-Synthélabo (data on file); Taylor and McAskill, 2000).

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The main conclusion of this meta-analysis is that combined 5-HT2/D2 receptor antagonism is not the only mechanism which makes an antipsychotic atypical. Mesolimbic selectivity of dopamine receptor blockade is another explanation for the low EPSE risk of some antipsychotics. This is an important finding for the development of new antipsychotic agents and for the understanding of the pathophysiology of schizophrenia. References Allison DB, Mentore JL, Heo M et al. (1999) Antipsychotic-induced weight gain: A comprehensive research synthesis. Am J Psychiatry 156:1686–96. Andreasen NC. (1989) Scale for the assessment of negative symptoms. Br J Psychiatry 155 (Suppl 7):53–8. Boyer P, Lecrubier Y, Puech AJ, Dewailly J, Aubin F. (1995) Treatment of negative symptoms in schizophrenia with amisulpride. Br J Psychiatry 166:68–72. Buckley PF. (1997) New dimensions in the pharmacologic treatment of schizophrenia and related psychoses. J Clin Pharmacol 37:363–78. Carrière P, Lempérière T, Bonhomme D for the Amisulpride Study Group. (2000) Amisulpride has superior benefit:risk profile to haloperidol in schizophrenia: results of a multicentre, doubleblind study. Eur Psychiatry 15:321–9. Colonna L, Saleem P, Dondey-Nouvel L, Rein W. (2002) Amisulpride study group: Long-term safety and efficacy of amisulpride in subchronic or chronic schizophrenia. Int Clin Psychopharmacol 15:13–22. Costa e Silva JA. (1989) Comparative double-blind study of amisulpride versus haloperidol in the treatment of acute psychotic states. Amisulpride (Expansion Scientifique Française: Paris) 93– 104. Coulouvrat C, Dondey-Nouvel L. (1999) Safety of amisulpride (Solian®): a review of 11 clinical studies. J Clin Psychopharmacol 14:209–18. Danion JM, Rein W, Fleurot O. (1999) Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Am J Psychiatry 156: 610–16. Delcker A, Schoon ML, Oczkowski B, Gaertner HJ. (1990) Amisulpride versus haloperidol in treatment of schizophrenic patients—results of a double-blind study. Pharmacopsychiatry 23:125–30. Kane JM, Honigfeld G, Singer J, Meltzer H and the Clozaril Collaborative Study Group. (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–96. Klein HE, Dieterle D, Rüther E, Eben E, Nedopil N, Hippius H. (1985) A double-blind comparison of amisulpride vs. haloperidol in acute schizophrenic patients. In: (Pichot P, Berner P, Wolf R, Thau K, eds.) Psychiatry. ‘The State of the Art’. (Plenum Press: New York), pp. 687–91. Leucht S, Pitschel-Walz G, Abraham D, Kissling W. (1999) Efficacy and extrapyramidal sideeffects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophrenia Res 35:51–68. Lôo H, Poirier-Littre MF, Theron M, Rein W, Fleurot O. (1997) Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. Br J Psychiatry 170:18–22. Martin S, Lôo H, Peuskens J et al. (2002) A double blind, randomised comparative trial of amisulpride versus olanzapine in the treatment of schizophrenia. Short-term results at two months. Curr Med Res Opin 18:355–62.

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Möller HJ, Boyer P, Fleurot O, Rein W. (1997) Improvement of acute exacerbations of schizophrenia with amisulpride: a comparison with haloperidol. Psychopharmacology 132:396– 401. Mulrow CD, Oxman AD. (1996) Cochrane Collaboration Handbook. (BMJ Publishing Group: London). Overall JE, Gorham DR. (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10: 790–812. Paillère-Martinot ML, Lecrubier Y, Martinot JL, Aubin F. (1995) Improvement of some schizophrenic deficit symptoms with low doses of amisulpride. Am J Psychiatry 152:130–4. Peuskens J, Bech P, Möller HJ, Bale R, Fleurot O, Rein W. (1999) Amisulpride study group: Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Psychiatry Res 88:107–17. Pichot P, Boyer P. (1988) Etude multicentrique controlée en double insu: amisulpride (Solian 200) versus halopéridol a forte dose dans les états psychotiques aigus. Ann Psychiatr 3:326–32. Pichot P, Boyer P. (1989) Controlled double-blind multi-centre trial of low dose amisulpride versus fluphenazine in the treatment of the negative syndrome of chronic schizophrenia. Amisulpride (Expansion Scientifique Française: Paris) pp. 125–38. Puech A, Fleurot O, Rein W. (1998) Amisulpride, an atypical antipsychotic, in the treatment of acute episodes of schizophrenia: a dose-ranging study vs. haloperidol. Acta Psychiatr Scand 98:65–72. Rosenthal R. (1991) Meta-analytic Procedures for Social Research (Sage Publications: New York). Roth BL, Meltzer H. (1995) The role of serotonin in schizophrenia. In: (Bloom FE, Kupfer DJ, eds) Psychopharmacology: The Fourth Generation of Progress. (Raven Press: New York) pp. 1215– 27. Rüther E, Blanke J. (1998) Therapievergleich von Aminosultoprid (DAN 2163) und Perazin bei schizophrenen Patienten. In: (Helmchen H, Hippius H, Tölle R, eds.) Therapie mit Neuroleptika—Perazin. (Georg Thieme Verlag: Stuttgart) pp. 65–72. Saletu B, Küfferle B, Gruenberger J, Földes P, Topitz A, Anderer P. (1994) Clinical, EEC mapping and psychometric studies in negative schizophrenia: comparative trials with amisulpride and fluphenazine. Pharmacopsychiatry 29:125–35. Sechter D, Peuskens J, Fleurot O, Rein W, Lecrubier Y. (2002) Amisulpride vs. risperidone in chronic schizophrenia: results of a 6-month, double-blind study. Neuropsychopharmacology 27:1071–81. Speller JC, Barnes TRE, Curson DA, Pantelis C, Alberts JL. (1997) One-year, low-dose neuroleptic study of in-patients with chronic schizophrenia characterised by persistent negative symptoms— Amisulpride v.haloperidol. Br J Psychiatry 171:564–8. Taylor DM, McAskill R. (2000) Atypical antipsychotics and weight gain—a systematic review. Acta Psychiatr Scand 101:416–32. Wahlbeck K, Cheine M, Essali A, Adams C. (1999) Evidence of clozapine’s effectiveness in schizophrenia: A systematic review and meta-analysis of randomized trials. Am J Psychiatry 156:990–9. Wetzel H, Grunder G, Hillert A et al. (1998) Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology—a double-blind controlled study comparing a selective D-2-like antagonist to a mixed D-1-/D-2-like antagonist. Psychopharmacology 137:223–32. Ziegler B. (1989) Study of the efficacy of a substituted benzamide amisulpride, versus haloperidol, in productive schizophrenia. Amisulpride (Expansion Scientifique Française: Paris) pp. 73–82.

chapter 6 Evidence from brain imaging for regional monoaminergic specificity in schizophrenia Jean-Luc Martinot and Marie-Laure Paillère-Martinot Investigating the regional specificity of dopaminergic dysfunction in schizophrenia involves determining the relationship between, on the one hand, clinical parameters related to diagnosis and symptomatology and, on the other hand, components of the dopaminergic systems that are measurable in patients in vivo. The effects of pharmacological treatments on their regional cerebral targets can thus be studied. In this chapter discussion will be limited to two types of brain receptor, the dopamine D2 receptor and the serotonin 5-HT2A receptor. Investigating diagnostic specificity: measurements of DOPA uptake in schizophrenia and depression The presynaptic metabolism of the dopamine precursor, DOPA (dihydroxyphenylalanine), can be investigated with PET. A Finnish team first demonstrated an increase in the presynaptic metabolism of DOPA in some schizophrenic patients (Hietela et al, 1995). In addition, a US group showed an abnormally increased release of dopamine in schizophrenic patients in response to administration of a dose of amphetamine, which transiently aggravated the productive (positive) symptoms of schizophrenia (Laruelle et al, 1996). Dao-Castellana et al (1997) investigated whether changes in DOPA metabolism may differentiate patients with different clinical presentations of schizophrenia. A PET method was used to calculate an uptake constant (Ki) of [18F]fluoro-L-DOPA for the caudate nuclei and the putamen. Six male patients with different subtypes of schizophrenia according to the DSM-III-R classification (two had undifferentiated subtypes, two had disorganized, one had schizoaffective and one had catatonic subtype) were evaluated. They were compared to seven healthy male control subjects of comparable mean age (Figure 6.1). Even though the mean value for Ki was not significantly different between patients and controls, a higher variance in Ki was observed in the patients. It was then investigated whether the difference in clinical subtype might be a factor contributing to this higher variance. The two patients with ‘undifferentiated’ type disorder (most ‘positive’ symptoms) were located 2 standard deviations (SD) above the controls, whereas patients with catatonic schizophrenia, whose clinical presentation was marked by negative symptoms and motor deficits, had the lowest values, i.e. 2 SD below the control group. This difference was noted both for the

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caudate nucleus and the putamen (Figure 6.1). Thus, clinical symptom variables more precise than overall diagnosis appear to be relevant factors to consider. Hence the abnormalities in dopamine metabolism observed may be related more to the clinical presentation than to the diagnosis of schizophrenia. Since the negative-symptom dimension is common to certain forms of schizophrenia and certain types of affective disorders, and because decreases in dopamine turnover have been postulated in depression (Willner, 1995), it was hypothesized that two clinically distinct subtypes of depression should present with a different dopaminergic function. Using the same methodology as in the previous study ([18F]fluoro-L-DOPA PET), two groups of patients fulfilling DSM-IV criteria for a major depressive episode were compared with each other and a healthy control group of comparable age and sex. For this purpose, the depressed patients were divided into two subgroups (described in detail in Paillère-Martinot et al, 2001): ‘impulsive’ patients, with high scores on the subscale for loss-of-control on the depressive mood scale and a high score of anxiety, and patients with ‘blunted affect and psychomotor retardation’, scoring high on the depressive retardation rating scale (ERD, Widlöcher and Ghozlan 1989) and the blunted affect subscale of the depressive mood scale.

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Figure 6.1 Uptake of [18F]-fluoro-LDOPA in the caudate and putamen in control subjects and schizophrenic patients. Data are presented as mean uptake rate constants (Ki). ■, caudate; □, putamen. The thin lines indicate the mean for each group, and the thick lines 2 standard deviations below and above the control group mean. Ki values for the two undifferentiated patients and the patient with catatonia were located above and below 2 SD respectively from the control group mean, in both the caudate and putamen. (Data reproduced with permission from Dao-Castellana et al, 1997.) The uptake constant for [18F]fluoro-L-DOPA (Figure 6.2) was significantly lower in the left caudate nucleus in the group with ‘blunted affect and psychomotor retardation’ compared to the ‘impulsive’ group and the control group, which were comparable to each other. No difference was observed between the three groups in the putamen.

Figure 6.2 Uptake of [18F]fluoro-LDOPA in the left caudate nucleus in

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different forms of depression. Data are presented as mean uptake rate constants (Ki) for control subjects (C, N=10), impulsive depressed subjects (I, N=6) and psychomotor retarded depressive subjects (R, N=6). SC ratio, striatum/cerebellum ratio. (Data reproduced with permission from Paillère-Martinot et al, 2001.) These data are consistent with others reported in the literature. A decrease in presynaptic dopaminergic function in the left caudate nucleus has been reported previously in patients with schizophrenia and depressive symptoms in Finland (Hietala et al, 1999). In addition, a decrease in glucose metabolism in the caudate nuclei was reported in clinically heterogeneous depressed subjects by Baxter et al (1985). The first analysis, which used the region of interest (ROI) method was supplemented with a voxel-based analysis using statistical parametric mapping (SPM software). This second analysis confirmed the decrease in [18F]fluoro-L-DOPA in the left caudate nucleus in depressed subjects with some ‘negative’ symptoms (blunted affect and psychomotor slowness), and also made it possible to detect differences in regions not investigated by the ROI method. A decrease in DOPA uptake was detected in the nucleus accumbens and the hippocampus, as well as in dorsal brainstem nuclei. Dopaminergic dysfunction related to a type of symptom (emotional deficit, psychomotor slowness) that can be discerned in two different psychiatric disorders was thus observed. This emphasizes the value of considering clinical presentation, rather than ‘categorical’ diagnosis, to understand better the underlying pathophysiological processes. Evidence for syndromal specificity: the primary negative dimension and dopaminergic neurotransmission In past decades, the primary negative symptoms of schizophrenia (i.e. symptoms present from the onset of the disease, also referred to as ‘deficit symptoms’; Carpenter et al, 1988), were considered to be a syndrome dimension that constituted the ‘hard core’ of schizophrenia, particularly refractory to antipsychotic medications (Johnstone et al, 1978; Meltzer, 1995). To account for this, Crow (1985) proposed a ‘two-syndrome’ model of schizophrenia which defined a therapy-responsive type, characterized by productive symptoms such as hallucinations and delusions (Type I), and a therapy-refractory type characterized by deficit or negative symptoms (Type II). This model hypothesized distinct pathophysiological mechanisms underlying each type: an increase in dopaminergic transmission in Type I and structural brain abnormalities in Type II. For Type I schizophrenia, this idea was based on the so-called ‘dopaminergic’ hypothesis of schizophrenia proposed following the discovery of the mechanism of action of antipsychotic agents, i.e. blockade of dopamine receptors (Carlsson and Lindqvist, 1963), and the subsequent demonstration that effective doses of antipsychotic drugs were

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correlated with the affinity and selectivity of such drugs for dopamine D2 receptors (Creese et al, 1976). For Type II schizophrenia, on the other hand, the aetiological hypothesis was based on MRI brain imaging data which frequently showed enlargement of the cerebral ventricles. However, other studies have provided arguments in support of decreased dopaminergic activity associated with negative symptomatology (Gerlach and Luhdorf, 1975; Mackay, 1980). The development of functional brain imaging techniques in the 1980s allowed direct access to neurotransmission in vivo in patients, using radioligands to measure dopamine D2 receptors (although initially only in the striatum), and thus to test the dopamine hypothesis directly. Results of such studies proved contradictory: in some, elevations of receptors were observed (Wong et al, 1986), whilst in others, including our own (Martinot et al, 1991), there was no marked difference compared to control subjects. The differences in results may be explained partly by methodological differences in imaging and also by the screening of often clinically very heterogeneous patients. We therefore took into account this heterogeneity, focusing on negative schizophrenic symptoms. The primary negative symptoms likely to be associated with a potential alteration of dopaminergic transmission were investigated at the level of the striatum. D2 receptors were assessed in the striatum by PET in 10 young patients untreated with antipsychotic agents and presenting with hebephrenic schizophrenia characterized, from the onset of the disease, by a large degree of negative symptomatology. The D2 receptor density was measured by PET using the radioligand [76Br]bromolisuride, allowing the estimation, in vivo, of an index of striatal D2 dopamine receptor density measured as the striatum/cerebellum ratio according to a previously validated method (Delforge et al, 1991). Compared to healthy control subjects, patients did not show a marked difference in the estimated density of D2 receptors. This result, in clinically very homogeneous patients with marked negative symptoms on the Andreasen SANS scale, reproduced the results that had been obtained previously by our team in a larger but more heterogeneous group (Martinot et al, 1991). Nevertheless, a strong negative correlation existed between the D2 receptor density index and the negative dimension measured by the total score on the SANS scale (Spearman rank correlation, r=−0.85, p=0.01). A similar correlation was found with the total psychomotor retardation score measured by the ERD scale (r=−0.70, p=0.03). Within the negative dimension, such a correlation (r=−0.73 p<0.02) was observed (Figure 6.3) with the ‘psychomotor poverty’ factor (Liddle, 1987) reflecting a blunting of affect and including SANS (Scale for Assessment of Negative Symptoms) scores for the following items: unchanging facial expression, decreased spontaneous movements, paucity of expressive gestures, affective non-responsivity, vocal inflections and poverty of speech. In contrast, no correlation was observed with the other two factors usually obtained from factorial analysis of the SANS; namely avolition-anhedonia (reflecting a dimension of the disorder in social relations), and disorganization (the items incongruent emotions and poverty of content of speech) (Keefe et al, 1992). These results suggest a close relationship between the negative dimension, in particular blunting of affect, and a decrease in dopaminergic transmission on a continuum ranging from normal to pathological, and for a clinical dimension common to

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Figure 6.3 Correlation between binding of [76Br]-bromolisuride to striatal D2 receptors, and psychomotor expressiveness. (Data reproduced with permission from Martinot et al, 1994.) schizophrenia and depressive states (Kulhara and Chadda, 1987). The nuances of this dimension may be expressed on a continuum of psychomotor expressiveness, ranging from maximum blunting of affect to overexpression of emotion (mannerisms). More recently, two groups have reported an analogous inverse relationship between emotional expressiveness and D2 striatal receptors or activity of the dopamine transporter in healthy subjects (Farde et al, 1997; Laasko et al, 2000), supporting the concept of such a continuum. Overall, these studies suggest that striatal D2 receptors participate in modulating clinical dimensions (psychomotor retardation, psychomotor expressiveness). However, this finding should be interpreted in the context of changes in the activity of other brain structures, such as the cortex, which are likely to modulate dopamine release in the striatum and whose dopaminergic innervation may be abnormal in schizophrenia (Akil et al, 1999). Evidence for biochemical specificity: serotonergic neurotransmission and schizophrenia Apart from the dopaminergic system, another neurotransmitter system, the serotonergic system, has also been implicated in schizophrenia. Based on post-mortem studies, some

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authors have postulated a decreased density of serotonin receptors in schizophrenia. In order to investigate this system in vivo, the density index of cortical 5-HT2A serotonin receptors was estimated in 14 untreated schizophrenic patients, compared to 15 healthy subjects, using PET and the radioligand [18F]setoperone. No significant difference was observed in the 5-HT2A receptor density index between patients and normal controls (Table 6.1).

Table 6.1 Binding of [18F]setoperone to 5-HT2A receptors in the cortex of schizophrenic patients and normal controls [18F]Setoperone binding potential Schizophrenics (N=14)

Controls (N=15)

Left

Right

Left

Right

Whole Cortex

1.29±0.31

1.22±0.30

1.26±0.24

1.16±0.26

Frontal cortex

1.14±0.30

1.22±0.31

1.17±0.24

1.16±0.25

Temporal cortex

1.22±0.48

0.99±0.29

1.21±0.34

1.00±0.24

Parietal cortex

1.40±0.49

1.22±0.30

1.34±0.33

1.15±0.26

Occipital cortex

1.40±0.46

1.27±0.36

1.41±0.48

1.25±0.33

From Trichard et al, 1998a.

It has been postulated that atypical antipsychotics have in common the ability to bind extensively to 5-HT2A receptors at therapeutic doses (Meltzer, 1989). Atypical antipsychotics are clinically defined as those antipsychotic drugs that present less induction of parkinsonian-like adverse events and therapeutic activity on certain symptoms (such as primary negative symptoms) usually not very sensitive to standard antipsychotic agents. These include risperidone, clozapine, olanzapine, amisulpride and quetiapine. To test this 5-HT hypothesis in vivo, binding to 5-HT2A receptors for different antipsychotic agents was measured, both for atypical (clozapine and amisulpride) and for typical (chlorpromazine) within the antipsychotic dose range, in 26 patients treated for schizophrenia (Trichard et al, 1998a). Like clozapine, chlorpromazine, at high doses, was shown to bind to 5-HT2A receptors, whereas amisulpride, over its entire dose range, did not (Figures 6.4 and 6.5). Thus, at therapeutic doses, clozapine is not unique in binding to 5-HT2A receptors, and affinity for this receptor does not seem to be a prerequisite for atypical antipsychotic activity.

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Figure 6.4 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 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 colour code refers to the percentage of injected radioactivity per litre of tissue (%IA/l). Striatum: compare an antipsychotic-free schizophrenic patient ((a) top), and

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patients treated with 600 mg/day of chlorpromazine ((b) top), 500 mg/day of clozapine ((b) bottom) or 600 mg/day of amisulpride ((a) bottom). 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 the 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 clozapine-treated patient could therefore be explained by the lower affinity of clozapine for dopamine D2 receptors than that of chlorpromazine. (Adapted with permission from Trichard et al, 1998a.) Evidence for dopaminergic specificity: responses to treatment The previous brain imaging results, illustrating the possible relationship between the dopaminergic system and certain negative symptoms in schizophrenia, on the one hand, and the absence of a relationship between 5-HT2A receptors and therapeutic specificity, has led us to re-evaluate the efficacy of low-dose amisulpride in schizophrenia. Data obtained from experimental animals (Guyon et al, 1993) suggest that the effect of low doses of amisulpride may involve dopaminergic facilitation, due to blockade of D2 or D3 dopamine autoreceptors, for which this compound has one of the highest affinities (Sokoloff et al, 1991). We therefore evaluated the efficacy of low-dose amisulpride on the negative dimension in 20 young subjects presenting with untreated hebephrenic schizophrenia (Paillère-Martinot et al, 1995). The patients were randomized into two groups of 10 subjects, to receive, in a double-blind design, either a very low dose (50–100 mg/day) or a placebo for 6 weeks. The patients studied had negative symptoms characterized by blunting of affect, avolition and anhedonia, as measured by the SANS rating scale. Data analysis showed a significant improvement in negative symptoms (total score on SANS)

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with amisulpride, with a more pronounced effect for subscales of avolition and attention deficit, and for the factor of psychomotor expressiveness previously described.

Figure 6.5 Relationship between available cortical 5-HT2A binding sites and plasma concentrations of chlorpromazine. The solid line represents the linear regression between the chlorpromazine dose and the percentage of available binding sites. (Adapted from Trichard et al, 1998a.) This shows that these negative symptoms are sensitive to treatment and supports the hypothesis of a link between these symptoms and decreased dopaminergic function. It should be noted that symptoms of avolition (lack of will power) and anhedonia manifest at the onset of overt clinical disease, reported as having poor prognostic potential in case of initial psychotic episode (Paillère-Martinot et al, 2000), and unrelated to the striatal D2 receptor occupancy index (Martinot et al, 1994), were not responsive to treatment. These clinical findings were completed by PET studies of the D2 dopamine receptor binding in the same patients. Eleven of these (active treatment with 50–100 mg/day N=7, or placebo N=4) were evaluated using [76Br]bromolisuride PET, both before and 3 weeks after treatment to examine treatment-related binding to striatal D2 receptors. In order to obtain a dose-receptor binding curve of this compound within the therapeutic dose range, this group was supplemented with four additional patients presenting with more productive symptoms and treated in an open-label design with higher doses of amisulpride.

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In patients treated with placebo, ratios of the binding density indices (before and during placebo treatment) were significantly correlated (r=0.92), showing a 5.8% testretest variability. Patients with negative symptoms, treated with low doses, presented a D2 receptor occupancy ranging between 4% and 26%. In these patients, the before-after treatment ratios were not significantly different, nor were they different from values obtained with placebo. 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 a high selectivity (Scatton et al, 1997). Furthermore, the data obtained from the four patients with productive symptoms demonstrate a curvilinear relationship between striatal D2 receptor occupancy and the therapeutic dose administered. In vivo studies in medicated patients had previously shown that treatments with traditional antipsychotic compounds such as haloperidol, consistently

Figure 6.6 Evaluation of striatal D2 dopamine receptor blockade by variable doses of amisulpride, using PET. [76Br]Bromolisuride PET was used to determine receptor occupancy. The arrows show the range of optimal doses (between 630 and 910 mg/day) and the dose for which the risk of adverse events is higher (approximately 1100 mg/day). (Data reproduced with permission from Martinot et al, 1996.)

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induce 70–80% occupancy of the striatal D2 receptors (Martinot et al, 1990). Work by Professor Sedvall’s team in Sweden has demonstrated that optimum binding to striatal D2 receptors for an antipsychotic effect without undesirable extrapyramidal side effects should be 70–80% (Farde et al, 1992). Therefore, the data with amisulpride would suggest that such a level of receptor occupancy would require a dose of 600–900 mg/day for optimal management of productive symptomatology (Martinot et al, 1996; Figure 6.6). This optimum therapeutic range was subsequently confirmed by results of a doseranging study conducted on 319 patients treated with amisulpride or haloperidol (Puech et al, 1998). Evidence for regional specificity: binding of typical and atypical antipsychotic agents in different brain regions In order to supplement results on binding of amisulpride to striatal D2 dopamine receptors (obtained with [76Br]bromolisuride, a ligand specific to these receptors having a nanomolar affinity), and to understand better the mechanisms underlying its antipsychotic effect, we sought to determine the effect of this drug on binding to D2 receptors in cortical regions, in particular the temporal lobe. The density of dopamine receptors in these regions is much lower than in the striatum, so it was necessary to develop a more sensitive imaging technique. To achieve this, [76Br]FLB457, a new marker for D2 receptors with picomolar affinity, was developed. The binding of amisulpride to extrastriatal receptors could then be evaluated with [76Br]FLB457 PET (Xiberas et al, 2001a). Eight schizophrenic patients treated with amisulpride at doses ranging from 50 mg/day to 1200 mg/day for at least five half-lives of the medication were evaluated, and binding to D2 receptors measured in the thalamus, temporal cortex and striatum.

Figure 6.7 Binding of amisulpride to corticolimbic and striatal dopamine receptors. PET images were obtained

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using [76Br]FLB457. The colour scale represents normalized concentrations of the radioligand in different regions. An elevated radioactivity represents low blockade of D2 receptors and vice versa, (a) Images from an untreated subject; (b) images from a patient with a low plasma concentration of amisulpride (61 ng/ml); (c) images from a patient with elevated concentrations of amisulpride (390 ng/ml). (a—c top) The striatum is visible in red. (a—c bottom) 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 dosedependent with this medication. Reproduced with permission from Xiberas et al, 2001a.)

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Figure 6.8 Relationship between dopamine D2 receptor occupancy and plasma amisulpride concentration. The curves were obtained by best-fit nonlinear regression analysis, (a) Binding index (BI) in the temporal cortex. BI=90.47*Plasma/(20.02+Plasma) (R2=0.83); the arrow on the curve in (a) indicates a patient with atrophy, (b) Binding index in the thalamus. BI=97.50*Plasma/(24.02+Plasma) (R2=0.94). (c) In the striatum, the precision of the fit of the curve was impaired by patients with the lowest plasma concentrations whose binding indices were very low. (Data reproduced with permission from Xiberas et al, 2001a.) A curvilinear relationship was observed between the binding of the radioligand to D2 receptors and plasma concentrations of amisulpride. The estimated occupancy of

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extrastriatal D2 receptors in the temporal cortex ranged from 50% to 60%, even for very low doses such as 50 mg/day (corresponding to plasma concentrations 30–61 ng/l), which did not result in pronounced binding to D2 striatal receptors. At higher doses of amisulpride (above 100 ng/l plasma concentration), at which extrapyramidal side effects may frequently appear, the estimated occupancy was 80–95% in the temporal lobe, with concomitant striatal binding of 35–60% (Xiberas et al, 2001a; Figures 6.7 and 6.8). This study was the first to investigate the action of amisulpride on cortical dopamine receptors using PET. The results suggest that the antipsychotic effects, both towards positive and negative symptoms, are probably to a large extent mediated by an action on dopamine receptors in cortical and corticolimbic areas. As a result of the characteristic profile of this drug, which is highly selective for dopaminergic systems, the therapeutic significance of its impact on this neurotransmitter system could be assessed.

Figure 6.9 Binding of haloperidol and three atypical antipsychotics to D2 dopamine receptors in the striatum and temporal cortex. Data are presented as per cent binding index measured by PET with [76Br]FLB457 following administration of standard doses of haloperidol (3–60 mg/day) and atypical antipsychotic agents (risperidone, 6–12 mg/day; clozapine, 200–400 mg/day; amisulpride, 400– 1200 mg/day; olanzapine, 5–20 mg/day). (Data reproduced with permission from Xiberas et al, 2001b.) To investigate further the regional specificity of antipsychotic agents for the D2 dopamine receptor in vivo, the binding of [76Br]FLB457 to cortical D2 receptors in patients treated with standard doses of the typical antipsychotic agent haloperidol, and of

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three atypical antipsychotic agents, risperidone, clozapine and olanzapine, was evaluated (Xiberas et al, 2001b). Chronically treated patients, receiving stable maintenance doses of the drugs were selected to study the therapeutic dose range. All the antipsychotics, both typical and atypical, bound to D2 receptors in the temporal cortex to a comparable extent, occupying 72–97% 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 6.9). Conclusions A so-called ‘atypical’ antipsychotic agent is defined as a compound with an antipsychotic effect which is at least equal to that of a standard antipsychotic agent such as haloperidol, but which produces few or no extra pyramidal side effects or tardive dyskinesia. It has been suggested that the superior adverse event profile of these drugs may be related to their preferential action on mesolimbic and mesocortical dopamine receptors rather than striatal receptors. Our results, obtained at therapeutically relevant doses, support this hypothesis. On the whole, the data from imaging studies strongly suggest that cortical D2 dopamine receptors are a common target of both traditional and atypical antipsychotic drugs as far as their therapeutic action is concerned. Thus, a putative antipsychotic drug with a high in vivo occupation index for D2 receptors in the (temporal) cortex, concomitantly associated with a lower occupation index in the basal ganglia could therefore present a favourable benefit-risk profile. Although the cortical D2 dopamine receptor is an interesting target for antipsychotic action, other sites in the cortex are related to the pathophysiology of the disorder. For instance, recently a dysfunction in the anterior cingulate cortex (Artiges et al, 2000) was reported, a region whose gyrification appears abnormal in a number of patients with schizophrenia (Le Provost et al, 2002). Therefore, the impact of D2 receptor occupancy by antipsychotic drugs in the (temporal) cortex, on the activity of other cerebral regions may be important to consider. References Akil M, Pierri JN, Whitehead RE et al. (1999) Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry 156:1580–9. Artiges E, Salamé P, Recasens C et al. (2000) The working memory control component in patients with schizophrenia: a PET study with random generation. Am J Psychiatry 157:1517–19. Baxter LR, Jr, Phelps ME, Mazziotta JC et al. (1985) Cerebral metabolic rates for glucose in mood disorders. Studies with positron emission tomography and fluorodeoxyglucose F 18. Arch Gen Psychiatry 42:441–7. Carlsson A, Lindqvist M. (1963) Effect of chlorpromazine and haloperidol on formation of 3methyltyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 20:140–4. Carpenter WT, Jr, Heinrichs DW, Wagman AM. (1988) Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry 145:578–83.

