Neurotransmitter Receptors in Actions of Antipsychotic Medications (Handbooks in Pharmacology and Toxicology)

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Neurotransmitter Receptors in Actions of Antipsychotic Medications

Pharmacology and Toxicology: Basic and Clinical Aspects Mannfred A. Hollinger, Series Editor University of California, Davis Published Titles Manual of Immunological Methods, 1999, Pauline Brousseau, Yves Payette, Helen Tryphonas, Barry Blakley, Herman Boermans, Denis Flipo, Michel Fournier CNS Injuries: Cellular Responses and Pharmacological Strategies, 1999, Martin Berry and Ann Logan Infectious Diseases in Immunocompromised Hosts,1998, Vassil St. Georgiev Pharmacology of Antimuscarinic Agents, 1998, Laszlo Gyermek Basis of Toxicity Testing, Second Edition, 1997, Donald J. Ecobichon Anabolic Treatments for Osteoporosis, 1997, James F. Whitfield and Paul Morley Antibody Therapeutics, 1997, William J. Harris and John R. Adair Muscarinic Receptor Subtypes in Smooth Muscle, 1997, Richard M. Eglen Antisense Oligodeonucleotides as Novel Pharmacological Therapeutic Agents, 1997, Benjamin Weiss Airway Wall Remodelling in Asthma, 1996, A.G. Stewart Drug Delivery Systems, 1996, Vasant V. Ranade and Mannfred A. Hollinger Brain Mechanisms and Psychotropic Drugs, 1996, Andrius Baskys and Gary Remington Receptor Dynamics in Neural Development, 1996, Christopher A. Shaw Ryanodine Receptors, 1996, Vincenzo Sorrentino Therapeutic Modulation of Cytokines, 1996, M.W. Bodmer and Brian Henderson Pharmacology in Exercise and Sport, 1996, Satu M. Somani Placental Pharmacology, 1996, B. V. Rama Sastry Pharmacological Effects of Ethanol on the Nervous System, 1996, Richard A. Deitrich Immunopharmaceuticals, 1996, Edward S. Kimball Chemoattractant Ligands and Their Receptors, 1996, Richard Horuk Pharmacological Regulation of Gene Expression in the CNS, 1996, Kalpana Merchant Experimental Models of Mucosal Inflammation, 1995, Timothy S. Gaginella Human Growth Hormone Pharmacology: Basic and Clinical Aspects, 1995, Kathleen T. Shiverick and Arlan Rosenbloom Placental Toxicology, 1995, B. V. Rama Sastry Stealth Liposomes, 1995, Danilo Lasic and Frank Martin TAXOL®: Science and Applications, 1995, Matthew Suffness Endothelin Receptors: From the Gene to the Human, 1995, Robert R. Ruffolo, Jr. Alternative Methodologies for the Safety Evaluation of Chemicals in the Cosmetic Industry, 1995, Nicola Loprieno Phospholipase A2 in Clinical Inflammation: Molecular Approaches to Pathophysiology, 1995, Keith B. Glaser and Peter Vadas Serotonin and Gastrointestinal Function, 1995, Timothy S. Gaginella and James J. Galligan Chemical and Structural Approaches to Rational Drug Design, 1994, David B. Weiner and William V. Williams Biological Approaches to Rational Drug Design, 1994, David B. Weiner and William V. Williams Direct and Allosteric Control of Glutamate Receptors, 1994, M. Palfreyman, I. Reynolds, and P. Skolnick Genomic and Non-Genomic Effects of Aldosterone, 1994, Martin Wehling Peroxisome Proliferators: Unique Inducers of Drug-Metabolizing Enzymes, 1994, David E. Moody

Pharmacology and Toxicology: Basic and Clinical Aspects Published Titles (Continued) Angiotensin II Receptors, Volume I: Molecular Biology, Biochemistry, Pharmacology, and Clinical Perspectives, 1994, Robert R. Ruffolo, Jr. Angiotensin II Receptors, Volume II: Medicinal Chemistry, 1994, Robert R. Ruffolo, Jr. Beneficial and Toxic Effects of Aspirin, 1993, Susan E. Feinman Preclinical and Clinical Modulation of Anticancer Drugs, 1993, Kenneth D. Tew, Peter Houghton, and Janet Houghton In Vitro Methods of Toxicology, 1992, Ronald R. Watson Human Drug Metabolism from Molecular Biology to Man, 1992, Elizabeth Jeffreys Platelet Activating Factor Receptor: Signal Mechanisms and Molecular Biology, 1992, Shivendra D. Shukla Biopharmaceutics of Ocular Drug Delivery, 1992, Peter Edman Pharmacology of the Skin, 1991, Hasan Mukhtar Inflammatory Cells and Mediators in Bronchial Asthma, 1990, Devendra K. Agrawal and Robert G. Townley

FM/Frame Page 2 Tuesday, May 23, 2000 12:53 PM

Neurotransmitter Receptors in Actions of Antipsychotic Medications Edited by

Michael S. Lidow, Ph.D.

CRC Press Boca Raton London New York Washington, D.C.


Library of Congress Cataloging-in-Publication Data Neurotransmitter receptors in actions of antipsychotic medications / edited by Michael S. Lidow. p. ; cm. — (Pharmacology and toxicology) Includes bibliographical references and index. ISBN 0-8493-0744-9 (alk. paper) 1. Antipsychotic drugs—Pharmacology. 2. Neurotransmitter receptors. 3. Schizophrenia—Chemotherapy. I. Lidow, Michael S. II. Pharmacology & toxicology (Boca Raton, Fla.) [DNLM: 1. Antipsychotic Agents—pharmacology. 2. Receptors, Neurotransmitter—drug effects. 3. Schizophrenia—drug therapy. QV 77.9 N4945 2000] RM333.5 .N47 2000 616.89′061—dc21 00-025387 CIP This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. All rights reserved. Authorization to photocopy items for internal or personal use, or the personal or internal use of specific clients, may be granted by CRC Press LLC, provided that $.50 per page photocopied is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. The fee code for users of the Transactional Reporting Service is ISBN 0-8493-0744-9/00/$0.00+$.50. The fee is subject to change without notice. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from CRC Press LLC for such copying. Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe.

© 2000 by CRC Press LLC No claim to original U.S. Government works International Standard Book Number 0-8493-0744-9 Library of Congress Card Number 00-025387 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper


Preface Schizophrenia is a debilitating mental disease affecting more than two million people in the U.S. alone. The drugs used in treatment of schizophrenia are referred to as antipsychotic medications. It is now well established that the therapeutic effects of these medications are related to their interactions with dopaminergic receptors. The classic antipsychotic drugs, however, are capable of alleviating only the florid symptoms of schizophrenia, particularly hallucinations and delusions. They are only marginally effective in treatment of chronic symptoms of the disease, such as apathy, affective blunting, and social withdrawal. Moreover, the binding of these drugs to a wide range of dopaminergic receptors results in significant side effects, often forcing patients to refuse prolonged treatment. It is not surprising that there is a significant interest in developing new antipsychotic drugs with improved therapeutic properties and reduced side effects. The research aimed at developing the new generation of antipsychotic drugs has been advancing in two major directions. The first direction is the investigation into possible therapeutic effects of drugs combining dopaminergic receptor-related activity with binding to selected nondopaminergic receptor sites in the hope of broadening the curative effects of antipsychotic medications. This direction is based on the observations that some antipsychotic drug-resistant symptoms of schizophrenia are similar to affective disorders responsive to drugs selective for serotonergic and adrenergic receptors. In addition, recent studies into the etiology of schizophrenia have suggested that this disease may be associated with abnormalities in the brain glutamatergic and GABAergic receptor sites which, therefore, should be the primary targets of antipsychotic medications. The second direction in the development of new antipsychotic drugs takes advantage of the discovery that dopaminergic receptors include five subtypes with distinct distribution and pharmacological properties. The researchers pursuing this direction study antipsychotic properties of chemicals targeting only selected dopaminergic receptor subtypes in the hope that, by limiting the scope of dopaminergic receptors bound by these drugs, it would be possible to eliminate the unpleasant side effects of the present medications while preserving their therapeutic activity. To our knowledge, this is the first book fully devoted to the neurotransmitter receptors as targets of antipsychotic medications. We believe that it will be of great interest for researchers studying antipsychotic medications as well as for scientists involved in schizophrenia research in general. It will also be useful for physicians who want to understand the mechanisms of actions of antipsychotic drugs and to put the use of these drugs on a more scientific basis. This book includes 15 chapters written by the leading specialists in the field of antipsychotic drug research. The first two chapters provide the basic knowledge of schizophrenic syndromes and give general descriptions of antipsychotic drugs available today. The next eight chapters describe the role of different receptors in action of antipsychotic drugs. The following four chapters will deal with special topics such as endogenous receptor occupation by antipsychotic drugs and the regulation of brain receptors by these drugs and others. The final chapter of this book discusses the perspectives of future antipsychotic drug design.



To two women in my life, Frida and Irina Lidow



Editor Michael S. Lidow, Ph.D., is a Professor of Neuroscience at the University of Maryland, Baltimore. He received his doctoral degree in the Program in Neuroscience at Northwestern University in Evanston, IL in 1985. Upon graduation, he moved to Yale University in New Haven, CT as a postdoctoral associate at the Section of Neuroanatomy. In 1990 he became associate professor at the Section of Neurobiology at Yale University School of Medicine. In this capacity, he was invited to join the then newly organized Center in Cortical Mechanisms in Schizophrenia headed by Dr. Patricia Goldman-Rakic. Under her guidance, Dr. Lidow became interested in the role of neurotransmitter receptors in the etiology of schizophrenia, as well as in their role as targets of antipsychotic medications. While still being an active participant in the Yale Center in Cortical Mechanisms in Schizophrenia, Dr. Lidow now resides in Baltimore where he is a Professor of Neuroscience at the Departments of Oral and Craniofacial Biological Sciences and Anatomy and Neurobiology of the University of Maryland. He is a recipient of several grants from the National Institutes of Health and private foundations and is a member of the New York Academy of Science, the American Association for the Advancement of Science, and the American Society for Neuroscience. He has also published extensively in the areas of neuroscience and psychopharmacology.


Contributors Anissa Abi-Dargham Department of Psychiatry Columbia College of Physicians and Surgeons New York, New York Amy F. T. Arnsten Section of Neurobiology School of Medicine Yale University New Haven, Connecticut Ian Creese Center for Molecular and Behavioral and Neural Sciences Rutgers University Newark, New Jersey W. Wolfgang Fleischhacker Department of Biological Psychiatry University of Innsbruck Innsbruck, Austria Ralf-Michael Frieboes Department of Psychiatry University of Kiel Kiel, Germany Donald C. Goff Psychotic Disorders Program Massachusetts General Hospital and Consolidated Department of Psychiatry Harvard Medical School Boston, Massachusetts J. David Jentsch Section of Neurobiology School of Medicine Yale University New Haven, Connecticut

Shitij Kapur Schizophrenia Program and PET Centre The Clarke Division of the Centre for Addiction and Mental Health Department of Psychiatry University of Toronto Toronto, Canada John Krystal Psychiatric Institute School of Medicine Yale University West Haven, Connecticut Akeo Kurumaji Department of Neuropsychiatry School of Medicine Tokyo Medical and Dental University Tokyo, Japan Peter F. Liddle Schizophrenia Division University of British Columbia Vancouver, Canada Michael S. Lidow Department of Oral and Craniofacial Biological Sciences and Department of Anatomy and Neurobiology University of Maryland Baltimore, Maryland Josef Marksteiner Department of Biological Psychiatry University of Innsbruck Innsbruck, Austria Yoshiro Okubo Department of Neuropsychiatry School of Medicine Tokyo Medical and Dental University Tokyo, Japan


Robert H. Roth Departments of Psychiatry and Pharmacology School of Medicine Yale University New Haven, Connecticut Ronald E. See Department of Physiology and Neuroscience Medical University of South Carolina Charleston, South Carolina Philip Seeman Departments of Pharmacology and Psychiatry University of Toronto Toronto, Canada

Axel Steiger Department of Psychiatry Max Planck Institute of Psychiatry Munich, Germany Lisa A. Taylor Center for Molecular and Behavioral Neural Sciences Rutgers University Newark, New Jersey Ashiwel S. Undie Department of Pharmaceutical Sciences and Program in Neuroscience University of Maryland Baltimore, Maryland

Adel A. Wassef University of Texas Health Sciences Center at Houston-Harris County Psychiatric Center Houston, Texas


Contents Chapter 1 Schizophrenic Syndromes..................................................................................................................1 Peter F. Liddle Chapter 2 General Overview of Contemporary Antipsychotic Medications ...................................................17 Michael S. Lidow Chapter 3 Effects of Antipsychotic Drugs on Dopamine Release and Metabolism in the Central Nervous System ............................................................................................................31 J. David Jentsch and Robert H. Roth Chapter 4 Antipsychotic Drugs, Dopamine D2 Receptors, and Schizophrenia ..............................................43 Philip Seeman Chapter 5 D1 Dopamine Receptors, Schizophrenia, and Antipsychotic Medications ....................................65 Akeo Kurumaji and Yoshiro Okubo Chapter 6 Serotonin Receptors as Targets of Antipsychotic Medications.......................................................79 Anissa Abi-Dargham and John Krystal Chapter 7 Role of Adrenergic Receptors in Effects of Antipsychotic Medications on Prefrontal Cortical Function ..........................................................................................................109 Amy F. T. Arnsten Chapter 8 Glutamate Receptors in Schizophrenia and Antipsychotic Drugs ................................................121 Donald C. Goff Chapter 9 The Antipsychotic Effects of Sigma Drugs...................................................................................137 Ralf-Michael Frieboes and Axel Steiger Chapter 10 GABAergic Drugs in Schizophrenia .............................................................................................153 Adel A. Wassef


Chapter 11 Receptor Occupancy by Antipsychotics — Concepts and Findings ............................................163 Shitij Kapur Chapter 12 Regulation of Neurotransmitter Receptors by Antipsychotic Drugs ............................................177 Lisa A. Taylor and Ian Creese Chapter 13 Modulation of Cellular Signaling Pathways by Antipsychotic Drugs..........................................199 Ashiwel S. Undie Chapter 14 The Role of Neurotransmitter Receptors in the Adversive Effects of Antipsychotic Drugs .......221 Ronald E. See Chapter 15 Future Perspectives in Antipsychotic Drug Development ............................................................243 W. Wolfgang Fleischhacker and Josef Marksteiner Index ..............................................................................................................................................247

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Schizophrenic Syndromes Peter F. Liddle

CONTENTS I. II. III.

Introduction ...............................................................................................................................1 The Type 1/Type 2 Hypothesis.................................................................................................2 The Three-Dimensional Model of Schizophrenia ....................................................................3 A. The Segregation of Symptoms .....................................................................................3 B. Neuropsychological Impairments Associated with Symptoms....................................3 C. Patterns of Cerebral Activity Associated with Syndromes ..........................................5 D. Reversibility of Aberrant Cerebral Activity Associated with the Three Syndromes...7 IV. The Developmental Disregulation Model ................................................................................9 References ........................................................................................................................................12

I. INTRODUCTION The symptoms of schizophrenia embrace virtually the full range of abnormal mental phenomena that afflict the human mind. These symptoms span the domains of perception, thought, emotion, volition, and behavior. The symptoms most characteristic of schizophrenia include delusions, hallucinations, formal thought disorder, inappropriate affect, blunted affect, impoverished thought, and diminished volition. In addition, many other symptoms that are common in other disorders, such as depressed mood, agitation, and anxiety, also occur in schizophrenia. The symptom profile differs markedly between cases and also varies over time within individual cases. Attempts to divide the illness into separate subtypes on the basis of clinical features have been unsuccessful because, whatever classification is proposed, there are a substantial number of cases with a mixture of the features of the proposed subtypes. In addition, some cases tend to shift between categories over time. The classic subdivision of schizophrenia into paranoid, hebephrenic, catatonic, and simple schizophrenia is inadequate because it is difficult to define clear boundaries between the different types. For example, Daniel Schreber, the intelligent and articulate appeals court judge from Leipzig, East Germany who exhibited the classic features of paranoid schizophrenia that he describes so clearly in his memoirs,1 also exhibited the bizarre, inappropriate patterns of thinking, emotion, and behavior more characteristic of hebephrenia and motor disturbances characteristic of catatonia during his most florid episodes of illness. He eventually regressed into a disorganized, inaccessible state before his death in Liepzig-Dösen asylum in 1911.2 Perhaps the most fruitful approach to understanding the heterogeneity of the clinical features of the illness has been the dimensional approach. In a dimensional model, the diverse clinical features are attributed to several underlying dimensions, each of which reflects a distinguishable pathological process that nonetheless might arise from a single primary cause. In this chapter we begin by describing two quite different dimensional models of schizophrenia, each of which has attempted to link clusters of observable symptoms to postulated underlying neuropathological mechanisms. First, we consider Crow’s type 1/type 2 model3,4 which is based on the assumption that there are two distinguishable, but related pathological processes in schizophrenia: one that is manifest in overt structural damage to the brain, while the other entails potentially reversible biochemical imbalance. Then we consider Liddle’s three-syndrome model5–7 according to 0-8493-0744-9/00/$0.00+$.50 © 2000 by CRC Press LLC

1


2


which three different clusters of characteristic symptoms arise from a neuropathological process that can affect one or more of three distinguishable neural systems responsible for the initiation, selection, and monitoring of self-generated mental activity, respectively. Finally, we present an integrated model according to which subtle, diffuse dysplasia disrupts the coordination between diverse cerebral areas, leading to several clusters of persistent symptoms, and, in addition, disrupts the regulation of neuromodulatory neurotransmitters, predisposing to acute exacerbations of symptoms at times of stress. We will call this model the developmental dysplasia model.

