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).

Evidence from brain imaging studies

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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

Dopamine in the pathophysiology and treatment of schizophrenia

16

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.

Evidence from brain imaging studies

17

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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18

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 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 (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 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 (p1000 >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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196

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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198

(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