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Creese I, Burt DR, Snyder SH. (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. J Neuropsychiatry Clin Neurosci 8:223– 6. Crow TJ. (1985) The two-syndrome concept: origins and current status. Schizophrenia Bull 11:471–86. Dao-Castellana MH, Paillère-Martinot ML, Hantraye P et al. (1997) Presynaptic dopaminergic function in the striatum of schizophrenic patients. Schizophrenia Res 23:167–74. Delforge J, Loc’h C, Hantraye P et al. (1991) Kinetic analysis of central [76Br]bromolisuride binding to dopamine D2 receptors studied by PET. J Cereb Blood Flow Metab 11:914–25. Farde L, Nordström AL, Wiesel FA et al. (1992) Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical antipsychotics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 49:538–44. Farde L, Gustavsson JP, Jonsson E. (1997) D2 dopamine receptors and personality traits. Nature 385:590. Gerlach J, Luhdorf K. (1975) The effect of L-dopa on young patients with simple schizophrenia, treated with antipsychotic drugs: a double-blind cross-over trial with Madopar and placebo. Psychopharmacologia 44:105–10. Guyon A, Assouly-Besse F, Biala G, Puech AJ, Thiebot MH. (1993) Potentiation by low doses of selected antipsychotics of food-induced conditioned place preference in rats. Psychopharmacology (Berl) 110:460–6. Hietala J, Syvalahti E, Vuorio K et al. (1995) Presynaptic dopamine function in striatum of antipsychotic-naive schizophrenic patients. Lancet 346:1130–1. Hietala J, Syvalahti E, Vilkman H et al. (1999) Depressive symptoms and presynaptic dopamine function in antipsychotic-naive schizophrenia. Schizophrenia Res 35: 41–50. Johnstone EC, Crow TJ, Frith CD, Carney MW, Price JS. (1978) Mechanism of the antipsychotic effect in the treatment of acute schizophrenia. Lancet i:848–51. Keefe RS, Harvey PD, Lenzenweger MF et al. (1992) Empirical assessment of the factorial structure of clinical symptoms in schizophrenia: negative symptoms. Psychiatry Res 44:153–65. Kulhara P, Chadda R. (1987) A study of negative symptoms in schizophrenia and depression. Compr Psychiatry 28:229–35. Laakso A, Vilkman H, Kajander J et al. (2000) Prediction of detached personality in healthy subjects by low dopamine transporter binding. Am J Psychiatry 157: 290–2. Laruelle M, Abi-Dargham A, van Dyck CH et al. (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 93:9235–40. Le Provost JB, Bartrés-Faz D, Paillère-Martinot ML et al. (2002) Paracingulate sulcus in men with early-onset schizophrenia. Br J Psychiatry 182:228–32. Liddle PF. (1987) The symptoms of chronic schizophrenia. A re-examination of the positivenegative dichotomy. Br J Psychiatry 151:145–51. Mackay AV. (1980) Positive and negative schizophrenic symptoms and the role of dopamine. Br J Psychiatry 137:379–83. Martinot JL, Paillère-Martinot ML, Loc’h C et al. (1990) Central D2 receptor blockade and antipsychotic effects of neuroleptics. Preliminary study with PET. Psychiatr Psychobiol 5:231– 40. Martinot JL, Paillère-Martinot ML, Loc’h C et al. (1991) The estimated density of D2 striatal receptors in schizophrenia. A study with positron emission tomography and 76Brbromolisuride. Br J Psychiatry 158:346–50. Martinot JL, Paillère-Martinot ML, Loc’h C et al. (1994) Central D2 receptors and negative symptoms of schizophrenia. Br J Psychiatry 16:27–34. Martinot JL, Paillère-Martinot ML, Poirier MF, Dao-Castellana MH, Loc’h C, Maziere B. (1996) In vivo characteristics of dopamine D2 receptor occupancy by amisulpride in schizophrenia. Psychopharmacology (Berl) 124:154–8.

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Meltzer HY. (1989) Clinical studies on the mechanism of action of clozapine: the dopamineserotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 99(Suppl):S18–S27. Meltzer HY. (1995) Clozapine: is another view valid? Am J Psychiatry 152:821–5. Paillère-Martinot ML, Lecrubier Y, Martinot JL, Aubin F. (1995) Improvement of some schizophrenic deficit symptoms with low doses of aminsulpride. Am J Psychiatry 152:130–4. Paillère-Martinot ML, Aubin F, Martinot JL, Colin B. (2000) A prognostic study of clinical dimensions in adolescent-onset psychoses. Schizophrenia Bull 26:789–99. Paillère-Martinot ML, Bragulat V, Artiges E, Dolle F, Jouvent R, Martinot JL. (2001) Decreased presynaptic dopamine function in the left caudate of depressed patients with affective flattening and psychomotor retardation. Am J Psychiatry 158: 314–16. Puech A, Fleurot O, Rein W. (1998) Amisulpride, and atypical antipsychotic, in the treatment of acute episodes of schizophrenia: a dose-ranging study vs. haloperidol. The Amisulpride Study Group. Acta Psychiatr Scand 98:65–72. Scatton B, Claustre Y, Cudennec A et al. (1997) Amisulpride: from animal pharmacology to therapeutic action. Int Clin Psychopharmacol 12(Suppl):S29–S36. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC. (1991) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146– 51. Trichard C, Paillère-Martinot ML, Attar-Levy D, Blin J, Feline A, Martinot JL. (1998a) No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET. Schizophrenia Res 31:13–7. Trichard C, Paillère-Martinot ML, Attar-Levy D, Recassens C, Monnet F, Martinot JL. (1998b) Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients. Am J Psychiatry 155:505–8. Widlöcher D, Ghozlan A. (1989) The measurement of retardation in depression. In: (Hindmarch I, Stonier PD, eds.) Human Psychopharmacology: Measures and Methods, Vol 2. (John Wiley & Sons: New York). Willner P. (1995) Animal models of depression: validity and applications. Adv Biochem Psychopharmacol 49:19–41. Wong DF, Wagner HN, Jr, Tune LE et al. (1986) Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234: 1558–63. Xiberas X, Martinot JL, Mallet L et al. (2001a) In vivo extrastriatal and striatal D2 dopamine receptor blockade by amisulpride in schizophrenia. J Clin Psychopharmacol 21:207–14. Xiberas X, Martinot JL, Mallet L et al. (2001b) Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry 179:503–8.

chapter 7 Dopamine, the prefrontal cortex, and a genetic mechanism of schizophrenia Daniel Weinberger Dopamine (DA) has been the centrepiece of schizophrenia research for over three decades. Evidence that antipsychotic drugs increase presynaptic DA metabolism, that they block dopamine receptors, and that dopamimetic drugs are psychotogenic led to the classic dopamine hypothesis of schizophrenia (Carlsson, 2001). In its earliest version, the dopamine hypothesis proposed that DA levels were increased in patients with schizophrenia. The initial tests of this hypothesis involved assays of DA and metabolites in peripheral fluids (e.g. blood, urine and CSF (cerebrospinal fluid)) and directly in postmortem brain tissue. In the main, these efforts were not confirmatory of increased DA levels, turnover, or metabolism (Laruelle, 2003). A variation on the DA theme soon emerged, suggesting that while DA metabolism might not be abnormal, there might be increased numbers of DA receptors in the striatum, primarily D2 receptors, the targets of antipsychotic drugs. While some studies of D2 receptor ligand binding both in post-mortem tissue and in vivo with PET (positron emission tomography) scanning found evidence of an abundance of D2 receptors (Bmax), the majority of studies did not, particularly if the effects of prior treatment with antipsychotic drugs were excluded (Kleinman et al, 1988; Laruelle, 2003). As novel DA receptor proteins were identified, investigators attempted to demonstrate increases in their numbers, again, with largely negative results (Murray et al, 1995). A third variation of the DA hypothesis emerged in the mid-1980s based on evidence that DA activity in the striatum was regulated by feedback from prefrontal cortex and that increased striatal DA activity could represent a loss of normal cortical regulation (Weinberger et al, 1986; Weinberger, 1987; Davis et al, 1991; Grace, 1993). Clinical studies increasingly implicated abnormal prefrontal cortical function as a primary abnormality in schizophrenia and also as a possible biological manifestation of genetic susceptibility, raising the possibility that DA neuronal activity might be abnormal as a ‘downstream’ effect of a primary cortical abnormality. This formulation appeared to reconcile much of the old and the new evidence implicating DA as playing a role in the pathophysiology of schizophrenia. In support of this latest version of the DA hypothesis is evidence of increased responsiveness of DA terminals to amphetamine administration in actively psychotic patients studied with D2 radioligand receptor imaging and PET (Laruelle et al, 1996; Breier et al, 1997), evidence of increased uptake of the DA precursor, DOPA (dihydroxyphenylalanine), also studied with PET (Reith et al, 1994; Hietala et al, 1995; Lindstrom et al, 1999; Meyer-Lindenberg et al, 2002), and the finding that both of these DA abnormalities are predicted in patients by measures of prefrontal cortical neuronal function (Bertolino et al, 2000a; Meyer-Lindenberg et al, 2002).

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A further elaboration of this version of the hypothesis implicates DA signalling at the prefrontal cortical level as a possible factor in the abnormal prefrontal function associated with schizophrenia (Weinberger et al, 1986; Weinberger, 1987). Evidence of diminished prefrontal cortical DA activity has been found in imaging studies of living subjects (Weinberger et al, 1988; Abi-Dargham et al, 2002) and decreased prefrontal DA innervation has been observed in post-mortem tissue (Akil et al, 1999). To make the elements of the story even more convergent, animal studies show that diminished prefrontal DA signalling is one of the factors that leads to a downstream upregulation of striatal DA activity (Jaskiw and Weinberger, 1992). In this chapter, the evidence that supports the latter version of the role of DA in schizophrenia will be reviewed. This version has offered not only a potentially mechanistic account of the relationship of prefrontal cortical dysfunction—a putatively primary pathophysiological aspect of schizophrenia—with upregulated striatal DA activity, but also a conceptual orientation for understanding the first genetic mechanism of risk for schizophrenia. First, the evidence that prefrontal cortical dysfunction is a primary factor in schizophrenia will be discussed; second, that prefrontal cortical dysfunction leads to a loss of tonic inhibition of striatal DA activity; and last, that these two scenarios represent the biological mechanism by which a variation in the COMT (catechol-O-methyltransferase) gene increases risk for schizophrenia. Prefrontal cortical malfunction as a primary deficit in schizophrenia The evidence of abnormal prefrontal cortical function in patients with schizophrenia is overwhelming. It includes data from many studies of neuropsychological and cognitive function (e.g. (Goldberg and Weinberger, 1988; Goldberg et al, 1988; Park and Holzman, 1992; Barch and Carter, 1998; Weickert et al, 2000), from neuroimaging (Ingvar and Franzen, 1974; Weinberger et al, 1986, 1988, 1992; Berman et al, 1992; Andreasen et al, 1996; Callicott et al, 1998, 2000b; Carter et al, 1998; Curtis et al, 1998; Stevens et al, 1998; Manoach et al, 1999), from studies of eye movements (Holzman et al, 1973; Shagass et al, 1974; Cegalis and Sweeney, 1979; Litman et al, 1997), and from electrophysiological studies (Abrams and Taylor, 1979; Karson et al, 1987; Guenther et al, 1988; Tauscher et al, 1998). An example of a functional magnetic resonance imaging (fMRI) study is presented in Figure 7.1. The presence of most of these abnormalities is not predicted by chronicity of illness or by the length of treatment. However, there is considerable variation, especially in the physiological data, depending on clinical state and on the nature of the experimental paradigm. Since the landmark report of reduced frontal lobe regional cerebral blood flow (rCBF) (i.e. ‘hypofrontality’) (Ingvar and Franzen, 1974), many studies have reported reduced prefrontal physiological activity in patients with schizophrenia (for a review, see Callicott and Weinberger, 1999). This result has been especially consistent during so-called executive cognition and working memory tasks, which are thought to depend on prefrontal activation (e.g. Weinberger et al, 1986, 1988; Berman et al, 1992; Catafau et al, 1994; Callicott et al, 1998; Carter et al, 1998; Stevens et al, 1998). It has been noted, however, that in most of these studies patients tended to perform less accurately than normals, leaving open the question of whether underactivation in the context of

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underperformance is necessarily an abnormal response. Studies of normal subjects pushed beyond their working memory capacities have suggested that this response in the patients is not pathological, per se (Goldberg et al, 1998; Callicott et al, 1999), although the diminished capacity of patients to perform prefrontal type tasks appears to be.

Figure 7.1 Hyperfrontality ‘inefficiency’ in schizophrenia. The images represent difference maps in fMRI activation between controls (N=13) and schizophrenics (N=18), with areas of significant differences indicated in red. In schizophrenics efficiency was markedly reduced in the dorsolateral prefrontal cortex (circled). (From Callicott et al, 2000b.) Another approach to characterize the prefrontal physiological abnormality in schizophrenia is to study patients whose working memory performance is or is near normal. Several recent fMRI studies of such patients have appeared and the results are surprisingly consistent in not showing hypofrontality (Stevens et al, 1998; Curtis et al, 1999; Manoach et al, 1999, 2000; Callicott et al, 2000b). Indeed, when patients are able to keep up with the information processing demands, their prefrontal response also tends to be abnormal, but in a surprisingly different manner. Under these circumstances, they overactivate their dorsolateral prefrontal cortices (DLPFC). In other words, when they can keep up with the demand, they process information less efficiently for a given level of performance accuracy. The neuronal circuitry involved in handling the information appears to have a poorer signal to noise (STN) response, and has more difficulty honing the most efficient or automatic neural strategy. This is analogous to the recruitment of

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extraneous neural activity that occurs in the early phases of a variety of learning paradigms; neural activation becomes more focused once a strategy for processing the information has become more automatic and efficient (Andreasen et al, 1995; Mattay et al, 1996; Dinse et al, 1997; Van Horn et al, 1998). Thus, patients with schizophrenia have abnormal prefrontal cortical function during performance of prefrontal cognitive tasks, regardless of their level of performance, but the ‘flavour’ of the abnormality does vary depending on how they are managing the demands of the task. They have diminished capacity to stay on task, which is represented as hypofrontality, and they have diminished STN within the prefrontal cortex when they are able to keep up with the task, which is seen in functional neuroimaging studies as hyperfrontality. The degree to which a patient or patient group will manifest either or both of these abnormalities will likely depend on the capacities of the patients and the characteristics of the task paradigm. The evidence from functional neuroimaging studies has been further elaborated by data from an in vivo intraneuronal neurochemical assay technique, proton magnetic resonance spectroscopy (MRS). MRS is the only clinically available method for the direct measurement of chemical moieties in the living brain. Proton MRS has been used to measure N-acetyl aspartate (NAA), an intracellular neuronal marker that indirectly reflects neuronal synaptic abundance. NAA is found almost exclusively in mature neurones and their processes (Urenjak et al, 1993), with highest concentrations in pyramidal glutamate neurones (Moffett and Namboodiri, 1995). NAA is a non-specific although sensitive measure of neuronal pathology, and NAA concentrations reflect mitochondrial energy metabolism and oxidative phosphorylation (Clark, 1998; Jenkins et al, 2000). As mitochondrial oxidative phosphorylation is driven in large part by synaptic activity, NAA levels appear to reflect the relative abundance of neuronal processes and synapses, which vary as a function of the connectivity, integrity and ‘health’ of neurones. Most studies of NAA concentrations in the brains of patients with schizophrenia have found reductions in DLPFC as well as some other regions, especially the hippocampal formation (for review see Weinberger and Laruelle, 2002). Again, the results are not dependent on stage of illness, chronicity or treatment history. The NAA data are consistent with a number of findings in the post-mortem literature implicating abnormalities of neuronal connectivity in prefrontal cortex, including decreased neuronal soma size and neuropil volume, decreased expression of a variety of synaptic markers (Lewis et al, 2001) and decreased expression of glutamate carboxypeptidase, an enzyme involved in NAA synthesis (Tsai et al, 1995). Taking NAA to be a measure of the overall synaptic abundance and functional connectivity of prefrontal neurones, investigators have asked whether the apparent cellular abnormality predicts other clinical and biological phenomena associated with manifest illness. Bertolino et al (2000b) measured NAA in various brain regions in patients who had also undergone PET rCBF studies of cortical activation during two different executive cognition paradigms (Bertolino et al, 2000b). They found that in patients who manifested the hypofrontality response, activation of the distributed working memory cortical network was predicted directly by NAA concentrations in DLPFC, i.e. the lower the DLPFC NAA, the lesser the activation of prefrontal, parietal, and cingulate cortices during the tasks (i.e. the more hypofrontal). Callicott et al (2000a) measured NAA in patients who showed the abnormal prefrontal overactivation response. Again, they found that the abnormal physiological response was predicted by NAA

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concentrations in DLPFC, i.e. the lower the DLPFC NAA, the greater the DLPFC activation. NAA concentrations in other brain regions or in normal subjects did not predict either of the abnormal physiological responses. The data of Bertolino et al (2000b) and Callicott et al (2000a) implicate a population of neurones in the DLPFC as being specific ‘effectors’ of the abnormal physiological activity of the working memory cortical network in schizophrenia, both its diminished capacity and its diminished efficiency, and as such, this distributed deficit in cortical function may be an emergent property of abnormal information processing in prefrontal neuronal circuitry. In addition to the foregoing data implicating abnormal prefrontal cortical information processing and cellular architecture as primary aspects of schizophrenia, considerable evidence also points to abnormal function of prefrontal cortex as a phenotypic expression of genetic risk for schizophrenia. In studies of MZ (monozygotic) twins discordant for schizophrenia, Goldberg and colleagues (Goldberg et al, 1993, 1995) found deficits in the unaffected twins in executive cognition/working memory, suggesting that shared genes accounted for these deficits, even though not accounting for the presence of illness, per se. In a study of MZ and DZ (dizygotic) twins discordant for schizophrenia, Cannon et al (2000) showed that the risk for working memory deficits was greater in MZ than in DZ twins, suggesting that the working memory deficits were heritable. In a large sample of healthy siblings of patients with schizophrenia (N=183), Egan et al (2000) found that working memory/executive function deficits were up to four times more frequent in the siblings as in the general population. Similar results also have been reported by other groups in smaller sibling samples (Yurgelun-Todd and Kinney, 1993; Cannon et al, 1994; Faraone et al, 1999). Finally, using the neuroimaging paradigm that has revealed evidence of inefficient prefrontal function in patients with schizophrenia, Callicott et al (2002) have reported that such physiological deficits are also found in healthy siblings of patients with schizophrenia who have no deficits in task performance. These various findings demonstrate that abnormal prefrontal cortical information processing is associated not just with schizophrenia, but also with increased genetic risk for schizophrenia and, thus, may be a reflection of the biological effects of susceptibility genes. DA and prefrontal cortical function The relatively high density of dopaminergic innervation of the striatum and the relatively sparse projections to the prefrontal cortex encouraged many DA researchers to focus on the striatal DA system. Some investigators interpreted the low concentrations of prefrontal DA to mean that DA played little if any role in the cortex. However, the landmark study of Brozoski et al (1979) demonstrated that the DA innervation of the prefrontal cortex in the primate plays an important role in prefrontal cortical function during tasks that involve working memory and executive cognition. The study showed that depleting prefrontal cortex of DA produced deficits on such tasks that were analogous to those seen after surgical ablations. Over the following decades, studies of cortical DA function have confirmed that it is critically important for modulating aspects of local prefrontal cortical circuitry, particularly the STN of information processing during working memory and other so-called executive cognitive functions.

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DA modulates prefrontal activity by affecting the excitability of pyramidal (glutamatergic) and local circuit (GABA, γ-aminobutyric acid) neurones. DA afferents to pyramidal neurones synapse on dendritic spines in close proximity to glutamate inputs from other cortical neurones, particularly inputs from hippocampal formation (Carr and Sesack, 1996). DA inputs to the dendritic shafts of local circuit neurones also appear to be in close proximity to glutamate terminals (Sesack et al, 1995). These anatomical observations suggest that DA gates the excitatory impact of associative cortical information mediated by intracortically projecting glutamate neurones and by locally recurrent collaterals of pyramidal neurones. The results of physiological experiments in behaving rats and monkeys support this notion, showing that DA neurones improve the signal to noise response characteristics of pyramidal neurones in a variety of behavioural contexts, including stress, reward, working memory and various learning paradigms (Schultz et al, 1993; Williams and Goldman-Rakic, 1995; Gurden et al, 1999; Schultz and Dickinson, 2000). Imaging studies in humans also have shown that pharmacological manipulation of DA activity improves prefrontal physiological STN during executive cognition and working memory tasks (Daniel et al, 1991; Mattay et al, 1996, 2000). The mechanisms by which DA modulates STN in local prefrontal information processing circuits have been studied with patch-clamp electrochemical techniques and also with computational modelling. These investigations suggest that the pattern of excitatory and inhibitory inputs to pyramidal neurones is critical for shaping the selectivity (i.e. SNR (signal/noise ratio)) of neural activity in these circuits. Electrochemical techniques have revealed that D1 receptor activation enhances N-methylD-aspastate (NMDA) and reduces AMPA postsynaptic currents in prefrontal pyramidal neurones (Yang et al, 1996; Zheng et al, 1999; Seamans et al, 2001) and also enhances a persistent Na+ current, while reducing a slowly inactivating K+ current and a dendritic Ca2+ current (Seamans et al, 1997). These effects are thought to potentiate responses related to coincident associations and to reduce responses to less relevant stimuli (i.e. distractions), as might be optimum during working memory. In the computational models of Durstewitz et al (2000), these dopaminergic effects should lead to an input-specific increased firing rate of delay-active neurones (i.e. increase of SNR during delay-type tasks), and reducing activity related to other stimuli (i.e. decrease in noise). The network simulation studies of Brunel and Wang (2001) predicted that activity of prefrontal excitatory-inhibitory circuits are protected against distracters by dopaminergic mechanisms in an inverted U-shaped function, consistent with physiological studies in animals in which either too much or too little D1 receptor mediated signalling can impact negatively on working memory performance and prefrontal neuronal activity (Williams and Goldman-Rakic, 1995; Cai and Arnsten, 1997; Zahrt et al, 1997). DA also may enhance STN by increasing GABA neurone excitation and effective local surround inhibition. The electrochemical studies of Seamans et al (2001) demonstrated that D1 agonists cause a delayed and long-lasting increase of the intrinsic excitability of interneurones, an effect that—together with the direct modulation of pyramidal neurone excitability—might serve to stabilize a contextually critical set of strongly active representations and diminish the probability of a response to additional inputs and noise (Figure 7.2). At the same time, weakly active representations of stimuli would be suppressed. These various experimental and computational models of the effects of dopamine signalling in prefrontal cortex indicate that an abnormality in DA

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signalling could be a factor in the abnormal prefrontal STN found in schizophrenia and in association with genetic susceptibility for the illness (Box 7.1).

Figure 7.2 DA signalling in the prefrontal cortex: a cellular substrate of the STN ratio? DA biases pyramidal neurones to respond to sustained or consistent (i.e. salient) inputs and not to transient inputs. In this way, DA focuses and stabilizes the response network. The D1 receptor is the relevant receptor subtype here. When D1 receptor function is suboptimal, as in (a), salient signals are not recognized and the STN ratio increases, (b) Optimal D1 receptor signalling. PFC, prefrontal cortex. (Adapted with permission from Seamans et al, 2001.) In fact, there is direct evidence that DA signalling in the prefrontal cortex is abnormal and diminished in schizophrenia. Studies of CSF concentrations of HVA (homovanillic acid), the principal metabolite of DA in the primate, have found reduced concentrations in patients with schizophrenia (Lindstrom, 1985). At the time, these were counterintuitive results, because the traditional DA hypothesis predicted that HVA concentrations should be increased, at least in the striatum. Studies in monkeys indicated that HVA levels in the CSF were correlated with DA metabolism in the cortex, and not in the striatum (Elsworth et al, 1987), but this fact was not known to the investigators of the original CSF studies. The first direct link between abnormal prefrontal cortical function in schizophrenia and

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Box 7.1 Some cellular effects of DA signalling in the prefrontal cortex Enhanced physiological STN ‘Tuning’ of pyramidal neuronal responses during working memory Enhanced NMDA currents in pyramidal neurones Reduced non-NMDA currents in pyramidal neurones Enhanced GABA neurone excitability prefrontal DA signalling came from a study of cortical rCBF during an executive cognition task. Weinberger et al (1988) reported that CSF HVA levels strongly predicted activation of the DLPFC during an executive cognition task, with no correlation during a task in which prefrontal DA function was not known to be critical (Figure 7.3). Akil et al (1999) measured the expression of the TH (tyrosine hydroxylase) protein with immunocytochemistry in brain specimens and reported decreased immunostaining in patients with schizophrenia. This study suggested an anatomical basis for the apparent functional deficiency in prefrontal DA signalling. The results of two recent neuroimaging studies of the abundance of prefrontal D1 receptors also have been interpreted to reveal decreased cortical DA signalling, but the results are not clearly consistent. Okubo et al (1997), using a non-specific D1 receptor ligand, reported decreased radioligand binding in DLPFC, and the degree of the reduction

Figure 7.3 Prefrontal DA function predicts prefrontocortical function in schizophrenics. Relationship between rCBF and levels of HVA in the CSF in schizophrenics during (a) control task, and (b) while carrying out an executive task. (Adapted with permission from Weinberger et al, 1988.)

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predicted executive cognition deficits. Abi-Dargham et al (2002), using a specific D1 PET imaging agent, found increased receptor density and a correlation with working memory deficits. The latter group interpreted their findings to reflect an upregulation of postsynaptic receptors faced with diminished afferent input. DA depletion studies in animals support this interpretation. However, the inconsistencies in the receptor binding data are not explained, and a study, which found no difference between patients and normal controls, has also been reported (Karlsson et al, 2002). Notwithstanding the inconsistencies in the D1 imaging data, there is independent evidence of decreased DA signalling in prefrontal cortex of patients with schizophrenia (Weinberger et al, 1988; Akil et al, 1999). This may be a factor that contributes to the deficits in prefrontal cortical STN found in these patients. It is interesting to note that diminished DA innervation in animals is associated with reduced spine density and dendritic arborization of target neurones (Ingham et al, 1998), both of which are findings reported in the post-mortem schizophrenic brain (Lewis, 1997). Decreased prefrontal cortex DA signalling may be a pathophysiological aspect of the illness and it may be a risk factor for illness. Alternatively or in addition, it may be an epiphenomenon of the state of illness. DA terminals are particularly sensitive to stress, both in terms of release of neurotransmitter and in terms of becoming depleted of neurotransmitter (Puglisi-Allegra et al, 1991). Recent evidence about the lack of DA transporter expression in cortical synapses (vide infra) may explain their sensitivity to depletion, as DA in cortical terminals appears to be synthesis dependent and not recycled via reuptake and repackaging into secretory vesicles. Thus, psychosis itself, or perhaps the chronic stress of managing complex environmental circumstances in the face of compromised prefrontal resources, may further exacerbate a tendency towards reduced prefrontal DA signalling, thus initiating and perpetuating a vicious cycle of abnormal prefrontal function. Prefrontal cortex function and striatal DA activity DA neurones in the brainstem receive direct excitatory inputs from prefrontal neurones and they also receive prefrontal information indirectly from inhibitory relay neurones in the striatum and in the substantia nigra. Recent anatomical studies in the rat indicate that the topography of these projections is fairly specific. Prefrontal neurones project monosynaptically to DA neurones that return to the prefrontal cortex, indicating feedforward positive control of cortical DA activity. In contrast, cortical projections to DA neurones that project subcortically, e.g. to striatum and amygdala, receive only indirect prefrontal inputs, mediated by GABA intermediates (Carr and Sesack, 2000). This suggests that prefrontal cortex tonically inhibits striatal DA activity (Figure 7.4). Animal studies confirm the functional implications of these connections. In the 1970s, studies by Thierry and colleagues (1978) found that prefrontal lesions increased the hyperlocomotion manifest by animals under stress, assumed to reflect increased striatal DA activity. A landmark study by Pycock et al (1980) showed that DA depletion of prefrontal cortex increased striatal DA turnover. Numerous subsequent reports in rodents and in primates have confirmed that changes in prefrontal function, and specifically variations in DA signalling, impact striatal DA activity in a predictable direction (Jaskiw

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and Weinberger, 1992; Weinberger et al, 2001). The results of these experiments in animals argue that a single mechanism could account for both abnormal prefrontal function (and presumably the cognitive deficits and other negative symptoms that have been associated with this deficit), as well as upregulated striatal DA activity (and the psychotic and other positive symptoms that have been associated with it) (Weinberger et al, 1986; Weinberger, 1987). This proposal is echoed in recent formulations of the cortex serving as a ‘brake’ on the striatal DA system (Carlsson, 2001).