II. THE TYPE 1/TYPE 2 HYPOTHESIS 3,4

Crow produced a formulation of the pathophysiology of schizophrenia which has had a seminal influence on subsequent attempts to link the phenomena of the illness to the diverse abnormalities of brain structure and function that are associated with schizophrenia. The foundation of this formulation was the observation that the positive symptoms of schizophrenia tend to be transient, while the negative symptoms tend to persist. Positive symptoms are clinical features that reflect aberrant mental activity not present in healthy individuals. They include delusions, hallucinations, and formal thought disorder. Negative symptoms are clinical features that reflect a diminution of mental activity normally present in healthy individuals and include blunted affect, poverty of speech, and decreased voluntary activity. Positive symptoms usually respond to treatment with dopamine blocking medication, whereas negative symptoms are less responsive.8 Indirect evidence linked negative symptoms with indicators of overt structural brain damage, such as ventricular enlargement.9 On the basis of these observations, Crow proposed that two pathophysiological processes occur in schizophrenia: type 1 and type 2. The type 1 process entails dopaminergic overactivity and generates positive symptoms. The type 2 process involves structural brain damage and is responsible for negative symptoms. In its most strict formulation, this proposal implies that positive symptoms might be alleviated by blockade of dopamine, while negative symptoms are irreversible. A substantial body of evidence provides at least partial support for Crow’s proposal. In particular, a review of X-ray computed tomography (CT) scan studies by Lewis10 revealed that approximately half of the studies that had investigated the issue had found that ventricular enlargement was correlated with negative symptoms. More recently, in a study employing single-photon emission tomography (SPET) to measure endogenous dopamine release in response to administration of amphetamine, Laruelle et al.11 obtained evidence suggesting that schizophrenic patients exhibit an abnormally large release of dopamine and, furthermore, the amount of dopamine released correlates with the severity of induced positive symptoms. Despite the evidence supporting Crow’s type 1/type 2 formulation, there are several respects in which it does not provide an adequate account of the observable clinical features of schizophrenia. 1. The positive/negative dichotomy does not take into account the full range of symptoms of schizophrenia. In particular, it ignores the fact that excitation and depression are prevalent in schizophrenia. 2. While a minority of studies of the relationships between symptoms support the hypothesis that the characteristic symptoms of schizophrenia segregate into positive and negative groups,12 the majority of studies demonstrate that the characteristic symptoms segregate into at least three groups.5,6,13–16 3. Negative symptoms vary in severity over time and, in particular, resolve at least partially as florid episodes of illness subside.17 4. While negative symptoms are relatively resistant to treatment, there is evidence that they do respond at least partially to atypical antipsychotic medication.18 5. In some cases, positive symptoms persist despite a high level of blockade of dopamine D2 receptors.19 A more comprehensive formulation of the relationships between symptoms, mechanisms, and causes is necessary.


Schizophrenic Syndromes

3

TABLE 1 Cognitive Deficits and Sites of Aberrant Regional Cerebral Activity Associated with the Three Characteristic Syndromes of Schizophrenia32 Symptoms Reality distortion Delusions Hallucinations

Disorganization Thought form disorder Inappropriate affect Psychomotor poverty Blunted affect Poverty of speech Decreased volition

Cognitive Deficit

Increased rCBF

Decreased rCBF

Monitoring and evaluation of mental activity

L parahippocampal gyrus L hippocampus L lateral frontal cortex Ventral striatum

R posterior cingulate L temporo-parietal cortex

Selection between competing mental activities

R anterior cingulate Thalamus

R ventrolateral frontal cortex L and R parietal cortex

Planning and initiation of mental activity

Caudate Thalamus

L and R frontal cortex L parietal cortex

Note: R = right, L = left, and rCBF = regional cerebral blood flow.

III. THE THREE-DIMENSIONAL MODEL OF SCHIZOPHRENIA A. THE SEGREGATION

OF

SYMPTOMS

The type 1/type 2 model implies that the distinction between symptoms based on symptom type is inextricably related to a distinction between acute and chronic symptoms. It does not account for the existence of chronic positive symptoms or transient negative symptoms. It does not answer the question of whether or not chronic positive symptoms and chronic negative symptoms arise from distinct pathophysiological processes. To address this issue, Liddle5,6 examined the relationships between symptoms in a group of schizophrenic patients with relatively homogeneous chronicity of illness. He recruited subjects with persistent symptoms during a stable phase of illness to test the hypothesis that even in such a sample, symptoms would segregate into positive and negative symptoms, as would be expected if the different types of symptoms reflected different neuropathological processes. He found that in the stable phase of chronic illness, the characteristic symptoms of schizophrenia segregated into distinguishable groups, but instead of two, there were three syndromes: reality distortion, disorganization, and psychomotor poverty, as shown in Table 1. This pattern of segregation of chronic symptoms has subsequently been reported by many other studies.13–16 It has also been reported in many studies that have examined patients who are heterogeneous with regard to chronicity of illness. It has been reported in patients with mixed psychotic diagnoses.20 Furthermore, it should be noted that the three syndromes embrace only the symptoms characteristic of schizophrenia; if the full gamut of symptoms that can occur in schizophrenia and other psychotic illnesses is examined, the number of distinguishable syndromes is at least five.21 In addition to the three characteristic schizophrenic syndromes, there are two syndromes, depression and psychomotor excitation, that are more characteristic of bipolar affective illness, but nonetheless are prevalent in schizophrenia.

B. NEUROPSYCHOLOGICAL IMPAIRMENTS ASSOCIATED

WITH

SYMPTOMS

In a study employing a neuropsychological battery that embraced a wide range of aspects of cognitive functioning, Liddle7 found that in patients with persistent illness, each of the three groups of characteristic schizophrenic symptoms was associated with a specific pattern of neuropsychological


4


impairment, which he interpreted as evidence that each group of symptoms might reflect dysfunction of a discrete neural system. On the basis on the types of impairment associated with each syndrome, and also taking account of the nature of the symptoms themselves, Liddle proposed that psychomotor poverty might reflect underactivity of a neural system linked to the lateral frontal cortex that is normally engaged in the initiation of mental activity; disorganization might reflect aberrant activity in a neural system linked to orbito-medial frontal cortex that is normally engaged in the selection between competing mental activities; while the reality distortion syndrome might arise from aberrant temporal lobe activity. In a subsequent study employing a battery of frontal lobe tasks, Liddle and Morris22 confirmed that chronic psychomotor poverty is associated with impaired performance in tasks that involve initiating a plan for mental action, while chronic disorganization is associated with impairments in tasks that demand the ability to select between competing responses. For example, psychomotor poverty was associated with diminished rate of word generation in a verbal fluency task. Such a task entails the execution of a self-directed generated strategy for search through an individual’s store of words. On the other hand, severity of disorganization was correlated with slower performance in the Stroop task, in which the participant is presented with a color name printed in ink that is incongruent with the color name and is required to specify the ink color. Successful performance entails suppression of the tendency to respond to word meaning. Disorganization was also associated with slower performance in the Trails B task, in which the participant is presented with a series of dots that are labeled with either a letter of the alphabet or a number and is instructed to join the dots in an order that alternates between letters and numbers. This demands repeated switching of search criterion. However, in that study, Liddle and Morris found no evidence that reality distortion is associated with impairment in frontal lobe tasks. Several subsequent studies have confirmed these findings. For example, Frith et al.23 found that psychomotor poverty symptoms are associated with decreased rate of word generation, while disorganization symptoms are associated with impaired performance in the Trails B task and also with an increased rate of errors of commission in a continuous performance task. Allen et al.24 found that psychomotor poverty is associated with a slowed rate of word generation during a verbal fluency task, while disorganization is associated with a tendency to select inappropriate or unusual words. Norman et al.25 also found that psychomotor poverty was associated with a decreased rate of word generation. Paradoxically, they interpreted their finding as a disconfirmation of the hypothesis that psychomotor poverty reflects malfunction of the dorsolateral frontal cortex because they considered word generation to be a test of orbital frontal function. However, abundant evidence from studies of lesions and from functional imaging studies demonstrates that left lateral frontal cortex is involved in word generation.26 Baxter and Liddle27 found that chronic psychomotor poverty was associated with slowed responses in a two-choice guessing task in which the patient was required to generate the strategy for choice, while also confirming that disorganization was associated with impaired performance in the Stroop task. Similarly, Ngan and Liddle28 found that in patients with persistent illness, psychomotor poverty symptoms were associated with slowed simple reaction time, while disorganization was associated with slowed choice reaction time and impaired Stroop performance. It is of interest to note that in the studies by Baxter and Liddle and also the study by Ngan and Liddle, the pattern of association between symptoms and neuropsychological impairment was different in patients with acute, remitting illness than in patients with persistent illness, an issue that we shall address in greater detail in Section IV. Overall, a preponderance of evidence confirms that in patients with persistent illness, psychomotor poverty is associated with impaired ability to initiate a plan of action or simply with slow execution of simple responses, while disorganization is associated with impaired ability to select between competing responses. The question of the neuropsychological correlates of reality distortion is less easily answered. In his initial study, Liddle7 had reported that the severity of reality distortion was weakly correlated



5

with impaired ability to discriminate between the figure and ground. Subsequent studies that have focused mainly on frontal lobe tasks have reported that reality distortion is not associated with neuropsychological impairment. However, a substantial number of studies have reported that either delusions or hallucinations are associated with impaired ability to process information in its correct context. For example, Morrison and Haddock29 found that the severity of hallucinations was associated with the degree of impairment of the ability to monitor whether or not an idea had been self-generated in a word-association task. Other studies have reported an association between reality distortion symptoms and the ability to monitor the source of self-generated actions. For example, Frith and Done30 found that the severity of delusions of control was correlated with impaired error correction in a task in which the ability to correct errors depended on the internal monitoring of self-generated activity. Consistent with this observation, Mlakar et al.31 found that delusions of control were associated with impaired ability to draw figures in the absence of visual feedback. Norman et al.25 reported that reality distortion was associated with memory impairments attributed to temporal lobe dysfunction. While the association of reality distortion with temporal lobe malfunction is plausible, the finding of a correlation between reality distortion and memory impairment should be regarded with caution until replicated. On balance, the evidence indicates that reality distortion is not associated with cognitive deficits that are as wide ranging as those associated with psychomotor poverty or disorganization. Nonetheless, it is associated with specific impairments in the domain of evaluation of information in context. Overall, the evidence supports the hypothesis that each of the three syndromes of characteristic schizophrenic symptoms is associated with a specific pattern of cognitive deficit. Each of the three syndromes is associated with malfunction of a particular aspect of executive function; psychomotor poverty is associated with impaired planning and initiation of activity, disorganization with impaired selection between competing responses, and reality distortion with impaired evaluation of information in context.

C. PATTERNS

OF

CEREBRAL ACTIVITY ASSOCIATED

WITH

SYNDROMES

The observation that each of the three syndromes is associated with a specific pattern of cognitive impairment suggests that each might be associated with a specific pattern of abnormal cerebral activity. This hypothesis might be tested employing a functional imaging technique such as positron emission tomography (PET), which provides images of regional cerebral blood flow (rCBF) or regional glucose metabolic rate (rCMRglu). Since rCBF and rCMRglu are tightly coupled to the level of local neuronal activity, these techniques provide images that reflect regional neural activity. Using PET to examine the patterns of rCBF associated with each of the three syndromes in a group of patients with persistent, stable illness, Liddle et al.32 confirmed that each syndrome was associated with a particular pattern of aberrant cerebral activity. In accord with this prediction, they found that psychomotor poverty was associated with underactivity in left lateral frontal cortex. Furthermore, the region of underactivity coincided with the region that is engaged during word generation in healthy subjects. In addition, psychomotor poverty was correlated with decreased rCBF in the left inferior parietal lobule, a region of association cortex that has strong reciprocal connections with the lateral frontal cortex, and bilaterally with increased rCBF in the basal ganglia and thalamus. Subsequently, Ebmeier et al.33 confirmed the finding of an association between psychomotor poverty and left frontal underactivity in an group of acutely ill schizophrenic patients, half of whom had never been treated with antipsychotic medication. Yuasa et al.34 confirmed that psychomotor poverty is associated with decreased frontal rCBF and with increased rCBF in basal ganglia and thalamus. Disorganization was associated with underactivity in the right ventro-lateral prefrontal cortex, contiguous insula cortex, and lateral parietal cortex bilaterally. It was also associated with overactivity in the anterior cingulate and medial frontal cortex and with overactivity in the thalamus. The site of overactivity in the anterior cingulate coincided with the site that is maximally active in


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healthy subjects during the performance of the Stroop task. The observation that disorganization is associated with overactivity of the right medial frontal cortex and anterior cingulate has been confirmed by Ebmeier et al.33 and Yuasa et al.34 One the other hand, in a study employing PET to measure CMRglu, Kaplan et al.35 did not observe a correlation with overactivity in the medial frontal cortex, though they did replicate the finding of an association between disorganization and underactivity of the lateral parietal cortex. On balance, the evidence provides strong support for the conclusion that disorganization is associated with overactivity of the medial frontal cortex and anterior cingulate and moderate support for an association with overactivity of the thalamus and underactivity of the lateral parietal cortex and ventro-lateral prefrontal cortex. This evidence, together with the evidence from studies of monkeys36 that ventro-lateral prefrontal cortex plays an important part in the suppression of inappropriate responses, suggests the speculation that in patients suffering from the disorganization syndrome, deficient function of the ventral prefrontal cortex predisposes to a tendency for inappropriate mental events to intrude into current mental processing. This would be expected to lead to overactivity of the anterior cingulate and medial frontal cortex, areas that are actively engaged when dealing with potential interference in the Stroop task. Liddle et al.32 found that the severity of reality distortion was correlated with increased rCBF in the left medial temporal lobe and in ventral striatum and with underactivity in the right posterior cingulate and left superior temporal gyrus. The finding that reality distortion is associated with overactivity in the left medial temporal lobe and ventral striatum received support from the observation by Silbersweig et al.37 that auditory hallucinations are associated with overactivity in the ventral striatum and in medial temporal structures including hippocampus and parahippocampal gyrus. Perhaps as important as the similarities between the findings of Silbersweig and those of Liddle are the differences. Most notably, Silbersweig did not observe any areas in which hallucinations were associated with a reduction in rCBF, whereas Liddle observed reality distortion to be associated with decreased rCBF in the superior temporal gyrus on the lateral aspect of the temporal lobe and in the right posterior cingulate cortex. This difference might reflect an important difference in methodology. Silbersweig et al. employed a longitudinal design in which they compared cerebral activity during the presence of hallucinations with that during the absence of hallucinations within the same patients, whereas Liddle employed a cross-sectional design that examined differences between patients who differed in the severity of reality distortion. Longitudinal designs can identify cerebral sites involved in the experience of a symptom, whereas cross-sectional designs might identify the loci involved in the experience of the symptom together with those loci associated with underlying predisposition to the symptom, though the two types of loci cannot be distinguished. It is noteworthy that several longitudinal studies37–39 of the cerebral activity associated with hallucinations have observed temporal lobe overactivity, but no evidence of temporal lobe underactivity. In contrast, the cross-sectional study by Liddle et al.32 found that reality distortion was associated with medial temporal overactivity and lateral temporal underactivity. The cross-sectional study by Ebmeier et al.33 found that reality distortion was associated with lateral temporal underactivity, but did not detect a relationship with medial temporal overactivity. These observations raise the possibility that underactivity in the lateral temporal cortex reflects a loss of neural function that creates a predisposition to the reality distortion, while overactivity in the medial temporal lobe reflects transient release of aberrant activity that is associated with the actual experience of the symptoms. The area of overactivity in the left medial temporal lobe identified by Liddle et al.32 included the site in the parahippocampal gyrus activated in healthy subjects during a task that entailed internal monitoring of self-generated movements.40 This is consistent with the hypothesis that reality distortion is associated with aberrant monitoring of self-generated mental activity. In summary, each of the three syndromes is associated with a distinct aberrant pattern of regional cerebral activity. Furthermore, for each syndrome the cerebral areas involved include the cardinal



7

sites that are engaged in healthy subjects while performing the type of mental activity implicated in that syndrome. Studies of the psychoto-mimetic glutamatergic antagonist ketamine provide indirect evidence about the cerebral sites likely to be involved in the expression of psychotic symptoms. Ketamine produces schizophrenia-like symptoms in healthy individuals and transient exacerbations of psychosis in schizophrenic patients.41 These symptoms include symptoms of disorganization as well as reality distortion. Lahti et al.42 demonstrated that ketamine increased rCBF in the anterior cingulate and contiguous medial frontal cortex in schizophrenic patients and in healthy controls. Furthermore, changes in positive symptoms induced by ketamine correlated with rCBF changes in the left medial temporal lobe and left ventral striatum, consistent with the finding by Liddle et al.32 and Silbersweig et al.37 that increased rCBF at these two sites is associated with reality distortion symptoms.