Figure 7.4 Inverse relationship between prefrontal function and striatal dopaminergic activity. The diagram illustrates the neural circuitry underlying the dynamics. For a complete description, see text. GLU, glutamic acid; GABA, γ-aminobutyric acid; DA, dopamine. Remarkably, two neuroimaging studies have found direct evidence for this brake in human beings, and for the conclusion that upregulated striatal DA function in schizophrenia is a downstream manifestation of abnormal cortical information processing. The activity of presynaptic striatal DA terminals has been studied in patients with schizophrenia using three pharmacological imaging protocols: (i) changes in D2 receptor binding after amphetamine administration (Laruelle et al, 1996; Breier et al,

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1997; Abi-Dargham et al, 1998, 2000); (ii) changes in D2 receptor binding after alphamethylparatyrosine (AMPT) administration (Abi-Dargham et al, 2000); and (iii) uptake of f-18fluorodopa (F-DOPA) by striatal DA terminals. Each of these paradigms has revealed evidence of upregulated presynaptic DA function in patients with schizophrenia (Weinberger and Laruelle, 2002). Bertolino et al (2000a) measured NAA concentrations with 1H-MRSI in patients who also underwent the first paradigm. NAA signals in DLPFC, and in no other brain region, strongly predicted the excessive response of striatal DA terminals to amphetamine (r2=0.58) (Bertolino et al, 2000a), i.e. lower DLPFC NAA predicted greater decrease in DA receptor availability after amphetamine administration (i.e. greater apparent amphetamine effect). Meyer-Lindenberg et al (2002) measured the cortical activation response using PET rCBF while patients underwent the third DA neuroimaging paradigm. They found a very strong relationship (r2=0.86) between prefrontal activation and striatal F-DOPA uptake, such that the more abnormal the prefrontal physiologic response, the greater the striatal uptake. These studies strongly implicate a cortical origin for the abnormalities of striatal DA function associated with schizophrenia. Prefrontal DA signalling, the COMT gene and genetic susceptibility If DA modulation of prefrontal cortical neuronal activity is an important factor in prefrontal STN during information processing, it is reasonable to hypothesize that a genetic polymorphism that has an impact on the efficacy of DA signalling in prefrontal cortex would affect prefrontal physiology and prefrontally mediated behaviour. If diminished prefrontal STN during executive information processing is related to genetic susceptibility for schizophrenia, it is reasonable to hypothesize that such a genetic polymorphism would also be a risk factor for schizophrenia. Recent data have implicated the gene for catechol-O-methyltransferase (COMT) as a likely candidate in both respects. Prefrontal DA signalling is critically dependent on presynaptic DA biosynthesis and postsynaptic inactivation, which occurs primarily via diffusion and methylation. The synaptic action of DA in the striatum is terminated primarily by transporter reuptake into presynaptic terminals and recycling into secretory vesicles (Giros et al, 1996). In the cortex, DA transporters appear to play little if any role in DA reuptake (Mazei et al, 2002), and are expressed in low abundance, primary extrasynaptically (Sesack et al, 1998) (Figure 7.5). Presumably as a result, methylation via COMT plays an important role in prefrontal DA metabolism in the cortex, but not in the striatum (Karoum et al, 1994). COMT knockout mice show increases in prefrontal DA levels (Gogos et al, 1998; Houtari, 2002), but no change in striatum and no change in NE levels (consistent with the abundance of prefrontal NE transporters). Moreover, COMT inhibitors improve working memory in rats (Khromova et al, 1997; Liljequist et al, 1997) and in humans (Gasparini et al, 1997) (Box 7.2).

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Figure 7.5 DA synapses in the striatum and the prefrontal cortex. In the striatum, DA 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 extrasynaptic, and DA is eliminated by metabolism by COMT. (Adapted from Sesack et al, 1998.) Thus, changes in COMT activity impact on prefrontal cortical function. In humans, the COMT gene contains a highly functional and common Box 7.2 Effects of COMT in the brain COMT accounts for >60% of DA degradation in the prefrontal cortex but <15% in the striatum (Karoum et al, 1994)

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COMT knockout mice have increased prefrontal DA and enhanced memory (Gogos et al, 1998; Kneavel et al, 2000; Houtari, 2002) COMT inhibitors enhance working memory (Khromova et al, 1997; Liljequist et al, 1997) variation in its coding sequence, at position 472 (guanine-to-adenine substitution), which translates into a valine-to-methionine (val/met) change in the peptide sequence (Lotta et al, 1995; Lachman et al, 1996). 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 (Lotta et al, 1995; Lachman et al, 1996). 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 (Weinshilboum et al, 1999). These data would suggest that individuals with val alleles would have relatively greater inactivation of prefrontal DA and therefore, relatively poorer prefrontal function. Egan et al (2001) found that COMT genotype predicted 4% of the variance in performance on the Wisconsin Card Sorting Test (WCST) in a large sample of subjects (N=458), with the val allele being associated, as predicted, with relatively poorer performance (i.e. more perseverative errors) and heterozygous subjects performing midway between homozygous val/val and met/met subjects (Egan et al, 2001b; Figure 7.6). Since the initial reports of this finding (Weinberger, 2000a, b) at least six other independent studies have reported a similar effect of the COMT genotype on prefrontal cognition (Bilder et al, 2002; Joober et al, 2002; Malhotra et al, 2002; Rosa et al, 2002) (A Diamond, personal communication; R Lipski, personal communication). Moreover, Goldberg et al (2002) recently reported similar genotype effects on the N-back working memory task. Egan et al (2001b) also studied the cortical physiologic response during a working memory task with fMRI, and found the predicted effect of genotype. Specifically, individuals with val/val genotypes were the least efficient (i.e. had the poorest prefrontal STN), while individuals with met/met genotypes were the most efficient, and val/met individuals were intermediate (Figure 7.7). Given the effect of COMT genotype on prefrontal information processing, presumably by virtue of its impact on prefrontal DA signalling, and the effect of prefrontal function on the regulation of striatal DA activity (vide supra), it also might be predicted that inheritance of val alleles would tend to decrease the tonic brake on the activity of striatally projecting DA neurones in comparison to inheritance of met alleles. Akil et al (2003) tested this hypothesis in a study of post-mortem brains of normal subjects grouped according to the presence of one or two val alleles. Consistent with predictions, they found a near two-fold increase in the expression of TH mRNA in mesencephalic DA neurones (TH being the rate limiting enzyme in DA biosynthesis and regulated in an activity dependent manner). Moreover, consistent with the topographic pattern of anatomical connections between prefrontal neurones and mesencephalic DA neurones, and the concept of tonic inhibition by prefrontal neurones specifically of those DA cells projecting subcortically, upregulation of TH mRNA was found only in the subcortically projecting DA neurone cell groups. mRNA from two other genes that is expressed constitutively within the same neurones was not different between genotype groups, further supporting the conclusion that the differences in TH mRNA expression reflected feedback regulation of the level of neuronal activity.

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Figure 7.6 Relationship between COMT genotype and executive task performance. A significant genotype effect was observed (p=0.04). Error rate in the WCST is presented as a function of COMT genotype in controls (green; N=58), schizophrenics (red; N=181), and in unaffected siblings of schizophrenics (blue; N=218). (Adapted from Egan et al, 2001b.) Because 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 and upregulated striatal DA activity is associated with schizophrenia, it follows that COMT genotype may be a contributing risk factor for schizophrenia. Earlier case-control association studies of COMT and schizophrenia comparing allele frequencies in ill and in well populations have been inconclusive, producing both positive (de Chaldee et al, 1999) and negative results (Daniels et al, 1996; Chen et al, 1997; Karayiorgou et al, 1998), although these studies were underpowered to find weak effect alleles and population stratification artefacts are especially likely to confound case-control studies of COMT genotypes (Palmatier et al, 1999). To avoid potential population stratification artefacts, the proportion of alleles transmitted from heterozygotic parents to ill offspring can be measured within families using the Transmission Disequilibrium Test (TDT) (Spielman et al, 1993). While families are more difficult to recruit for studies than are cases and

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Figure 7.7 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 working memory task, with areas of significant differences indicated in red. Activation was greater in val/val (three patients) than in met/val (five patients), who were in turn more activated than met/met patients (three patients). Note the large red areas in the DLPFC (circled). (From Egan et al, 2001.) controls, and in general the TDT compromises power, it is immune to stratification artefacts. Egan et al (2001) studied 104 parents-offspring trios, and found that the valallele was transmitted significantly more frequently to the schizophrenic offspring than would be predicted by random assortment (60% transmission of val, p<0.04). Though a weak statistical effect in a relatively underpowered sample, it is consistent with three earlier TDT analyses in two independent samples (Li et al, 1996, 2000; Kunugi et al, 1997). There are thus four positive TDT reports in three independent samples showing excessive transmission of COMT val alleles to schizophrenic offspring, the allele associated with abnormal prefrontal cortical function and upregulated mesencephalic DA activity. A negative family association study, based on a sample of trios from China, has also been reported (Fan et al, 2002). Earlier conflicting case-control studies of COMT genotype becloud the validity of the COMT association. In particular, both the case-control and TDT studies have been relatively underpowered, and the possibility has been raised that the val allele might not be the causative mutation, but an SNP (single nucleotide polymorphism) in linkage disequilibrium with the ‘true’ risk polymorphism (Egan et al, 2001b). The latter

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possibility, however, is virtually discounted by evidence that the val/met polymorphism accounts for over 90% of variance in COMT enzyme activity in peripheral tissues (Weinshilboum et al, 1999) and that COMT knockout mice show increased prefrontal DA and enhanced cognition (Gogos et al, 1998; Kneavel et al, 2000). 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. However, this effect must be viewed in the context of the complex genetics of schizophrenia and the likelihood 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, COMT genotype may contribute risk differently across populations, perhaps because of protective or modifying alleles at other loci. Similar results have been reported for apolipoprotein (APO) E4, which does not appear to increase risk for Alzheimer’s disease in individuals of recent African ancestry (Tang et al, 1998). 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 biological effect of COMT val on prefrontal function and mesencephalic DA regulation and the relevance of these phenomena for schizophrenia implicate a mechanism by which this allele increases liability for this disorder. In the case of polygenic disorders such as schizophrenia, even strong statistical evidence of association is not likely to be sufficient to validate that a causative gene has been found (Altshuler et al, 2000; Weiss and Terwillger, 2000). As recently argued with respect to the weak effect of a susceptibility gene for Type II diabetes (Horikawa et al, 2000), the endgame in identifying causative genes for complex, polygenic disorders will depend on clarification of the biology of the allele and how it relates to the biology of the illness. 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 7.3).

Box 7.3 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 DA function Predicted adverse effects on executive cognition and prefrontal crotical physiology and on mesencephalic DA regulation that relate to core biological aspects of schizophrenia Positive family association studies (Li et al, 1996, 2000; Kunugi et al, 1997; Egan et al, 2001a Odds ratio for val/val is 1.8 (CI=1.3–2.4) Population attributable risk in USA is 200 000 cases

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chapter 8 Models of schizophrenia: from neuroplasticity and dopamine to psychopathology and clinical management Manfred Spitzer The concept of schizophrenia originated from clinical description (Kraepelin, 1899 (reprinted in 1999); Bleuler, 1911; Schneider, 1980), and was linked to the neurobiology of the dopamine system via the discovery of therapeutic agents (Carlsson, 1988, 2000, 2001a, b). For several decades, this state of affairs left psychiatry in a highly unsatisfactory situation regarding one of its most prominent disorders. On the one hand, the disorder is characterized by profound changes in the way a person relates to the environment and experiences self, other people and the world (American Psychiatric Association, 1994). On the other hand, it is treated with substances that act upon a pathway within the brain whose function was hardly known for decades, except for its role in motor and neuroendocrine functions, which are related to the side effects, but not to the therapeutic effects of the drugs. In this chapter, some recent discoveries regarding the function of the prefrontal cortex and the mesocortical and mesolimbic dopaminergic pathways will be described, and the findings will be related to the psychopathology of schizophrenia. Models of neuronal functioning at the systems level have reached a degree of sophistication such that, for the first time, they have clinical implications with respect to pharmacological and non-pharmacological intervention strategies, and the long-term management of this disorder. Neuroplasticity One of the most fascinating results that emerged during the ‘Decade of the Brain’ was the finding that the brain changes constantly according to the information it has to process. This phenomenon is termed neuroplasticity, and it exerts itself over different scales of space and time (Table 8.1). In the synapse, learning-dependent changes of biochemical events occur whenever two connected neurones are active at the same time. The existence of such a ‘coincidence detection’ was speculated upon by William James in 1892 (reprinted in 1984), although he merely referred to points in the cortex, since the concept of the neurone had not been firmly established at that time. It was again proposed by Donald Hebb in 1949 (Hebb, 1949) and finally demonstrated to occur in 1973 (Bliss and Lomo, 1973). Since then, this important feature of synaptic connections has been clarified in great detail. The processes involved, long-term potentiation (LTP) and longterm depression (LTD), are the means by which the synaptic coupling changes in strength

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according to the incoming information processed by the neurones. Although these changes are small, whenever they reflect any structured information and not just noise, this will become engrained in the synaptic connections between neurones. This is how nervous systems transform fleeting events of patterns of activation lasting for milliseconds into internal representations lasting for hours to decades. The functional biochemical changes in synapses are triggers for subsequent structural changes to synapses that occur during learning. For example, a second dendritic spine may grow, thereby increasing the area of contact between the presynaptic and the postsynaptic sites (Figure 8.1).

Table 8.1 Neuroplasticity occurs at difference levels* Level

Process

Space

Time

Synapse

LTP, LTD

nm to µm

msec to hours

Neurone

Growth

µm to mm

Days and weeks

Cortical map

Representational change

mm to cm

Months to years

*That is, on different scales of space and time. LTP, long-term potentiation; LTD, long-term differentiation.

Figure 8.1 Morphological change in synapses upon learning (redrawn from Toni et al, 1999; cf. also Engert and Bonhoffer 1999). When two connected neurones are active at the same time, the connecting strength of the synapse between them will increase. This increase first occurs on a biochemical level, and later on a structural level (shown on the right). The story of neuronal growth has unfolded during the past few years leading to a radical change in the previously held views of neuroscientists that neurones form a stable population of cells (Unger and Spitzer, 2000; Macklis, 2001). Kempermann et al (1997),

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showed that, although they are postmitotic, new neurones can grow in the hippocampus of adult mice living in an enriched environment and 1 year later the same process was shown to occur in human beings (Ericksson et al, 1998). Although initially it was not clear whether these newly grown neurones served any purpose (Gould et al, 1999), further experiments employing first a lesion model (Scharff et al, 2000), and subsequently a physiological trace-conditioning model (Shors et al, 2001), established their role in naturally occurring learning. As hippocampal neurones are subject to cell death under conditions of stress, their ability to regrow and to form the relevant connections for learning is highly encouraging from a clinical perspective, since a number of mental disorders are either known to be caused by, or are at least related to, neuronal death. At the cortical level, we know that the cortex forms and maintains experiencedependent maps of representations. Such topographic maps of ordered representations of features were first demonstrated in the human cortex by Penfield and Boldrey (1937). Most importantly, it was discovered that the body surface is not represented in relation to its size, but in relation to its importance and use. Obviously, sensations of touch from the hands and the lips, for example, are much more important than touch sensations coming from the back. Accordingly, the lips and the hands occupy more space on this surface map than the back. Because hands and lips get more computational surface, signals from these parts of the body surface can be processed more precisely than signals from the back. For the survival of the organism, this is obviously highly adaptive. This discovery became famous, not least because it was published in a new ingenious graphic representation by drawing a man with distorted proportions, such that the resulting homunculus displays the size of the cortical areas coding the body surface (Penfield and Rasmussen, 1950). Penfield’s homunculi are so widely known and reproduced in every textbook on neurology and neuroscience that the basic message sometimes gets lost: there are maps in the cortex on which input signals (in this case, the sensations of touch) are represented according to the principles of similarity, frequency and importance. It is not only the tactile sense that is based upon cortical maps. The human visual system consists of more than a dozen retinotopic maps, i.e. topographically ordered maps on which the points correspond to points of the retina. Like the homunculus discussed above, these retinotopic maps form a distorted image of the retina, in that the part of the retina that gives us the sharpest images (the fovea) is represented by the largest of the retino-topic maps. In addition, tonotopic maps exist for the auditory system where the frequencies of tones are represented as an ordered frequency map. As argued elsewhere (Spitzer, 1995, 1997, 1999; Spitzer and Neumann, 1996), there is no reason to doubt that cortical areas whose representational structures have not yet been described contain representations in a topographically structured form. This hypothesis can be derived from neural network models of features of cortical anatomy. Rules in the prefrontal lobes For quite some time, schizophrenic symptoms have been related to prefrontal lobe function and dysfunction (reviewed in Andreasen, 1994). Hypofrontality, the decreased

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activity of parts of the prefrontal lobes at rest or during specific tasks which normally engage prefrontal structures, has been proposed to be as a major cause of negative symptoms (which are characterized by the lack of motivation, emotional involvement, and goal-directed thinking and behaviour). However, the evidence for this has turned out to be inconclusive, depending both upon the task involved and upon the clinical state of the patients. If patients and normal controls are matched for performance, the evidence for hypofrontality in functional neuroimaging studies may disappear (Callicott, 2000; Walter and Wolf, 2002). There has been more than a century of debate on the functions of the prefrontal cortex. As this is the part of the human brain that diverges the most from the brains of other primates, direct experimental evidence is limited. Inferences have to be made from small regions of the monkey brain to homologous, but much larger, regions of the human brain. In addition, while low level vision, touch, audition and motor behaviour can be studied with nicely controlled tasks and settings, the functions of will, context-dependency, planning, decision making, motivation, emotion, and rule detection do not easily lend themselves to simple experimental paradigms. Nonetheless, progress has been made. Miller and Cohen (2001) provide a detailed review of frontal lobe functions within the context of neural network modelling of cognitive control. They argue quite convincingly that the various parts of the prefrontal cortex subserve similar functions (i.e. context updating, inhibition of reflexive drive directed behaviour and planning) as applied to different aspects of high-level information processing (Fuster, 1995; Ivry and Knight, 2002). For example, whereas in the dorsolateral prefrontal cortex abstract rules of language (left) and visuospatial thinking are processed and (therefore in the long term) represented, the orbitofrontal cortex deals with the output of systems related to reward and motivation, and hence, comes to represent goals, emotive experiences, and values in the long run. From the many neuroimaging studies of prefrontal cortical functioning, one recent study on the automatic perception of rules appears to be of particular relevance for understanding a particular aspect of schizophrenic psychopathology, i.e. the tendency of the patients to form delusional perceptions and delusions. Huettel et al (2002) used functional magnetic resonance imaging (fMRI) to identify parts of the brain involved in the formation of rules, when in fact there were no such rules in the stimuli. Normal subjects were shown a completely random succession of circles and squares on a screen, for two seconds each (Figure 8.2). Subjects were told explicitly that the sequence was random, and that they simply had to watch the stimuli and to press one of two buttons, one whenever they saw the square and the other when they saw the circle. The experiment lasted for 1 hour during which more than 1600 such circles and squares were presented. Any random sequence contains short strands of subsequent stimuli that appear to be in a specific order. This is why people spend so much time and money on gambling, going after these apparent rules. To people, there is no such thing as complete randomness. The study showed that the reason for this is that the human brain cannot help but detect rules, even if there are none and the subject is told exactly that, and even if the subject does not look for any rules. This was a convincing demonstration that rule detection happens automatically in the brain. For example, if four squares appeared in a row, automatic mental processes produced the expectation of yet another square. This can be seen by

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merely looking at the subjects’ reaction times, which decreased with the number of previous repetitions. Even rules other than repetitions were automatically detected. For example, if there was a sequence of alternate circles and squares, automatic mental processes, upon perceiving a square, anticipated the appearance of a circle. Again, this could be inferred (although with a smaller effect size) from reaction times. In short, whenever a small bit of apparent order appeared within the random sequence, automatic processes registered this order, and this led to a decrease in response time for the next stimulus that appeared to follow the rule governing the order. It also led to an increase in response time if the stimulus did not follow the rule.

Figure 8.2 Schematic representation of the experimental paradigm used by Huettel et al (2002). Subjects viewed a random succession of squares and circles, which appeared for 1750 milliseconds (msec) followed by a brief inter-stimulus interval of 250 msec. Subjects had to respond by pressing one of two buttons. Response times were measured and turned out to depend upon the apparent order within the random sequence. Whenever there appeared to be a rule within the sequence response times decreased.

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Analysis of subjects’ fMRI scans showed that regions in the frontal lobe were activated when orders were violated, and that this activation was parametrically dependent upon how well the order had been established before, i.e. on how often the

Figure 8.3 Reaction times decrease upon stimulus repetition and increase upon violation of apparent rules. (a) The better the apparent rule has been previously established, the larger the decreases and increases. (b) The MR signal at various frontal sites combined followed the same pattern, i.e. its increase upon a violation of an apparent rule was parametrically dependent upon the number of

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previous stimuli that established this rule. As there was a new stimulus every 2 seconds and as the MR signal showed a systematic difference even after six or seven previous stimuli have been shown, one has to conclude that the brain automatically registers a stimulus that happened 14 seconds before, and takes into account whether that stimulus has something in common with the present stimulus. (Data from Huettel et al, 2002.) apparent sequence had appeared prior to the crucial stimulus. In other words, activated regions of the brain had increased their activity in a predictable manner. To take the most striking example, there was a slightly higher activation after a series of seven stimuli than after a series of six stimuli (Figure 8.3). This implies that the brain automatically takes into account what has happened 12–14 seconds before a current stimulus, and responds accordingly. Evidence from studies in which single cell recordings were combined with rule learning paradigms in monkeys further clarified the role of the prefrontal cortex in rule based behaviour (Wallis et al, 2001). Two monkeys were trained to behave according to two different rules (Figure 8.4). They had to choose one of two pictures after they had been shown one of the pictures together with another stimulus that indicated the rule they had to follow: the rule was either to choose the same stimulus as previously shown (same rule) or to choose the stimulus that was different to the previously shown stimulus (different rule). The monkeys were given a cue that signified the rule they had to follow. In order to make sure that they acted according to the abstract rule and not just according to some trivial aspect of the stimulus, two distinct cues from different sensory modalities were used to indicate the same rules. In contrast, cues signifying different rules were from the same modality. Thus the neural activity related to the physical properties of the cue from the rule that it signified could be separated. For the first monkey, the presence of a blue background or a drop of juice indicated that it had to follow the same rule, whereas a green background or the absence of juice indicated that the different rule had to be followed. For the second monkey, the same rule was indicated by juice or a low frequency tone, and the different rule was indicated by a high frequency tone and no juice. Hence, it can be concluded that the rules could not be derived from any simple characteristics of the stimuli. Recordings from 492 neurones located in the dorsolateral prefrontal cortex, the ventrolateral cortex, and the orbitofrontal cortex clearly demonstrated that the abstract rule (‘choose the same stimulus’ versus ‘choose the stimulus that is different’) was represented in the monkey’s prefrontal cortex by 41% of the neurones. However, there was no specific prefrontal area that represented the rule. In contrast, 27% of the neurones represented the stimuli indicating the rule and 14% represented the picture stimulus to

Dopamine in the pathophysiology and treatment of schizophrenia

Figure 8.4 Paradigm used by Wallis et al (2001). The monkeys held a lever and watched the screen. There, a stimulus was present for 800 msec, and at the same time the monkeys got a cue as to which rule (the same or the different rule) they had to follow. Then there was a pause for 1500 msec, and then a stimulus was shown for 500 msec, which was either identical or not to the first stimulus. Depending upon the rule they had to follow, the monkeys had to release the lever either when the stimulus was identical (i.e. follow the same rule) or when the stimulus was different (i.e. follow the different rule). To make sure that the monkeys kept paying attention, in half the trials (i.e. whenever there was no response upon the test stimulus at test 1), yet another stimulus was shown for 500 msec after another pause of 1500 msec. The stimulus was chosen such that at this time the monkeys had to respond to this stimulus.

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which the monkey had to respond. This implies that the prefrontal cortex contains representations of general rules and relations rather than properties of single stimuli. These rules are constantly sought for in the stream of experience, derived from it, and, if frequently encountered, stored as synaptic weight changes in the very cortical areas that perform the processing. Thus, general rules governing the events in the environment become part of the internal representations of an organism processing these events. Input and output: anatomy by numbers Approximately 2.5 million axons arrive in the brain from the various sense organs, which work as analogue-digital transducers and provide up to 300 action potentials per second per axon. These action potentials carry information by their presence or absence and may be thought of as single bits of information. Thus, every second the brain has to process nearly 2.5 million×300 bits of information, i.e. about 100MB (megabytes) of input data. Its task is to produce a stream of around 60MB of output data, which leave the brain via 1.5 million fibres. The processing has to occur almost in real time, as we need, and are able to run quickly to the right if we spot danger on the left. Given this enormous task of information processing, the brain has to have systems for the quick evaluation of stimuli that are important, so that it can disregard (and hence, need not process) the information that is unimportant at any given moment. As discussed above, the frontal lobes are busy finding regularities in whatever input patterns arrive from lower level cortical areas. However, if something unexpected happens, it may be dangerous (negative) or rewarding (positive). It turns out that these two types of evaluation are performed—not exclusively but to a large extent—by different brain systems. Negative aspects of incoming information are quickly relayed to the amygdala, where they are associated with fear and anxiety and where behavioural programmes dealing with fight, flight, and fright are set into action. The muscles are tightened, and heart rate as well as blood pressure rises (LeDoux, 1994, 2002). Whenever something happens that is better than predicted the dopaminergic reward system becomes activated (Figure 8.5). This has been nicely demonstrated in an experiment carried out by Tremblay and Schultz (1999) and Watanabe (1999). They offered monkeys a piece of lettuce or a piece of apple. The monkeys preferred the apple, upon which neurones in the orbitofrontal cortex fired. These neurones, however, do not code for anything related to the features of the apple per se, but rather represent the comparative preference of the monkeys. This was demonstrated by having the monkeys choose between an apple and a banana. In this instance, the same neurone fired when the banana was given but not when the apple was given. Hence, the authors concluded that the neurone represents the salience of the stimulus, i.e. its value for the animal. Dopamine, reward and salience There are four dopaminergic pathways in the brain: (i) cells located in area A9, projecting to the dorsal striatum, modulate motor function and, if damaged, cause Parkinson’s disease; (ii) cells in the hypothalamus inhibit the release of prolactin, and hence, the

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blockade of dopamine can lead to hyperprolactinaemia with its clinical signs and symptoms; (iii) cells in area 10 project either to the ventral striatum where the dopamine signal causes peptidergic fibres to release their transmitters, mainly endogenous opioids,

Figure 8.5 Paradigm used by Tremblay and Schultz (1999) to show neuronal representations of value judgements (after Watanabe, 1999). The oscilloscope shows the neuronal response of a neurone in the orbitofrontal cortex of the monkey. Upon pressing the lower wide lever, a cue appears on the screen, either to the left or to the right. The monkey has to remember the location of the cue, and 2 seconds later, has to press the small lever underneath the side where the cue was presented. A triangle predicts reward with lettuce, and a square

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predicts reward with an apple. (a) Because the monkey likes apple more than lettuce, the orbitofrontal neurone fires more upon the monkey seeing the square. (b) As the monkey, however, prefers bananas over apples, the neurone will fire modestly for apples when the alternative reward is a banana. diffusely into the prefrontal lobes; and (iv) other cells in area 10 project directly to the prefrontal cortex, where dopamine is released widely and diffusely. Pathways (iii) and (iv) are called the mesolimbic system, and the mesocortical system, respectively (Figure 8.6). Within recent years, their function has been worked out to some extent by different groups of researchers, working in diverse areas such as animal learning and single cell recordings on the one hand, and the effects of music on the brain in functional neuroimaging on the other hand.

Figure 8.6 Four dopaminergic pathways can be distinguished in the human brain. In the nigrostriatal

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system, neurones in the substantia nigra (area A9) project to the dorsal striatum. The tuberoinfundibular system consists of fibres from the hypothalamus to the pituitary gland. The mesolimbic and the mesocortical systems consist of a few thousand cells residing in the ventral tegmental area (area A10) of the brain. This sends fibres to the nucleus accumbens (a part of the limbic system) and to the prefrontal cortex. When these systems are stimulated in normal subjects as well as in individuals with schizophrenia, dopamine is directly and diffusely released in the prefrontal cortex; and at the same time dopamine release in the nucleus accumbens triggers neurones that release endogenous opioids in the prefrontal cortex. Variations in the patterns of such release have been associated with schizophrenia. Whenever something positive happens, the mesolimbic and the mesocortical systems become active. They are considered to be part of the brain’s reward system. This was shown in early neuroimaging studies, using a very strong ‘positive stimulus’, e.g. the reintroduction of intravenous cocaine to a cocaine addict who was in prolonged and absolute withdrawal (cold-turkey; Breiter et al, 1997). More recent investigations have demonstrated that the same system is activated in normal human beings upon eating chocolate (Small et al, 2001), hearing nice music (Blood and Zatorre, 2001), winning a game (Koepp et al, 1998) and even looking at an attractive face (Aharon et al, 2001) or an attractive car (Erk, 2002). A seminal study using single cell recordings and a learning paradigm in monkeys clarified the function of the dopamine systems in question (Waelti et al, 2001; see also Schultz, 2002). According to classic learning theory, a stimulus is learned if it is coupled with a reward. If, for example, a visual stimulus is followed by a mouthful of juice, this stimulus will be learned by the monkey, i.e. the animal will start licking at the well from which the juice comes out (Figure 8.7). However, if a second stimulus is displayed together with the first it is not learned if it is not predictive. In the second step of learning in the paradigm shown in Figure 8.7, only the novel stimulus Y is learned (it indicates juice), whereas the novel stimulus X is not

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learned (as stimulus A already indicated juice, and therefore, the additional stimulus X has no further relevance). The learning of X is blocked, and hence, the effect has become known as the blocking effect and had already been described by L Kamin in the 1960s (James et al, 1990).

Figure 8.7 Schematic representation of the paradigm used by Waelti et al (2001). In the first step, stimulus A is learned and produces licking

Dopamine in the pathophysiology and treatment of schizophrenia

behaviour, whereas stimulus B does not. In the second step, two novel stimuli X and Y are introduced. Whenever A is presented, X is also presented and the monkey is rewarded with juice. Upon the presentation of B, Y is also presented and the monkey also gets juice. Classic learning theory predicts that the monkey should learn to associate both of the novel stimuli X and Y with juice, but this does not happen. Instead, learning of X is blocked, and hence, this entire learning paradigm is called blocking paradigm.

Figure 8.8 Schematic representation (after Waelti et al, 2001) of the dopaminergic response upon reward (Step 1 top) and the prediction of

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reward (Step 1 bottom). When the novel stimuli are displayed in addition, the dopaminergic response happens upon the already learned stimulus A (Step 2 top) and the reward (upon stimulus BY). After learning, the stimuli AX and BY both cause the response, i.e. are predictive of reward (Step 2 bottom). When this paradigm was used in conjunction with single cell recordings from dopaminergic neurones (Figure 8.8), it was found that these neurones not only respond to reward and learn to respond to predicted reward, but also appear to ‘label’ the novel stimuli according to their predictive power. In the crucial test (Figure 8.9), the novel stimulus that did not predict reward (although it had been coupled with reward dozens or even hundreds of times!) did not cause dopaminergic cells to fire, whereas the novel stimulus that predicted reward led to a marked increase in the firing rate of dopaminergic neurones. Thus, it was demonstrated that it is not reward per se, but rather the predictive power of a stimulus with respect to reward, which determines its relevance at the behavioural level of learning and at the neuronal level of dopaminergic firing.

Figure 8.9 The activity of dopaminergic neurones corresponds to the blocking effect (after Waelti et al, 2001). When the new stimulus X is presented alone, no increased activity is observed (blocking), whereas a marked increase can be noted upon stimulus Y.

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The very same neurones, which are involved in cocaine addiction, our appetitive approach to chocolate, the enjoyment of music and the social response to the fleeting sight of a face or car, signal, quite generally, the importance of a stimulus. As mentioned above, all organisms are bombarded with a large number of stimuli and have to sort out the few that are important from the many that are unimportant. In the study by Waelti et al (2001), the dopamine system was shown to be the signal that becomes attached to the stimuli when the ‘sorting out’ function is applied. The dopamine system is active upon the occurrence of a salient, important stimulus, but it remains silent if the stimulus does not contain new information. In other words, the dopamine system is able to calculate saliency and assign ‘meaning’ (i.e. it fires) when some stimulus configurations are received, and it remains silent (i.e. it does not fire) when other stimulus configurations are received. From this study, we may conclude that dopamine is intimately coupled with the assignment of importance or irrelevance to incoming stimuli. The neurobiology of first rank symptoms In schizophrenia, the dopamine system is dysfunctional in that it is no longer appropriately fine tuned, becoming either hyperactive in the acute phase of the illness or hypoactive during more chronic states. Within this framework of neurobiological function of the mesolimbic and mesocortical dopamine systems, some aspects of the psychopathology of schizophrenia become plausible. If the brain system which assigns saliency (meaning) to incoming stimuli is too active, we would expect many impressions which are normally disregarded by the organism to become salient, even though they are not. In other words, specific salience and meaning will be assigned to various kinds of trivial stimuli. The schneiderian first rank symptom of delusional perception (i.e. a normal perception gets an unusual meaning) can be easily interpreted as caused by an overly active mechanism of the assignment of meaning, and salience, to stimuli. By analogy, symptoms such as delusions (which often build upon delusional perceptions) and auditory hallucinations may be reframed in terms of an overly active mechanism of meaning assignment. Just as important as the psychopathological consequences of an overly active dopamine system are the symptoms that result from too little dopaminergic activity in this system. A hypoactive dopamine system no longer produces much (or any) meaningful experience. Even stimuli which are normally automatically considered meaningful and worth further consideration, such as social interactions, become uninteresting and boring and hence do not capture cognitive resources for elaborate processing. Thus, the world is experienced as not worth the effort of getting out of bed. Neuromodulation Previous models of dopamine function and the psychopathology of schizophrenia (Servan-Schreiber et al, 1990; Cohen and Servan-Schreiber, 1992, 1993) have emphasized tonic effects of dopamine firing rates upon general processing characteristics of the cortex, drawing hypothetical inferences from neural network models of brain

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functioning. Within this framework, dopamine is viewed as a neuromodulatory agent, which acts upon gross and widely distributed cortical and subcortical structures, like other neuromodulatory agents, such as 5-HT, noradrenaline, and acetylcholine, to name but a few. From this work, the concept of signal to noise ratio in neuronal information processing has been derived, and it was demonstrated that dopamine can modulate this parameter. As argued elsewhere (Spitzer 1995, 1997, 1999), this view can account for some forms of schizophrenic pathology, especially formal thought disorder (cognitive disorganization) and, possibly, chronic delusions. In this respect, the fact that dopamine release has been related to learning-induced (i.e. experience-dependent) cortical remodelling may hint at the role of dopamine during the rehabilitation of such patients (Bao et al, 2001). This view rests upon certain assumptions regarding tonically increased or decreased dopaminergic activation. In contrast, the activity of the dopaminergic reward system is phasic, i.e. it is linked to specific stimuli that are processed by the cortex and found to be salient by cortical comparative processes, which put stimuli into context, and calculate the probability of further events. Just as the cortex is able to tell the opiate system from the context of measures for pain relief (i.e. from swallowing a pill, or from watching somebody in a white coat putting a needle under one’s skin and injecting a fluid into one’s veins) that endogenous opioids should be released to act as pain relievers (Petrovic et al, 2002), the cortex should be able to tell the dopamine system that something better than expected has been happening. Upon receiving this information, dopamine is released from the fibres of A10 neurones, projecting into the nucleus accumbens and directly into the prefrontal cortex. No conscious cognitive effortful processes are involved. It is unlikely that the tonic and phasic dopaminergic signals are not related. The exact nature of such a relationship is likely to inform us about the nature of acute and chronic psychopathology. Further modelling work as well as further studies on the effects of neuromodulatory agents of cognitive functions in human beings have to be performed in order to disentangle the tonic and phasic effects of dopamine as well as their relatedness. Consequences for therapeutic interventions It used to be tacitly assumed that neurobiological theories of psychiatric symptoms have consequences for biological therapeutic approaches, whereas psychological models of symptom generation bear upon psychological approaches to therapy. This simple distinction between the biological and the psychological, with its neat consequence of a separation between entire schools of thought regarding psychiatric care, is no longer tenable. Just as we know that the neurobiology of the dopamine system is intricately linked with the generation of meaningful subjective experiences, we know that subjective experiences shape the brain throughout life. In particular, we further know from experimental work in monkeys that social life shapes the activity of the dopamine system (Morgan et al, 2002). In other words, there are complex interactions of neurobiological processes and the environment, the most important part of which is the social environment. From this perspective, we may conjecture that a good treatment strategy for a schizophrenic patient includes anything from the right neuroleptic drug to the right living

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conditions regarding housing and social interactions. We must always be aware of the fact that the automatic processes of the generation of meaningful events is dysfunctional in the patient, which is why he or she will be vulnerable to failures of handling even the simplest aspects and situations of everyday life. Nevertheless, it should also be clear that people with schizophrenia can and should have opportunities to relearn and rebuild normality. Of course, this must occur within humane environments which foster respect for the dignity of persons and appreciation of the human ability to grow beyond the limitations and obstacles imposed by illness, personal circumstances and other people. More specifically, helpful approaches in clinical settings may include facilitating familiarity with arts and crafts, which play a major role in the everyday life of psychiatric patients in Europe. In this respect, it is clear that a great variety of activities should be offered to the patients. To put it simply: ‘Pottery for everybody’ is bad because there are some people who just do not like doing pottery. These people will not be motivated to engage in the activity and the many social interactions for which it provides opportunities. Hence, the craft will not work for these patients. Even with respect to the appropriate medication, the approach presented here has clear implications. If we want patients to relearn during treatment, we must not use medications that make them drowsy or, even worse, interfere with their motivation and emotion. It should be stressed that this is precisely what typical antipsychotic medications, such as chlorpromazine and haloperidol can do, especially when used in high doses to maintain sedation and behaviour control and to eliminate positive symptoms of the disorder. Therefore, schizophrenic patients should be treated with atypical antipsychotic medications, as studies have shown that these drugs can decrease negative symptoms by presumably bringing back the dopamine system to a normal range of function (see Chapters 6, 7 and 9). The newer, atypical antipsychotic medications are currently administered because they cause fewer acute motor side effects and possibly fewer long-term motor side effects (tardive dyskinesia). Within the framework outlined here, these medications, in addition, should be administered because they enable the patients to experience the world more normally, that is to say, more meaningfully. To put it very simply again: ‘Don’t combine silk painting and haloperidol’, as the typical neuroleptic may interfere with motivation to an extent that renders learning activities futile. Conclusions Neuroscience has come a long way to become an integrated part of clinical psychiatry. It no longer amounts to mere lip service to speak of schizophrenia as a brain disorder. Instead, this view provides us with an understanding of even the most subjective aspects of the disorder, i.e. the generation of meaningful subjective experiences. As this chapter has tried to show, even the few things we know about dopamine, cognition and schizophrenia have clinical consequences. Further work, especially in normal subjects using cognitive tasks, functional neuroimaging, and drug challenge paradigms (see, for example, Spitzer et al, 2001) should provide us with the data we need to put together a more fine-grained view of the disorder which will ultimately be even more helpful to provide to our patients the care they need.

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Koepp MJ, Gunn RN, Lawrence AD et al. (1998) Evidence for striatal dopamine release during a video game. Nature 393:266–8. LeDoux J. (1994) Emotion, memory and the brain. Scientific American, June, pp. 32–9. LeDoux J. (2002) Synaptic self. (Viking: New York). Macklis JD. (2001) New memories from new neurones. Nature 410:314–7. Miller EK, Cohen JD. (2001) An integrative theory of prefrontal cortex function. Annu Rev Neurosci 24:167–202. Morgan D, Grant KA, Gage HD et al. (2002) Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nature Neurosci 5:169–74. Penfield W, Boldrey E. (1937) Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain 60:389–443. Penfield W, Rasmussen T. (1950) The Cerebral Cortex of Man: A Clinical Study of Localization and Function. (Macmillan: New York). Petrovic P, Kalso E, Petersson KM, Ingvar M. (2002) Placebo and opioid analgesia—imaging a shared neuronal network. ScienceExpress (February), pp. 1–6. Scharff C, Kirn JR, Grossman M, Macklis JD, Nottebohm F. (2000) Targeted neuronal death affects neuronal replacement and vocal behavior in adult songbirds. Neuron 25:481–92. Schneider K. (1980) Klinische Psychopathologie, 12th edn. (Thieme: Stuttgart). Schultz W. (2002) Getting formal with dopamine and reward. Neuron 36:241–63. Servan-Schreiber D, Printz H, Cohen JD. (1990) A network model of catecholamine effects: gain, signal-to-noise ratio, and behavior. Science 249:892–5. Shors TJ, Miesegaes G, Beylin A et al. (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372–6. Small DM, Zatorre RJ, Dagher A, Evans AC, Jones-Gotman M. (2001) Change in brain activity related to eating chocolate. From pleasure to aversion. Brain 124:1720–33. Spitzer M. (1995) A neurocomputational approach to delusions. Compr Psychiatry 36: 83–105. Spitzer M. (1997) A cognitive neuroscience view of schizophrenic thought disorder. Schizophrenia Bull 23:29–50. Spitzer M. (1999) The Mind Within the Net. (MIT Press: Cambridge, MA). Spitzer M, Neumann M. (1996) Noise in models of neuropsychiatrical and psychiatric disorders. Int J Neural Systems 7 (Special Issue: The Role and Control of Random Events in Biological Systems): 355–61. Spitzer M, Fischer B, Walter H et al. (2001) Enantio-selective cognitive and brain activation effects of N-ethyl-3, 4-methylenedioxyamphetamine in humans. Neuropharmacology 41:263–71. Toni M, Buchs P-A, Nikonenko I, Bron CR, Muller D. (1999) LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402:421–5. Tremblay L, Schultz W. (1999) Relative reward preference in primate orbitofrontal cortex. Nature 398:704–8. Unger J, Spitzer M. (2000) Bildung neuer Nervenzellen in alten Gehirnen? Nervenheilkunde 19:65–8. Waelti P, Dickinson A, Schultz W. (2001) Dopamine responses comply with basic assumptions of formal learning theory. Nature 412:43–8. Wallis JB, Anderson KC, Miller EK. (2001) Single neurones in prefrontal cortex encode abstract rules. Nature 411:953–6. Walter H, Wolf RC. (2002) Von der Hypofrontalität zur dynamischen frontalen Dysfunktion. Nervenheilkunde 21:392–9. Watanabe M. (1999) Attraction is relative not absolute. Nature 398:661–3.

chapter 9 Multiple neurotransmitters involved in antipsychotic drug action Man can regain sanity by means other than dopamine D2 receptor blockade Herbert Meltzer

Schizophrenia is the most devastating of the major psychoses, affecting approximately 1% of the population, irrespective of culture, social status or sex. 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 manicdepressive 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. 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 (Andreasen, 1997; Meltzer and McGurk, 1999). About 25% of patients with schizophrenia exhibit significant depression at any time and about 10% commit suicide (Meltzer, 2001). It is important to realize that the extent to which any individual symptom is present in a patient with schizophrenia may vary considerably. In addition, the importance of specific symptoms again may vary over time within the same patient. 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

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improve mood and cognitive function. Moreover, these drugs displayed serious and 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 (EPSE) (see Meltzer, 1997, for a review). For this reason, clozapine was classed as an ‘atypical’ antipsychotic, i.e. an antipsychotic which does not produce clinically significant EPSE in most patients at clinically effective doses, not just the minimally effective dose (Meltzer, 2000). 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 haematological 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 (Kane et al, 1988). The past 10 years have seen the introduction of several such novel atypical drugs (Figure 9.1). These can be divided into two main classes: first, the substituted benzamide drugs, such as remoxipride and amisulpride, and, second, the mixed serotonin-dopamine receptor antagonists, namely risperidone, olanzapine, quetiapine, ziprasidone and sertindole. Olanzapine and quetiapine are close structural analogues of clozapine, whereas the other atypicals are chemically distinct. All these agents show a low propensity for producing EPSE at effective antipsychotic doses, the essential component of an ‘atypical’ antipsychotic drug (Meltzer, 2000). However, for some of these drugs, there is also evidence that they have greater efficacy on negative symptoms, mood and cognitive function and, at least for clozapine, may also be useful to treat patients resistant to typical antipsychotics.

Figure 9.1 Structure of some atypical antipsychotic drugs.

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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 (Meltzer and Stahl, 1976) and on the ability of antipsychotic drugs such as chlorpromazine and haloperidol to block dopaminergic activity (Carlsson, 1978). Although direct evidence for a dopaminergic dysfunction in the aetiology or symptomatology of schizophrenia has remained elusive, a role for this neurotransmitter in the action of antipsychotic drugs has been clearly established (see Chapter 2). Recent studies with amphetamine administration and positron emission tomography (PET) have provided some of the first evidence for increased dopamine release in schizophrenia (Breier et al, 1997; Laruelle and Abi-Dargham, 1999). 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 (Carlsson and Lindqvist, 1963; Carlsson, 1978). There are three principal dopaminergic pathways in the brain: the nigrostriatal pathway, originating in the substantia nigra and projecting to the striatum, which is involved in extrapyramidal motor control and cognitive function; the mesolimbic system, projecting from the ventral tegmental area to limbic structures such as the nucleus accumbens and amygdala, thought to be involved in psychosis, emotional activity, reward and motivation; and, lastly, the mesocortical system, projecting from the ventral tegmental area to the prefrontal cortex, thought to be involved in cognitive processing, motivation, and, through influence over the mesolimbic dopamine neurones, psychosis as well (Pycock et al, 1980). These three dopaminergic pathways may respond differently to different classes of antipsychotic drugs, and in addition, are probably involved to different extents in the different symptom clusters presented by schizophrenic patients. Although dopamine has received the lion’s share of attention in attempts to unravel the biological basis of schizophrenia and of antipsychotic drug action, other neurotransmitter systems are almost certainly involved. There is now considerable evidence to suggest that changes in the activity of neuronal systems using serotonin, glutamate, acetylcholine and noradrenaline may be important. Provocative clues to their roles have come from observations that drugs that modulate these systems can provoke experimental psychoses in experimental animals and in man. Examples include 5-HT2A receptor agonists, such as LSD (lysergic acid diethylamide) (Abraham and Aldridge, 1993), and NMDA (N-methylD-aspartate) receptor antagonists, such as phencyclidine (Allen and Young, 1978) and ketamine (Krystal et al, 1994). The phenomenology of psychoses induced by 5-HT2A receptor agonists, NMDA receptor antagonists and prodopaminergic drugs is somewhat different, but all share certain features with symptoms characteristic of some patients with schizophrenia at various phases of the illness. In addition, these drugs can exacerbate psychoses in patients with schizophrenia (Angrist et al, 1980; Abraham and Aldridge, 1993; Lahti et al, 1995). Animal models using these agents may be useful to identify novel antipsychotic drugs acting through neurotransmitter systems other than dopamine (Tiedtke et al, 1990; Wettstein et al, 1999).

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Dopamine D2 receptors Historically, the D2 receptor has received the most attention as the biological target of antipsychotic drugs. The advent of radioligand binding studies in the 1970s demonstrated unequivocally that all the principal classes of antipsychotic drugs available at that time bound to this receptor (Burt et al, 1975; Seeman et al, 1975). This was true of phenothiazines, butyrophenones, benzamides, clozapine and other structurally unrelated drugs such as α-flupenthixol and pimozide. In addition, it was demonstrated that clinical dosage correlated with affinity at the D2 receptor for many of these drugs (Creese et al, 1976; Seeman et al, 1976), although it should be pointed out that, in some cases, the clinical dosages chosen were based on doses which produced EPSE, rather than on equivalent efficacy to treat psychosis in comparable clinical populations. Although many of the early antipsychotic drugs bind to a wide variety of monoamine receptors, certain drugs are highly specific for D2 (and D3) receptors. This is particularly true for the substituted benzamide class, including amisulpride, raclopride and remoxipride (Chivers et al, 1988). Interaction with the D2 and possibly D3 receptor may thus well be sufficient to explain the therapeutic effects of the substituted benzamide class. On the other hand, the action of certain drugs, such as clozapine, which have a more complex and extensive therapeutic action, may not be adequately explained by interaction with D2 receptors alone. The introduction of neuroimaging studies for central dopamine receptors in the late 1980s allowed the demonstration that most antipsychotic drugs did indeed occupy D2 receptors in the striatum of schizophrenics who were receiving adequate clinical doses of drugs (Farde et al, 1988, 1992; Nordstrom et al, 1993). For the majority of these, it was observed that between 70% and 80% of striatal receptor occupancy was required to produce a satisfactory therapeutic effect. On the other hand, occupation of striatal D2 receptors by therapeutic doses of clozapine was considerably lower (Farde et al, 1992). Similar findings were obtained with quetiapine (Gefvert et al, 1998), suggesting that these two atypical antipsychotics may be working elsewhere in the brain to provide relief of symptoms. However, olanzapine (Nordstrom et al, 1998) and risperidone (Farde et al, 1995) produce levels of striatal receptor occupancy commensurate with those of typical antipsychotics. However, this is only part of the story. The occupancy of extrastriatal D2 receptors, e.g. those in the cortex, thalamus, amygdala, the ventral tegmentum and nucleus accumbens is much lower with the atypical antipsychotic drugs, including risperidone and olanzapine, than is the case for haloperidol (Stephenson et al, 2000; Kessler and Meltzer, in preparation). It seems clear that blockade of D2 receptors can adequately explain the beneficial effects of typical antipsychotic drugs on the positive symptoms that manifest themselves in acute psychotic episodes. Blockade of D2 receptors also contributes to the antipsychotic effect of the serotonindopamine antagonists, although it is probably not the only mechanism responsible for their benefits, even for this component of schizophrenia. This is clearly the case for the ability of clozapine to improve positive symptoms in many patients with neuroleptic-resistant delusions and hallucinations. In addition, the EPSE and prolactin elevations produced by the antipsychotic drugs can be satisfactorily accounted

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for by antagonism of dopaminergic neurotransmission mediated by D2 receptors in the striatum (which is part of the extrapyramidal nervous system) for the extrapyramidal symptoms and in the tuberoinfundibular system of the hypothalamus for the neuroendocrine side effects. On the other hand, it is not possible to explain the beneficial effects of atypical antipsychotics on the negative symptoms of schizophrenia as well as on mood and cognition, by D2 receptor blockade alone, since such properties are not shared by potent D2 receptor antagonists such as the butyrophenones. Moreover, as mentioned above, clozapine and quetiapine are therapeutically efficacious at doses which provide only low levels of D2 receptor occupancy, at least in the striatum. In the case of risperidone and olanzapine, some other mechanism must be involved in order to explain the lack of EPSE at doses which produce significant levels of D2 receptor occupancy in PET imaging studies. It has recently been hypothesized that the difference between typical and atypical antipsychotics may be explained by the kinetics of their interaction with the D2 receptor (Kapur and Seeman, 2001). This theory, originally postulated by Burki (1986) to explain the low incidence of EPSE of clozapine and fluperlapine (which is also a mixed serotonin-dopamine receptor antagonist, as explained below), proposes that drugs with a fast off-rate from the receptor will produce less attenuation of tonic dopaminergic tone, and thus less EPSE, than do drugs with a slow off-rate. The dissociation rate from the receptor is related to the affinity according to the law of mass action with Ki=Kon/Koff, with low affinity drugs such as clozapine having faster dissociation rates. Although it is certainly true that clozapine and quetiapine do have fast dissociation rates, this is definitely not the case for most other atypical antipsychotics, including olanzapine, risperidone, sertindole and ziprasidone. This theory is addressed in more detail in Chapter 3. Overall, D2/D3 receptor antagonism may be sufficient to explain the antipsychotic effects of atypical drugs of the substituted benzamide class, such as amisulpride, and may be necessary to observe a powerful antipsychotic effect for the serotonin-dopamine antagonists. However, this does not seem to be a sufficient explanation to account for the multiple advantages of the serotonin/dopamine atypical antipsychotics. Other dopamine receptor subtypes The central nervous system contains four subtypes of dopamine receptor other than the D2 receptor, and it is conceivable that these may be involved in the clinical action of current antipsychotic drugs, or maybe potential targets for future ones. At the moment, however, the data supporting this idea are not encouraging, with the possible exception of the D3 receptor. The other principal class of dopamine receptor is the D1 receptor, which is positively coupled to (i.e. activates) the enzyme adenylate cyclase. D1 receptors are blocked by phenothiazines and related antipsychotics, but not by butyrophenones such as haloperidol. Clozapine is a D1 receptor agonist (Salmi and Ahlenius, 1996). Specific D1 receptor antagonists have been developed and evaluated in the treatment of schizophrenia, but no clear evidence of beneficial therapeutic activity was obtained in pilot studies (Gessa et al, 1991; Karlsson et al, 1995). The D5 receptor has very similar

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properties to the D1 receptor, and it can probably also be rejected as a potential target for antipsychotic drugs. The cloning of the D4 receptor provoked much interest in the possibility that this was a key mechanism in the action of atypical antipsychotic drugs. This idea originated first from the observation that clozapine differed from other antipsychotics in having significantly, albeit slightly, higher affinity for the D4 receptor than for the D2 receptor (Van Tol et al, 1991), second from suggestions that the D4 receptor density may be elevated in the schizophrenic brain, and finally, that transmission of polymorphisms in the D4 receptor gene may be a risk factor for schizophrenia (Seeman and Van Tol, 1994). However, these initial findings of potential D4 receptor abnormalities in schizophrenia have not been confirmed in more extensive studies (Reynolds, 1996). In addition, certain atypical antipsychotic agents such as amisulpride and remoxipride have little or no affinity for the D4 receptor (Seeman and Van Tol, 1994). Interest in the D4 receptor as a target for antipsychotic drugs has waned after the completion of large randomized clinical trials with the D4 receptor antagonists fananserin (Truffinet et al, 1999) and L-745 870 (Kramer et al, 1997). Fananserin is a mixed D4 and 5-HT2A receptor antagonist with very little affinity for the D2 receptor, and L-745 870 is a pure D4 receptor antagonist. No evidence for efficacy in the treatment of schizophrenia was obtained with either of these agents. The D3 receptor has many similarities with the D2 receptor in terms of distribution, sequence and recognition properties. Some highly selective D3 antagonists have been identified in recent years. Judging from data obtained in preclinical studies, these appear promising candidates for antipsychotic drugs, and clinical trials with several of these agents are underway or imminent. Serotonin 5-HT2A receptors Many antipsychotic drugs also bind with high affinity to serotonin 5-HT2A receptors. This was the case for certain of the early drugs, including chlorpromazine and spiroperidol, and also for all the atypical drugs with the exception of the substituted benzamides. What characterizes this subgroup of atypicals, however, is that they have substantially higher affinity for the 5-HT2A receptor than they do for the D2 receptor (Table 9.1) A number of these compounds, including clozapine, melperone and sertindole, were identified independently, and only later found to share these properties. Subsequently, risperidone, quetiapine and olanzapine, as well as ORG-522 and ziprasidone, were developed specifically to match this pharmacological profile. Indeed, all compounds which have been investigated and which fit this model have proved to have atypical antipsychotic properties. Neuroimaging studies with some of these atypical antipsychotics have confirmed that, at clinically active doses, they occupy a high proportion of 5-HT2A receptors in the human cortex (Nyberg et al, 1993; Farde et al, 1995; Kapur et al, 1998; Travis et al, 1998). Meltzer et al proposed over 10 years ago that the 5-HT2A receptor affinity of clozapine may be an essential component of its atypicity (Meltzer, 1989; Meltzer et al, 1989). This hypothesis has been reinforced by the clinical properties of a large number of mixed 5-HT2A/D2 receptor antagonists developed over the past decade

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(the five recent atypicals, as well as at least 15 drugs once or currently in clinical development).

Table 9.1 Affinity of various antipsychotic drugs for dopamine D2 and serotonin 5-HT2A receptors in the rat brain. Antipsychotics in bold are considered to be atypicals D2 receptor§ Amisulpride† Chlorpromazine Clozapine

‡

α-Flupenthixol Fluphenazine Haloperidol

*

*

0.003

25

19

1.32

150

3.3

45.5

3.0

13

0.231 0.148

4.4

45

0.098

‡

17

1.9

8.9

3.6

25

0.144

310

120

2.6

1400

>10 000

<0.140

3.3

0.16

20.6

7.4

0.85

8.7

0.68

0.59

1.15

130

>10 000

<0.013

63

16

3.9

4.5

36

0.125

4.4

24

0.183

9.7

0.31

31.3

‡

Risperidone

†

‡

Sertindole‡

Sulpiride

5600

25

Remoxipride

Spiperone

14

3.7

*

Quetiapine

D2/5-HT2A ratio§

*

Olanzapine pimozide

*

5-HT2A receptor§

*

†

Thioridazine Thiothixene

*

*

Trifluoperazine Ziprasidone

‡

*

§

Data are presented as IC50 concentrations in nM. Peroutka and Snyder, 1980 (Ki values). † Chivers et al, 1988. ‡ Schotte et al, 1996. *

The reason why 5-HT2A receptor antagonism may confer atypicity on these antipsychotic drugs may reside in the ability of 5-HT2A receptors to modulate the activity of dopaminergic neurones differentially in different parts of the brain. 5-HT2A receptors are present on pyramidal cells in the cerebral cortex; these glutamatergic neurones project rostrally to midbrain brain nuclei containing cell bodies of monoaminergic neurones and regulate their firing rate (Jakab and Goldman-Rakic, 1998; Martín-Ruiz et al, 2001).