D. REVERSIBILITY OF ABERRANT CEREBRAL ACTIVITY ASSOCIATED THE THREE SYNDROMES

WITH

Whether or not the aberrant cerebral activity associated with each of the three syndromes is reversible is a question of major clinical importance. For each syndrome the observed pattern of cerebral activity includes areas of underactivity and areas of overactivity. It is possible that the regions of overactivity represent disinhibition of neural activity which results from failure of inhibitory input from those regions that are underactive. For example, in reality distortion, it is plausible that the predisposition to symptoms is created by a deficit in neural function, while the actual experience of symptoms is associated with consequent disinhibited activity elsewhere in the brain. In such circumstances, it would be anticipated that the symptoms might be treated successfully by pharmacological means using drugs that have an inhibitory influence in the relevant brain area. The available evidence from functional imaging studies that have examined the relationship between changes in regional cerebral metabolism and the reductions in symptom severity after antipsychotic treatment provides support for the hypothesis that antipsychotic medication acts by decreasing overactivity at the cerebral sites implicated in the reality distortion and disorganization syndromes. In a study of the effects of the novel antipsychotic risperidone on cerebral metabolism in previously unmedicated first episode schizophrenic patients, Liddle et al.43 found that the degree of reduction in metabolism in the left hippocampus observed 90 min after the first dose of risperidone was a significant predictor of the degree of alleviation of reality distortion during subsequent treatment. Furthermore, after 6 weeks of treatment, there was a more extensive region of reduced metabolism in the left temporal lobe. These findings indicate not only that temporal lobe metabolism decreases as symptoms resolve, but also that the reduction is discernable 90 min after the first dose before any substantial reduction in reality distortion symptoms would be expected. This suggests that the reduction in hippocampal metabolism is not merely a consequence of symptom resolution, but actually plays a causal role in the therapeutic effect. Ngan et al.44,45 found that risperidone produces a reduction in metabolism in the right medial frontal cortex that is discernable after the first dose of risperidone and becomes more extensive after 6 weeks of treatment. The degree of reduction in the right medial frontal cortex showed a strong trend toward significant correlation with a magnitude of the reduction in severity of disorganization (Pearson’s correlation coefficient, r = 0.59). These findings support the hypothesis that reduction of the right medial frontal metabolism is a component of the mechanism by which risperidone alleviates disorganization, but this interpretation should be regarded with caution until the finding has been replicated. Overall, for both the reality distortion syndrome and the disorganization syndrome, the evidence supports the hypothesis that predisposition to the symptoms comprising these syndromes is associated with underactivity at certain cerebral sites (see Table1), but the actual expression of symptoms is


8


due to a weakening of inhibitory control that leads to overactivity at other cerebral locations (also shown in Table 1), and, furthermore, that antipsychotic medication acts by reducing this overactivity. The pattern of cerebral activity associated with psychomotor poverty also includes sites of overactivity and underactivity. However, unlike the reality distortion and disorganization syndromes, in which there is overactivity at the sites normally engaged during the type of cognitive process implicated in the syndromes (see Table 1), in the psychomotor poverty syndrome there is underactivity at the site in the left lateral frontal cortex in the region that is normally engaged during word generation. Reduced speech is one aspect of psychomotor poverty. Hence, it likely that the psychomotor symptoms are a direct manifestation of the observed neural underactivity. The observed overactivity at other sites, such as in the basal ganglia, might simply be an incidental consequence of the primary deficit. In such circumstances, the potential for pharmacological alleviation of the symptoms would depend on whether or not the underactivity at the cardinal site in the lateral frontal cortex is reversible. In instances where the underactivity arises from irreversible neural damage, pharmacological treatment might have little effect. The question of whether or not pharmacological treatment can alleviate the lateral frontal underactivity associated with psychomotor poverty remains unanswered. However, there is evidence that even in cases with severe persistent psychomotor poverty, the underactivity does not reflect irreversible loss of neural function. In a PET study of regional cerebral activity during paced word generation in a group of patients with severe persistent schizophrenia, Frith et al.46 found that the magnitude of activation in the left lateral frontal cortex was similar to that observed in healthy subjects producing words at the same rate. Furthermore, left lateral frontal activation of normal magnitude was observed in the subgroup of six patients who had marked psychomotor poverty.47 Thus, even in cases of severe, persistent illness, the left lateral frontal cortex can be activated under circumstances where the task is relatively simple and performance is paced. However, Frith et al.46 observed that the normal magnitude of left lateral frontal activation during word generation in schizophrenic patients was accompanied by an absence of the suppression of activity in the superior temporal lobe that is observed in healthy subjects. The normal suppression of temporal lobe activity during word generation (relative to a control condition in which subjects articulated a list of words provided by the investigator) probably reflects a mechanism for minimizing interference from external auditory stimuli while words are being generated internally. The absence of this suppression in schizophrenic subjects might make them vulnerable to distraction or even to misinterpretation of internally generated words as if it were externally generated speech. In a reanalysis of Frith’s data, Liddle et al.48 examined the patterns of covariance over six scans (within each subject) between rCBF in the left lateral frontal cortex and rCBF in all other cerebral gray matter pixels. They found that the pattern of covariance differed from that in healthy controls not only for the relationship between the left frontal cortex and left lateral temporal lobe, but also for the relationship between the frontal cortex and thalamus and between the frontal cortex and medial parietal cortex. Patients differed from healthy controls insofar as patients showed a positive covariance between the frontal cortex and left lateral temporal cortex, while the corresponding covariance was negative in healthy controls. In both patients and controls the covariance between the left lateral frontal cortex and medial parietal cortex was negative, but significantly more negative in patients than in controls. In contrast, the covariance between the left lateral frontal cortex and thalamus was positive in both patients and controls, but significantly less so in the patients. Overall, these observations support the proposal that the cardinal functional abnormality in schizophrenia is a defect in the coordination of cerebral activity. The findings that the left lateral frontal cortex can be activated even in schizophrenic patients with severe, persistent psychomotor poverty suggest that lateral frontal underactivity associated with the psychomotor poverty syndrome is not due to an irreversible focal loss of neural function. The observation that left lateral frontal activation is associated with aberrant coordination of activity between the frontal cortex and other sites such as the thalamus, temporal lobe, and medial parietal cortex implies that there is a dynamic imbalance between neural activity in different cerebral regions.



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Since the strength of neurotransmission between cerebral regions is, at least in principle, subject to influence by modulatory monoamine neurotransmitters such as dopamine and serotonin, these findings suggest that the prospects for alleviation of negative symptoms is not as bleak as is implied by Crow’s concept of type 2 schizophrenia. This conclusion is consistent with the accumulating evidence that novel antipsychotics can alleviate negative symptoms,18 though the question of whether or not currently available antipsychotics can relieve persistent negative symptoms remains a subject of debate.

IV. THE DEVELOPMENTAL DISREGULATION MODEL While the type 1/type 2 model of schizophrenia provides a plausible explanation for the variation in degree of persistence of symptoms, the three-syndrome model provides a more satisfactory account of the heterogeneity of symptom type. In particular, the evidence supports the hypothesis that the pathophysiology of schizophrenia disrupts the function of a diverse set of cerebral sites and that the type of symptoms is largely determined by the nature of function of the affected cerebral regions. Any comprehensive account of the pathophysiology of schizophrenia must take account not only of the diverse types of symptoms that occur within the illness, but also of the time course of the illness. Several major longitudinal studies of childhood development, such as the study49 of the cohort born in Britain in March 1946 and the study50 of the cohort born in March 1958, have demonstrated that the earliest signs of illness can be detected, at least with hindsight, in early childhood development. For example, in the 1946 birth cohort, the odds ratio that a preschizophrenic child would fail to develop speech by age two was 4.8 compared with the remainder of the birth cohort. In both this birth cohort and in the 1958 birth cohort, the preschizophrenic children exhibited significant impairment in a range of cognitive and social functions. The cognitive deficits were most marked in the domains of language and arithmetical skills, while the behavioral development of the preschizophrenic children was characterized by social unease and inconsequential behaviors. It is important to note that many preschizophrenic children perform in the normal range in cognitive tasks and some even achieve a superior level of function. However, the evidence from studies of identical twins discordant for schizophrenia indicates that even when both twins perform in the normal range, the affected twin usually performs less well than the unaffected co-twin, indicating that the illness has led to a relative impairment.51 Furthermore, despite the observation that the cognitive impairments in schizophrenia cover a wide range of aspects of cognition, there is great variability between cases,52 and the possibility that domains of high performance might co-exist with subtle defects in other areas remains to be excluded. Typically, in adolescence a more discernible prodrome, characterized by social withdrawal and episodes of anxiety or depressive symptoms, develops.53 In many cases, this prodrome lasts for several years before the development of overt psychosis. The first psychotic episode is likely to include symptoms of reality distortion and/or marked disorganization and psychomotor excitation. Though psychomotor excitation is common, in some cases negative symptoms become worse, and in a substantial proportion of cases there is significant depression.54 In over half of the treated first episode cases, the initial florid episode abates within 3 months, and in about 85% of cases there is at least a partial remission within 1 year.55 Subsequently, the illness is characterized by further acute episodes superimposed on a state of enduring disability, cognitive impairment, and residual symptoms. The severity of the enduring residual symptoms and of social and occupational disability varies greatly between cases. In some cases, the person functions well, apart from an undue sensitivity to stress. In the most severe cases, the patient is unable to perform the essential functions of daily life. The long-term prognosis is also variable, but in over 50% of cases there is a gradual resolution with full or partial recovery after several decades.56 In a minority of cases, the illness progresses to a state of profound cognitive impairment that resembles dementia, although in such cases there is no increase in the pathological features of Alzheimer’s disease.57


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The characteristic time course of illness indicates that the underlying pathophysiological mechanism is neither a progressive dementia nor a static encephalopthy. In general, the time course reflects the characteristics of a developmental disorder,58,59 though unlike many developmental disorders the degree of disability in schizophrenia does not usually achieve a stable level even in adulthood. Instead, during the younger adult years there are episodic exacerbations and then in later adulthood a tendency toward resolution in many cases. This time course suggests a disorder in which a neuronal deficit progresses during childhood development. The florid episodes in young adulthood, which are often precipitated by stressful events or by stimulant drug abuse, suggest that the putative developmental deficit has weakened the regulation of the modulatory monoamine neurotransmitters, especially dopamine. Dopamine modulates the function of the various cortical and subcortical areas implicated in the expression of the three syndromes.60 Consequently, poorly regulated changes in the levels of modulatory neurotransmitters in response to stresses of various kinds might be expected to exacerbate any preexisting impairment of coordination between these cerebral sites. This would increase the likelihood of overt symptoms in previously asymptomatic cases or exacerbate symptoms in those with preexisting symptoms. In later adult life, age-related diminution in activity of the modulatory neurotransmitters would result in a tendency toward resolution of the illness. The excessive release of endogenous dopamine following amphetamine administration in schizophrenic patients demonstrated by Laruelle et al.11 provides evidence that disregulation of monoamine neurotransmission does, in fact, occur in schizophrenia. Furthermore, Laruelle et al. found that the magnitude of the release of dopamine correlated with the severity of the positive symptoms induced by amphetamine administration. There is also evidence that the disregulation of dopamine might arise from subtle structural deficits. Breier et al.61 demonstrated that an increase in production of the dopamine metabolite, homovanillic acid, in response to the stress of transient glucose deprivation is abnormally large in schizophrenia. The magnitude of this effect is inversely correlated with frontal lobe volume. The molecular mechanism by which a structural deficit might produce disregulation of dopamine remains speculative. Pycock et al.62 were the first of many investigators to report that lesions of the frontal lobes produce changes in subcortical dopaminergic function in rats. While the details of these findings have remained controversial, subsequent studies show that frontal lobe lesions in animals lead to increased dopamine release in the nucleus accumbens (homologous to the ventral striatum in man).63 It is likely that the structural defects in schizophrenia are due, at least in part, to abnormal brain development. Subtle developmental anomalies are prevalent in schizophrenia.64 In particular, there is evidence of disordered development of coordination between diverse brain areas. For example, Woodruff et al.65 reported that the normal correlation between frontal lobe volume and temporal lobe volume is decreased in schizophrenia. Since this correlation is thought to reflect the function linkage between these brain areas, the lack of correlation in schizophrenia implies a lack of coordination during development. In summary, the time course of the illness, together with the evidence regarding the nature of the cerebral abnormalities of schizophrenia that we have reviewed, suggests that schizophrenia might best be described as a disorder arising from developmental disregulation of cerebral function. According to this hypothesis, the primary pathological process is a subtle dysplasia that affects coordination between cerebral regions. Impaired coordination of function results in enduring cognitive deficits and also causes impaired regulation of monoaminergic neuromodulatory transmitters. At times of stress or following administration of stimulant drugs, there is a tendency for excessive monoamine release leading to florid psychosis. The proposed links between causal factors, pathophysiological processes, and symptom profiles are illustrated in Figure 1. This developmental disregulation hypothesis predicts that cases in which the developmental dysplasia mainly affects the regulation of monoaminergic transmission will exhibit few residual symptoms, apart from oversensitivity to stress, and relatively minor cognitive impairments during stable phases of



11

FIGURE 1 The pathophysiology of schizophrenia.

the illness. In contrast, cases with extensive dysplasia affecting multiple cerebral areas would suffer substantial persistent symptoms and cognitive impairments. Nonetheless, in such cases, symptoms might be exacerbated by excessive monoaminergic neurotransmitter release at times of stress. The proposed pathological mechanism leads to several predictions about the observable relationships between symptoms, cognitive deficits, and underlying neuronal abnormalities. In particular, in the stable phase of the illness, the profile of cognitive impairment, and also of persisting symptoms, will be determined largely by the location of cerebral regions that are affected by the primary dysplasia. Monoamine disregulation would be expected to play a relatively minor role in the stable phase. It would be predicted that in this phase of illness, symptom profile and pattern of cognitive impairment would show consistent relationships, as found in the studies reviewed in Section III.B. However, during episodes of acute florid disturbance, variation between subjects in the type and severity of symptoms will be determined not only by the location of the regions affected by the primary dysplasia, but also by variation in the severity of monoamine disregulation. In this phase of illness, the factors influencing the severity of symptoms and cognitive impairment would be much more complex. The developmental disregulation hypothesis predicts that patients with persistent, severe illness will have relatively marked disruption of coordination between the cerebral sites implicated in one or more of the three syndromes at all phases of the illness. In such patients, a strong correlation between the severity of a particular group of symptoms and severity of impairment of the cognitive processes that engage the cerebral sites implicated in relevant syndrome would be expected. However, the hypothesis also predicts that patients with remitting illness will have a relatively minor disruption of coordination between the cerebral sites implicated in the syndromes at baseline. In these cases, the major abnormality is impaired regulation of the monoamine neurotransmitters. During florid episodes of illness, the severity of both symptoms and cognitive impairments will be determined mainly by the severity of monoamine disregulation. Because the effects of monoamine disregulation are not confined to the neural pathways linking cerebral sites implicated in the syndromes, the relationship between symptoms and cognitive impairment would be expected to be weaker. The studies by Baxter and Liddle27 and Ngan and Liddle28 that have compared patterns of correlations between symptoms and cognitive impairments in cases with severe persistent illness with those in patients with remitting illness have confirmed this prediction. Baxter and Liddle27 demonstrated that in patients with persistent illness, the severity of psychomotor poverty was correlated with impairment in a two-choice guessing task that tested the ability to produce a response that was entirely self-generated. This correlation was absent in patients


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with remitting illness. Ngan and Liddle28 demonstrated that in patients with persistent illness, psychomotor poverty was associated with slowed simple reaction time, while disorganization was correlated with impaired choice reaction time. In patients with remitting illness, these relationships were much weaker. The developmental disregulation hypothesis predicts that florid symptoms will respond to treatment with medication that reduces monoaminergic neurotransmission, especially dopaminergic neurotransmission. The more enduring symptoms and cognitive deficits that are a direct consequence of the primary dysplasia would be expected to be less responsive to treatment. Nonetheless, insofar as the evidence indicates that the primary problem is impaired coordination of activity between cerebral areas rather than overt loss of neurons, there is potential for successful treatment by agents that modulate neurotransmission. Assuming that regularly active connections tend to be reinforced, the hypothesis predicts that symptoms that persist for prolonged periods will be reinforced. Conversely, alleviation of the baseline abnormalities of coordination between cerebral areas is likely to require prolonged treatment, whether using psychological strategies or pharmacological agents that promote healthy patterns of coordination between cerebral areas.