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Cortical pyramidal cells also bear 5-HT1A receptors and this may also be important in the action of antipsychotic drugs, as will be discussed below. Exactly how 5-HT2A receptor antagonists may modulate dopaminergic activity differentially in the nigrostriatal, mesolimbic and mesocortical systems has been evaluated in a series of microdialysis studies. Administration to rodents of selective D2 receptor antagonists, such as haloperidol and sulpiride, produces a large increase in extracellular dopamine concentrations in the neostriatum and in the nucleus accumbens, whereas in the prefrontal cortex the rise in extracellular dopamine is at most modest (Moghaddam and Bunney, 1990; Pehek and Yamamoto, 1994; Kuroki et al, 1999). In contrast, clozapine increased dopamine levels in all three brain regions (Moghaddam and Bunney, 1990; Pehek and Yamamoto, 1994). The administration of a selective 5-HT2A receptor antagonist, ritanserin, alone had little effect on the release of dopamine in any brain region (Andersson et al, 1995). However, when ritanserin is combined with a selective D2 receptor antagonist raclopride, a stimulation of the release of dopamine in

Figure 9.2 Stimulation of dopamine release in the rat medial prefrontal cortex by raclopride and M 100 907. Data are presented for the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). The indicated doses of the antipsychotic, or vehicle (VEH) were administered subcutaneously at

Multiple neurotransmitters involved

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the arrow. (With permission from Westerink et al, 2001.) the prefrontal cortex is observed (Andersson et al, 1995). Dopamine release evoked by raclopride in the neostriatum was unaffected. Similar observations have been obtained with another 5-HT2A receptor antagonist, M 100 907 (Westerink et al, 2001; Figure 9.2). A recent study of the dose-response relationship for this effect has produced the important finding that the synergy between M 100 907 and haloperidol is greatest at low doses of haloperidol (Liegeois et al, 2002). This suggests that it may be possible to generate a clozapine-like profile with doses of haloperidol which have little impact on nigrostriatal function by addition of a 5-HT2A receptor antagonist. These observations suggest that concomitant blockade of 5-HT2A and D2 receptors may cause a relative stimulation of the mesocortical dopamine pathway with respect to the nigrostriatal and mesolimbic pathways. This idea has received further support from data obtained with a series of mixed 5-HT2A/D2 receptor antagonists, including the atypical antipsychotics risperidone, olanzapine and ziprasidone, which all cause a marked rise in extracellular dopamine concentrations in mesocortical projection areas (Volonté et al, 1997; Kuroki et al, 1999; Westerink et al, 2001; Figure 9.3). However, quetiapine does not seem to follow this pattern (Volonté et al, 1997). If mesocortical dopaminergic activity is important for the antipsychotic action of these drugs, especially with respect to impact on negative symptoms and cognition, this relative activation of the mesocortical system with respect to the nigrostriatal system may explain why the atypical drugs show incisive antipsychotic effects at doses which do not produce EPSE. These neurochemical results have been supported by behavioural studies showing that 5-HT2A receptor antagonists can potentiate effects of D2 receptor antagonists in animal models of antipsychotic drug action. An example is shown in Figure 9.4, where ritanserin increased the effect of raclopride in conditioned avoidance responding in rats (Wadenberg et al, 1996). Translating this hypothesis to the clinic, it has been observed that augmentation of low-dose haloperidol with ritanserin increases the extent of the antipsychotic response without the appearance of EPSE (Vanden Bussche, 1990; Duinkerke et al, 1993). Although ritanserin is probably unsuitable for routine use in man due to its cardiovascular side effects, a more detailed appraisal of the clinical interest of augmentation therapy with 5-HT2A receptor antagonists such as M 100 907, SR 4639B or AC 103 will be important to perform. The concomitant 5-HT2A/D2 receptor blockade hypothesis also explains satisfactorily why 5-HT2A receptor antagonists without D2 receptor blocking action do not show prominent antipsychotic activity when administered alone. Such drugs include ritanserin (Lieberman, 1993), fananserin (Truffinet et al, 1999) and M 100 907 (De Paulis, 2001). However, recent results with SR 46439B, another drug with 5-HT2A receptor blocking properties devoid of D2 antagonism, suggest that this drug may have useful clinical properties when used alone (Meltzer et al, in preparation). The difference between SR 46439B and, for example, M 100 907, may be attributable to an interaction with 5-HT2C receptors (see below). The ability of atypical antipsychotics to stimulate dopaminergic activity in the prefrontal cortex may underlie the demonstrated benefit of such drugs on cognitive performance (Green et al, 1997; Honey et al, 1999; Sharma, 1999; Purdon, 2000). It has been demonstrated in monkeys that this neuronal system is important for optimal performance in psychomotor tasks, via activation of local D1 receptors (Sawaguchi and

Dopamine in the pathophysiology and treatment of schizophrenia

Figure 9.3 Stimulation of dopamine release by (a) risperidone and (b) olanzapine in the rat brain as determined by microdialysis. Data are presented for the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). The indicated doses of the antipsychotic, or vehicle (VEH) were

162

Multiple neurotransmitters involved

163

administered subcutaneously at the time indicated by the arrow. (With permission from Kuroki et al, 1999.)

Figure 9.4 Potentiation of the effect of raclopride on conditioned avoidance behaviour by ritanserin in rats. Response rates were compared in animals treated with the indicated dose of raclopride alone (open columns) and by raclopride in combination with ritanserin (2 mg/kg/sec; filled columns). The asterisk indicates a significant (p<0.05; Student’s t-test). DA, dopamine. (With permission from Wadenberg et al, 1996.) Goldman-Rakic, 1991). Improving cognitive function is an important attribute of certain atypical antipsychotics, helping to maintain adequate social integration of the patient (Meltzer and McGurk, 1999; McGurk and Meltzer, 2000). Nonetheless, clozapine causes impairment of working memory after 1 or 2 months of treatment, which nevertheless normalizes after 6 months of treatment (Hagger et al, 1993; Lee et al, 1999). This memory deficit appears at the same time as other measures of cognitive function start to improve, and is not observed with other atypical antipsychotics. It is possible that this effect could be attributed to excessive release of dopamine and overstimulation of D1 receptors. It should be noted that clozapine is also an agonist at the D1 receptor (Salmi and Ahlenius, 1996), and this could lead to excessive stimulation. Ichikawa et al (1998) studied the effect of amperozide, an atypical antipsychotic drug which is a 5-HT2A antagonist without appreciable D2 antagonism, clozapine, olanzapine,

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164

risperidone, haloperidol and S(-)-sulpiride on extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens of awake, freely moving rats, using in vivo microdialysis with dual probe implantation. Risperidone and clozapine significantly increased extracellular 5-HT levels in the medial pref rental cortex and the nucleus accumbens, respectively. Amperozide significantly increased extracellular 5-HT levels in both regions. Olanzapine, S(-)-sulpiride, haloperidol and the selective 5-HT2A receptor antagonist M 100 907 had no significant effect on extracellular 5-HT levels in either region. Thus, the ability to increase extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens by these antipsychotic drugs is not directly related to their affinity for 5-HT2A receptors since olanzapine and M 100 907 had no significant effect on extracellular 5-HT levels. A variety of mechanisms other than those involving 5-HT2A receptors, such as reuptake inhibition (amperozide) and blockade of α2adrenoceptors (olanzapine and clozapine), may contribute to the ability to increase extracellular 5-HT levels in the brain. The increase in extracellular 5-HT levels in the medial prefrontal cortex or nucleus accumbens following amperozide, clozapine, or risperidone administration may not be related to the effect on psychotic symptoms but could be related to effects on other types of psychopathology such as depression, negative symptoms or cognition. Somewhat similar results were reported by Antoniou et al (2000) in acute and chronic studies of serotonin turnover in the hippocampus, who found that risperidone but not haloperidol could effectively increase 5-HT release acutely. There is also evidence that antipsychotic drugs acting at 5-HT2A receptors may improve mood. The notion that serotonergic neurotransmission is involved in the control of mood has been popular for a long time, and this is the neurochemical target of many of the most widely used antidepressant drugs (Nutt, 2002). In particular, certain 5-HT2A receptor antagonists are used in the treatment of major depressive disorders, namely trazodone and nefazodone (De Vane, 1998), whereas ritanserin has been shown to be useful in the treatment of dysthymia (Lapierre, 1994). It has been demonstrated that augmentation treatment with risperidone (Ostroff and Nelson, 1999) or olanzapine (Shelton et al, 2001) can improve outcome in patients with treatment resistant depression treated with selective serotonin reuptake inhibitors (SSRIs), although patient numbers in these trials were small. Nonetheless, these studies have generated much interest in the notion that such atypical antipsychotics may have a more universal clinically useful effect on mood (Thase, 2002). In the context of improving mood in schizophrenic patients treated with antipsychotic drugs, it has long been recognized that clozapine has a more beneficial effect on mood than do typical antipsychotic medications (Ranjan and Meltzer, 1996; Anonymous, 1998). In several of the recent clinical trials of mixed D2/5-HT2A receptor antagonists in schizophrenia, improvement on clinical rating scales for depression has been manifest (Anonymous, 1998), although significant differences with comparators have not always been observed. Serotonin 5-HT2C receptors Many drugs that bind to 5-HT2A receptors with high affinity also bind to some extent to the structurally related 5-HT2C receptor. This receptor has received relatively little

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165

attention in studies of antipsychotic drugs, but may well be important in explaining some of the differences observed between the various antipsychotic drugs, and in pointing the way for future antipsychotic drug development. mRNA for the 5-HT2C receptor is present in both the cell bodies and the terminal fields of dopaminergic neurones of the nigrostriatal and mesolimbic systems (Pompeiano et al, 1994). It is also located on the soma of ventral tegmental and substantia nigra dopamine neurones, where it plays a key role in regulating the tonic activity of these neurones (see below). Roth et al (1992) demonstrated that high affinity binding to the 5-HT2C receptor did not distinguish between typical and atypical antipsychotic drugs. Although certain atypical antipsychotics, such as clozapine, aripiprazole, olanzapine and ziprasidone bind to 5HT2C receptors with relatively high affinity, comparable to their affinity for 5-HT2A or D2 receptors, quetiapine, risperidone and sertindole do not (Table 9.2). Aripiprazole is unusual in having higher affinity for 5-HT2C receptors than for 5-HT2A receptors. Among the 5-HT2A antagonists which lack appreciable D2 receptor affinity, ritanserin, M 100 907 and SR 46439B also have significant 5-HT2C receptor antagonist properties. Certain specific ligands for this receptor which are devoid of 5-HT2A receptor affinity have been developed, including the agonist Ro 60–0175 and the antagonists SB 242 084 and SB 206 553. The latter is also a 5-HT2B receptor antagonist.

Table 9.2 Comparative affinity of antipsychotic and other drugs for serotonin 5-HT2A and 5-HT2C receptors 5-HT2A receptor‡

5-HT2C receptor‡

5-HT2A/5-HT2C‡ ratio

Aripiprazole

20

7

2.86

Clozapine

3.3

13

0.254

Haloperidol

45

>10 000

<0.005

Olanzapine

1.9

7

0.271

Quetiapine

120

3820

0.031

Risperidone

0.16

63

0.003

Sertindole

0.85

>1000

27

0.24

1.0

0.24

Ritanserin M 100 907

*

0.63

20.0

0.032

†

SR 46 439B

5.8

120

0.048

*

79.4

0.40

199

*

1995

3.98

501

*

398

79.4

5.0

SB 242 084 SB 206 553

Ro 60–0175 ‡

Data presented as IC50 concentrations in nM. Data taken from Schotte et al (1996) except for *taken from Gobert et al (2000) and †from RinaldiCarmona et al (1992).

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166

Striatal 5-HT2C receptors exert a facilitatory control on basal DA efflux, which appears to be both tonic and phasic (Lucas and Spampinato, 2000). 5-HT2C receptors appear to mediate the tonic inhibitory serotonergic tone on dopamine neurones in the ventral tegmental area (Prisco et al, 1994; Kelland and Chiodo, 1996; Di Matteo et al, 1999; Gobert et al, 2000). The consequence of this is that administration of 5-HT2C receptor antagonists can directly increase dopamine release in the nucleus accumbens and in the prefrontal cortex. It will be recalled that the selective 5-HT2A receptor antagonist M 100 907 only does this when D2 dopamine receptors are also blocked. Stimulation of dopamine release in these areas has been demonstrated with SB 242 084 (Millan et al, 1998) and SB 205 553 (Di Matteo et al, 1999a; Gobert et al, 2000; Figure 9.5). Activity at 5-HT2C receptors may also explain why SR 46 439B is able to stimulate dopamine release in the medial prefrontal cortex (Bonaccorso et al, 2002). These findings suggest that the combination of 5-HT2A and 5-HT2C receptor blockade may be a more efficient way of augmenting antipsychotic action than either alone. For

Figure 9.5 Stimulation of dopamine release in the rat brain by the 5-HT2C receptor antagonist SB 206 553. (a) Striatum; (b) nucleus accumbens; (c) medial prefrontal cortex. DA, dopamine. (With permission from Di Matteo et al, 1999 and Gobert et al, 2000.)

Multiple neurotransmitters involved

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the moment, neither a selective 5-HT2C antagonist nor a true mixed 5-HT2A/5-HT2C antagonist have been evaluated in schizophrenia. This mechanism may contribute to explaining the apparently superior efficacy of SR 46 439B. Behavioural studies with SB 228 357, a selective 5-HT2C/2B antagonist and using selective 5-HT2A and 5-HT2B antagonists as controls, indicate that 5-HT2C receptor antagonism can produce a significant reversal of haloperidol-induced catalepsy (Reavill et al, 1999; Figure 9.6). Serotonin 5-HT1A receptors The 5-HT1A receptor is perhaps the best characterized 5-HT receptor subtype from a functional point of view, and plays an important role in controlling the activity of monoaminergic neurones. This receptor subtype can be considered as functionally antagonistic to the 5-HT2A receptor, both at the presynaptic and at the postsynaptic level. Activation of inhibitory 5-HT1A autoreceptors on the cell bodies in the raphé nucleus attenuates firing of these neurones (Sprouse and Aghajanian, 1986; Blier and De Montigny, 1987). Activation of 5-HT2A receptors, in contrast, generally leads to activation of serotonergic neurones by multiple mechanisms, including an indirect mechanism via inhibition of γ-aminobutyric acid (GABA)ergic inhibitory interneurones and a direct effect through excitation of glutamatergic afferents and other neurones

Figure 9.6 Reversal of haloperidolinduced catalepsy by SB 228 357 in rats. The asterisks indicate significance (*, p<0.05, **, p<0.01; Student’s t-test) differences from vehicle. (From Reavill et al, 1999.)

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(Celada et al, 2001). Postsynaptically, both 5-HT1A and 5-HT2A receptors are localized on the pyramidal output neurones in the cortex, where the former receptor subtype inhibits neuronal output by activation of a hyperpolarizing potassium current, and the latter facilitates output via activation of phospholipase C (Martín-Ruiz et al, 2001). This opposition between the two 5-HT receptor subtypes suggested that agonists at 5HT1A receptors may modulate dopaminergic neurotransmission in the brain in a similar fashion to 5-HT2A antagonists. Consistent with this, 5-HT1A agonists can stimulate the release of DA in the prefrontal cortex as well as potentiate the effect of D2 receptor blockers on DA release (Ichikawa and Meltzer, 1999). This effect is antagonized by the selective 5-HT1A receptor antagonist WAY 100 635 (Figure 9.7). Since clozapine has been shown to be a partial agonist at 5-HT1A receptors (Assié et al, 1997; Newman-Tancredi et al, 1998), the possibility arises as to whether the effects of clozapine on mesocortical dopamine release might be mediated by activation of this receptor subtype. This idea is supported by the observation that the stimulatory effects of clozapine are attenuated by WAY 100 635 (Rollema et al, 1997; Figure 9.7). This finding has since been extended to ziprasidone and quetiapine, which are also 5-HT1A receptor partial agonists (Newman-Tancredi et al, 1998), and more surprisingly, to risperidone and olanzapine, which are not (Rollema et al, 2000; Ichikawa et al, 2001). In addition, the facilitatory effects of M 100 907 (Ichikawa et al, 2001; Figure 7) and SR 46 439B (Bonaccorso et al, 2002) on sulpiride or haloperidol evoked dopamine release are also abolished by WAY 100 635. Taken together, these results suggest that atypical antipsychotics, and maybe 5-HT2A receptor antagonists, in general, exert their effects on

Figure 9.7 Effect of the 5-HT11A receptor antagonist WAY 100 635 on evoked dopamine release in the rat medial prefrontal cortex. Data are shown for stimulation with (a) clozapine and (b) M 100 907. (From Ichikawa et al, 2001.)

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dopaminergic neurotransmission, at least in part, indirectly, via activation of 5-HT1A receptors (Millan, 2000). This concept has important clinical implications, suggesting that 5-HT1A receptor agonists may be of use in combination with D2 receptor blockade for the development of future generations of atypical antipsychotics with a wide spectrum of action (Bantick et al, 2001). That this may be possible has been supported by two small pilot studies, one doubleblind, of augmentation of low-dose haloperidol treatment by the 5-HT1A receptor agonist tandospirone (Sumiyoshi et al, 2001). Both studies showed a beneficial effect of tandospirone augmentation on cognitive function over conventional antipsychotic treatment alone. Activity at 5-HT1A receptors may contribute to the efficacy of the novel antipsychotic agent aripiprazole, which has very recently been approved for the treatment of schizophrenia. This drug was originally developed as a presynaptic dopamine receptor partial agonist, with some postsynaptic D2 receptor antagonist properties (Kikuchi et al, 1995). However, aripiprazole is more effective and better tolerated than previously studied partial dopamine agonists (Kane et al, 2002). This may be because aripiprazole also has potent 5-HT1A receptor partial agonist activity, with an affinity of 17 nM. It may thus well be that this combination of 5-HT1A receptor partial agonism with a dopaminergic mechanism is what endows aripiprazole with its powerful and comprehensive antipsychotic action. Another drug with D2 receptor partial agonism and 5-HT1A receptor partial agonism is DU 127 090, currently in clinical trials in patients with schizophrenia. Unlike aripiprazole, it lacks 5-HT2A receptor antagonism. It will be interesting to see whether this agent is also effective and well tolerated. Adrenergic receptors Interest in interactions of antipsychotics with α1-adrenoceptors has largely concerned side effects. Many of the earlier typical antipsychotics, including chlorpromazine and haloperidol, as well as clozapine, have relatively high affinity for this receptor subtype (Peroutka and Snyder, 1980), which is believed to contribute to their sedative effects. Non-sedative antipsychotics, such as sulpiride, tend to have little affinity for α1 receptors. The newer generation of atypicals, with the exception of olanzapine and risperidone, are largely devoid of α1-receptor blocking properties (Schotte et al, 1996). Binding to this receptor in the periphery may contribute to the autonomic side effects of some of the earlier drugs, such as orthostatic hypertension (Richelson, 1984). With the exception of clozapine, and to a lesser extent olanzapine, antipsychotics as a class have limited affinity for α2 receptors (Richelson, 1984). These receptors are localized on the cell bodies and nerve terminals of monoaminergic neurones, where they inhibit neuronal firing and transmitter release. Stimulation of ventral tegmental dopamine neurones with clonidine, an α2 agonist, regularized the firing of these neurones. This effect was blocked by idazoxan, an α2 antagonist, indicating the firing rate of these neurones was under tonic α2 adrenergic antagonism (Grenhoff and Svensson, 1989). Systemic administration of idazoxan induced burst firing of these neurones and markedly increased dopamine output in the medial prefrontal cortex, whereas it failed to affect dopamine efflux in the striatum or in the nucleus accumbens (Hertel et al, 1999a, b). Idazoxan also potentiated the ability of raclopride, a D2/D3 antagonist to increase

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dopamine release in the rat prefrontal cortex (Hertel et al, 1999b). Idazoxan has been used as an augmentation therapy in patients who responded poorly to haloperidol and was reported to be beneficial (Litman et al, 1993; Pickar et al, 1994; Litman et al, 1996). Relief of inhibition of noradrenergic and serotonergic neurones by α2 antagonists is believed to improve mood, and may be involved in the mechanism of action of drugs such as mianserin and mirtazapine (Westenberg, 1999). Such a mechanism may also contribute to the beneficial effects of clozapine and olanzapine on mood (Hertel et al, 1999a). Acetylcholine receptors Muscarinic receptor blockade is found with some, but not all, typical and atypical antipsychotics (Peroutka and Snyder, 1980; Richelson, 1984). This can have useful effects in the treatment of schizophrenia, in particular to limit EPSE (Miller and Hiley, 1974). Dopamine and acetylcholine are functionally antagonistic in the basal ganglia, so that simultaneous blockade of both transmitter systems will preserve extrapyramidal function to some extent. Before the advent of the recent atypicals, antipsychotics with high affinity for the muscarinic receptor, such as thioridazine and α-flupenthixol were often chosen for their low incidence of neurological side effects. In addition, blockade of muscarinic receptors produces a certain degree of sedation, which may be useful in the management of agitated patients. On the other hand, affinity for the muscarinic receptor increases the risk of unacceptable autonomic side effects. It is also possible that the transient impairment of memory produced by clozapine (see above) is attributable to blockade of central muscarinic receptors, for which this drug has particularly high affinity. It is important to recognize that differences in affinity for the five different muscarinic receptor subtypes, which all subserve different physiological functions, can significantly influence the properties of a given drug. For example, clozapine and zotepine have highest affinity for the M1 receptor subtype (Bolden et al, 1992). In addition, intrinsic activity at the different receptor subtypes may differ, as has been demonstrated for clozapine (Zorn et al, 1994). Modification of cholinergic transmission in the cortex may also directly affect schizophrenic symptoms. Muscarinic antagonists used to treat extrapyramidal symptoms, such as biperiden have been reported to ameliorate negative symptoms of schizophrenia (Tandon et al, 1992), whilst the experimental drug xanomeline, which is an agonist at M1 and M4 receptors, has also been reported to improve psychotic symptoms (Felder et al, 2001). There is considerable interest at this time in developing selective M1 or M4 agonists as possible antipsychotic agents. The clinical spectrum of atypical antipsychotics may owe some of its originality to their ability to promote acetylcholine release in the prefrontal cortex. This would be expected to have beneficial effects on cognitive function, and possibly on negative symptomatology. Such an effect was first reported for clozapine using in vivo microdialysis (Parada et al, 1997), and has since been extended to olanzapine, risperidone and ziprasidone (Ichikawa et al, 2002). Such effects on acetylcholine release are observed neither in the neostriatum nor in the nucleus accumbens, using an identical protocol, nor are they shared by haloperidol, sulpiride or thioridazine (Ichikawa et al, 2002). Unlike the

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effect of these same drugs on dopamine release in the prefrontal cortex, this stimulation of acetylcholine release (except in the case of quetiapine) does not appear to be mediated by 5-HT1A receptors (Ichikawa et al, 2002). Conclusions Historically, the emphasis for antipsychotic drug action has been placed on D2 dopamine receptor blockade. Selective D2 receptor blockade may be seen as one of several principles to achieve an antipsychotic action, but this is far from optimal because of the risk of EPSE and the limited impact on negative symptoms and cognition, which do not appear to be due to excessive D2 receptor stimulation. To improve upon the efficacy of such drugs, much interest has revolved around complementing or replacing this dopaminergic mechanism by an action on serotonergic transmission. 5-HT2A receptor blockade, along with weaker D2 receptor blockade, may contribute to the ability of atypical antipsychotic drugs to increase dopamine levels in the medial prefrontal cortex while having a smaller effect on limbic dopamine efflux. This may contribute to their advantages for cognition, negative symptoms and antipsychotic activity. Antagonism at 5-HT2C receptors may be useful for improving cortical function, although it could possibly be detrimental for limbic function. The use of 5-HT1A receptor agonists may substitute for 5-HT2A antagonism and achieve the same benefits in combination with weak D2 receptor blockade. Some new antipsychotic drugs, such as aripiprazole, combine weak D2 antagonism, or partial D2 agonism, with 5-HT1A partial agonism. Aripiprazole may owe its efficacy to 5-HT1A receptor blockade along with 5HT2A receptor antagonism. Cholinergic, muscarinic, GABA and glutamate receptor mediated actions are also clearly capable of contributing to the impact of drugs on psychosis and modulate other aspects of antipsychotic drug action, including EPSE and cognition, through a variety of direct and indirect mechanisms. The role of glutamate, in particular NMDA receptors, in schizophrenia has been investigated extensively, and this is reviewed in Chapter 10. Further research is needed to determine how to use this information to design more effective antipsychotic drugs which can then be modulated by more selective agents. For most patients, more complex agents, such as the atypical antipsychotics, have greater potential for regulating several different elements of the neural circuitry which underlies the multiple deficits of schizophrenia. References Abraham HD, Aldridge AM. (1993) Adverse consequences of lysergic acid diethylamide. Addiction 88:1327–34. Allen RM, Young SJ. (1978) Phencyclidine-induced psychosis. Am J Psychiatry 135: 1081–4. Andersson JL, Nomikos GG, Marcus M et al. (1995) Ritanserin potentiates the stimulatory effects of raclopride on neuronal activity and dopamine release selectivity in the mesolimbic dopaminergic system. Naunyn Schmiedebergs Arch Pharmacol 352:374–85. Andreasen NC. (1997) The evolving concept of schizophrenia: from Kraepelin to the present and future. Schizophrenia Res 28:105–9.

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chapter 10 Dopaminergic and glutamatergic influences in the systems biology of schizophrenia Carol Tamminga and Deborah Medoff Schizophrenia is an illness with an unknown pathophysiology and aetiology and inadequate treatments. However, data have accumulated which are progressively contributing to a characterization of illness mechanisms. In this chapter, the ‘systems’ aspect of pathophysiology and therapeutics in schizophrenia will be emphasized. Schizophrenia is not merely an illness of a single brain region, and probably not of any one single neurotransmitter system. Rather, it appears that, during the manifestation of disease symptoms, an entire neural system (in the authors’ view, the limbic system) behaves abnormally when performing mental tasks, and abnormally influences related neocortical and subcortical brain areas. Dysfunction of the anterior cingulate cortex and the hippocampus occur most regularly in psychotic states of the illness, both at rest and with task stimulation (Figure 10.1). Moreover, in another study, when volunteers were engaged in a task, persons with schizophrenia who were performing similarly to the normal comparison group, also show regional cerebral blood flow (rCBF) defects in the anterior cingulate cortex (data not shown). Although the exact nature and location of the lesion has not yet been identified, it can be said that changes in neuronal activity in the limbic pathways are associated with symptoms of psychosis and cognitive change (Figure 10.2). We know that the change in neuronal activity that occurs in schizophrenia is not principally neurodegenerative (as occurs in Alzheimer’s disease) or principally episodically hyperactive (as occurs in epilepsy), but probably is due to a dysregulation of the activity of systems of neurones, and consequently of conscious information flow within the central nervous system (CNS). The present authors’ own data consistently support the hypothesis that demanding tasks of learning and memory involve the limbic cortex, and activate associated neocortical systems in a task specific fashion. Learning and memory tasks involve sensory input, processing, synthetic output functions and coordinated brain activity (i.e. the neural circuit) (Holcomb et al, 1999, 2000). While normal volunteers utilize neural systems smoothly during task performance, volunteers with schizophrenia, even while performing the task similarly, do not activate their limbic cortex (unpublished observations). A number of different techniques have been used to identify and evaluate the systems component of cerebral activation and compared rCBF parameters in normal and schizophrenia groups. These approaches have led to the conclusions that limbic system function, especially for tasks of learning and memory, is abnormal in schizophrenia. It is our contention that treatments for the illness should be targeted at correcting the neuronal activity of an entire ‘psychosis’ system in schizophrenia.

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Figure 10.1 These data show the only brain regions (the cingulate cortex (ACC) and the hippocampal cortex (HC)) identified as abnormal in a fluorodeoxyglucose PET study comparing regional changes in the rate of cerebral glucose metabolism in schizophrenic (red columns) and normal subjects (blue columns) at rest. No change is observed in the amygdala (Amy). rCMRglu, regional cerebral glucose metabolism rate. Clinical pharmacology studies in schizophrenia have identified two major neurotransmitter pathways, the dopaminergic and glutamatergic systems, which both appear to influence symptoms of the illness. Dopamine is an important transmitter in the basal ganglia thalamocortical (BGTC) pathway (Alexander et al, 1986; DeLong, 1990), while glutamate is a key transmitter system in the cortex, particularly in limbic areas. Of the two, the more widely known in the field of schizophrenia is the dopaminergic system, with D2 dopamine receptor blockade diminishing psychotic symptoms (Davis, 1969). In the half century of research since this pivotal association was established, our knowledge has expanded greatly (Gunne et al, 1982; Carlsson and Carlsson, 1990; Laruelle et al, 1996; Kapur et al, 1998). Most recently, symptoms of acute psychosis have been associated with increased dopamine release in the striatum (see Chapter 2). Moreover, the effects of D2 dopamine receptor blockade are modified by serotonin receptor antagonism (especially at the 5-HT2A receptor), in a fashion not yet fully defined, to diminish the

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motor effects of antipsychotic drugs and to enhance their impact on cognitive symptoms (Leiberman et al, 1998). Studies of antipsychotic actions in laboratory animals have advanced our knowledge of the regional and systems effects of these drugs in humans (Gao et al, 1998; Sakai et al, 2001). Dopamine inhibits neuronal activity in its primary terminal field, the striatum, and disinhibits the cortex through the BGTC circuit. Thus, blockade of dopamine receptors in the basal ganglia will tend to attenuate cell firing in the cortex.

Figure 10.2 A significant linear relationship exists between the extent of positive psychotic symptoms measured on the BPRS rating scale in persons with schizophrenia (vertical axis) and neuronal activity in the limbic cortex, measured as cerebral glucose metabolism (horizontal axis). rCMRglu, regional cerebral glucose metabolism rate. The other neurotransmitter system shown to affect psychosis in schizophrenia is the glutamatergic system, in particular by antagonism of N-methyl-D-aspartate (NMDA) sensitive glutamate receptors. Not only does NMDA receptor antagonism in normal humans reproduce some of the symptoms of the illness, but patients with schizophrenia report an exacerbation of their own psychotic symptoms with administration of a noncompetitive antagonist such as ketamine (Figure 10.3). Unlike other psychotomimetic compounds which produce a similar standard behavioural repertoire when given to persons with schizophrenia (Thaker et al, 1983), ketamine administration usually exacerbates an individual’s symptom profile (Lahti et al, 1995, 2001). Because ketamine alters neuronal firing in limbic grey matter regions (hippocampus and anterior cingulate), this psychotomimetic characteristic is probably mediated by alterations in the activity of the limbic system. This implies that glutamate may modulate the expression of psychosis at some relevant set of CNS synapses that

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compose a circuit, and thereby may be involved in generating certain aspects of the symptoms manifested in schizophrenia.

Figure 10.3 Ketamine increased the magnitude of psychotic symptoms in persons with schizophrenia (N=9) and produced a syndrome in normal persons (N=7) which included psychotic symptoms very similar to those observed in schizophrenia. (a) BPRS total score; (b) BPRS psychosis score; (c) BPRS withdrawal score; (d) BPRS anxiety score. SZ, schizophrenia; NC, normal controls; pbo, placebo. A role for the dopaminergic and glutamatergic systems in schizophrenia, is suggested by the ability of pharmacologically selective drugs for these receptors to modify specifically schizophrenic symptoms. Pharmacological manipulation of several other neurotransmitter systems can also generate psychosis or psychotomimetic states, for example the GABA (γ-aminobutyric acid) system with muscimol (Thaker et al, 1983) or the serotonergic system with LSD (lysergic acid diethylamide). However, in none of these examples does the drug, when administered to persons with schizophrenia, modify

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their own symptoms per se. In contrast, for both dopaminergic and glutamatergic drugs, the symptoms of schizophrenia are modified. This evidence, while not definitively excluding a role for these other systems, may suggest that the dopaminergic and glutamatergic systems are more pertinent targets for drug therapy. Dopamine Blockade of dopamine D2 receptor mediated transmission reduces psychosis in schizophrenia. The antipsychotic action of any dopamine antagonist that penetrates the CNS, is correlated roughly with its affinity for the D2 receptor (Creese, 1976); this applies both to indirectly as well as to directly acting dopamine antagonists (Walinder et al, 1976; Tamminga, 1986). This is undoubtedly the most widely and consistently replicated observation in schizophrenia pharmacology. Although we have had this specific pharmacological knowledge for many years, the question of which brain mechanisms are responsible for which of the behavioural actions of D2 antagonists (antipsychotic effects; extrapyramidal signs) has only recently been considered. Decades of research into the neural basis of Parkinson’s disease has clarified much of the circuitry used by dopamine to exert its effects on the frontal cortex through the BGTC pathways (Alexander et al, 1986; Nauta, 1989; DeLong, 1990). Studies of the actions of haloperidol on regional neuronal activity in humans are consistent with the idea that when antipsychotics act in the striatum to block D2 receptors, a signal is transmitted from the striatum, through the thalamus to the frontal cortex, in particular the anterior cingulate and the dorsolateral frontal cortex (Holcomb et al, 1996; Figure 10.4). Via the BGTC circuit, it is in precisely these areas of the frontal cortex where the full and final action of these antipsychotic drugs is probably exerted on cortically mediated human behaviours. Additional actions of antipsychotics mediated by monoaminergic and other systems are probably exerted directly in the frontal cortex. The latter extrastriatal effects may represent an important difference between typical and atypical antipsychotic drugs (Tamminga, 1998). Studies in laboratory animals provide evidence for effects of chronic (6 months) antipsychotic drug treatment in all of the BGTC regions, and also differentiate between motor and putative cognitive actions. The data demonstrate the overall systems activity of antipsychotic drugs through an initial, direct action in the striatum. Haloperidol administration to rats at doses that produce therapeutic plasma levels in humans, influences the activity of neurones and their activity within the entire BGTC system (Figure 10.5). Haloperidol upregulates D2 receptors throughout the striatum and increases the activity of inhibitory striatal GABA neurones (increased expression of GAD67[glutamic acid decarboxylase-67] (mRNA), suggesting that its actions are exerted on neurones diffusely within these frontal circuits. Specifically, activated striatal projections to the globus pallidus overinhibit pallidal neurones, thus diminishing GABA release and upregulating GABAA receptors in the pallidum (Shirikawa et al, 1994; Sakai et al, 2001). By a similar mechanism, in the substantia nigra pars reticulata (SNR), GABAA receptors are upregulated and dopamine D1 receptors are downregulated—changes which are

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associated with vacuous chewing movements (a putative animal model of tardive dyskinesia) (Tamminga et al, 1990; Figure 10.6).

Figure 10.4 Evidence suggests that the blockade of D2 dopamine receptors by haloperidol occurs in the caudate/putamen of the human brain. That action is then transmitted through the BGTC circuit to have a final action in the frontal and cingulate cortex. Gp, globus pallidus; SNr, substantia nigra pars reticula; DA, dopamine; EAA, excitatory amino acid; rCMRglu, regional cerebral glucose metabolism rate.

Figure 10.5 BGTC circuitry in the untreated brain (a) and after

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administration of haloperidol (b). The different neuronal types are shown in different colours: yellow (glutamate); blue (GABA/substance P); orange (dopamine). THE ‘+’ symbols indicate excitatory synapses, and the ‘−’ symbols inhibitory synapses. Within the BGTC circuit, chronic administration of haloperidol causes predictable changes in the activity of the dopamine, peptidergic and GABA systems. It is the changes in the substantia nigra pars reticulata that most closely correlate with hyperactive oral movements (vacuous chewing) in the rats (a putative model of tardive dyskinesia). Glu, glutamate; SP, substance P; GP, globus pallidus; DA, dopamine; STN, subthalamic nucleus; SNr, substantia nigra pars reticulata; SNc, substantia nigra pars compacta.

Figure 10.6 In the SNr there is a significant relationship between changes in the expression of the

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GABAA receptor and the D1 dopamine receptor. Moreover, the ratio of change of these two measures is correlated with the magnitude of dyskinesia in the mouse. SNr, substantia nigra pars reticulata.

Figure 10.7 Changes in GABAA receptor binding in the mediodorsal thalamus and in GAD67 mRNA in the reticular thalamus in response to haloperidol (H), olanzapine (O) and sertraline (S). While only haloperidol increased GABAA receptor binding, all three drugs increase GAD67 mRNA. Because haloperidol is the only one of these three drugs that produces deleterious motor side effects, the changes observed in the reticular thalamus are probably associated with the antipsychotic actions of the drugs.

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In the thalamus, GABAA receptors in the ventromedial nucleus are altered, but only in those animals with vacuous chewing movements. However, all animals show GABAA receptor changes in the neurones of the reticular nucleus, suggesting that this mediates non-motor antipsychotic drug actions (Figure 10.7). The observation that atypical antipsychotic drugs also have this action in the reticular nucleus, in spite of producing very limited motor effects reinforces the hypothesis of a potential non-motor antipsychotic effect in the reticular nucleus of the thalamus. Several additional lines of evidence also suggest the involvement of the thalamus in schizophrenia (Andreasen et al, 1994) and in mediating antipsychotic drug actions (Carlsson and Carlsson, 1990). In humans, chronic antipsychotic treatment also provides evidence for the same kind of systems-wide effect (see Figure 10.4), confirming the idea that antidopaminergic actions in the striatum will lead to inhibition in the cortex. Haloperidol produces its most profound effect in the basal ganglia (caudate and putamen) and has lesser action in the thalamus and the middle frontal and anterior cingulate cortex. So in both the human and the rat, changes in cerebral patterns of neuronal activation are consistent with the idea that the human brain is using a system (the BGTC circuit) to carry an antipsychotic action to the frontal cortex. Glutamate Ketamine produces an exacerbation of psychosis in schizophrenia and a mild psychostimulant effect in normal persons (Krystal et al, 1994; Lahti et al, 1995; Breier et al, 1997) (see Figure 10.3). These findings have stimulated attempts to document the neural substrates and circuits mediating this pharmacological action, a problem that can be addressed by assessing rCBF. In normal volunteers, ketamine elevates rCBF in the anterior cingulate and inferior frontal cortex (Holcomb et al, 2001) and depresses rCBF in the cerebellum. In schizophrenia, the effects of ketamine on rCBF are similar to those seen in normal controls, except that in this group rCBF is also depressed in the hippocampus and elevated to a greater extent in the anterior cingulate (Figure 10.8; Medoff et al, 2001). Moreover, in the anterior cingulate cortex, the extent of activation correlates with the magnitude of the exacerbation of psychosis (unpublished observations). Thus, the psychotomimetic action of ketamine appears to be mediated through limbic circuit structures and by NMDA receptor blockade. The present authors have investigated the effect of phencyclidine on the expression of regional immediate early genes. The limbic cortex reacts strongly to phencyclidine administration, and to a greater extent than neocortical areas. Moreover, phencyclidine alters NMDA receptor binding in the hippocampus and interferes with hippocampally mediated learning in mouse paradigms. Curiously, many of these actions in animals are blocked not only by D-cycloserine, but also by a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug (unpublished observations). This suggests that the effects of phencyclidine, mediated by blockade of NMDA receptor ion channels within the limbic circuit, can be functionally antagonized by a dopamine receptor antagonist. Presumably, this occurs through overlapping system interactions in the neocortex,

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possibly in the limbic cortex. These findings in animals are somewhat surprising, given that phencyclidine or ketamine-induced behavioural phenomena in humans are not blocked by antipsychotics at therapeutically active doses. The explanation for this dilemma will require additional study. However, it does seem clear that in experimental animals or in human volunteers, drug actions on cerebral systems can interact.

Figure 10.8 Volunteers with schizophrenia who received ketamine showed a significantly greater elevation of rCBF in the cingulate cortex (red line) than in normal controls (blue line) when followed for 66 minutes. The grey line corresponds to values obtained in normal controls who received vehicle. Dopamine and glutamate Basic brain biology suggests multiple sites where dopamine and glutamate could interact: (i) at a single neurone, (ii) within local neuronal circuits, and (iii) within interacting longtract neural systems. Based on the results of human functional imaging studies and other sources of data, the importance of cerebral systems in mediating complex behavioural functions has become clearer. At least two systems are well described in the existing literature, in this regard: (i) the BGTC system and its involvement with the manifestations of Parkinson’s disease, and (ii) the limbic system, extensively involved with learning and memory and affective load (Box 10.1).

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It is the first of these systems in which dopamine has a major modulatory influence. Either the loss of dopamine (as in Parkinson’s disease) or a full blockade of D2 dopamine receptors (as with antipsychotic drugs) disinhibits GABAergic medium spiny neurones in the striatum (through loss of an inhibitory dopaminergic influence in striatum); this action, transmitted through the thalamus to the frontal neocortical and limbic structures, inhibits regions within the frontal cortex, producing parkinsonian symptoms (in Parkinson’s disease) and an antipsychotic response (in schizophrenia). The limbic cortex uses glutamate as its major excitatory neurotransmitter and is highly plastic, mediating responses to novel and learned events. Glutamate mediates transmission of information forward from the hippocampus to the anterior cingulate cortex, then on to the frontal neocortex. Moreover, glutamate mediates local and regional feedback systems, which modulate overall system activity (tone) and probably learning systems.

Box 10.1 Dopamine-glutamate interactions Dopamine Glutamate Antagonists decrease neuronal activity in ACC

Blockers increase neuronal activity in ACC

Antagonists normalize rCBF perfomance correlates in ACC

Blockers obscure rCBF performance correlates in ACC

Antagonists alter frontal cortex rCBF regionally

Blockers modify frontal cortex rCBF

Antagonists alter frontal cortex and ACC through BGTC circuit

Blockers alter frontal cortex and ACC through limbic system circuit

ACC, anterior cingulate cortex; rCBF, regional cerebral blood flow; BGTC, basal ganglia thalamocortical.

Dopamine and glutamate each appear to have preferential systems of influence: the frontal cortex-BGTC circuit for dopamine and the limbic circuit for glutamate. This is illustrated by the demonstration that noncompetitive blockade of NMDA glutamate receptors alters function primarily in the limbic and frontal cortex, as can be seen by alterations in immediate early gene expression in response to phencyclidine in rodents (Gao et al, 1998) or in rCBF in response to ketamine in humans (Lahti et al, 1995). Although the initial site of action of the NMDA antagonist is a change in the firing of hippocampal neurones, the influence of the limbic system on related neocortical and subcortical structures is so extensive that neuronal function is altered downstream in the frontal cortex and even in the limbic striatum. Thus, a convergent projection area of both of these systems, the frontal neocortex and limbic cortex, is shared by both dopaminergic and NMDA-glutamatergic transmission (Figure 10.9). Thus, while dopamine and glutamate act primarily on distinct neural systems, each delivers their ‘information’ to common brain regions in a highly interactive/overlapping fashion, through well characterized neuronal circuits.

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Figure 10.9 Schematic depictions of the long-track pathways in the BGTC circuit and in the limbic circuit showing that the final common target of these pathways is the frontal neocortex and anterior cingulate regions. The yellow arrows indicate excitatory glutamatergic pathways and the blue arrows inhibitory GABAergic pathways. GP, globus pallidus; STN, subthalamic nucleus; SNr, substantia nigra pars reticulata; SNc, substantia nigra pars compacta; MB, mamillary body; DG, dentategyrus. Treatment of schizophrenia Schizophrenia is a disease of disordered mental productivity and organization that can be conceptualized essentially as a neural system disorder of the CNS. This suggests that it is the overall function of the system, rather than that of any single component, that is abnormal in the illness and results in the ensuing symptoms. In consequence, a systems approach can also be used to explain how current antipsychotic treatment works, whereby

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it is not necessarily the primary pathology of schizophrenia, but rather the disordered system ‘output’ that is treated. Because dopamine and glutamate strongly modulate neural systems that have overlapping tertiary targets, (i.e. the frontal cortex and limbic striatum) the same kind of pharmacological action (i.e. antipsychotic) could be delivered to different brain regions regulating motor, cognitive or affective processing by altering activity in, for example, the frontal cortex. Thus, it is not only a drug’s action at a discrete neural target within the brain, but also its overall action on related neural systems which determines its overall actions on neurally mediated behaviours and illnesses, such as schizophrenia. Known antipsychotic drugs which block D2 dopamine receptors are likely to produce their therapeutic action on functions of the frontal cortex indirectly, mediated through changes in the activity of the BGTC neuronal circuit. Psychotomimetic agents like ketamine appear to act primarily within the limbic cortex, but also modulate indirectly the function of frontal cortical regions. It would follow from this, that neither of these drug effects seems to be exerted primarily in the area of delivery but result from an indirect projection effect to the frontal cortex from different but overlapping neuronal networks. The development and testing of drugs that modulate the neuronal circuits of interest for psychosis in other ways may provide novel approaches for modulating neuronal activity in the frontal cortex and provide original antipsychotic effects. References Alexander GE, DeLong MR, Strick PL. (1986) Parallel organisation of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–81. Andreasen NC, Arndt S, Swayze VW II et al. (1994) Thalamic abnormalities in schizophrenia visualised through magnetic resonance image averaging. Science 266:294–8. Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D. (1997) Association of ketamineinduced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 154:805–11. Carlsson M, Carlsson A. (1990) Interactions between glutamatergic and monoaminergic systems within the basal ganglia—implications for schizophrenia and Parkinson’s disease. Trends Neurosci 13:272–6. Creese I. (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–3. Davis JM. (1969) Review of antipsychotic drug literature. In: (Klein DF, Davis JM, eds.) Diagnosis and Drug Treatment of Psychiatric Disorders. (Williams and Wilkins Co: Baltimore). DeLong MR. (1990) Primate models of movement disorders of basal ganglia origin. Trends Neurosci 13:281–5. Gao XM, Hashimoto T, Tamminga CA. (1998) Phencyclidine (PCP) and dizocilpine (MK801) exert time-dependent effects on the expression of immediate early genes in rat brain. Synapse 29:14–28. Gunne LM, Growdon J, Glaeser B. (1982) Oral dyskinesia in rats following brain lesions and neuroleptic drug administration. Psychopharmacology 77:134–9. Holcomb HH, Cascella NG, Thaker GK, Medoff DR, Dannals RF, Tamminga CA. (1996) Functional sites of neuroleptic drug action in the human brain: PET/FDG studies with and without haloperidol. Am J Psychiatry 153:41–9. Holcomb HH, Lahti AC, Medoff DR, Weiler M, Dannals RF, Tamminga CA. (2000) Brain activation patterns in schizophrenic and comparison volunteers during a matched-performance auditory recognition task. Am J Psychiatry 157:1634–45.

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Holcomb HH, Lahti AC, Medoff DR, Weiler M, Tamminga CA. (2001) Sequential regional cerebral blood flow brain scans using pet with h(2)(15)o demonstrate ketamine actions in CNS dynamically. Neuropsychopharmacology 25:165–72. Holcomb HH, Lahti AC, Weiler M, Medoff DR, Tamminga CA. (1999) Neuroleptic treatment of schizophrenic patients: how do haloperidol and clozapine normalise brain blood flow patterns associated with a difficult tone recognition task? In: (Gattaz WF, Hafner H, eds.) Proceedings of the IVth Search for the Causes of Schizophrenia, Vol iv Balance of the Century. (Steinkopff Verlag: Darmstadt) pp. 355–65. Kapur S, Zipursky, RB, Remington G et al. (1998) 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 155:921–8. Krystal JH, Karper LP, Seibyl JP et al. (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214. Lahti AC, Koffel B, LaPorte D, Tamminga CA. (1995) Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13:9–19. Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25: 455–67. Laruelle M, Abi-Dargham A, van Dyck CH et al. (1996) Single photon emission computerised tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 93:235–40. Lieberman JA, Mailman RB, Duncan G et al. (1998) Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychol 44:1099–117. Medoff DR, Holcomb HH, Lahti AC, Tamminga CA. (2001) Probing the human hippocampus using rCBF: contrasts in schizophrenia. Hippocampus 11:543–50. Nauta WJH. (1989) Reciprocal links of the corpus striatum with the cerebral cortex and limbic system: a common substrate for movement and thought? In: (Mueller J, ed.) Neurology and Psychiatry: A Meeting of Minds. (Karger: Basel) pp. 43–63. Sakai K, Gao XM, Hashimoto T, Tamminga CA. (2001) Traditional and new antipsychotic drugs differentially alter neurotransmission markers in basal ganglia-thalamocortical neural pathways. Synapse 39:152–60. Shirakawa O, Tamminga CA. (1994) Basal ganglia GABAA and dopamine D1 binding site correlates of haloperidol-induced oral dyskinesias in rat. Exp Neurol 127:62–9. Tamminga CA. (1986) Dopamine agonist treatment of schizophrenia with Npropylnorapomorphine. Arch Gen Psychiatry 43:398–402. Tamminga CA. (1998) Principles of the pharmacotherapy of schizophrenia. In: (Bunney BS, ed.) Neurobiology of Psychiatric Disorders. (Oxford University Press: New York) pp. 272–85. Tamminga CA, Dale JM, Goodman L, Kaneda H, Kaneda N. (1990) Neuroleptic-induced vacuous chewing movements as an animal model of tardive dyskinesia: a study in three rat strains. Psychopharmacology 102:474–8. Thaker GK, Hare TA, Tamminga CA. (1983) GABA system: clinical research and treatment of tardive dyskinesia. Mod Probl Pharmacopsychiatry 21:155–67. Walinder J, Skott A, Carlsson A, Roos BE. (1976) Potentiation by metyrosine of thioridazine effects in chronic schizophrenics. A long-term trial using double-blind crossover technique. Arch Gen Psychiatry 33:501–5.

chapter 11 Pharmacogenomics of antipsychotic drugs Robert Kerwin, Maria Arranz and Dalu Mancama Clinical psychiatry can benefit greatly from recent advances in pharmacogenomic research. The application of pharmacogenomic strategies to antipsychotic treatment will have obvious advantages including selecting the drug most likely to produce beneficial results, according to the genetic predisposition of the individual. The main benefits of this will be better recovery levels and the reduction of adverse reactions. Additional benefits include the validation of therapeutic targets to assist the development of more selective and improved drugs. Recent studies supporting this optimistic view include the identification of genetic variants associated with the development of side effects and the development of a test for predicting treatment response using genetic information. However, in the field of schizophrenia there is limited epidemiological evidence supporting the hypothesis that gene mutations influence the response of an individual with schizophrenia to drug therapy, with only a few studies reporting monozygotic twin concordance in drug response (Vojvoda et al, 1996; Horacek et al, 2001; Mata et al, 2001). 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 11.1). In addition, the complexity of response assessment and phenotype definition hampers the identification of genes related to response. Nevertheless, recent years have seen a series of reports associating genetic variability and clinical phenotypes and recent advances, both in the genetic information available (Sachidanandam et al, 2001) and in analytical techniques, should improve our knowledge of the mechanism of action of antipsychotic drugs and on the genes involved. The influence of polymorphisms in metabolic enzymes on the response to antipsychotic drugs Initial investigations in pharmacogenetic research concentrated on mutations in single genes coding for metabolic enzymes that affect drug transformation and elimination. In the main, antipsychotic drugs are metabolized by cytochrome P450 (CYP) enzymes although with wide inter-individual variability, resulting in considerable differences in steady-state plasma concentrations for the same dose of a given drug. This variability has been attributed, in part, to the numerous polymorphisms that occur in CYP enzymes that in some cases have a direct effect on metabolic rates. For example, CYP2D6, an enzyme involved in the biotransformation of a large number of antipsychotic drugs such as haloperidol, chlorpromazine and risperidone (Otani and Aoshima, 2000), exists in

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different forms, including two variants that confer slow or ultra rapid metabolism (Eichelbaum and Evert, 1996; Jerling et al, 1996; Bertilsson et al, 2002). An individual possessing two copies of the same altered variant may accumulate drug metabolites or rapidly eliminate them, both situations resulting in altered therapeutic activity. Similar functional polymorphisms have been discovered in other CYP enzymes involved in the

Figure 11.1 A combination of genes, either in the metabolic pathways and/or the sites of action of psychotropic drugs may influence treatment response. metabolism of psychiatric drugs (Nebert and Dieter, 2000) and intensive research is required to investigate their possible influence on drug activity. Evidence suggesting that these mutations influence clinical outcome has been gathered in recent years and, as will be discussed further below, links have been established between certain CYP polymorphisms and the development of antipsychotic-induced adverse events. In addition, the frequency of many CYP mutations varies along populations: individuals with two copies of the slow metabolic CYP2D6 variant (also known as poor metabolizers) are more frequently found among Caucasian (5–7%) than in Asian populations (1%) (Bertilsson and Dahl, 1996; Eichelbaum and Evert, 1996). Population variations in the frequency of mutations in other CYP enzymes involved in the metabolism of antipsychotic drugs have also been reported (Britzi et al, 2000; Tayeb et al, 2000; Dandara et al, 2001; Dickmann et al, 2001; Eiselt et al, 2001). These differences may explain in part the variability in treatment response observed between ethnic groups. Further information on the role of polymorphisms in metabolic enzymes in the response

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to antipsychotic drugs can be found in the reviews by Dahl (2002), Scordo and Spina (2002) and Staddon et al (2002). Metabolic polymorphisms are suggested to have a major impact on the dose required to obtain therapeutic effects with a given drug and may also affect the accumulation of toxic metabolites. Knowledge of the metabolic status of an individual may therefore help to adjust the therapeutic dose or simply to select alternative treatments not affected by altered metabolic pathways. Pharmaceutical companies regularly use genotypic characterization to monitor the metabolic status of individuals participating in clinical trials. Rapid high-throughput methods using microarray techniques are already available for the characterization of large samples, although more economical and simpler techniques for individual genotyping are also performed in clinical laboratories. It is expected that, in the near future, metabolic genotyping will be routine clinical practice and the number of toxic reactions or treatment failures due to inappropriate dosing in individuals with altered metabolic enzymes will be drastically reduced. Efficacy of antipsychotic drugs as a function of polymorphisms in neurotransmitter receptors Although mutations in the genes of metabolic pathways may have an important influence on clinical outcome, they are unlikely to account for all of the variability observed in the response to antipsychotic drugs. A combination of interactive or additive genetic effects is more likely to explain this variability and, in recent years, attention has turned to the neurotransmitter systems targeted by psychiatric drugs that may also play an important part in determining treatment success or failure. All antipsychotics have multireceptor actions, to a greater or lesser extent (Table 11.1). Typical antipsychotics have high affinities for dopamine receptors, particularly the D2 receptors, but they may also target other neurotransmitter systems. Atypical antipsychotics generally have their highest affinities 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. Several polymorphisms in both dopamine and serotonin receptors have been linked to response to a variety of antipsychotic drugs (Table 11.2). For the D2 receptor, a -141C Ins/del, in the promoter region of the gene, has been associated with short-term (Malhotra et al, 1999) but not long-term (Arranz et al, 1998a) response to clozapine as well as the anxiolytic and antidepressive effects of treatment with bromperidol and nemonapride (Suzuki et al, 2001). Another polymorphism in the 3′ flanking region of the gene, the Taq 1 locus, has been related to early therapeutic response to haloperidol (Schafer et al, 2001) and nemonapride (Suzuki et al, 2000). 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. Although the functional significance of this mutation is not clear, two groups have reported that the Gly/Gly genotype is more frequent in responders to clozapine than in non-responders (Shaikh et al, 1996; Scharfetter et al, 1999), although

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this was not confirmed by a third study (Malhotra et al, 1998; Figure 11.2). However, a combined analysis of the three studies further substantiated a significant association between this polymorphism and clozapine response (Scharfetter et al, 1999). A similar association has been observed with neuroleptics (Krebs et al, 1998). In addition, the results of a pilot study indicate that the Ser9Gly polymorphism may be relevant to the improvement of positive symptoms (Staddon et al, 2002), thereby further validating the D3 receptor as a therapeutic target.

Table 11.1 Binding affinities (nM) of antipsychotic drugs for neurotransmitter receptors Drug

Receptor D1

D2 D3

D4

5555HT1A HT2A HT2C HT3

Halo peridol

120 1.3 3.2

2.3 >1000

78 >1000 >1000

Cloza pine

141

83 200

20

6.5

2.5

Risperi done

75 3.1 9.6

7.0

488

Olanza pine

31

11

50

Ziprasi done

130 3.1 7.2

Quetia pine

455 160 940

α1

α2 360

1.9

3.9

11.6

155 >1000

2.0

3.0

10

7.0

1.9

19

228

76

47

5100

13

310

4100

11

120

7.0

87

0.2

25.8 >1000

2000

27 >1000

5.0

11.3

32

0.4

0.7

57

295 >1000 >1000

M1

46

11

2200 >1000

H1

6000 >1000 >1000

95

2.5

8.6

5HT6

23

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

Table 11.2 Polymorphisms in dopamine and serotonin receptors associated with response to antipsychotic drugs Receptor

Polymorphism

Associated with

Reference

D2

-141C Ins/del

Clozapine

(Malhotra et al, 1999)

D2

Taq I

Nemonapride

(Suzuki et al, 2000)

D2

Taq I

Haloperidol

(Schafer et al, 2001)

D3

Ser9Gly

Clozapine

(Shaikh et al, 1996)

D3

Ser9Gly

Clozapine

(Scharfetter et al, 1999)

D3

Ser9Gly

Neuroleptics

(Krebs et al, 1998)

D4

48bp repeat

Clozapine

(Shaikh et al, 1993)

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D4

48bp repeat

Neuroleptics

(Hwu et al, 1998)

D4

48bp repeat

Neuroleptics

(Cohen et al, 1999)

5-HT2A

-1438-G/A

Clozapine

(Arranz et al, 1998b)

5-HT2A

102-T/C

Clozapine

(Arranz et al, 1995, 1998b)

5-HT2A

102-T/C

Neuroleptics

(Joober et al, 1999)

5-HT2A

His452Tyr

Clozapine

(Arranz et al, 1996; Masellis et al, 1998)

5-HT2C

Cys23ser

Clozapine

(Sodhi et al, 1995)

5-HT2C

VNTR

Clozapine

(Arranz et al, 2000a)

5-HT6

267-C/T

Clozapine

(Yu et al, 1999)

bp, base pair; VNTR, variable nucleotide tandem repeat

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 10, may affect the pharmacological profile of the receptor, although there does not appear to be a simple relationship between loop length and activity (Wong et al, 2000). In addition there is considerable ethnic variation in allele distribution (Chang et al, 1996). Cohen et al (1999) found that patients responding to typical neuroleptics carried the allele for the 7-repeat form less frequently than those responding to clozapine or controls, whilst Hwu et al (1998) found that a homozygous 4-repeat allele was associated with good neuroleptic response during acute

Figure 11.2 D3 Ser9Gly and clozapine response: frequencies of the Gly9 allele. Purple columns, responders; white columns, non-responders. (Data from Institute of Psychiatry (IoP) studies I, II and III (unpublished data), Malhotra et al, 1998 and Scharfetter et al, 1999.)

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treatment, and a lower prevalence of negative symptoms at remission, especially in male schizophrenic patients. Finally, a marginal association was found between this polymorphism and poor response to clozapine, although it was not confirmed in other studies (Shaikh et al, 1993, 1994, 1997). Polymorphisms that affect drug response have been found in three serotonin receptors, namely, 5-HT2A, 5-HT2C and 5-HT6. A silent base pair change, 102-T/C, in the 5-HT2A gene has been associated with response to clozapine (Arranz et al, 1995), as well as poor long-term outcome and response to typical neuroleptics (Joober et al, 1999), with the C102/C102 genotype being more frequent amongst non-responders. The results regarding clozapine, however, were not confirmed by several other studies (Masellis et al, 1995; Nöthen et al, 1995; Malhotra et al, 1996; Nimgaonkar et al, 1996), although in all cases the genotype and allele frequencies followed the same trend as in the original report by Arranz et al (1995). Moreover, a meta-analysis of the results available has shown a clear association between the polymorphism and clozapine response (Arranz et al, 1998c; Figure 11.3). In addition a polymorphism in the promoter region, -1438-G/A, also associated with clozapine response (the -1438G allele being higher amongst responders than nonresponders; Arranz et al, 1998b) is in complete linkage disequilibrium with 102-T/C (Spurlock et al, 1998). It has therefore been proposed that -1438-G/A may be functional with respect to gene expression, thereby having an influence on clinical response and thus explaining the effect of the silent polymorphism (Arranz et al, 1998c; Spurlock et al, 1998).