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18. Tollefson, G. D. and Sanger, T. M., Negative symptoms: a path analytic approach to a double-blind, placebo and haloperidol-controlled clinical trial with olanzapine, Am. J. Psychiatry, 154, 466, 1997. 19. Wolkin, A., Barouche, F., and Wolf, A. P., Dopamine blockade and clinical response: evidence for two biological sub-groups of schizophrenia, Am. J. Psychiatry, 146, 905, 1989. 20. Maziade, M., Roy, M.-A., Martinez, M., Cliché, D., Fournier, J.-P., Garneau, Y., Nicole, L., Montgrain, N., Dion, C., Ponton, A.-M., Potvin, A., Lavalée, J.-C., Pirès, A., Bouchard, S., Boutin, P., Brisebois, F., and Mérette, C., Negative, psychoticism, and disorganized dimensions in patients with familial schizophrenia or bipolar disorder: continuity and discontinuity between the major psychoses, Am. J. Psychiatry, 152, 1458, 1995. 21. Kay, S. R., Positive and Negative Syndromes in Schizophrenia, Brunner Mazel, New York, 1991. 22. Liddle, P. F. and Morris, D. L., Schizophrenic syndromes and frontal lobe performance, Br. J. Psychiatry, 158, 340, 1991. 23. Frith, C. D., Leary, J., Cahill, C., and Johnstone, E. C., Disabilities and circumstances of schizophrenic patients — a follow-up study. IV. Performance on psychological tests, Br. J. Psychiatry, 159 (Suppl. 13), 26, 1992. 24. Allen, H. A., Frith, C. D., and Liddle, P. F., Negative features, retrieval processes and verbal fluency in schizophrenia, Br. J. Psychiatry, 163, 769, 1993. 25. Norman, R. M. G., Malla, A. K., Morrison-Stewart, S. L., Helmes, E., Williamson, P. C., Thomas, J., and Cortese, L., Neuropsychological correlates of syndromes in schizophrenia, Br. J. Psychiatry, 170, 134. 1997. 26. Frith, C. D., Friston, K. J., Liddle, P. F., and Frackowiak, R. S. J., Willed action and the prefrontal cortex in man: a study with PET, Proc. R. Soc. London Ser. B, 244, 241, 1991. 27. Baxter, R. D. and Liddle, P. F., Neuropsychological deficits associated with schizophrenic syndromes, Schizophr. Res., 30, 239, 1998. 28. Ngan, E. T. C. and Liddle, P. F., Reaction time and schizophrenic symptoms, Schizophr. Res., in press. 29. Morrison, A. P. and Haddock, G., Cognitive factors in source monitoring and auditory hallucinations, Psychol. Med., 27, 669, 1997. 30. Frith, C. D. and Done, D. J., Experiences of alien control in schizophrenia reflect a disorder in the central monitoring of action, Psychol. Med., 19, 359, 1989. 31. Mlakar, J., Jensterle, J., and Frith, C. D., Central monitoring deficiency and schizophrenic symptoms, Psychol. Med., 24, 557, 1994. 32. Liddle, P. F., Friston, K. J., Frith, C. D., Jones, T., Hirsch, S. R., and Frackowiak, R. S. J., Patterns of cerebral blood flow in schizophrenia, Br. J. Psychiatry, 160, 179, 1992. 33. Ebmeier, K. P., Blackwood, D. H. R., Murray, C., Souza, V., Walker, M., Dougall, N., Moffoot, A. P. R., O’Carroll, R. E., and Goodwin, G. M., Single photon emission tomography with 99mTc-exametazime in unmedicated schizophrenic patients, Biol. Psychiatry, 33, 487, 1993. 34. Yuasa, S., Kurachi, M., Suzuki, M., Kadono, Y., Matsui, M., Saitoh, O., and Seto, H., Clinical symptoms and regional cerebral blood flow in schizophrenia, Eur. Arch. Psychiatry Clin. Neurosci., 246, 7, 1995. 35. Kaplan, R. D., Szechtman, H., Franco, S., Szechtman, B., Nahmias, C., Garnett, E. S., List, S., and Cleghorn, J. M., Three clinical syndromes of schizophrenia in untreated subjects: relation to brain glucose activity measured by positron emission tomography (PET), Schizophr. Res., 11, 47, 1993. 36. Iverson, S. D. and Mishkin, M., Perseverative interference in monkeys following selective lesions of the inferior frontal convexity, Exp. Brain Res., 11, 376, 1970. 37. Silbersweig, D. A., Stern, E., Frith, C. D., Cahill, C., Holmes, A., Grootoonk, S., Seaward, J., McKenna, P., Chua, S. E., Schnorr, L., Jones, T., and Frackowiak, R. S. J., A functional neuroanatomy of hallucinations in schizophrenia, Nature, 378, 176, 1995. 38. Suzuki, M., Yuasa, S., Minabi, Y., Murata, M., and Kurachi, M., Left superior temporal blood flow increases in schizophrenic and schizophreniform patients with auditory hallucinations: a longitudinal case study using 13I-IMP SPECT, Eur. Arch. Psychiatry Clin. Neurosci., 242, 257, 1993. 39. McGuire, P. K., Shah, G. M. S., and Murray, R. M., Increased blood flow in Broca’s area during auditory hallucinations in schizophrenia, Lancet, 342, 703, 1993. 40. Frith, C. D., Friston, K. J., Liddle, P. F., and Frackowiak, R. S. J., PET imaging and cognition in schizophrenia, J. R. Soc. Med., 85, 222, 1992.


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Neurotransmitter Receptors in Actions of Antipsychotic Medications 41. Heresco-Levy, U., Javitt, D. C., Ermilor, M., Mordel, C., Horowitz, A., and Kelly, D., Double-blind, placebo controlled, cross-over trial of glycine adjuvant therapy for treatment resistant schizophrenia, Br. J. Psychiatry, 169, 610, 1996. 42. Lahti, A. C., Holcomb, H. H., Weiler, M. A., Zhao, M., Medoff, D., Chen, L.-W., and Tamminga, C. A., Regional correlations between ketamine-induced actions on psychosis and regional cerebral blood flow (rCBF), Schizophr. Res., 24, 167, 1997. 43. Liddle, P. F., Lane, C. M. J., and Ngan, E. T. C., Immediate effects of risperidone on cortico-striatothalamic loops and the hippocampus, in preparation. 44. Ngan, E. T. C., Lane, C. J., and Liddle, P. F., Immediate and long term effects of risperidone on cerebral metabolism in schizophrenia, Schizophr. Res., 29, 173, 1998. 45. Lane, C. J., Ngan, E. T. C., and Liddle, P. F., Effects of risperidone on cerebral activity and positive symptoms in first-episode schizophrenic subjects, NeuroImage, 7, 236, 1998. 46. Frith, C. D., Friston, K. J., Herold, S., Silbersweig, D., Fletcher, P., Cahill, C., Dolan, R. J., Fracowiak, R. S. J., and Liddle, P. F., Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task, Br. J. Psychiatry, 167, 343, 1995. 47. Liddle, P. F., Associations between regional brain abnormalities and specific syndromes in schizophrenia, in Search for the Causes of Schizophrenia, Vol. 2, Häfner, H. and Gattaz, W. F., Eds., Springer, Berlin, 1995, 150. 48. Liddle, P. F., Passmore, M., Friston, K. J., and Frith, C. D., Functional connectivity during word generation in schizophrenia, Schizophr. Res., 24, 168, 1997. 49. Jones, P., Rodgers, B., and Murray, R., Child development risk factors for adult schizophrenia in the British 1946 birth cohort, Lancet, 344, 1398, 1994. 50. Done, D. J., Crow, T. J., Johnstone, E. C., and Sacker, A., Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11, Br. Med. J., 309, 699, 1994. 51. Goldberg, T. E., Ragland, D. R., Gold, J., Bigelow, L. B., Torrey, E. F., and Weinberger, D. R., Neuropsychological assessment of monozygotic twins discordant for schizophrenia, Arch. Gen. Psychiatry, 47, 1066, 1990. 52. Shallice, T., Burgess, P. W., and Frith, C. D., Can the neuropsychological case-study approach be applied to schizophrenia?, Psychol. Med., 21, 661, 1991. 53. Maurer, K. and Hafner, H., Methodological aspects of onset assessment in schizophrenia, Schizophr. Res., 15, 265, 1995. 54. Knights, A. and Hirsch, S. R., “Revealed” depression and drug treatment for schizophrenia, Arch. Gen. Psychiatry, 38, 806, 1981. 55. Lieberman, J. A., Jody, D., Geisler, S., Alvir, J., Loebel, A., Symanski, S., Woerner, M., and Borenstein, M., Biologic correlates of treatment response in first-episode schizophrenia, Arch. Gen. Psychiatry, 50, 369, 1993. 56. Harding, C. M., Zubin, J., and Strauss, J. S., Chronicity in schizophrenia: revisited, Br. J. Psychiatry, 161 (Suppl. 18), 27, 1992. 57. Powchik, P., Davidson, M., Haroutunian, V., Gabriel, S. M., Purohit, D. P., Perl, D. P., Harvey, D. P., and Davis, K. L., Postmortem studies in schizophrenia, Schizophr. Bull., 24, 325, 1998. 58. Weinberger, D. R., The pathogenesis of schizophrenia: a neurodevelopmental disorder, in The Neurobiology of Schizophrenia, Nasrallah, H. and Weinberger, D. R., Eds., Elsevier, Amsterdam, 1986, 397. 59. Murray, R. M. and Lewis, S. W., Is schizophrenia a neurodevelopmental disorder?, Br. Med. J., 295, 681, 1987. 60. Mogenson, G. J., Brudzynski, S., Wu, M., Yang, C. R., and Yim, C. R., From motivation to action: a review of the dopaminergic regulation of limbic — nucleus accumbens — ventral pallidum — pediculopontine nucleus circuitries involved in limbic-motor integration, in The Mesolimbic Motor Circuit and Its Role in Neuropsychiatric Disorders, Kalivas, P. and Barnes, C., Eds., CRC Press, Boca Raton, FL, 1993, 193. 61. Breier, A., Davis, O. R., Buchanan, R. W., Moricle, L. A., and Munson, R. C., Effects of metabolic perturbation on plasma homovanillic acid in schizophrenia: relationship to prefrontal cortex volume, Arch. Gen. Psychiatry, 50, 541, 1993. 62. Pycock, C. J., Kerwin, R. W., and Carter, C. J., Effect of lesion of cortical dopamine terminals on subcortical dopamine in rats, Nature, 286, 74, 1980.



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63. Jaskiw, J. F., Karoum, F. K., and Weinberger, D. R., Persistent elevations of dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex, Brain Res., 534, 321, 1990. 64. Davis, J. O. and Bracha, H. S., Prenatal growth markers in schizophrenia: a monozygotic co-twin control study, Am. J. Psychiatry, 153, 1166, 1996. 65. Woodruff, P. W. R., Wright, I. C., Shuriquie, N., Russouw, H., Howard, R. J., Graves, M., Bullmore, E. T., and Murray, R. M., Structural brain abnormalities in male schizophrenics reflect fronto-temporal dissociation, Psychol. Med., 27, 1257, 1997.



2

General Overview of Contemporary Antipsychotic Medications Michael S. Lidow

CONTENTS I. Introduction .............................................................................................................................17 II. Chemical Classes of Antipsychotic Drugs .............................................................................17 III. Typical and Atypical Medications ..........................................................................................23 IV. Potency and Efficacy of Antipsychotic Drugs .......................................................................25 V. Receptor Binding Profiles of Antipsychotic Medications......................................................26 VI. Conclusion...............................................................................................................................28 References ........................................................................................................................................28

I. INTRODUCTION Antipsychotic drugs may be defined as medications effective in palliative treatments of psychotic disorders, most notably schizophrenia. It addition to schizophrenia, the beneficial actions of antipsychotic drugs have been found in a variety of conditions ranging from postsurgical delirium and amphetamine intoxication to paranoia, mania, psychotic depression, and agitation of Alzheimer’s dementia.1 Thus, in general, antipsychotic medications are not disease specific and provide clinical benefits for a range of syndromes. Over the years, diverse classification schemes for antipsychotic drugs have been proposed. Some of these classifications are based on the chemical structure of the drugs, while others are based on their potency, efficiency, and side-effect profiles, and still others are based on their neurotransmitter receptor binding profiles. This chapter provides a review of the major types of these classifications, as well as a general overview of the antipsychotic drugs used in contemporary psychiatric practice.

II. CHEMICAL CLASSES OF ANTIPSYCHOTIC DRUGS At the present time, drugs used in treatment of psychotic patients belong to ten chemical classes: phenothiazines, thioxanthenes, phenylbutylpiperidines, diphenylbutylpiperidines, indoles, substituted benzamines, dibenzazepines, imidazolines, benzohazoles, and benzisothiazoyls (Figure 1). In spite of this chemical diversity, the molecular structure of all antipsychotic drugs adheres to the aromatic chain-amine three-sectioned model which has been shown to impart chemical and physical properties essential for these drugs to reach and bind their targets in the brain.2 In this model, the nitrogen of the amine group acts as a base, accepting protons from the physiological solvent system and allowing absorption to occur. In addition, the amine group often plays a key role in the receptor site–drug interaction by acting directly on the membrane surface and enzymatic proteins. The 0-8493-0744-9/00/$0.00+$.50 © 2000 by CRC Press LLC

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aromatic portion of the compound confers solubility, allowing the compound to be absorbed and transported into the central nervous system. The aromatic ring is also usually the largest, spaceoccupying portion of the molecule, which dominates the overall steric arrangement of the compound and, therefore, is important in determining its pharmacological activity. The third section of this model is the connecting chain of carbon atoms connecting the aromatic and amine groups. This part of the molecule is the major determinant of the geometry of the compound and, consequently, impacts the functional activity of the drug. Phenothiazines are the oldest and largest class of antipsychotic drugs. They include the prototypical antipsychotic chlorpromazine, which in the 1950s launched the present era of pharmacologic treatment of psychiatric disorders.3 The drugs belonging to this class are three-ring heterocyclic compounds in which two aromatic rings are linked by a third ring containing sulfur and nitrogen atoms. Seven phenothiazines are presently commercially available in the U.S.4 They are chlorpromazine, mesorandile, perphenazine, prochlorperazine, trifluoperazine, fluphenazine, and thioridazine (Figure 1a). They differ from each other by the composition of the side chains linked to the nitrogen atom (position 10) and to the 2-position of the phenothiazine nucleus. These differences in chemical structure result in individual phenothiazines displaying distinct levels of potency, with fluphenazine and trifluoperazine being the most potent among the drugs of this chemical class.2 These two compounds are also characterized by a strong propensity to elicit extrapyramidal side effects such as Parkinsonism, dystonia, akathisia, and tardive dyskinesia.4 This is in contrast to another phenothiazine, thioridazine, which produces relatively low levels of the extrapyramidal side effects.2 The drugs belonging to the second chemical class of antipsychotic medications, thioxanthenes, are closely related to phenothiazines. The nucleus of thioxanthenes differs from that of phenothiazines in the substitution of a carbon atom for a nitrogen atom in the central ring. Only one thioxanthene is presently in use in the U.S.4 This compound is thiothixene (Figure 1a). The other compound of this class, flupentixol, is available in Europe.2 The third class of antipsychotic medications is phenylbutylpiperidines, also known as butyrophenones. The general structure of butyrophenones includes a tertiary amine containing at least one aromatic ring linked to the amine nitrogen by a keto group attached by an intermediate chain of three alkyl groups. This chemical class includes haloperidol, the most widely used antipsychotic drug (Figure 1b). Haloperidol was introduced to the market in 1959 and until recently was consumed at the rate of 2.3 million kg/year.2 This compound, however, is prone to inducing severe extrapyramidal side effects5 and is now being replaced by a new generation of safer drugs of different chemical classes. A nuclear structure of the fourth class of antipsychotic drugs, diphenylbutylpiperidines, is that of phenylbutylpiperidines in which the α-keto group has been replaced by a 4-fluorophenylmethine moiety. Only one compound of this class is available for use in the U.S.4 This compound, pimozide (Figure 1b), is characterized by an unusually prolonged duration of its action and somewhat lower incidence of the extrapyramidal side effects as compared with most established antipsychotic medications.6 Pimozide, however, is rarely used in psychotic patients. It is employed mainly in treatment of Tourette’s syndrome of severe tics and involuntary vocalization.4 The fifth class of antipsychotic drugs is enantiomeric substituted benzamides, which comprise a large group of compounds that have some structural similarities to phenylbutylpiperidines. None of these compounds are approved for antipsychotic use in the U.S., although some drugs of this class are available in this country for treatment of other illnesses. For example, the widely used gastroenterologic agents metoclopramide and cisapride are benzamides.1 Two compounds of this chemical class, sulpiride and amisulpiride, are used for treatment of psychiatric patients in Europe2 (Figure 1b). The third compound, remoxipride, was recently taken from the market because administration of this drug has been associated with several cases of aplastic anemia.7 All three of these antipsychotic benzamides are characterized by a low propensity to induce extrapyramidal side effects and produce little sedation.8


General Overview of Contemporary Antipsychotic Medications

Phenothiazines 6 7 8 9

5 S

Thioxanthenes

4

5 S

6 3

10 N

19

7 8 R2

1

9

(CH2)3 Cl

R2

1

R1 Thiothixene (NAVANE)

Chlorpromazines (THORAZINE)

R2:

3

10 C

R1

R1:

4

N(CH3)2

R1:

CH(CH2)2

R2:

SO2

N

N

CH3

Mesoridazine (SERENTIL) R1:

N(CH3)2

(CH2)2 N

R1:

SCH3

CH3

O Perphenazine (TRILAFON) R1:

(CH2)3

R2:

Cl

N

N

(CH2)2

OH

Trifluoperazine (STELAZINE; SUPRAZINE) R1:

(CH2)3

R2:

CF3

N

N

CH3

N

CH3

Prochlorperazine (COMPAZINE) R1:

(CH2)3

R2:

Cl

N

Fluphenazine (PERMITIL; PROLIXIN) R1:

(CH2)3

R2:

CF3

N

N

(CH2)2

OH

Thioridazine (MELLARIL; MILLAZINE)*? R1:

(CH2)2

R2:

SCH3

N CH3

FIGURE 1a Chemical classes of antipsychotic medications. Chemical classes are typed in bold letters; subclasses are typed in italic letters; drug names are typed in plain letters; trade names are in parenthesis; related chemical classes are presented in parallel columns; and typical antipsychotics are marked with an asterisk. The drugs whose atypicity is controversial are marked by an asterisk combined with a question mark.

The sixth class of antipsychotic medications, indoles, is structurally related to reserpine. The main member of this class is molindone (Figure 1), which is available for treatment of psychotic patients in the U.S.4


20


Phenylbutylpiperidines (Butyrophenones)

Diphenylbutylpiperidines

Haloperidol (HALDOL; HALPERON)

Pimozide (ORAP)

OH

O F

C

(CH2)3

N

(CH2)3

N

O

CH

F

N

Cl

F NH

Benzamides Sulpiride (ABILIT; DOGMATIL; MIRADOL; SERVENIN; SYNEDIL; TRILAN)*?

N

CONHCH2

Remoxipride (ROXIOM)*7

C2H5 COH2

CH3O

O N H

H2NSO2

H

Amisulpiride (SOCIAN; SOLIAN)*?

N

OCH3 Br CONHCH2 C2H5 COH2

H2NSO3 NH2

Indoles Molindone (MOBAN) O CH2CH3 O

N

CH2 N

CH3

FIGURE 1b (continued)

The seventh class of antipsychotic medication is dibenzepins, which are derivatives of the piperazine tricyclic molecules. At the present time, the antipsychotic drugs of this class belong to four chemical subclasses: 1. Compounds with two nitrogen atoms in the central ring are called dibenzodiazepines. This subclass includes the prototypical new generation drug clozapine (Figure 1c) which is characterized by a virtual lack of extrapyramidal side effects, the ability to ameliorate refractory schizophrenia, and the capacity to improve the quality of life in psychotic patients far above that achieved by other established antipsychotic drugs.9–12 While this compound represents the standard against which all other antipsychotic agents are being



21

Dibenzapines Dibenzodiazepines Clozapine (CLOZARIL)* H

Dibenzoxazepines

N

Cl

Loxapine (LOXITANE)*?

Dibenzothiazepines

O

N

Quetiapine (SEROQUEL)*

N

S

N Cl

N

N

N CH3 N

N

Thienobenzodiazepines

CH3

Olanzapine (ZYPREXIA)* H

N

N

O OH CH3

N

S N

N CH3

Benzisoxazoles

Benzisothiazoyls

Risperidone (RISPERDAL)*

Ziprazidone (ZELDOX)*

F

S O

N N

N

N N Cl CH3

O

N N

NH

O

FIGURE 1c (continued)

measured, it is far from being perfect. Treatment with clozapine is associated with a range of severe side effects which limit its use largely to cases unresponsive to other antipsychotic drugs. The most dangerous side effect is agranulocytosis.4 This side effect is responsible for the fact that while clozapine was patented in 1960, the U.S. Food and Drug Administration approved its use in human patients only in 1989.13 Clozapine has


22


Imidazolines Setrindole (SERLECT)* Cl

F

N

N N

NH O

FIGURE 1d (continued)

been available for prescription by American physicians since 199013 and requires weekly blood monitoring.4 Agranulocytosis, however, affects only 1 to 2% of clozapine-treated individuals10 and, therefore, is not the most prevalent side effect of this drug. For everyday life, the most unpleasant consequences of clozapine use are extensive salivation and weight gain which occur in about one third of the patients.5 The use of clozapine is also associated with increased incidence of seizures, sedation, and constipation10 and a decline in high order executive aspects of learning and memory.9 The often-stated goal of new antipsychotic drug development is the discovery of a compound which is as therapeutically effective and extrapyramidal side effect free as clozapine, but which lacks the previously mentioned negative aspects associated with this drug. 2. Compounds with oxygen replacing the second nitrogen atom in the central ring are known as dibenzoxazepines. This subclass is represented by loxapine (Figure 1c). This compound lacks most of the advantages of clozapine, although at lower doses it is less prone to induce extrapyramidal side effects than most other established antipsychotic drugs.14 3. Dibenzothiazepines are compounds in which the central ring contains atoms of nitrogen and sulfur. This subclass includes quetiapine (Figure 1c), which represents a new generation of antipsychotic drugs with higher efficacy and lower incidence of extrapyramidal side effects.10–12 It was introduced into clinical practice in the U.S. in 1997.15 4. The last subclass of dibenzepins has two nitrogen atoms in the central ring with one of the side aromatic rings being replaced by thiophene ring. This subclass is known as thienobenzodiazepines. It contains another new generation, extrapyramidal effects free drug, olanzapine10–12 (Figure 1c). This drug has been marketed in the U.S. since 1996.15 The eighth class of antipsychotic medications, imidazolines, includes a new generation, low extrapyramidal side effect drug, setrindole (Figure 1d). While this drug has been approved for use in the U.S., it has never been marketed in this country because of its potential serious cardiovascular side effects.14 However, it is presently available in Europe. The ninth class of antipsychotic drugs, benzisoxazoles, is represented by risperidone (Figure 1c). This new generation drug does not produce extrapyramidal side effects at doses below 6 mg/day.10–12 At higher doses, it induces the same level of extrapyramidal side effects as most conventional antipsychotic drugs.10–12 Resperidone has been available in the U.S. since 1993.15 The tenth and last chemical class of contemporary antipsychotic drugs, benzisothiazoyls, is structurally related to benzisoxazoles. This class includes a new, promising benzisothiazoyl piperazine, ziprazidone (Figure 1c), which has recently completed clinical trails and is expected to be available in the U.S. for clinical practice in the near future.11 While being widely used in the literature, the classification of antipsychotic medications by chemical structure has only limited practical usefulness. First, it lacks any kind of underlining theoretical scheme, which makes it into an ever-expanding list of chemical names as new drugs



23

are synthesized, rather than into a true classification. Second, division of drugs by chemical classes does not provide any information about their therapeutic properties and associated side effects which is essential for a classification to be of any use for physicians and patients.

III. TYPICAL AND ATYPICAL MEDICATIONS The most widely used property-based classification of antipsychotic medication divides them into typical and atypical drugs. Unfortunately, the parameters which distinguish typical from atypical drugs have not been well defined. The narrowest definition distinguishing typical from atypical drugs relates to their capacity to induce extrapyramidal side effects. All the earlier drugs, such as chlorpromazine, fluphenazine, thiothixene, and haloperidol, were found to have a strong tendency to generate extrapyramidal side effects, leading to their being referred to as neuroleptics (“seize the neuron”).1,2,16 It should be mentioned, however, that the contemporary association of the term “neuroleptics” with induction of such active movement disorders as dystonia, akathisia, and tardive dyskinesia evolved over time from the earlier-defined “neuroleptic syndrome” which emphasized only the induction Parkinsonism and was defined as inhibition of spontaneous movement and operant behavior with preservation of spinal reflexes.17 A strong link of the early antipsychotics with the extrapyramidal side effects led some scientists to believe that these effects are an essential part of antipsychotic effectiveness.17 The fault of this concept was demonstrated by the introduction of clozapine, whose therapeutic effectiveness was not paired with notable extrapyramidal activity. This generated a concept of typical antipsychotic medications highly prone to generation of extrapyramidal side effects and atypical antipsychotic drugs with decreased or absent propensity to produce such effects. According to this definition, all the new generation antipsychotic medications, which reached the market within the last decade, can be considered as atypical drugs. These include clozapine, olanzapine, sertindole, quetiapine, risperidone, sulpiride, amisulpiride, and remoxipride (Table 1). Not all investigators, however, believe that the three substituted benzamines on this list, sulpiride, amisulpiride, and remoxipride, are true atypical drugs, since the atypical profile is characteristic only for the low dosages of these drugs.8,18,19 As mentioned earlier, risperidone can also be classified as a typical drug at doses above 6 mg/day. It has also been pointed out that according to the extrapyramidal side effect-based definition, some of the older drugs may be classified as atypical medications.11,14 For example, thioridazine and low doses of loxapine have been demonstrated to produce therapeutic effects without generating extensive motor effects 2,11,14 (Table 1). The definition of atypical drugs often includes low capacity to elevate prolactin levels. An increase in prolactin secretion, usually associated with treatment by typical antipsychotics, results in galactorrhea, menstrual changes in women, and impotence in men.20 Clozapine, olanzapine, sertindole, and quetiapine either produce transient increase or no elevation in prolactin levels and, therefore, can be considered atypical by this criterion.12 In contrast, sulpiride, amisulpiride, remoxipride, and risperidone, while deemed atypical by the more narrow standard, produce dose-dependent elevation in prolactin secretion and, thus, should be classified as typical by this extended standard.12,21 Recently, the third requirement for atypical drugs is being mentioned — the ability to ameliorate the so-called negative and cognitive signs of schizophrenia. It is widely accepted that all antipsychotics have similar efficacy in treatment of the delusional and hallucinatory thought processes that comprise the positive or florid symptoms of schizophrenia.1 The chronic apathy, emotional blunting, and social withdrawal which constitute the negative or deficit symptoms of schizophrenia are much more resistant to antipsychotic treatment.22,23 It has been argued that clozapine and, although to a somewhat lesser degree, other new generation drugs such as olanzapine, sertindole, quetiapin, and resperidone may be capable of palliating these negative symptoms of the disease.12,15 These claims, however, are controversial, with the controversy centering not so much on the ability of the aforementioned drugs to induce schizophrenic patients to be more interactive with their environment


24


TABLE 1 Daily Dosages and Side Effect Profiles of Antipsychotic Medication Side Effects Drug Fluphenazine Thiothexene Haloperidol Pimozide Perphenazine Chlorpromazine Thioridazine Clozapine Quetiapine Risperidone* Olanzapine* Sertindole* Sulpiride*

Dose (mg/day)

Sedation

Autonomic Side Effects

Extrapyramidal Side Effects

2–20 2–30 2–20 2–20 8–64 100–600 100–600 200–600 300–900 4–12 10–30 8–24 600–1800

+ + + (+) ++ +++ +++ +++ ++(+) ++ + + (+)

+ +(+) + + ++ ++ +++ +++ ++ ++ +(+) ++ +

+++ +++ +++ ++ ++ + (+) (+) (+) + (+) (+) +(+)

Note: +++ strong effect; ++ moderate effect; + low effect; (+) very low effect. Asterisks mark the drugs whose side effect profiles differ from the ones predicted based on their potency (compiled based on References 5, 10-12, 14, and 39).

and to increase social interaction, but on whether these effects are truly related to the ability of the drug to treat the disease-associated negative symptoms or simply reflect the low level of extrapyramidal side effects characteristic of these drugs. Indeed, when present, extrapyramidal side effects may cause significant negative-like signs in affected patients.10 For example, medication-associated bradykinesia and rigidity impair social and occupational function, leading to deterioration in these areas. The decline in social function is even more severe for those patients who develop dystonia and tardive dyskinesia, which often prevents normal social interaction. Bradykinesia may contribute to reduced facial expression, loss of expressive gestures, and flattening of vocal inflection, which can be mistaken for negative symptoms of the illness. Finally, the severe extrapyramidal side effects also result in dysphoria and depression, which may further intensify the already present negative symptoms. It is obvious that the drugs with low propensity to produce the extrapyramidal side effects would avoid all of these secondary negative signs seen in schizophrenic patients. The drugrelated improvement in the primary negative symptoms arising directly from the pathophysiology of schizophrenia is much more difficult to establish. So far, the claim of such improvement has been made by only two studies which used a path-analytical approach to statistically separate the effects of risperidone and olanzapine on primary vs. secondary symptoms.24,25 Path analysis, however, does not examine primary symptoms directly, but instead considers all effects not attributable to secondary symptoms. Therefore, it is unclear whether the path analysis is sufficient to distinguish primary from secondary symptoms, and any assertion that some antipsychotics are effective in treating the primary negative syndromes should be looked upon as very premature. The effect of antipsychotic medications on the schizophrenia-associated deficits in cognitive abilities such as short-term memory, attention, and executive function is also rather complex.9 First, the cognitive deficits can also be divided into primary and secondary types. The latter type of deficits is associated with adjuvant anticholinergic treatments used to alleviate antipsychoticinduced extrapyramidal syndromes, since anticholinergic drugs adversely affect memory, learning, and other cognitive functions.26 Therefore, one can assume that the drugs with low potential to



25

generate extrapyramidal side effects would generate no secondary cognitive deficits. Unfortunately, the majority of such drugs, including clozapine and olanzapine, are by themselves muscarine acetylcholine receptor antagonists and, thus, are prone to induce the cognitive deficits.10–13 To make the matter even more complex, studies in clozapine-treated patients demonstrated that this drug both improves and worsens different aspects of cognition. While improving the performance of cognitive tasks demanding rapid motor actions, attention, and verbal fluency, it induces a decline in the performance of tasks involving nonverbal learning and conceptual speed.9 In summary, while the goal of achieving the medication-induced improvement in the negative and cognitive deficits of schizophrenia is worthy of vigorous pursuit, the presently available antipsychotic medications have, at best, only marginal therapeutic effects on these deficits.