Figure 11.3 A meta-analysis of genetic variation in 5-HT2A receptors and clozapine response: frequencies of C102/C102 (Arranz et al, 1998c). Comb, combined studies; purple columns, responders; white columns, non-responders. (Data from Institute of Psychiatry (IoP) studies I and II

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(Arranz et al, 1995, 1998c), Masellis et al, 1995, Nöthen et al, 1995, Nimgaonkar et al, 1996 and Malhotra et al, 1996.) 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 (Arranz et al, 1996, 1998b; Badri et al, 1996; Masellis et al, 1998), although in two other studies this did not reach statistical significance (Nöthen et al, 1995; Malhotra et al, 1996). However, a meta-analysis has confirmed an association between the His452Tyr polymorphism and clozapine response (Figure 11.4; Arranz et al, 1998c). It is perhaps interesting that the Tyr542 variant of 5-HT2A has been associated with altered Ca2+ mobilization in vitro (Ozaki et al, 1997). 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 Sodhi et al, (1995) have reported that 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), influences response to clozapine (Arranz et al, 2000a). In the 5-HT6 receptor the 267-C/T base pair change has been linked to clozapine response, patients with the homogygote 267T/T genotype having a better response than 267C/C homogygotes or 267C/T heterozygotes (Yu et al, 1999).

Figure 11.4 A meta-analysis of genetic variation in 5-HT2A receptors and clozapine response: frequencies of Tyr452/Tyr452 (Arranz et al, 1998c). Comb, combined studies; purple columns, responders; white columns, non-responders. (Data from Institute of Psychiatry (IoP) studies I and II

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(Arranz et al, 1996, 1998b, c), Badri et al, 1996, Nöthen et al, 1995, Malhotra et al, 1996.) To date no polymorphisms in histamine (Mancama et al, 2000a), muscarinic (Mancama et al, 2000b) or α-adrenergic receptors (Bolonna et al, 2000; Tsai et al, 2001) have been linked to responsiveness to antipsychotic drugs although, as discussed further below, a mutation in the H2 receptor (−1018-G/A) may contribute to clozapine response. These studies serve a double purpose: identification of response determining mutations and validation of drug targets. The identification of response influential mutations can be useful for the pretreatment prediction of response, an application that will be discussed later. The identification of such mutations in targeted receptors will prove their mediation in therapeutic activity. This validation of drug targets will help to design more selective and improved drugs. However, in spite of the apparent success of the studies discussed above, their main drawback is the difficulty of replicating significant findings by independent groups, thus limiting their credibility and possible clinical applications. However, the reasons for these apparent failures could be several including insufficient sample size, duration of treatment, method of response assessment and ethnic origin (Arranz et al, 2000c). Several strategies have been suggested to overcome this problem: analysis of extreme and/or specific phenotypes will improve the reliability of results and increase the chances of finding significant associations (Nebert, 2000; Reitschel et al, 1999). This approach has been successful in finding genes associated with drug-induced adverse reactions. Prediction of drug-induced adverse reactions Despite the clear benefits of antipsychotic therapy, the prescribing of these drugs is often limited by their ability to induce adverse reactions. In the case of classic antipsychotics long-term treatment is frequently associated with the production of movement disorders that include akathisia and tardive dyskinesia. For the atypical antipsychotics, weight gain and sedation are the most often reported adverse reactions, in addition to which clozapine induces severe agranulocytosis in 1% of treated patients. Given the often serious implications of these side effects, ongoing studies are trying to identify the genes responsible. Variants of the metabolic enzymes CYP2D6 (Kapitany et al, 1998; Scordo et al, 2000) and CYP1A2 (Basile et al, 2000), the main metabolizing enzymes for clozapine (Jerling et al, 1997) and olanzapine (Ring et al, 1996) have been implicated in susceptibility to antipsychotic-induced movement disorders (Kapitany et al, 1998; Basile et al, 1999, 2000; Ellingrod et al, 1999). In addition, the glycine allele of the Ser9Gly polymorphism in the D3 receptor has been associated with antipsychotic-induced acute akathisia (Eichhammer et al, 2000) and tardive dyskinesia (Steen et al, 1997; Basile et al, 1999; Segman et al, 1999; Lovlie et al, 2000; Liao et al, 2001). This association is supported by the results of a meta analysis of published studies (Lerer et al, 2002). In spite of strong evidence suggesting that D2 occupancy is directly related to adverse reactions, no polymorphism of the dopamine D2 receptor has been coupled with any movement

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disorders resulting from antipsychotic treatment (Mihara et al, 2000b; Hori et al, 2001; Kaiser et al, 2002). However, the Taq 1 polymorphism has been linked to the prolactin response to nemonapride (Mihara et al, 2000a) and bromperidol (Mihara et al, 2001). Basile et al (2001) investigated 10 polymorphisms across 10 candidate genes for their possible contribution to clozapine-induced weight gain but only found non-significant trends implicating α-adrenergic1A, α-adrenergicB3 and 5-HT2C receptors along with tumour necrosis factor-α. However, Reynolds et al (2002) have found significantly less drug-induced weight gain in patients with a -759-T variant of the 5-HT2c gene than in those without this allele. Evidence for an influence of genetic mechanisms on clozapine-induced agranulocytosis has also been uncovered, where variants within the major histocompatibility complex, and to a lesser extent the heat shock protein gene and tumour necrosis factor gene, have been implicated (Turbay et al, 1997; Reznik and Mester, 2000). At present many of the above findings are undergoing extensive validation through independent replication, although from existing evidence it is clear that genetic variants in other systems may also be involved and these still remain to be identified and examined. It is, however, anticipated that this knowledge will facilitate the development of protocols for predicting outcome to these undesirable effects, and will ultimately improve patient compliance. Clinical applications of pharmacogenomic research to schizophrenia Current pharmacogenetic findings in schizophrenia are of limited clinical value as the individual associations reported have a relatively small predictive value. As discussed above, a more realistic view proposes the involvement of several genes in determining an individual’s response to antipsychotic treatment. 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, Arranz et al (2000b) have shown that a combination of six mutations in four different genes could predict response to the antipsychotic clozapine with some accuracy (>78% success, p<0.001). These polymorphisms were in genes coding for three neurotransmitter receptors: 5-HT2A (102-T/C and His452/Tyr); 5-HT2C (330-GT/-244-CT and Cys23Ser) and H2 (-1018-G/A) as well as a mutation in the promoter region of a serotonin transporter protein, 5-HTTLPR. In addition, possession of both the T102/- and His452/His452 phenotypes in the 5-HT2A receptor was associated with good response to clozapine in 80% of the patients. Although only about 50% of the patients showed this genotype combination, this could provide a simple method of identifying individuals likely to benefit from clozapine treatment. A similar approach has been used in a study investigating patients with Alzheimer’s disease where a combination of mutations in key genes could also be used to predict treatment response (Cacabelos et al, 2000). It has been shown in pilot studies that prediction of response to other antipsychotic drugs such as olanzapine and risperidone is also plausible using combinations of genetic variants (unpublished data).

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Although these findings have yet to be validated, they show the feasibility of applying pharmacogenomic strategies for the pretreatment prediction of clinical outcome. Obviously, further research is required and replication of these results in different ethnic groups by independent investigators is essential to prove the reliability of the methods. Additional improvement can be obtained using the growing information available about key genes. Intensive search and study of mutations contained in human genetic databanks (Sachidanandam et al, 2001) will facilitate the identification of those relevant to response and improve prediction levels. Higher levels of prediction can also be obtained by analysing gene/specific phenotype associations. Conclusions Pharmacogenomic research is expected to produce significant advances in the field of psychiatry. Current clinical applications include monitoring of enzyme polymorphisms associated with deficient drug metabolism. Genetic methods for the pretreatment prediction of drug response are also in development and are expected to be clinically available in the next decade. These advances will significantly improve psychiatric treatment by enabling the selection of the most beneficial treatment according to an individual’s genetic predisposition. References Arranz M, Collier D, Sodhi M et al. (1995) Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet 346:281–2. Arranz MJ, Collier DA, Munro J et al. (1996) Analysis of a structural polymorphism in the 5HT2A receptor and clinical response to clozapine. Neurosci Lett 217:177–8. Arranz MJ, Li T, Munro J et al. (1998a) Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response. Pharmacogenetics 8:481–4. Arranz MJ, Munro J, Owen MJ et al. (1998b) Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Mol Psychiatry 3:61–6. Arranz MJ, Munro J, Sham P et al. (1998c) Meta-analysis of studies on genetic variation in 5HT2A receptors and clozapine response. Schizophrenia Res 32:93–9. Arranz MJ, Bolonna AA, Munro J et al. (2000a) The serotonin transporter and clozapine response. Mol Psych 5:124–5. Arranz MJ, Munro J, Birkett J et al. (2000b) Pharmacogenetic prediction of clozapine response. Lancet 355:1615–16. Arranz MJ, Munro J, Osborne S, Collier D, Kerwin RW. (2000c) Difficulties in replication of results. Lancet 356:1359–60. Badri F, Masellis M, Petronis A et al. (1996) Dopamine and serotonin system genes may predict clinical response to clozapine. Am J Hum Genet 59:A247. Basile VS, Masellis M, Badri F et al. (1999) Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia. Neuropsychopharmacology 21:17–27.

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Basile VS, Ozdemir V, Masellis M et al. (2000) A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia. Mol Psychiatry 5:410–17. Basile VS, Masellis M, McIntyre RS et al. (2001) Genetic dissection of atypical antipsychoticinduced weight gain: novel preliminary data on the pharmacogenetic puzzle. J Clin Psychol 62:45–66. Bertilsson L, Dahl ML. (1996) Polymorphic drug oxidation: Relevance to the treatment of psychiatric disorders. CNS Drugs 5:220–3. Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A. (2002) Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 53: 111–22. Bolonna AA, Arranz MJ, Munro J et al. (2000) No influence of adrenergic receptor polymorphisms on schizophrenia and antipsychotic response. Neurosci Lett 280: 65–8. Britzi M, Bialer M, Arcavi L et al. (2000) Genetic polymorphism of CYP2D6 and CYP2C19 metabolism determined by phenotyping Israeli ethnic groups. Ther Drug Monit 22:510–16. Cacabelos R, Alvarez A, Fenandez-Novoa L, Lombardi VR. (2000) A pharmacogenomic approach to Alzheimer’s disease. Acta Neurol Scand Suppl 176:12–19. Chang FM, Kidd JR, Livak KJ, Pakstis AJ, Kidd KK. (1996) The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. Hum Genet 98: 91–101. Cohen BM, Ennulat DJ, Centorrino F et al. (1999) Polymorphisms of the dopamine D4 receptor and response to antipsychotic drugs. Psychopharmacology (Berl) 141:6–10. Dahl ML. (2002) Cytochrome p450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing? Clin Pharmacokinetics 41:453–70. Dandara C, Masimirembwa CM, Magimba A et al. (2001) Genetic polymorphism of CYP2D6 and CYP2C19 in east- and southern African populations including psychiatric patients. Eur J Clin Pharmacol 57:11–17. Dickmann LJ, Rettie AE, Kneller MB et al. (2001) Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol 60:382–7. Eichelbaum M, Evert B. (1996) Influence of pharmacogenetics on drug disposition and response. Clin Exp Pharmacol Physiol 23:983–5. Eichhammer P, Albus M, Borrmann-Hassenbach M et al. (2000) Association of dopamine D3receptor gene variants with neuroleptic induced akathisia in schizophrenic patients: a generalization of Steen’s study on DRD3 and tardive dyskinesia. Am J Med Genet 96:187–91. Eiselt R, Domanski TL, Zibat A et al. (2001) Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics 11:447–58. Ellingrod VL, Schultz SK, Arndt S et al. (1999) Association between cytochrome P4502D6 (CYP2D6) genotype, neuroleptic exposure and abnormal involuntary movement scale (AIMS) score. Schizophrenia Res 36:1–3. Horacek J, Libiger J, Hoschl C, Borzova K, Hendrychova I. (2001) Clozapineinduced concordant agranulocytosis in monozygotic twins. Int J Psch Clin Prac 5: 71–3. Hori H, Ohmori O, Shinkai T, Kojima H, Nakamura J. (2001) Association between three functional polymorphisms of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia. Am J Med Genet 105:774–8. Hwu HG, Hong CJ, Lee YL, Lee PC, Lee SF. (1998) Dopamine D4 receptor gene polymorphisms and neuroleptic response in schizophrenia. Biol Psychol 44:483–7. Jerling M, Dahl ML, Aberg-Wistedt A et al. (1996) The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clin Pharmacol Ther 59:423–8. Jerling M, Merle Y, Mentre F, Mallet A. (1997) Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method. Br J Clin Pharmacol 44:447– 53.

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Joober R, Benkelfat C, Brisebois K et al. (1999) T102C polymorphism in the 5-HT2A gene and schizophrenia: relation to phenotype and drug response variability. J Psychol Neurosci 24:141– 6. Kaiser R, Tremblay PB, Klufmoller F, Roots I, Brockmoller J. (2002) Relationship between adverse effects of antipsychotic treatment and dopamine D(2) receptor polymorphisms in patients with schizophrenia. Mol Psychiatry 7:695–705. Kapitany T, Meszaros K, Lenzinger E et al. (1998) Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophrenia. Schizophrenia Res 32:101–6. Krebs MO, Sautel F, Bourdel MC et al. (1998) Dopamine D3 receptor gene variants and substance abuse in schizophrenia. Mol Psychiatry 3:337–41. Lerer B, Segman RH, Fangerau H et al. (2002) Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. Neuropsychopharmacology 27:105–19. Liao DL, Yeh YC, Chen HM et al. (2001) Association between the Ser9Gly polymorphism of the dopamine D3 receptor gene and tardive dyskinesia in Chinese schizophrenic patients. Neuropsychobiology 44:95–8. Lovlie R, Daly AK, Blennerhassett R, Ferrier N, Steen VM. (2000) Homozygosity for the Gly-9 variant of the dopamine D3 receptor and risk for tardive dyskinesia in schizophrenic patients. Int J Neuropsychopharmacol 3:61–5. Malhotra AK, Goldman D, Ozaki N et al. (1996) Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine. Am J Psychol 153:1092– 4. Malhotra AK, Goldman D, Buchanan RW et al. (1998) The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. Mol Psychiatry 3:72–5. Malhotra AK, Buchanan RW, Kim S et al. (1999) Allelic variation in the promoter region of the dopamine D2 receptor gene and clozapine response. Schizophrenia Res 36:92–3. Mancama D, Arranz MJ, Munro J, Makoff A, Kerwin AW. (2000a) The histamine 1 and histamine 2 receptor genes—candidates for schizophrenia and clozapine response. Gene Screen 1:29–34. Mancama D, Munro J, Arranz MJ, Makoff A, Kerwin AW. (2000b) Association analysis of muscarinic acetylcholine receptor polymorphisms in clozapine treated schizophrenics. Am J Genet 96:269. Masellis M, Paterson AD, Badri F et al. (1995) Genetic variation of 5-HT2A receptor and response to clozapine. Lancet 346:1108. Masellis M, Basile V, Meltzer HY et al. (1998) Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology 19:123–32. Mata I, Madoz V, Arranz MJ, Sham P, Murray RM. (2001) Olanzapine: concordant response in monozygotic twins with schizophrenia. Br J Psychol 178:86. Mihara K, Kondo T, Suzuki A et al. (2000a) Prolactin response to nemonapride, a selective antagonist for D2 like dopamine receptors, in schizophrenic patients in relation to Taq1A polymorphism of DRD2 gene. Psychopharmacology (Berl) 149:246–50. Mihara K, Suzuki A, Kondo T et al. (2000b) No relationship between Taq1 a polymorphism of dopamine D(2) receptor gene and extrapyramidal adverse effects of selective dopamine D(2) antagonists, bromperidol, and nemonapride in schizophrenia: a preliminary study. Am J Med Genet 96:422–4. Mihara K, Suzuki A, Kondo T et al. (2001) Relationship between Taq1 A dopamine D2 receptor (DRD2) polymorphism and prolactin response to bromperidol. Am J Med Genet 105:271–4. Nebert DW. (2000) Extreme discordant phenotype methodology: an intuitive approach to clinical pharmacogenetics. Eur J Pharmacol 410:107–20. Nebert DW, Dieter MZ. (2000) The evolution of drug metabolism. Pharmacology 61: 124–35. Nimgaonkar VL, Zhang XR, Brar JS, DeLeo M, Ganguli R. (1996) 5-HT2 receptor gene locus: association with schizophrenia or treatment response not detected. Psychiatr Genet 6:23–7.

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Nöthen MM, Rietschel M, Erdmann J et al. (1995) Genetic variation of the 5-HT2A receptor and response to clozapine. Lancet 346:908–9. Otani K, Aoshima T. (2000) Pharmacogenetics of classical and new antipsychotic drugs. Ther Drug Monit 22:118–21. Ozaki N, Manji H, Lubierman V et al. (1997) A naturally occurring amino acid substitution of the human serotonin 5-HT2A receptor influences amplitude and timing of intracellular calcium mobilization. J Neurochem 68:2186–93. Reitschel M, Kennedy JL, Macciardi F, Meltzer HY. (1999) Application of pharmacogenetics to psychotic disorders: the first consensus conference. Schizophrenia Res 37: 191–6. Reynolds GP, Zhang ZJ, Zhang XB. (2002) Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 359:2086–7. Reznik I, Mester R. (2000) Genetic factors in clozapine-induced agranulocytosis. Isr Med Assoc J 2:857–8. Ring BJ, Catlow J, Lindsay TJ et al. (1996) Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J Pharmacol Exp Ther 276:658–66. Sachidanandam R, Weissman D, Schmidt SC et al. (2001) A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409:928–33. Schafer M, Rujescu D, Giegling I et al. (2001) Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D(2) receptor gene. Am J Psychol 158:802–4. Scharfetter J, Chaudhry HR, Hornik K et al. (1999) Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients. Eur Neuropsychopharmacol 10:17– 20. Scordo MG, Spina E. (2002) Cytochrome P450 polymorphisms and response to antipsychotic therapy. Pharmacogenomics 3:201–18. Scordo MG, Spina E, Romeo P et al. (2000) CYP2D6 genotype and antipsychotic-induced extrapyramidal side effects in schizophrenic patients. Eur J Clin Pharmacol 56:679–83. Segman R, Neeman T, Heresco-Levy U, Finkel B, Karagichev L et al. (1999) Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 4:247–53. Shaikh S, Collier D, Kerwin RW et al. (1993) Dopamine D4 receptor subtypes and response to clozapine. Lancet 341:116. Shaikh S, Kerwin RW, Sham P, Sharma T, Collier D. (1994) D4 polmorphisms in schizophrenic patients. Schizophrenia Res 15:165–6. Shaikh S, Collier DA, Sham PC et al. (1996) Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia. Hum Genet 97:714–9. Shaikh S, Makoff A, Collier D, Kerwin RW. (1997) Dopamine D4 receptor: potential therapeutic implications in the treatment of schizophrenia. CNS Drugs 8:1–11. Sodhi MS, Arranz MJ, Curtis D et al. (1995) Association between clozapine response and allelic variation in the 5-HT2C receptor gene. Neuroreport 7:169–72. Spurlock G, Heils A, Holmans P et al. (1998) A family based association study of T102C polymorphism in 5-HT2A and schizophrenia plus identification of new polymorphisms in the promoter. Mol Psychiatry 3:42–9. Staddon S, Arranz MJ, Mancama D, Mata I, Kerwin RW. (2002) Clinical applications of pharmacogenetics in psychiatry. Psychopharmacology (Berl) 162:18–23. Steen VM, Lovlie R, MacEwan T, McCreadie RG. (1997) Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients. Mol Psychiatry 2:139–45. Suzuki A, Mihara K, Kondo T et al. (2000) The relationship between dopamine D2 receptor polymorphism at the Taq1 A locus and therapeutic response to nemonapride, a selective dopamine antagonist, in schizophrenic patients. Pharmacogenetics 10:335–41.

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Suzuki A, Kondo T, Mihara K et al. (2001) The -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter region is associated with anxiolytic and antidepressive effects during treatment with dopamine antagonists in schizophrenic patients. Pharmacogenetics 11:545–50. Tayeb MT, Clark C, Ameyaw MM et al. (2000) CYP3A4 promoter variant in Saudi, Ghanian and Scottish Caucasian populations. Pharmacogenetics 10:753–6. Tsai SJ, Wang YC, Yu Younger WY et al. (2001) Association analysis of polymorphism in the promoter region of the alpha2a-adrenoceptor gene with schizophrenia and clozapine response. Schizophrenia Res 49:53–8. Turbay D, Lieberman J, Alper CA et al. (1997) Tumor necrosis factor constellation polymorphism and clozapine-induced agranulocytosis in two different ethnic groups. Blood 89:4167–74. Vojvoda D, Grimmell K, Sernyak M, Mazure CM. (1996) Monozygotic twins concordant for response to clozapine. Lancet 347:61. Wong AH, Buckle CE, Van Tol HH. (2000) Polymorphisms in dopamine receptors: what do they tell us? Eur J Pharmacol 410:183–203. Yu YW, Tsai SJ, Lin CH et al. (1999) Serotonin-6 receptor variant (C267T) and clinical response to clozapine. Neuroreport 10:1231–3.

chapter 12 Key issues and unmet needs in schizophrenia Stephen Stahl This chapter will address some of the key issues regarding dopamine and schizophrenia today, many of which have been covered in greater detail in other chapters of this book. In addition, areas of unmet needs where research and innovation could provide some answers will be reviewed. The subjects to be discussed include (i) the theories linking dopamine to the mechanism of action of antipsychotic drugs and the ways in which they interact with dopamine receptors, (ii) the efficacy of these drugs in improving cognitive symptoms and preventing recurrence and progression, (iii) the tolerability of currently available agents, and (iv) ways to improve the efficacy and tolerability of antipsychotics. Dopamine and antipsychotic drugs Schizophrenia is a chronic psychotic disorder that consists of multiple symptom dimensions (Figure 12.1). 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 (EPSE), tardive dyskinesia and hyperprolactinaemia. The more recently introduced atypical antipsychotics show efficacy comparable 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 EPSE or hyperprolactinaemia (Borison et al, 1995; Stahl, 2000). Thus, there are significant differences in efficacy and tolerability between the conventional and atypical antipsychotics, despite the fact that both classes have dopamine D2 receptor antagonist properties. These differences between the conventional and atypical antipsychotics may best be explained through their additional properties, the quality of their actions on D2 receptors, or both. There are four main dopamine pathways in the brain (Figure 12.2). The nigrostriatal pathway projects from the substantia nigra to the neostriatum and is thought to be a major component of the extrapyramidal motor system. Blockade of postsynaptic D2 receptors in the postsynaptic projection areas of this pathway is considered to be responsible for extrapyramidal symptoms. In addition, long-term blockade of this pathway may cause receptor up-regulation with the clinical consequence of tardive dyskinesia.

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Figure 12.1 Schizophrenia is a multiple symptom disorder. (Adapted with permission from Stahl, 2000.) The mesolimbic pathway, projecting from the midbrain ventral tegmental area to the nucleus accumbens and other related limbic structures, is thought to be involved in behaviours such as pleasurable sensations, the euphoria of drug abuse and the delusions and hallucinations of psychosis. Blockade of postsynaptic D2 receptors in this pathway is thought to mediate the ‘antipsychotic’ efficacy of the antipsychotic drugs and their ability to reduce or block positive symptoms. The mesocortical pathway projects from the midbrain ventral tegmental area to the limbic cortex where it may be involved in the production of positive and negative psychotic symptoms, as well as the cognitive deficits observed in schizophrenia. Blocking D2 receptors in this pathway may produce blunting of emotions and cognitive side effects, which can mimic the negative symptoms of schizophrenia. The tuberoinfundibular pathway projects from the hypothalamus to the pituitary gland and controls prolactin secretion. Blockade of D2 receptors here causes a rise in prolactin levels that can in some instances lead to galactorrhoea. Our current pharmacological dilemma is to try, in the same brain at the same time, to reduce dopaminergic activity in the mesolimbic pathway, while increasing it in the mesocortical pathway and leaving the activity in the nigrostriatal and tuberoinfundibular pathways unaffected. Mechanism of action of typical and atypical antipsychotic drugs

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As mentioned above, all antipsychotic drugs bind to D2 dopamine receptors. However, since typical and atypical drugs have quite different clinical profiles, it is important to understand what pharmacological mechanisms are responsible for this difference. This information will be critical for the development of future generations of improved antipsychotic drugs. Several hypotheses have been put forward to explain these differences, and these will be briefly reviewed here.

Figure 12.2 Dopamine pathways in the brain: a, the nigrostriatal pathway; b, the mesolimbic pathway; c, the mesocortical pathway; d, the tuberoinfundibular pathway. (Adapted with permission from Stahl, 2000.) Serotonin-dopamine antagonism One explanation for the properties of atypical antipsychotics is that many of these drugs, as well as being D2 receptor antagonists, are also potent antagonists of serotonin 5-HT2A receptors (Table 12.1). The normal physiological action of serotonin is to inhibit dopaminergic output. It is therefore proposed that in some areas of the brain, this 5-HT2A receptor mediated blockade by atypical antipsychotic drugs may stimulate dopamine release and thus provide a functional antagonism of the D2 receptor blockade. Functional

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antagonism between 5-HT2A and D2 receptor blockade is thought to be particularly important in two brain areas. In the basal ganglia, serotonergic neurones project from the midbrain raphé nuclei, and blockade of their activity could minimize EPSE. In the cortex, antagonism of 5-HT2A receptors could have beneficial effects on cognition. (See Chapter 9 for more details.) However, it should be noted that some atypical antipsychotics, such as amisulpride, have no significant affinity for 5-HT2A receptors.

Table 12.1 Affinity (nM) of antipsychotic drugs for dopamine D2 receptors and serotonin 5-HT2A receptors D2 receptor

5-HT2A receptor

Haloperidol

1.4

25

Amisulpride

3

2000

Clozapine

150

3.3

Olanzapine

17

1.9

Quetiapine

310

120

Risperidone

3.3

0.16

Sertindole

7.4

0.85

Ziprasidone

9.7

0.31

Kinetic differences in receptor binding—the ‘hit and run hypothesis’ One characteristic that distinguishes antipsychotics is the kinetic nature of their interaction with dopamine receptors. A conventional antipsychotic binds tightly to the D2 receptor and has a long association time (Figure 12.3). It has been hypothesized that this long association time may block the underlying dopaminergic tone in the basal ganglia, and thus may be responsible for the appearance of EPSE. Conversely, atypical antipsychotics may bind by what can be termed the ‘hit and run’ or ‘fast on-fast’ hypothesis (Figure 12.3; Kapur and Seeman, 2001; Stahl, 2001c; Chapter 3 in this book). The idea is that although the drugs, such as clozapine and quetiapine, bind long enough to block phasic dopaminergic activity important for an antipsychotic action, the rapid dissociation rate has less antagonist action towards tonic dopaminergic activity, thus reducing the risk of producing EPSE. One of the first drugs to be developed that might bind in this fashion is amisulpride, although this might not have been realized until now (Seeman, 2002). Dopamine receptor stabilizers—the ‘Goldilocks hypothesis’ Another hypothesis involves the stabilizing or normalizing concept, a theme discussed by A Carlsson in Chapter 1. The idea is that a molecule with partial agonistic properties can

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have different effects in different neuronal pathways depending on the level of background tone (see Figure 12.4). A partial agonist will activate dopamine receptors at synapses with a low dopaminergic tone, but attenuate receptor activation in areas with high intrinsic tone. This has also been termed the ‘Goldilocks’ concept as the drug will cool down porridge that is too hot and warm up porridge that is too cold, making everything just the right temperature (or, in this case, normalizing dopaminergic activity) (Stahl, 2001a). A dopamine stabilizer may produce enough conformational changes in the receptor to allow sufficient receptor blockade to reduce positive symptoms, but not enough to exacerbate negative and cognitive symptoms or to cause EPSE (Stahl, 2001a, b). Molecules that might be included in this category are aripiprazole (Burris et al, 2002) and (-)-OSU6162 (see Chapter 1). In addition, presynaptic autoreceptors on dopamine neurone terminals inhibit dopamine release and are thus functionally antagonistic to postsynaptic dopamine receptors. It is possible that an appropriate mix of pre- and postsynaptic receptor blockade can generate the same stabilizing effect at the level of the synapse as do partial agonists at the level of the receptor. This may be one of the keys to understanding the atypical profile of amisulpride.

Figure 12.3 Binding properties of antipsychotics. (a) Conventional antipsychotics bind to dopamine D2 receptors tightly and have a long association time; (b) atypical antipsychotics have lower affinity for D2 receptors than the conventional drugs and a shorter dissociation time. (Adapted with permission from Stahl, 2002.)

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Figure 12.4 (a) Excessive activation of D2 dopamine receptors by dopamine may produce psychosis; (b) blockade of D2 dopamine receptors by a neuroleptic drug has an antipsychotic action and will also produce extrapyramidal side-effects; (c) the partial agonist action of a dopamine stabilizer allows antipsychotic action whilst maintaining sufficient dopaminergic activity to avoid extrapyramidal side effects. (Adapted with permission from Stahl, 2002.) Neurodevelopmental and neurodegenerative theories of schizophrenia The results of Lieberman et al (1996) and Levander et al (2001), discussed further below, bear on the question of whether schizophrenia is a wholly neurodevelopmental disorder or whether a neurodegenerative process is also involved. The natural history of schizophrenia, depicting the classic downhill course, is depicted in Figure 12.5. The neurodevelopmental theory suggests a problem in the formation of synapses and neuronal migration during the prenatal and early childhood stages. Neurones that fail to migrate to the correct parts of the brain and form appropriate connections might break

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down when used by the individual in adolescence and early adulthood (Figure 12.6). Cell death by apoptosis during normal neurodevelopment eliminates unwanted neurones. Inappropriate apoptosis at this time might select the wrong neurones with the consequence that the wrong connections are made (Lewis, 1997; Lieberman et al, 1997). 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.