IV. POTENCY AND EFFICACY OF ANTIPSYCHOTIC DRUGS While all antipsychotics are affective against the florid symptoms of psychosis, they differ in the dosages required to achieve their palliative effects. Therefore, one of the oldest classification schemes for antipsychotic drugs is based on their potency. The potency of antipsychotic drugs has been traditionally expressed in equivalency units as compared to 100 mg of chlorpromazine, the prototypic antipsychotic drug.2 The drugs are usually divided into high, medium, and low potency groups. The high potency drugs have chlorpromazine equivalencies in the range of 1 to 5 mg, with their daily doses ranging from 1 to 30 mg (Table 1). This group of antipsychotics is represented by such drugs as fluphenazine, thiothixene, haloperidol, and pimozide. The medium potency group includes perphenazine, molindone, and loxapine. These drugs have chlorpromazine equivalencies in the range of 10 to 25 mg and are used at daily doses of 10 to 150 mg. The chlorpromazine equivalencies for the low potency group range from 25 to 100 mg, and their daily doses are 40 to 1000 mg. Thioridazine, clozapine, and quetriapine represent this group of drugs. The usefulness of this classification is that the potency is generally predictive of the side effects produced by the drug. The ability to induce extrapyramidal side effects usually directly correlates with the potency of the drugs27 (Table 1). On the other hand, the potency inversely correlates with the nonneurologic adverse effects such as sedation, weight gain, constipation, seizures, and cardiovascular effects, particularly orthostatic hypotension28 (Table 1). The aforementioned relationship between potency and side effects can be illustrated best by comparison of two representative compounds from the high potency and low potency groups — haloperidol and clozapine. As a high potency drug, haloperidol is used at very low doses of 2 to 20 mg/day, and it is highly prone to inducing all types of the extrapyramidal side effects. The side effects of this drug, however, do not extend much beyond the abnormal motor activity. It produces very little sedation or autonomic side effects. In contrast, the low potency drug clozapine causes practically no extrapyramidal side effects at the therapeutic doses of 200 to 600 mg/day. Instead, clozapine produces extensive sedation, seizures, and such autonomic effects as constipation, orthostatic hypotension, and weight gain. The reason for the correlation between potency and specific side effects is that the potency of antipsychotic drugs is proportional to their ability to block D2 dopaminergic receptors, which is also the cause for the extrapyramidal side effects.29 The low potency drugs have relatively low affinity to D2 sites and, therefore, are used at higher dosages, which are sufficient for their therapeutic action, but are below those required to induce unwanted motor effects. Unfortunately, the high doses required for therapeutic effect of the low potency drugs bring them into a range at which they begin to affect nondopaminergic sites such as muscarinic, adrenergic, and histaminergic receptors to which these compounds have affinities comparable to those for D2 sites.2 This results in the nonneurologic side effects characteristic of low potency medications. While the potency–side effect relationship described previously holds for the majority of older antipsychotics, several of the new generation drugs do not adhere to this rule. For example,


26


risperidone, olanzapine, and sertindole are all high potency drugs, yet they possess little propensity to induce extrapyramidal side effects12 (Table 1). Also, sulpiride and amisulpiride are low potency drugs which produce virtually no sedation or autonomic side effects2 (Table 1). Therefore, the classification of antipsychotic medications by their potency may have outlived its usefulness. When it is stated that all antipsychotic drugs are equally effective in treatment of positive syndromes of schizophrenia, it assumed that the patients involved are responsive to antipsychotic treatment. However, up to 30% of psychotic patients are not responsive to antipsychotic drugs.30 The only compound which has, so far, been proven effective in treatment of patients with refractive schizophrenia is clozapine. It has been estimated that the use of this drug leads to significant improvements in 30 to 50% of refractory patients.31 No other drugs, including the new generation compounds, are capable of even approaching these results.11,12,14 This puts clozapine into a separate class of high efficacy drugs which, at the present time, includes no other chemical compounds.

V. RECEPTOR BINDING PROFILES OF ANTIPSYCHOTIC MEDICATIONS The roles of neurotransmitter receptors in the action of antipsychotic medications are described in detail in other chapters of this book. Here, only a brief overview will be provided of the receptor binding profiles of contemporary antipsychotic drugs. From early on, studies of antipsychotic medications have shown that antagonism to D2 dopaminergic receptors is a central component of the pharmacology of these drugs. This conclusion is supported by the observation that the therapeutic potencies of antipsychotic drugs directly correlate with their affinities for D2 sites.29 Furthermore, selective D2 antagonists, such as pimozide, sulppiride, amisulpiride, and remoxipride, are effective antipsychotic drugs.1 Antagonism to D2 dopaminergic receptors is also a reason for the extrapyramidal side effects often accompanying antipsychotic treatments.10 However, the D2 sites involved in the therapeutic activity of antipsychotic drugs and the D2 sites responsible for side effects of these drugs are apparently situated in different brain regions.32 The therapeutic activity most likely involves receptors associated with the mesolimbic and mesocortical dopaminergic innervation, while the motor side effects result from blockade of receptors in the nigrostriatal dopaminergic system. The only challenge to the idea of the importance of D2 antagonism for antipsychotic activity of chemical compounds came from clozapine, since the therapeutically effective doses of this drug are significantly smaller than would be predicted on the basis of its relatively low affinity for D2 sites.33 Since clozapine binds with high affinity to a variety of receptors, several hypotheses suggest that these other receptors might be responsible for the unusual antipsychotic profile of this compound. In particular, it was proposed that the high affinity of this drug to D1 dopaminergic sites and/or to the recently cloned D4 subtype of the D2 receptor class of dopaminergic receptors is the reason for antipsychotic activity of clozapine.33,34 This resulted in a flurry of activity to synthesize and clinically test D1- and D4-selective antagonists. Unfortunately, the clinical tests of such drugs were disappointing,35–37 which once again raised the question of the pharmacological basis for the antipsychotic activity of clozapine. Some answers to this puzzle have recently been obtained in studies of the D2 receptor occupancy by clozapine in different brain areas of schizophrenic patients. These studies have demonstrated that, in contrast to the low levels of D2 receptor occupancy by clozapine in the striatum, the occupancy of the limbic D2 sites by clinical doses of this drug is comparable to that of other antipsychotic medications.38 Therefore, clozapine appears to be similar to other antipsychotics in its ability to block those D2 receptors which, as was mentioned earlier, are involved in therapeutic activity of these drugs, but it is a poor blocker of the D2 sites involved in the extrapyramidal motor regulation. Apart from the small group of selective D2 antagonists, the majority of antipsychotic drugs have high affinities to a variety of receptors in addition to D2 sites (Table 2). While any involvement



27

TABLE 2 Receptor Binding Profiles of a Representative Group of Antipsychotic Medications Neurotransmitter Receptors Drugs Chlorpromazine Perphenazine Fluphenazine Thioridazine cis-Thiothixene Haloperidol Pimozide Sulpiride Clozapine Loxapine Olanzapine Quetiapine Sertindole Risperidone Ziprazidone

Dopaminergic D1 D2a — — — + — — — — ++ + + + — — +

+++ +++ +++ +++ +++ +++ +++ +++ ++ ++ ++ + +++ +++ +++

Serotonergic 5-HT2

Adrenergic α1

Cholinergic Muscarinic

Histaminergic H1

++ ++ + ++ + + — — +++ ++ +++ + +++ +++ +++

+++ ++ + +++ ++ + — — +++ + ++ +++ ++ +++ ++

++ — — ++ + — — — +++ — +++ — — — —

++ ++ — + ++ — — — ++ ++ ++ ++ — — —

Note: +++ high affinity (Ki < 20 nM); ++ intermediate affinity (Ki between 10 and 150 nM); + low affinity (Ki > 150 nM); — no detectable binding (Ki > 1000 nM) (compiled based on References 5, 8, 10, 11, 13, and 14). a

D2 subtype of the D2 receptor class.

of these receptors in therapeutic properties of antipsychotic drugs still remains to be demonstrated, the types of nondopaminergic receptors bound by a given antipsychotic compound determines, to a large degree, the scope of its side effects. For example, a high affinity to histaminergic receptors, which is characteristic for such drugs as chlorpromazine, perphenazine, thiothixene, clozapine, loxapine, olanzapine, and quetiapine (Table 2), results in sedation, drowsiness, and weight gain.39 A high affinity for α1-adrenergic sites, characteristic of chlorpromazine, thioridazine, clozapine, and sertindole (Table 2), produces orthostatic hypotension, dizziness, and tachycardia.10 The ability to block muscarinic cholinergic sites seen in chlorpromazine, thioridazine, clozapine, and olanzapine (Table 2) reduces extrapyramidal side effects, but produces a variety of other adverse reactions.10,14 These reactions include dry mouth, sinus tachycardia, constipation, urinary retention, and memory dysfunction.39 A particular focus of interest in recent years has been the ability of some antipsychotics to bind 5-HT2 serotonergic receptors. It has been proposed that the high affinity for these sites reduces the capacity of antipsychotic drugs to generate extrapyramidal side effects, since this prevents a decrease in dopaminergic function in the nigrostriatal pathways induced by the blockade of striatal D2 receptors.40,41 Furthermore, it was estimated that in order for a drug to have a low propensity for induction of motor side effects, the logarithm of its affinity for 5-HT2 receptors divided by the logarithm of its affinity for D2 receptors must be higher than 1.40,41 This equation, however, does not always hold, as is demonstrated by chlorpromazine which, while having affinities for 5-HT2 and D2 receptors required by the equation, still induces significant extrapyramidal side effects.14 Nevertheless, several new generation drugs such as risperidone, olanzapine, sertindole, and ziprazidone, which were specifically designed to have the affinity for 5-HT2 receptors exceeding the affinity for D2 sites, have been shown to possess a reduced capacity for generation of extrapyramidal side effects.10–14 Therefore, a high affinity for 5-HT2 receptors is often listed among the obligatory features of atypical antipsychotic medications.


28


VI. CONCLUSION Since introduction of the first true antipsychotic drug, chlorpromazine, in 1952,3 significant progress has been achieved both in understanding the mechanism of action and in the development of antipsychotic compounds. As a consequence, a new generation of drugs has reached the market during the last decade. These drugs are characterized by a very low propensity to generate extrapyramidal side effects, which is one of the major drawbacks of the earlier antipsychotic medications. However, several problems still remain. So far only clozapine has shown to be effective in treatment of refractory schizophrenia. Furthermore, none of the available drugs are capable of ameliorating the primary negative syndromes of schizophrenia. Therefore, creation of more effective and safe antipsychotic medications remains one of the major targets of the pharmaceutical industry, and new drugs are continuously being designed and tested.

REFERENCES 1. Baldesarini, R. J., Drugs and the treatment of psychiatric disorders, in The Pharmacological Basis of Therapeutics, 9th ed., Hardman, J. G., Limbird, L. E., Molinnoff, P. B., Ruddon, R. W., and GoodmanGilman, A., Eds., McGraw-Hill, New York, 1996, chap. 18. 2. Munchin, S. A. and Csernansky, J. G., Classification schemes for antipsychotic drugs, in Antipsychotics, Csernansky, J. G., Ed., Springer, Berlin, 1996, chap. 1. 3. Delay, J., Deniker, P., and Harl, J. M., Traitement des etats d’excitation et d’agitation par une methode medicamenteuse derivee de l’hibernotherapie, Ann. Med. Psychol., 110, 267, 1952. 4. Physicians’ Desk Reference, Medical Economics Co., Montvale, NJ, 1999. 5. Peacock, L. and Gerland, J., Antipsychotic-induced side effects related to receptor affinity, in Antipsychotics, Csernansky, J. G., Ed., Springer, Berlin, 1996, chap. 13. 6. Tueth, M. J. and Cheong, A. J., Clinical uses of pimozide, South. Med. J., 86, 344, 1993. 7. Laidlaw, S. T., Snowden, J. A., and Brown, M. J., Aplastic anaemia and remoxipride, Lancet, 342, 1245, 1993. 8. Sedvall, G., Ed., Development of a new antipsychotic remoxipride, Acta Psychiatr. Scand., 82 (Suppl.) 358, 1990. 9. Bilder, R. M., Neurocognitive impairment in schizophrenia and how it affects treatment options, Can. J. Psychiatry, 42, 255, 1997. 10. Jibson, M. D. and Tandon, R., New atypical medications, J. Psychiatr. Res., 32, 215, 1998. 11. Blin, O., A comparative review of new antipsychotics, Can. J. Psychiatry, 44, 235, 1999. 12. Markowitz, J. S., Brown, C. S., and Moore, T. R., Atypical antipsychotics. Part I: pharmacology, pharmacokinetics and efficacy, Ann. Pharmacotherapy, 33, 73, 1999. 13. Sramek, J. J., Cutler, N. R., Kurtz, N. M., Murphy, M. F., and Carta, A., Optimizing the Development of Antipsychotic Drugs, John Wiley & Sons, New York, 1997, chap. 3. 14. Richelson, E., Receptor pharmacology of neuroleptics: relation to clinical effects, J. Clin. Psychiatr., 60 (Suppl. 10), 5, 1999. 15. Buckley, P., New antipsychotic agents: emerging profiles, J. Clin. Psychiatr., 60 (Suppl. 1), 12, 1999. 16. Tandon, R., Milner, K., and Jibson, M. D., Antipsychotics from theory to practice: integrating clinical and basic data, J. Clin. Psychiatr., 60 (Suppl. 8), 21, 1999. 17. Caldwell, A. E., History of psychopharmacology, in Principles of Psychopharmacology, Clark, W.G. and del Giudice, J., Eds., Academic Press, New York, 1978, 9. 18. Harnryd, C., Bjerkenstedt, L., Bjork, K., Gullberg, B., Oxenstierna, G., Sedvall, G., Weisel, F.-A., Wik, G., and Aberg-Wistedt, A., Clinical evaluation of sulpiride in schizophrenic patients — a doubleblind comparison with chlorpromazine, Acta Psychiatr. Scand., 69 (Suppl. 311), 7, 1984. 19. Gerlah, J., Behnke, K., Heltberg, H., Munk-Andersen, E., and Nielsen, H., Sulpiride and haloperidol in schizophrenia: a double-blind cross-over study of of therapeutic effect, side effects and plasma concentrations, Br. J. Psychiatry, 147, 283, 1985. 20. Buvat, J., Lemaire, A., and Buvat-Herbaut, M., Hyperprolactinemia and sexual function in men, Horm. Res., 22, 196, 1985.



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21. Meltzer, H. Y., The mechanism of action of novel antipsychotic drugs, Schizophr. Bull., 17, 263, 1991. 22. Carpenter, W. T., Heinrichs, D. W., and Alphs, L. D., Treatment of negative symptoms, Schizophr. Bull., 11, 440, 1985. 23. Kane, J. M. and Mayerhoff, D., Do negative symptoms respond to pharmacological treatment?, Br. J. Psychiatry, 155 (Suppl. 7), 115, 1989. 24. Moller, H.-J., Muller, H., Borison, R. L., Schooler, N. R., and Chouinard, G., A path-analysis approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients, Eur. Arch. Clin. Neurosci., 245, 45, 1995. 25. Tollefson, G. D. and Sanger, T. M., Negative symptoms: a path analysis approach to double-blind, placebo- and haloperidol-controlled clinical train with olanzapine, Am. J. Psychiatry, 154, 466, 1997. 26. Frith, C. D., Schozophrenia, memory and anticholinergic drugs, J. Abnorm. Psychol., 93, 339, 1984. 27. Casey, D. E., Neuroleptic-induced acute extrapyramidal syndromes and tardive dyskinesia, Psychiatr. Clin. North Am., 16, 589, 1993. 28. Perry, P. J., Alexander, B., and Liskow, B. I., Psychotropic Drugs Handbook, Harvey Whitney Books, Cincinnati, OH, 1988. 29. Seeman, P., Lee, T., Chua-Wong, M., and Wong, K., Antipsychotic drugs doses and neuroleptic/dopamine receptor, Nature, 261, 717, 1976. 30. Samuelian, J. C., Incidence of the deficit form in refractory schizophrenia, Encephale, 22, 19, 1996. 31. Kane, J., Hinigfeld, G., Singer, J., and Meltzer, H., Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine, Arch. Gen. Psychiatry, 45, 789, 1988. 32. Carlsson, A., Antipsychotic drugs, neurotransmitters and schizophrenia, Am. J. Psychiatry, 135, 165, 1978. 33. Seeman, P., Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4, Neuropsychopharmacology, 7, 261, 1992. 34. Waddington, J. L., Therapeutic potential of selective D1 dopamine receptor agonists and antagonists in psychiatry and neurology, Gen. Pharmacol., 19, 55, 1988. 35. Den Boer, J. A., van Megen, H. J. M., Fleischhacker, W. W., Louwerens, J. W., Saap, B. R., Westenberg, H. G. M., Burrows, G. D., and Srivastava, O. N., Differential effects of the D1-D1A receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia, Psychopharmacology, 121, 317, 1995. 36. Karle, J., Clemmens, L., Hansen, L., Andersen, M., Andersen, J., Fensbo, C., Sloth-Nielsen, M., Skrumsager, B. K., Lubin, H., and Gerlach, J., NNC01-0687, a selective dopamine D1 receptor antagonist, in the treatment of schizophrenia, Psychopharmacology, 121, 328, 1995. 37. Bristow, L. J., Collinson, N., Cook, G. P., Curtism, N., Freedman, S. B., Kulagowski, J. J., Leeson, P. D., Patel, S., Ragan, C. I., Ridgill, M., Saywell, K. L., and Tricklebank, M. D., L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic like profile in rodent behavioral tests, J. Pharmacol. Exp. Ther., 283, 1256, 1997. 38. Pilowsky, L. S., Mulligan, R. S., Acton, P. D., Ell, P. J., Costa, D. C., and Kerwin, R. W., Limbic selectivity of clozapine, Lancet, 350, 490, 1997. 39. Bezchlibnyk-Butler, K. Z., Jeffries, J. J., and Martin, B. A., Clinical Handbook of Psychotropic Drugs, Hogrefe and Huber, Seattle, WA, 1994. 40. Meltzer, H. Y., Matsubara, S., and Lee, J. C., Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D2 and serotonin-2 pKi values, J. Pharmacol. Exp. Ther., 251, 238, 1989. 41. Stockmeier, C. A., DiCarlo, J. J., Zang, Y., Thompson, P., and Meltzer, H. Y., Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin-2 and dopamine-2 receptors, J. Pharmacol. Exp. Ther., 266, 1374, 1993.



3

Effects of Antipsychotic Drugs on Dopamine Release and Metabolism in the Central Nervous System J. David Jentsch and Robert H. Roth

CONTENTS I. Introduction .............................................................................................................................31 II. Mesotelencephalic Dopamine Systems ..................................................................................32 III. Biochemical Pharmacology of Dopamine Neurons ...............................................................32 IV. Effects of Typical Antipsychotic Drugs on Mesotelencephalic Dopamine Systems ............33 V. Effects of Atypical Antipsychotic Drugs on Mesotelencephalic Dopamine Systems...........34 VI. Antipsychotic Drug Effects in an Animal Model of Schizophrenia......................................35 VII. An Hypothesis for Atypical Antipsychotic Drug Action .......................................................37 References ........................................................................................................................................37

I. INTRODUCTION The antagonism of central dopamine receptors by antipsychotic drugs has been postulated as a critical determinant of the therapeutic efficacy of this class of drugs. It is clear, however, that drugs with clinically antipsychotic effects influence dopamine transmission at several levels, including transmitter synthesis, release, and metabolism. Indeed, the “dopamine hypothesis” of schizophrenia was originally offered based upon studies of the alterations in brain dopamine metabolism produced by haloperidol and chlorpromazine in mice.1 The dopamine hypothesis later came to be supported by the finding that classical neuroleptic drugs such as haloperidol and chlorpromazine occupy dopamine D2-like receptors in the brain.2,3 After the demonstration of the superior efficacy of dopamine,4 a new generation of “atypical” antipsychotic drugs, including risperidone and olanzapine, has been developed, and the superior therapeutic efficacy of these drugs appears not to be related only to actions at the dopamine D2 receptor.5–7 Moreover, the atypical antipsychotic drugs have been shown to profoundly affect forebrain dopamine metabolism and release after acute or chronic administration.8–18 This chapter provides a review of the effects of typical and atypical antipsychotic drugs on dopamine release and metabolism in the central nervous system. In particular, the distinct effects of different classes of antipsychotic medications on heterogeneous sets of mesotelencephalic dopamine neurons will be emphasized. Moreover, these effects will be integrated with new animal models of schizophrenic pathophysiology that may provide new insights regarding vulnerable circuits that may be targeted by novel antipsychotic drugs.

0-8493-0744-9/00/$0.00+$.50 © 2000 by CRC Press LLC

31


32


II. MESOTELENCEPHALIC DOPAMINE SYSTEMS Studies in rats that utilized histochemical fluorescence techniques demonstrated that the dopaminergic innervation of the forebrain arises largely from the ventral mesencephalon (VM) and that subcortical structures, such as the caudate nucleus, are innervated by lateral regions of the VM, the substantia nigra pars compacta.19 Subsequently, dopaminergic innervation of the frontal cortex was also identified,20 and the cortical dopamine terminals were reported to arise largely from the medial regions of the VM (ventral tegmental area).21 More recently, the mesencephalic origin of dopamine innervation of the cerebral cortex and caudate-putamen in the monkey has been shown to be much more widespread and overlapping, not following the anatomical distinctions present in the rodent.22 Nevertheless, there remains a great deal of support for the notion that dopaminergic neurons that innervate the frontal cortex are functionally different than those that innervate subcortical regions in both rodents and primates.23 The dopaminergic neurons that innervate the frontal cortex are more densely packed within the VM and express lower levels of mRNA for the dopamine transporter and dopamine D2-like receptor.24 These differences may contribute to different neuronal responses of cortically and subcortically projecting dopamine neurons, as reviewed later.

III. BIOCHEMICAL PHARMACOLOGY OF DOPAMINE NEURONS Since the discovery that dopamine acted as a neurotransmitter independent of its role as a precursor for noradrenaline, the biochemical mechanisms that subserve the synthesis, release, and metabolism of dopamine have been elucidated (reviewed in Reference 25). Dopamine is formed from the conversion of l-tyrosine to l-3-(3,4-dihydroxy-O-phenyl)alanine (DOPA) to dopamine by tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase, respectively. TH is the rate-limiting step in the synthesis of dopamine, and this enzyme is allosterically regulated by a number of influences. Increases in impulse flow, cyclicAMP accumulation (that stimulates protein kinase A), and intracellular calcium (Ca++) can lead to phosphorylation of TH, producing increases in its kinetic activity. In contrast, increases in nonvesicular dopamine concentrations can produce end product inhibition of TH that is phosphorylation dependent. Following synthesis, vesicular dopamine is packaged into synaptic vesicles by the vesicular monoamine transporter (VMAT). These vesicles typically remain “docked” at the synaptic cleft until a local increase in the intracellular Ca++ concentration triggers fusion of the vesicle with the cell membrane and release of the amine into the synaptic space. This rapid (“phasic”) increase in synaptic dopamine levels is believed to be the mechanism by which postsynaptic dopamine receptors are sufficiently stimulated to achieve behavioral consequences. After release of the transmitter, extracellular dopamine must be rapidly removed from the synaptic cleft, and there appears to be three principle substrates to subserve this effect. First, dopamine can be metabolized within the synaptic cleft by the enzyme catechol-O-methyl transferase (COMT). The main product of this pathway is 3-methoxytyramine (3-MT), and this metabolite, though it exists in extremely low levels in the brain, has been argued to be the only true metabolite measure of dopamine release in vivo. Second, dopamine itself can stimulate presynaptic dopamine receptors, termed autoreceptors, and stimulation of these receptors results in decreases in dopamine synthesis (by inhibition of TH), dopamine release (by inhibition of Ca++ channels), as well as impulse flow (by activation of K+ channels). Third, dopamine can be transported back into the presynaptic dopamine terminal by a high-affinity dopamine transporter. Dopamine is metabolized by the enzyme monoamine oxidase to 3,4-dihydroxy-O-phenylacetic acid (DOPAC) and further catabolized by COMT to 4-hydroxy-3-methoxy-O-phenylacetic acid (homovanillic acid or HVA). As noted earlier, dopaminergic neurotransmission is modulated by presynaptic autoreceptors. Dopamine neurons express D2-like dopamine receptors at the cell body (somatodendritic) and terminal levels, and stimulation of these receptors by released dopamine provides feedback inhibition of dopamine release, synthesis, and impulse flow.26 Dopamine agonists, such as apomorphine and


Effects of Antipsychotic Drugs on Dopamine Release and Metabolism in the CNS

33

(+)-PPP, reduce dopamine release, synthesis and impulse flow by actions on presynaptic dopamine receptors.27–29 Moreover, dopamine D2 receptor antagonists (such as the typical neuroleptics) increase dopamine release, synthesis, and impulse flow, in part, by blocking autoreceptors.1,27,28,30 Dopamine terminals that innervate the cerebral cortex are somewhat different to those that synapse in the striatum. First, the cortical dopamine terminals that innervate the rostral regions of the cerebral cortex lack synthesis- and impulse-regulating autoreceptors.23,25,31 Second, the dopamine transporter is expressed in considerably lesser amounts in the frontal cortex than in the striatum, and furthermore, it is located primarily extrasynaptically.32 These differences in the biochemical pharmacology of cortical and subcortical dopamine neurons have important functional consequences. First, cortically projecting dopamine neurons show reduced sensitivity to autoreceptor-mediated inhibition of firing and synthesis.26,29,31 This reduction in autoreceptor-mediated control of mesocortical dopamine neurons is expressed in higher basal rates of physiological activity and increased rates of dopamine turnover within its terminal fields relative to nigrostriatal dopamine neurons. Moreover, the exaggerated sensitivity of mesocortical dopamine neurons to mild stressors33,34 may be related to altered autoreceptor-mediated regulation of mesocortical dopamine neurons.

IV. EFFECTS OF TYPICAL ANTIPSYCHOTIC DRUGS ON MESOTELENCEPHALIC DOPAMINE SYSTEMS After acute administration of typical antipsychotic drugs such as haloperidol and chlorpromazine, there is a substantial increase in dopamine release and turnover in the striatal complex, with a corresponding but much smaller increase in dopamine release and metabolism in the frontal cortex.1,8,12,31,35,36 These increases in dopamine release and metabolism are associated with increases in the firing rate of nigrostriatal dopamine neurons and are thus related, in part, to changes in impulse flow.37–39 This preferential activation of subcortical vs. cortical dopamine neurotransmission appears to be mediated by two pharmacological effects of the typical neuroleptics: (1) an interaction with presynaptic dopamine D2-like autoreceptors and (2) blockade of postsynaptic dopamine D2-like receptors within the striatum that participate in feedback control of dopamine neurons within the VM. It is clear that the typical antipsychotic drugs all increase striatal dopamine release, in part, by blocking presynaptic somatodendritic and terminal-level dopamine autoreceptors that are of the D2-like dopamine receptor family (Figure 1). Antagonism of D2-like receptors by typical antipsychotic drugs leads to increased firing rates of dopamine neurons that project to the striatum.30,39,40 While the increase in firing rate can itself lead to augmented transmitter release, the typical antipsychotic drugs also block presynaptic, release-regulating autoreceptors within the striatum.26,29 Moreover, there is an increase in tyrosine hydroxylation produced by typical antipsychotic drugs via their interaction with synthesis-regulating dopamine.27 Providing support for the functionality of these mechanisms, drugs that interact with presynaptic dopamine receptors can modulate dopamine synthesis and release even after cessation of impulse flow.27–29 Within the striatum, dopamine D2-like receptors are also expressed by gamma-aminobutyric acid (GABA)-containing neurons that project back to the VM (the striatonigral pathway). Blockade of these postsynaptic D2 receptors by typical neuroleptic drugs leads to reductions in GABAmediated inhibition within the VM, resulting in increased firing of dopamine neurons that project back to the striatum (Figure 1). In support of the functionality of this substrate, lesions of the striatonigral pathway profoundly attenuate the increase in striatal dopamine turnover produced by chlorpromazine or haloperidol.41 After repeated administrations of typical antipsychotic drugs, dopamine neurons within subregions of the VM develop reduced activity and responsivity to stimulation, a phenomenon known as “depolarization blockade”37,39,42,43 (but, see also Melis et al.44). Several reports have confirmed reduced extracellular dopamine levels in the striatum after chronic haloperidol.43,45 It is noteworthy,


34


Blocks impulse-regulating somatodendritic autoreceptors to increase firing rate

Blocks terminal-level autoreceptors to increase dopamine synthesis and release

Blocks postsynaptic D2 receptor to decrease nigrostriatal feedback inhibition

D2 Receptor Antagonist VM Neuron Dopamine D2 Receptor

Striatal Neuron Nigrostriatal Dopamine

Striatonigral GABA

FIGURE 1 Dopamine D2 receptor antagonists, including haloperidol and chlorpromazine, increase nigrostriatal dopamine function after acute administration. Blockade of impulse-regulating autoreceptors increases the firing rate of nigrostriatal neurons, and blockade of terminal-level presynaptic D2 receptors increases dopamine synthesis and release. Moreover, blockade of postsynaptic D2 receptors within the striatum results in decreased striatonigral feedback inhibition of VM dopamine neurons.

however, that increased dopamine turnover has been reported in the frontal cortex after long-term administration of typical neuroleptic drugs.44 Thus, there are clear indications that striatal dopaminergic function is reduced after chronic exposure to typical antipsychotic drugs, and it has been hypothesized that the ability of chronic administration of typical neuroleptic drugs to produce depolarization blockade of nigrostriatal dopamine neurons may be related to the extrapyramidal side effects of long-term treatment with this class of drugs.37

V. EFFECTS OF ATYPICAL ANTIPSYCHOTIC DRUGS ON MESOTELENCEPHALIC DOPAMINE SYSTEMS A variety of novel drugs have, to date, been characterized as atypical antipsychotic drugs (clozapine, olanzapine, risperidone, amperozide, and ziprasidone), and it has become quite in vogue to attribute their beneficial actions to a preferential increase in dopamine release in the frontal cortex relative to the striatum. Each of these drugs has been shown to profoundly, if not preferentially, increase cortical, vs. subcortical, dopamine release in a pattern unlike that found for typical antipsychotic drugs.8,9,11–14,16–18,47,48 Moreover, this increase in cortical dopamine efflux is directly related to increased impulse flow of mesocortical dopamine neurons.38 The salience of the argument that this effect may be related to the superior efficacy of this class of drugs arises, in part, from the notion that the schizophrenic illness may include a component of frontal cortical dopaminergic hypofunction.49–51 The pharmacological mechanisms by which atypical antipsychotic drugs increase cortical dopamine efflux are currently unknown, but several possibilities predominate. Many of the atypical antipsychotic drugs have relatively less activity at dopamine D2 receptors than do typical antipsychotic drugs,5–7 and for reasons discussed earlier, actions at this receptor cannot explain the preferential increase in cortical dopamine release produced by atypical antipsychotic drugs. Many atypical drugs are potent antagonists (or partial inverse agonists) of the serotonin 5-HT2A receptor. Schmidt and Fadayel52 reported that M100907, selective 5-HT2A receptor antagonist, could increase cortical dopamine efflux; however, this finding has proven difficult to replicate.53,54 Moreover, 5HT2C receptor antagonists can facilitate cortical catecholamine release.55 Many atypical antipsychotic drugs are potent



35

antagonists of the α2-noradrenergic receptor, and recent studies have implicated actions at this receptor in the ability of atypical antipsychotic drugs to increase cortical dopamine efflux.56 Finally, recent studies have highlighted the apparent activation of serotonin 5-HT1A receptors in the ability of clozapine to increase cortical dopamine efflux.57 5-HT1A receptor agonists increase cortical dopamine turnover and release,57–59 and WAY100365, a specific 5-HT1A receptor antagonist, can block clozapine-induced increases in cortical dopamine efflux.57 Nevertheless, any single pharmacological action of the atypical antipsychotic drugs may not completely explain their neurochemical or behavioral actions, and further studies may reveal that multiple receptor interactions are critical for these effects.60 As with typical neuroleptic drugs, chronic administration of atypical antipsychotic drugs appears to affect dopaminergic systems in distinct ways. There have been reports of depolarization blockade in neurons within the ventral tegmental area, but not substantia nigra, after chronic clozapine;42 however, it appears that basal cortical, but not subcortical, dopamine efflux is increased after chronic clozapine.16,17 Thus, after chronic clozapine, there may be a functional disconnection between impulse flow and release, possibly due to an emphasis on terminal-level-dependent regulation of transmitter release. In any regard, it appears that atypical antipsychotic drugs can facilitate cortical dopamine transmission after acute or chronic exposure, and this relative activation of cortical vs. subcortical dopamine release may subserve the superlative therapeutic effects in the absence of severe extrapyramidal side effects.