Figure 12.5 Schizophrenia as a neurodegenerative disorder. I, a premorbid stage with normal functioning; II, a prodromal stage with subtle symptoms but little or no loss of functioning; III, the chaotic symptoms of mental illness with disruption of social and occupational function and hypothetical triggering of apoptosis or necrosis; IV, a ‘burn-out’ stage in which the chaotic symptoms are gone but residual negative and cognitive symptoms and treatment nonresponsiveness predominate. (Adapted with permission from Stahl, 2000.)

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Figure 12.6 The neurodevelopmental theory of schizophrenia. During development one or a combination of the factors illustrated might lead to inadequate synaptic architecture. (Adapted with permission from Stahl, 2000.) A current hypothesis is that this may be caused by excitotoxicity mediated by excess glutamate (Figure 12.7; Stahl, 2000; Deutsch et al, 2001). The excitotoxic mechanism would begin with a pathological process that triggers excessive glutamate release. This leads to a receptor mediated excess of calcium entering the cell that in turn leads to abnormal enzyme activation, with possible mitochondrial damage and excess free radical production (Mahadik et al, 2001) that can further damage cellular components, with ensuing cell death. If excitotoxic and free radical damage are occurring in schizophrenia then, as discussed by Deutch et al (2001) and Mahadik et al (2001), the therapeutic implications will need to be adequately explored. C Tamminga has discussed the role of glutamate in the biology of schizophrenia in detail in Chapter 10 of this book. Unmet medical needs 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

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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. Further references to this can be found in Meltzer et al (1999).

Figure 12.7 The excitotoxic theory of neuronal damage. The spectrum of excitation by glutamate can range from normal neurotransmission through excess transmission causing pathological symptoms to excitotoxicity resulting in neuronal degeneration. (Adapted with permission from Stahl, 2000.) Better efficacy and faster onset Even positive symptoms may not significantly improve after 4–12 weeks of treatment. Antipsychotic drugs generally improve psychosis but rarely produce complete or lasting remission. Most patients will experience a partial response, with a 20–50% drop in total Brief Psychiatric Rating Scale (BPRS) scores. Responses of greater than 50%, though occurring occasionally are rare and are an unrealistic goal of treatment (Figure 12.8). 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.

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Figure 12.8 Clinical improvement over time for patients taking a conventional antipsychotic (orange columns) or risperidone (green columns) as measured using the Positive and Negative Symptom Scale. (Adapted with permission from Mahmoud, from Merideth et al, 1998.) Another characteristic of antipsychotic drugs is the time required to see a significant response in many patients. The data in Figure 12.8 come from one effectiveness trial that compared real-world treatment outcomes for 684 patients who were treated with risperidone or conventional antipsychotics. Fifty per cent of patients on risperidone reached a 20% clinical improvement, as measured by PANSS (Positive And Negative Symptom Scale) scores by 4 months, rising to 65% at 12 months. For a 60% clinical improvement at 4 months only 11% of the patients had achieved this target, rising to 21% after 1 year. Response rates with risperidone were significantly higher than those achieved with a conventional antipsychotic at 4 months for a 20% response, but not until 8 months for a 60% response. 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. We need to have a more realistic expectation of what drugs can deliver and when they can do it. One of the things that is not done in practice, but which the available data suggest could provide important information, and possibly increased benefit to patients, is to extend the trial duration. Where this is feasible for the patients, trial length could usefully be extended from 8 weeks to 20–26 weeks. 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. In a 5-year

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follow up of 70 schizophrenic patients, Lieberman et al (1996) have demonstrated that the mean time to remission rose from approximately 45 days after the first episode to 70 days after the second and to more than 120 days after the third episode (Figure 12.9). Similar results have been described by Levander et al (2001), who found in a retrospective study of 100 patients that responsiveness to treatment was 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. As discussed above, this also raises the question of whether the pathophysiology of the disorder is neurodevelopmental, neurodegenerative or both. Non-responders A significant minority of schizophrenic patients fail to respond to first-line monotherapy with even a 30% response. At the present time 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 (Stahl, 1999). However, antipsychotic polypharmacy is probably neither the most efficient nor the cheapest way to improve response (see below). In addition, it exposes the patient to a potentially wider range of side effects than would the use of a single antipsychotic drug.

Figure 12.9 Time to remission with successive episodes of schizophrenia in 10 schizophrenic patients. Mean (green columns) and median (blue columns) remission times are presented. (Reproduced with permission from Lieberman et al, 1996.)

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Box 12.1 Common augmentation strategies found in the literature that are claimed to boost antipsychotic efficacy in the treatment of schizophrenia Valproic acid/sodium valproate Other anticonvulsants (e.g. carbamazepine) Lithium Benzodiazepines An alternative way of enhancing efficacy may be the use of augmentation strategies with other classes of drugs, although many of these have not formally demonstrated their usefulness in randomized clinical trials (Box 12.1). Of particular interest is the use of mood stabilizers such as valproate. For example, Casey et al (2003) have demonstrated that it may be effective in increasing the size of treatment responses, not only in psychotic mania but also in schizophrenia. In a multicentre double-blind trial, Casey et al (2003), the combination of valproate with either risperidone or olanzapine produced a significantly greater fall in the total score on the PANSS scale than did antipsychotic alone on all days except the endpoint (4 weeks) (Figure 12.10). Valproate has also been reported to augment haloperidol activity in preliminary studies in schizophrenics (Wassef et al, 2000, 2001). However, to date no other trial has been reported which has tested the efficacy or safety of augmentation therapies in schizophrenia. Tolerability of atypical antipsychotics—the metabolic syndrome Although the modern atypical antipsychotics clearly produce less EPSE and neuroendocrine side effects 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 schizophrenia, characterized by rapid and significant weight gain, accompanied by atherogenic dyslipidaemia, insulin resistance and hypertension (Masand, 1998; Allison et al, 1999; Taylor and McAskill, 2000; Sussman, 2001). Although there is some disagreement as to whether one drug is worse than another in this respect, weight gain with conventional antipsychotics has been known for a long time (Doss, 1979), and there is evidence of an increasing incidence of diabetes with all classes of antipsychotic drugs (Figure 12.11) (Kwong et al, 2001). The mechanism by which these drugs produce this metabolic syndrome is unknown. However, data from animal studies have suggested a possible role for serotonergic mechanisms in weight gain (Bernstein, 1988), and this idea has been supported by the observation that transgenic mice in which expression of the 5-HT2C receptor has been suppressed become spontaneously obese (Tecott et al, 1995). In addition, there may be a receptor mediated phenomenon acting peripherally to change insulin secretion, independent of monoamine receptors, but this remains to be identified. It is extremely important to identify the pharmacological basis of this metabolic syndrome so that it can be eliminated from future generations of antipsychotic drugs.

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Figure 12.10 Effect of valproate in augmenting the efficacy of risperidone (R) or olanzapine (O) in the treatment of schizophrenia. Data represent change from baseline of PANSS. Green, antipsychotic monotherapy (risperidone 6 mg or olanzapine 15 mg); blue, combination therapy (valproate 1500–3000 mg with either risperidone 6 mg or olanzapine 15 mg); *p<0.05. (Adapted with permission from Casey et al, 2003.) The risk of development of a metabolic syndrome needs to be carefully monitored in all patients taking atypical antipsychotics. Risk factors for cardiovascular disease and diabetes should be assessed before initiating treatment. At each visit, weight and body mass index should be measured, and where possible lipid profiles and fasting blood glucose levels determined regularly. Awareness of the need to do this and the provision of appropriate resources is now increasing. Physicians need to become more aware of the importance of potential risk factors, and more comfortable with the management of Type II diabetes in schizophrenic patients taking atypical antipsychotics.

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Figure 12.11 Incidence of diabetes mellitus in patients taking conventional or atypical antipsychotics as compared to the general patient population. (Reproduced with permission from Kwong et al, 2001, copyright Eli Lilly and Company.) Treatment strategies—polytherapy versus monotherapy Initial treatment of schizophrenia will involve the use of appropriate first-line monotherapy (Figure 12.12). The four first-line monotherapies available in the USA, which are the treatment options with the best evidence for the management of acute psychotic episodes within their therapeutic ranges, are the atypical antipsychotics risperidone, olanzapine, quetiapine and ziprasidone. These are generally better tolerated and more comprehensively efficacious than previous generations of antipsychotics such as haloperidol. In other countries, other atypical antipsychotics may be available that fulfil the same criteria, such as amisulpride. If first-line monotherapy fails, alternative strategies need to be initiated. Currently, polypharmacy with several antipsychotic drugs is routinely used in non-responders who show less than 30% response. Before initiating polypharmacy, it should be ensured that the previous ‘failed’ monotherapy has been used optimally. It is important that these drugs be used at appropriate doses and for sufficient lengths of time to determine whether or not they have been effective. Non-optimal use of monotherapy with atypical antipsychotics may lead to unnecessary use of high doses or of polypharmacy, with the associated risk of more side effects (EPSE, metabolic disturbances, drug interactions, etc).

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Figure 12.12 Treatment strategies for schizophrenia. Proposed California treatment algorithm. Each individual strategy should be used for sufficient time (16–20 weeks) before moving on to the next. If first-line monotherapy really has failed, the most conservative option is to switch to monotherapy with another atypical antipsychotic. Such treatments are less expensive than many of the other strategies used for perceived failures of monotherapy and should be utilized prior to attempting other options. Only if several drugs continue to fail in optimized monotherapy treatment regimes should other options be considered. The first of these should be augmentation therapy with valproate, followed by switching to clozapine or to typical antipsychotics. Polypharmacy with more than one antipsychotic medication should only be considered as a last resort. Conclusions All currently effective agents for schizophrenia have dopamine-linked mechanisms of action. Understanding the pathophysiology of how these mechanisms link to nondopamine-related mechanisms might lead to novel therapeutics with increased efficacy for positive symptoms and cognitive symptoms. The real therapeutic goal should be not just 20–30% improvement in 8 weeks but real ‘awakeners’ with the capacity to halt progression and prevent treatment resistance. Other unmet needs include drugs with a

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rapid onset of action and no metabolic side effects. This will reduce the need for polypharmacy and lead to more cost effective therapies. References Allison DB, Mentore JL, Heo M et al. (1999) Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychol 156:1686–96. Bernstein JG. (1988) Psychotic drug induced weight gain: mechanisms and management. Clin Neuropharmacol 11(Suppl 1):S194–S206. Borison RL. (1995) Clinical efficacy of serotonin-dopamine antagonists relative to classic neuroleptics. J Clin Psychopharmacol 15(Suppl 1):S24–S29. Burris KD, Molski TF, Xu C et al. (2002) Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302:381–9. Casey DE, Daniel DG, Wassef AA et al. (2003) Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology 28:182–92. Deutsch SI, Rosse RB, Schwartz BL, Mastropaolo J. (2001) A revised excitotoxic hypothesis of schizophrenia: therapeutic implications. Clin Neuropharmacol 24: 43–9. Doss FW. (1979) The effect of antipsychotic drugs on body weight: a retrospective review. J Clin Psychiatry 40:528–30. Kapur S, Seeman P. (2001) Fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 158:360–9. Kwong K, Cavazzoni P, Hornbuckle K et al. (2001) Higher incidences of diabetes mellitus during exposure to antipsychotics—findings from a retrospective cohort study in the US. In: NCDEU, 2001. (Phoenix: Arizona). Levander S, Jensen J, Grawe R, Tuninger E. (2001) Schizophrenia—progressive and massive decline in response readiness by episodes. Acta Psychiatr Scand Suppl 408: 65–74. Lewis DA. (1997) Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology 16: 385–98. Lieberman JA, Alvir JM, Koreen A et al. (1996) Psychobiologic correlates of treatment response in schizophrenia. Neuropsychopharmacology 14(Suppl 3):S13–S21. Lieberman JA, Sheitman BB, Kinon BJ. (1997) Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity. Neuropsychopharmacology 17:205–29. Mahadik SP, Evans D, Lal H. (2001) Oxidative stress and role of antioxidant and omega-3 essential fatty acid supplementation in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 25:463–9. Mahmoud RA, Engelhart LM et al. (1998) Risperidone vs. Conventional antipsychotics in usual care: a prospective randomized effectiveness trial of outcomes for patients with schizophrenia and schizoaffective disorder. 21st CINP Conference: Glasgow. Masand PS. (1998) Weight gain associated with a typical antipsychotic. J Psychot Disord 2:4–6. Meltzer HY, Park S, Kessler R. (1999) Cognition, schizophrenia, and the atypical antipsychotic drugs. Proc Natl Acad Sci USA 96:13591–3. Merideth C, Mahmoud RA, et al. (1998) Clinical and quality of life superiority of risperidone over conventional antipsychotics under usual care conditions: a prospective randomized trial in schizophrenia and schizoaffective disorder. Presented at the 151st Annual Meeting of the APA, Toronto, Canada. May 30-June 4. Seeman P. (2002) Atypical antipsychotics: mechanism of action. Can J Psychiatry 47: 27–38. Stahl SM. (1999) Antipsychotic polypharmacy, Part 1: Therapeutic option or dirty little secret? J Clin Psychiatry 60:425–6.

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Stahl S. (2000) Essential Psychopharmacology 2nd edn. (Cambridge University Press: New York). Stahl SM. (2001a) Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 1, ‘Goldilocks’; actions at dopamine receptors. J Clin Psychiatry 62:841–2. Stahl SM. (200 1b) Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 2: illustrating their mechanism of action. J Clin Psychiatry 62:923–4. Stahl SM. (2001c) ‘Hit-and-Run’ actions at dopamine receptors, part 2: Illustrating fast dissociation from dopamine receptors that typifies atypical antipsychotics. J Clin Psychiatry 62:747–8. Stahl SM. (2002) Essential Psychopharmacology of Antipsychotics and Mood Stabilisers (Cambridge University Press: New York). Sussman N. (2001) Review of atypical antipsychotics and weight gain. J Clin Psychiatry 62(Suppl 23):S5–S12. Taylor DM, McAskill R. (2000) Atypical antipsychotics and weight gain—a systematic review. Acta Psychiatr Scand 101:416–32. Tecott LH, Sun LM, Akana SF et al. (1995) Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 374:542–6. Wassef AA, Dott SG, Harris A et al. (2000) Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia. J Clin Psychopharmacol 20:357–61. Wassef AA, Hafiz NG, Hampton D, Molloy M. (2001) Divalproex sodium augmentation of haloperidol in hospitalized patients with schizophrenia: clinical and economic implications. J Clin Psychopharmacol 21:21–6.

Index Note: page references in italics denote illustrations and tables 5-HT receptors antagonists 180 binding profiles 71, 73 neurotransmitter function 111–28 receptor affinity 185 serotonin 5-HT1A receptors 193–6 serotonin 5-HT2A receptors 9–10, 184–91, 185, 228, 229, 240, 240 serotonin 5-HT2c receptors 191–3 setoperone binding 117–20, 118, 119 ACC see anterior cingulate cortex acetylcholine receptors 197–8 acute schizophrenia, amisulpride 74–82 adrenergic receptors 196–7 adverse reactions, prediction 230–1 amisulpride 178–9 acute schizophrenia 74–82 atypical characteristics 50–8, 53 binding 119, 120–2, 122–5, 123, 124 binding affinity 225, 240 binding profile 71 clinical profile 69–91 clinical studies 82–6 comparisons 76–82 cf. conventional antipsychotics 74–6, 82–6 D2 receptors 70–2, 72, 73, 120–2 dissociation rates 57 dopaminergic specificity 120–2 cf. flupenthixol 74–6, 75 functional outcomes 86–8 cf. haloperidol 74–6, 75, 77, 82–6, 83, 84 long-term effects 85–6, 86 maintenance therapy 82–6, 83, 84, 85, 86 mechanism of action 70–2, 72 meta-analysis 93–109 negative symptoms effects 76–82, 80, 81, 85–6, 86 cf. olanzapine 74–6, 75 paradox 73 patient well-being 86–8 psychosis effect 82–5 receptor affinity 185

Index

224

cf. risperidone 74–6, 75, 78, 82–6, 83, 85, 86–8 short-term patient management 74–82 social functioning 86–8 structure 179 symptoms effects 76–82, 80, 81 amperozide 190 amphetamine-induced DA release 24–32, 25, 26 baseline DA activity 27–9 cortical DA parameters 30–2 illness exacerbation 26–7 anterior cingulate cortex (ACC), defects 207, 208 antipsychotics consequences for 171–2 dopamine and 237–9 modes of action 59–63, 61, 179–80, 239–40 pharmacogenomics 221–36 see also atypical antipsychotics; conventional antipsychotics; named drugs aripiprazole atypical characteristics 50–8 receptor affinity 192 structure 179 atypical antipsychotics 178–80, 179 characteristics 50–8, 58, 241 classes 178 comparisons 76–82 cf. conventional antipsychotics 182–3 meta-analysis 93–109 autoreceptors 4–7 basal ganglia thalamocortical pathway (BGCT) 209, 216–18, 218 baseline DA activity, amphetamine-induced DA release 27–9 BGCT see basal ganglia thalamocortical pathway binding amisulpride 119, 120–2, 122–5, 123, 124 chlorpromazine 119, 120 clozapine 119, 125 different brain regions 122–5 haloperidol 125 ‘hit and run’ hypothesis 241, 241–3, 242 kinetic differences 241–3 olanzapine 125 risperidone 125 setoperone 117–20, 118, 119 binding affinity 224–5, 225, 240, 240 receptor affinity 185, 192 binding profiles 71 blocking paradigm, dopaminergic pathways 166–9, 167, 168, 169, 242 catechol-O-methyltransferase (COMT)

Index

225

effects, brain 143 evidence, genetic 147 genetics 141–7, 144 prefrontal DA signalling 141–7, 142 cell death 157 chlorpromazine binding 119, 120 dissociation rates 57 historical aspects 1, 3 receptor affinity 185 clozapine atypical characteristics 50–8, 178 binding 119, 125 binding affinity 225, 240 binding profile 71 dissociation rates 57 receptor affinity 185, 192 structure 179 cognitive symptoms 245 COMT see catechol-O-methyltransferase conventional antipsychotics cf. amisulpride 74–6, 82–6 cf. atypical antipsychotics 182–3 cf. risperidone 246 cortex prefrontal see prefrontal cortex topographic maps 157–8 cortical DA parameters, amphetamine-induced DA release 30–2 corticostriatal-thalamocortical loops 18–20 corticothalamic pathways 18–20, 19 cytochrome P450 (CYP) enzymes, polymorphisms 222–3 D1 receptors amphetamine-induced DA release 30, 30–2, 31 binding profiles 71 imaging studies 23 D2 receptors 181–3 amisulpride 70–2, 72, 73, 120–2 amphetamine-induced DA release 32 antipsychotic effect 49–67 antipsychotic interactions 56–8 binding 117–20 binding affinity 240, 240 binding profiles 71 density 116–17 differential effects 53–4 dissociation rates 56–8 focus 62 imaging studies 22–3 modulation 49–67 neurotransmitter function 111–28

Index

226

occupancy similarities/differences 52–5 receptor affinity 185 striatal vs. extrastriatal 53–4, 116–17 D3 receptors 227 amisulpride 70–2, 72, 73, 183–4 binding profiles 71 D4 receptors 183–4, 226–7 diabetes 249, 250 dissociation rates, D2 receptors 56–8, 57 DOPA metabolism, PET 111–14, 113, 114 dopaminergic neurotransmission 115–17 dopaminergic pathways 17, 165–9 blocking paradigm 166–9, 167, 168, 169, 242 mesocortical system 17–18, 164–9, 166, 238–9, 239 mesolimbic system 17–18, 164–9, 166, 238–9, 239 nigrostriatal system 164–9, 166, 180, 238–9, 239 tuberoinfundibular system 164–9, 166, 238–9, 239 dopaminergic specificity 120–2 dopaminergic systems 17–24 dopaminergic projections 17–20 dopaminergic receptors 20–2 imaging studies 22–4 role 210–11 efficacy 245–7 antipsychotic drugs 29 valproate 249 EPSE see extrapyramidal side effects excitotoxic theory 244–5, 245 extrapyramidal side effects (EPSE) 237 meta-analysis 103–4 flupenthixol cf. amisulpride 74–6, 75 meta-analysis 95–108, 96–108 receptor affinity 185 fluphenazine meta-analysis 95–108, 96–108 receptor affinity 185 future directions 1–13 GABAergic pathways (g-amino butyric acid) 7–10, 8, 9, 10, 18–20, 213–14 glutamate-DA interactions 33–8, 215–18 imaging studies 36–8, 37 neuronal circuitry model 34–6, 35 NMDA hypofunction hypothesis 33–4, 36–8 glutamatergic deficiency model, schizophrenia 7–10 glutamatergic system 209–11 ‘Goldilocks’ hypothesis 242–3

Index

227

haloperidol cf. amisulpride 74–6, 75, 77, 82–6, 83, 84 binding 125 binding affinity 225, 240 binding profile 71 dissociation rates 57 meta-analysis 95–108, 96–108 modes of action 211–15, 212, 213, 214 receptor affinity 185, 192 hippocampal cortex (HC), defects 208 historical aspects 1–13 ‘hit and run’ hypothesis, binding 241, 241–3, 242 hypofrontality 131–5, 158 see also prefrontal cortex hypotheses 129–31 ‘Goldilocks’ hypothesis 242–3 ‘hit and run’ hypothesis 241, 241–3, 242 NMDA hypofunction hypothesis 33–4, 36–8 revised dopamine hypothesis 15–17 illness exacerbation, amphetamine-induced DA release 26–7 imaging studies dopaminergic systems 22–4 glutamate-DA interactions 36–8, 37 neurotransmitter function 111–28 see also magnetic resonance spectroscopy; positron emission tomography; single photon emission photometry input and output, models, schizophrenia 163–4 ketamine 209–10, 210, 215, 215 key issues 237–53 koff considerations 56–8, 57 learning, morphological changes due to 156–8 limbic system 208, 216–18, 218 defects 207 long-term differentiation (LTD) 156, 156 long-term potentiation (LTP) 156, 156 LSD see lysergic acid diethylamide LTD see long-term differentiation LTP see long-term potentiation lysergic acid diethylamide (LSD) 180, 210–11 M 100 907; 9–10, 186–9, 195 receptor affinity 192 magnetic resonance spectroscopy (MRS) prefrontal cortex 133–5 prefrontal cortex, rules formation 159–63, 160, 161, 162 maintenance therapy, amisulpride 82–6, 83, 84, 85, 86

Index

228

maps retinotopic 158 topographic 157–8 MDL-100 907 10 mesocortical system, dopaminergic pathway 17–18, 164–9, 166, 238–9, 239 mesolimbic system, dopaminergic pathway 17–18, 164–9, 166, 238–9, 239 meta-analysis amisulpride 93–109 atypical antipsychotics 93–109 conclusion 107–8 dropout rates 104–6 efficacy, overall 99, 100 EPSE 103–4 methodology 94–5 negative symptoms effects 99–102 olanzapine 99–108 quetiapine 99–108 risperidone 99–108 serotonin 5-HT2A receptors 228, 229 sertindole 99–108 MK-801 8–10, 10 models, schizophrenia 155–75 consequences, therapeutic interventions 171–2 input and output 163–4 neuromodulation 170–1 neuroplasticity 156, 156–8 prefrontal cortex 158–63 symptoms neurobiology 169–70 modes of action, antipsychotics 59–63, 61 monotherapy, vs. polytherapy 250–2 morphological changes due to learning 156–8 MRS see magnetic resonance spectroscopy N-acetyl aspartate (NAA), measuring 133–5 N-methyl-D-aspartate (NMDA) receptors antagonists 7–10, 180 glutamate-DA interactions 33–4, 36–8 hypofunction hypothesis 33–4, 36–8 NAA see N-acetyl aspartate negative symptoms effects 182 amisulpride 76–82, 80, 81, 85–6, 86 meta-analysis 99–102 neurodegenerative theories 243, 243–5 neurodevelopmental theories 243–5, 244 neuromodulation 170–1 neuronal circuitry model, glutamate-DA interactions 34–6, 35 neuronal death 157 neuroplasticity 156, 156–8 neurotransmitter function 111–28 dopaminergic 115–17 serotonergic 117–20

Index

229

neurotransmitter receptors, polymorphisms 224–30, 226 neurotransmitters, antipsychotic drug action 177–205 nigrostriatal system, dopaminergic pathway 164–9, 166, 180, 238–9, 239 NMDA see N-methyl-D-aspartate receptors non-responders 247–8 olanzapine 178–9, 248 cf. amisulpride 74–6, 75 atypical characteristics 50–8, 53 binding 125 binding affinity 225, 240 binding profile 71 dissociation rates 57 dopamine release stimulation 188 meta-analysis 99–108 receptor affinity 185, 192 structure 179 valproate 249 pathways, dopaminergic see dopaminergic pathways patient well-being, amisulpride 86–8 PET see positron emission tomography pharmacogenomics antipsychotics 221–36 clinical applications 231–2 phencyclidine 180, 216 pimozide, receptor affinity 185 polymorphisms enzyme 222–3 neurotransmitter receptors 224–30, 226 polytherapy, vs. monotherapy 250–2 positron emission tomography (PET) DOPA metabolism 111–14, 113, 114 dopaminergic systems 22–4 glutamate-DA interactions 36–8, 37 postsynaptic markers, imaging studies 22–3 prefrontal cortex 129–54 delusions 159–63 function, DA 135–9 function, striatal DA activity 139–41, 140 functions 159–63 hypofrontality 131–5, 158 malfunction 131, 131–5 rules 158–63 rules formation 159–63, 160, 161, 162 signalling 136–9, 137, 141–7 presynaptic markers, imaging studies 24 presynaptic metabolism, DOPA 111–14 quetiapine 178–9 atypical characteristics 50–8, 53

Index

230

binding affinity 225, 240 binding profile 71 dissociation rates 57 meta-analysis 99–108 receptor affinity 185, 192 structure 179 raclopride, potentiation 189 receptor affinity 185, 192 binding affinity 224–5, 225, 240, 240 recurrence, preventing/managing 247 remission 247–8 remoxipride 178–9 atypical characteristics 50–8, 53 receptor affinity 185 structure 179 reserpine, historical aspects 1–3 retinotopic maps 158 revised dopamine hypothesis 15–17 reward system, dopamine 164–9, 165–9 risperidone 178–9, 248 cf. amisulpride 74–6, 75, 78, 82–6, 83, 85, 86–8 atypical characteristics 50–8, 53 binding 125 binding affinity 225, 240 binding profile 71 cf. conventional antipsychotics 246 dopamine release stimulation 188 functional outcomes 86–8 meta-analysis 99–108 receptor affinity 185, 192 structure 179 valproate 249 ritanserin, receptor affinity 192 Ro 60–0175; 192 rules formation, prefrontal cortex 159–63, 160, 161, 162 salience, reward system, dopamine 164–9 SB 206 553; dopamine release stimulation 193 receptor affinity 192 SB 228 357; 194 SB 242 084; receptor affinity 192 schizophrenia glutamatergic deficiency model 7–10 incidence 177 as a syndrome 177–8 serotonergic neurotransmission 117–20 serotonin 5-HT1A receptors 193–6 serotonin 5-HT2A receptors 184–91, 185, 240

Index

231

binding affinity 240, 240 M 100 907; 9–10, 186–9 meta-analysis 228, 229 mood 190–1 serotonin 5-HT2c receptors 191–3 serotonin-dopamine antagonism 240 sertindole 178–9 atypical characteristics 50–8 binding affinity 240 dissociation rates 57 meta-analysis 99–108 receptor affinity 185, 192 structure 179 setoperone binding 117–20, 118, 119 short-term patient management, amisulpride 74–82 signalling, prefrontal cortex 136–9, 141–7 single photon emission photometry (SPECT) dopaminergic systems 22–4 glutamate-DA interactions 36–8, 37 social functioning, amisulpride 86–8 SPECT see single photon emission photometry spiperone, receptor affinity 185 SPM see statistical parametric mapping SR 46 439B; 187–9 receptor affinity 192 stabilization dopamine 4–7 receptors 242–3 statistical parametric mapping (SPM), DOPA metabolism 114 striatal DA activity, prefrontal cortex 139–41, 140 striatal DA parameters, imaging studies 22–4 striatal vs. extrastriatal D2 receptors 53–4, 116–17 sulpiride, receptor affinity 185 symptoms 237–8, 238 cognitive 245 efficacy, antipsychotic drugs 29 negative symptoms effects 99–102, 182 negative symptoms effects, amisulpride 76–82, 80, 81 neurobiology 169–70 systems biology 207–20 dopamine 211–15, 216–18 glutamate 215–18 treatment, schizophrenia 218–19 therapeutic interventions, consequences for 171–2 thioridazine, receptor affinity 185 thiothixene, receptor affinity 185 topographic maps, cortex 157–8 transmission, dopamine 15–47 transporters, DA, amphetamine-induced DA release 29 treatment, schizophrenia

Index

232

strategies 250–2, 251 systems biology 218–19 trifluoperazine, receptor affinity 185 tuberoinfundibular system, dopaminergic pathway 164–9, 166, 238–9, 239 twins studies 134–5 unmet needs 237–53 valproate 248 efficacy 249 olanzapine 249 risperidone 249 WAY 100 635; 195 ziprasidone 178–9 atypical characteristics 50–8, 53 binding affinity 225, 240 receptor affinity 185 structure 179