VI. ANTIPSYCHOTIC DRUG EFFECTS IN AN ANIMAL MODEL OF SCHIZOPHRENIA As noted previously, the ability of antipsychotic drugs to stimulate dopaminergic transmission, particularly within the frontal cortex, has received a great deal of attention, in part, because of the notion that schizophrenic patients may have reduced cortical dopamine transmission.50,52 The concept of reduced cortical dopamine transmission and associated cognitive and behavioral effects has long been central to neurobiological hypotheses of schizophrenia49,51,61 and to animal models of the disorder.50,62 Recently, we have characterized the behavioral and neurochemical consequences of subchronic exposure to the psychotomimetic N-methyl-D-aspartate/glutamate receptor antagonist phencyclidine (PCP) in an attempt to model some of the primary behavioral and neurobiological pathophysiology of schizophrenia. Our results indicate that repeated, intermittent exposure to PCP produces persistent decreases in frontal cortical dopaminergic transmission and associated performance deficits on tasks related to frontal cortical cognitive function.50,63,64 We have also reported that clozapine improves, while haloperidol exacerbates, cognitive deficits in monkeys after long-term PCP treatment.63,65 Clozapine administration impairs cognitive performance in normal monkeys,63,66 in marked contrast to the effects of the drug in PCP-treated monkeys. These data suggest that the response to antipsychotic drugs may be altered in pathological states. Figure 2 shows the results of recent studies designed to examine the neurochemical consequences of clozapine and haloperidol administration in rats after subchronic exposure to PCP, relative to normal subjects. As predicted, subchronic PCP administration results in reduced, basal extracellular dopamine levels in the prefrontal cortex (Figure 2), but not nucleus accumbens. Administration of clozapine (15 mg/kg i.p.) leads to a greater increase in dopamine efflux in the prefrontal cortex in rats repeatedly exposed to PCP relative to saline-treated controls (Figure 2, left), while the response to haloperidol (1 mg/kg i.p.) was unaltered (Figure 2, right). In contrast, the increase in nucleus accumbens dopamine release produced by haloperidol (0.1 mg/kg i.p.), but not clozapine (15 mg/kg i.p.), was potentiated by subchronic PCP treatment (not shown). Thus, it appears that typical and atypical antipsychotic drugs exert distinct effects on cortical versus subcortical dopamine efflux (as discussed earlier), and these effects are differently modulated by subchronic exposure to PCP. Thus, these data further the argument that the neurochemical and behavioral consequences of pharmacological therapies should be examined in pathological as well as normal subjects.


36


2.0

Dopamine (fmol/ul)

1.8

0.8

Saline-Treated PCP-Treated

1.6

Saline-Treated PCP-Treated

0.6

1.4 1.2

0.4

1.0 0.8

0.2

0.6 0.4 0.2 -60 -40 -20

0

-20 -40 -60 -80 -100 -120

0.0

-60 -40 -20

Clozapine (15 mg/kg)

0

-20 -40 -60 -80 -100 -120

Haloperidol (1.0 mg/kg)

Time (Min) FIGURE 2 Repeated, intermittent exposure to PCP (5 mg/kg twice daily for 7 days) results in decreased basal, extracellular dopamine levels in the prefrontal cortex of the awake rat. However, after challenge with clozapine (15 mg/kg i.p.), dopamine levels rise above that in matched control subjects (left). In contrast, the increase in dopamine release produced by haloperidol (1 mg/kg i.p.) is unaltered by prior exposure to PCP (right). *, **: p < 0.05 and 0.01 significantly different from saline-matched controls subjects. N = 6 to 10 for each group.

Dopamine-Deficit State (e.g., Subchronic PCP)

After Clozapine Administration

Prefrontal Cortex Neuron


Dopamine Terminal

Dopamine Terminal

DA DA

DA


DA

DA DA DA DA DA DA

Clozapine


Dopamine D1 Receptor




Dopamine Transporter

Dopamine Transporter

FIGURE 3 In a state of reduced dopamine efflux (left), stimulation of the dopamine D1 receptor is suboptimal for proper prefrontal cortical cognitive functioning. However, after clozapine administration, dopamine release is markedly increased, and clozapine has low or negligible affinity for the dopamine D1 receptor. The result is “restoration” of dopamine transmission at this critical dopamine receptor subtype. This effect may be related to the cognitive effects of clozapine reported previously.63 (Adapted from Sesack, S. R., et al., J. Neurosci., 18, 2697, 1998.)



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VII. AN HYPOTHESIS FOR ATYPICAL ANTIPSYCHOTIC DRUG ACTION As discussed earlier, atypical antipsychotic drugs appear to preferentially increase cortical dopamine efflux. This effect may be related to the superlative effects of these compounds on negative and cognitive symptoms of schizophrenia and their beneficial behavioral effects in animal models of the idiopathic disorder. We have integrated these findings into an hypothesis of atypical antipsychotic drug action that has, at its core, indirect activation of dopamine D1 receptors in the frontal cortex. Clozapine and other atypical antipsychotic drugs have low or negligible affinity for dopamine D1 receptors at therapeutic doses.5–7 Thus, after clozapine administration, synaptic dopamine levels are high with very little occupancy of the dopamine D1 receptor by clozapine, resulting in an indirect activation of this particular dopamine receptor (Figure 3). In contrast, clozapine has moderate to high occupancy of dopamine D2 and D4 receptors.5–7 Moreover, haloperidol only weakly stimulates cortical dopamine efflux (see earlier), and it only does so at doses of the drug that likely occupy both cortical dopamine D1-like and D2-like receptors. As dopamine D1 receptors appear to be particularly important for working memory function,67 it may be that indirect activation of this receptor by clozapine-induced increases in cortical dopamine release is related to its cognitive effects. This hypothesis predicts that activation of cortical dopamine transmission should alleviate cognitive dysfunction in schizophrenia, and results to date support this notion.68–72 However, all the treatments utilized to date have nonspecific actions on multiple neurotransmitter systems. Indeed, at doses of clozapine that produce cognitive improvement in PCP-treated monkeys, the drug has considerable antimuscarinic actions (that likely limit the cognitive improvement produced by the drug).6 Moreover, while d-amphetamine clearly can improve cognitive dysfunction in schizophrenic patients,68,72 the drug also has a potential liability for exacerbating positive symptoms of the disorder and for abuse. Our hypothesis suggests that direct dopamine D1 receptor agonists may be particularly effective in modulating the cognitive dysfunction in schizophrenia. A recent study in PCP-treated rats suggests that, in fact, dopamine D1 agonists are highly effective in alleviating cognitive dysfunction associated with reduced cortical dopamine transmission (our unpublished observations). Further investigations of the cognitive effects of dopamine D1 receptor agonists in normal and schizophrenic subjects are clearly warranted. The concept of directly or indirectly modulating cortical dopamine D1 receptors as a treatment for cognitive dysfunction in schizophrenia must, however, be viewed in the perspective of recent studies that demonstrate that working memory can be impaired by both insufficient and excess stimulation of the dopamine D1 receptor33,73 (see Chapter 7) and that these effects are due to D1 receptor-mediated modulation of the memory-related firing of prefrontal neurons.74 In summary, the available data suggest that atypical antipsychotic drugs may exert their superlative effects on cognitive performance in schizophrenia, in part, by actions on cortical dopamine transmission. It is thus critical to understand the action of future pharmacological therapies in the context of both direct receptor actions of the drug, as well as indirect effects on neurotransmitter release and disposition. Moreover, it is important to consider the potential for different responses to therapeutic intervention in normal and pathological subjects. These principles may be critical for future identification of mechanisms of antipsychotic drug action.

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Neurotransmitter Receptors in Actions of Antipsychotic Medications 48. Westerink, B. H., de Boer, P., de Vries, J. B., Kruse, C. G., and Long, S. K., Antipsychotic drugs induce similar effects on the release of dopamine and noradrenaline in the medial prefrontal cortex of the rat brain, Eur. J. Pharmacol., 361, 27, 1998. 49. Davis, K. L., Kahn, R. S., Ko, G., and Davidson, M., Dopamine in schizophrenia: a review and reconceptualization, Am. J. Psychiatry, 148, 1474, 1991. 50. Jentsch, J. D. and Roth, R. H., The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia, Neuropsychopharmacology, 20, 201, 1999. 51. Knable, M. B. and Weinberger, D. R., Dopamine, the prefrontal cortex and schizophrenia, J. Psychopharmacol., 11, 123, 1997. 52. Schmidt, C. J. and Fadayel, G. M., The selective 5-HT2A receptor antagonist, MDL 100,907, increases dopamine efflux in the prefrontal cortex of the rat, Eur. J. Pharmacol., 273, 273, 1995. 53. Gobert, A. and Millan, M. J., Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats, Neuropharmacology, 38, 315, 1999. 54. Iyer, R. N. and Bradberry, C. W., Serotonin-mediated increase in prefrontal cortex dopamine release: pharmacological characterization, J. Pharmacol. Exp. Ther., 277, 40, 1996. 55. Millan, M. J., Dekeyne, A., and Gobert, A., Serotonin 5-HT2C receptors tonically dopamine (DA) and noradrenaline (NA), but not serotonin (5-HT), release in the frontal cortex in vivo, Neuropharmacology, 37, 953, 1998. 56. Hertel, P., Nomikos, G. G., and Svensson, T. H., the antipsychotic drug risperidone interacts with auto- and heteroreceptors regulating serotonin output in the rat frontal cortex, Neuropharmacology, 38, 1175, 1999. 57. Rollema, H., Lu, Y., Schmidt, A. W., and Zorn, S. H., Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation, Eur. J. Pharmacol., 338, R3, 1997. 58. Rasmusson, A. M., Goldstein, L. E., Deutch, A. Y., Bunney, B. S., and Roth, R. H., 5-HT1a agonist +/-8-OH-DPAT modulates basal and stress-induced changes in medial prefrontal cortical dopamine, Synapse, 18, 218, 1994. 59. Arborelius, L., Nomikos, G. G., Hacksell, U., and Svensson, T. H., R-OH-DPAT preferentially increases dopamine release in rat medial prefrontal cortex, Acta Physiol. Scand., 148, 465, 1993. 60. Hertel, P., Fagerquist, M. V., and Svensson, T. H., Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha2 adrenoceptor blockade, Science, 286, 105, 1999. 61. Weinberger, D. R., Berman, K. F., and Chase, T. N., Mesocortical dopaminergic function and human cognition, Ann. N.Y. Acad. Sci., 537, 330, 1988. 62. Brozoski, T. J., Brown, R. M., Rosvold, H. E., and Goldman, P. S., Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey, Science, 205, 929, 1979. 63. Jentsch, J. D., Redmond, D. E., Elsworth, J. D., Taylor, J. R., Youngren, K. D., and Roth, R. H., Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine, Science, 277, 953, 1997. 64. Jentsch, J. D., Taylor, J. R., Elsworth, J. D., Redmond, D. E., and Roth, R. H., Altered frontal cortical dopaminergic transmission in monkeys after subchronic phencyclidine exposure: involvement in frontostriatal cognitive deficits, Neuroscience, 90, 823, 1999. 65. Jentsch, J. D., Taylor, J. R., Redmond, D. E., Elsworth, J. D., Youngren, K. D., and Roth, R. H., Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys, Psychopharmacology, 142, 78, 1999. 66. Murphy, B. L., Roth, R. H., and Arnsten, A. F. T., Clozapine reverses the spatial working memory deficits induced by FG7142 in monkeys, Neuropsychopharmacology, 16, 433, 1997. 67. Sawaguchi, T. and Goldman-Rakic, P. S., D1 dopamine receptors in prefrontal cortex: involvement in working memory, Science, 251, 947, 1991. 68. Carter, C. S., Barch, D., Cohen, J. D., and Braver, T. S., CNS catecholamines and cognitive dysfunction in schizophrenia, Schizophr. Res., 24, 211, 1997. 69. Daniel, D. G., Berman, K. F., and Weinberger, D. R., The effect of apomorphine on regional cerebral blood flow in schizophrenia, J. Neuropsychiatry, 1, 377, 1989. 70. Daniel, D. G., Weinberger, D. R., Jones, D. W., Zigun, J. R., Coppola, R., Handel, S., Bigelow, L. B., Goldberg, T. E., Berman, K. F., and Kleinman, J. E., The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia, J. Neurosci., 11, 1907, 1991.



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71. Dolan, R. J., Fletcher, P., Frith, C. D., Friston, K. J., Frackowiak, R. S. J., and Grasby, P. M., Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia, Nature, 378, 180, 1995. 72. Goldberg, T. E., Bigelow, L. B., Weinberger, D. R., Daniel, D. G., and Kleinman, J. E., Cognitive and behavioral effects of the coadministration of dextroamphetamine and haloperidol in schizophrenia, Am. J. Psychiatry, 148, 78, 1991. 73. Zahrt, J., Taylor, J. R., Mathew, R. G., and Arnsten, A. F. T., Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance, J. Neurosci., 17, 8528, 1997. 74. Williams, G. V. and Goldman-Rakic, P. S., Modulation of memory fields by dopamine D1 receptors in prefrontal cortex, Nature, 376, 572, 1995.



4

Antipsychotic Drugs, Dopamine D2 Receptors, and Schizophrenia Philip Seeman

CONTENTS I. II.

Introduction .............................................................................................................................43 Do the Clinical Potencies of Antipsychotics Correlate with the Dissociation Constants at D2? ......................................................................................................................................44 III. Do Therapeutic Concentrations of Antipsychotics Occupy the Same Levels of Brain D2 Receptors?...............................................................................................................44 IV. Does Endogenous Dopamine Raise the Antipsychotic Concentration Needed for D2 Block? ...............................................................................................................................49 V. What is the Basis for the Apparently Low D2 Occupancy by Clozapine and Quetiapine?..............................................................................................................................50 VI. What is the Receptor Basis of Antipsychotic Drugs which Elicit Little or No Parkinsonism? ...................................................................................................................52 VII. Does Blockade of Serotonin Receptors Alleviate Parkinsonism? .........................................53 VIII. Clinical Implications ...............................................................................................................54 A. Is D2 Block a Necessary Minimum for Antipsychotic Action? ................................54 B. Do “Therapy-Resistant” Patients Respond to Clozapine or Remoxipride via D2 Block? ...................................................................................................................55 C. Why Do Many Patients Suddenly Relapse When Stopping Clozapine?...................56 D. Why Are Low Doses of Clozapine or Remoxipride Effective in Treating L-DOPA Psychosis? ....................................................................................................56 IX. The Dopamine Hypothesis of Schizophrenia.........................................................................57 Acknowledgments ............................................................................................................................58 References ........................................................................................................................................59

I. INTRODUCTION 1. The clinical potencies of antipsychotic drugs, including clozapine, are directly related to their affinities for the dopamine D2 receptor. The therapeutic concentrations of antipsychotic drugs in the plasma water or the spinal fluid exactly match the antipsychotic dissociation constants at the dopamine D2 receptor. 2. The fraction of brain D2 receptors occupied by any antipsychotic drug is consistently 75%, as calculated from the therapeutic concentration and the antipsychotic dissociation constant. For different antipsychotic drugs, D3 and D4 receptors are not consistently occupied, ranging from 0 to 85% for D3 and 0 to 95% for D4. 0-8493-0744-9/00/$0.00+$.50 © 2000 by CRC Press LLC

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44


3. Human brain imaging reveals that therapeutic doses of all antipsychotic drugs occupy 60 to 80% of D2 receptors, with the exception of clozapine and quetiapine which occupy low levels of 4 to 50%. The observed fraction of D2 receptors occupied by clozapine or quetiapine, however, depends on the radioligand used, with high occupancy seen when using [11C]raclopride and low occupancy seen with [11C]methylspiperone (which is tightly bound to D2). This dependence on the radioligand occurs because clozapine and quetiapine are loosely bound to D2. Thus, clozapine and quetiapine occupy high levels of D2 in the absence of any radioligand. 4. The “loose” binding of clozapine and quetiapine to D2 permits endogenous dopamine to displace these antipsychotic drugs at least 100 times more quickly than haloperidol or other antipsychotic drugs. In addition, the small dose of radioactive raclopride injected (in brain imaging) can displace some of the D2-bound clozapine. Thus, the observed low level of D2 occupancy by clozapine in patients may arise from a combination of the previous three factors: the ligand dependency, the endogenous dopamine, and the displacement by the imaging dose. 5. Parkinsonism and extrapyramidal effects occur with antipsychotics which have a high affinity for D2 and which are, therefore, “tightly” bound to D2. Clozapine and quetiapine have a low affinity for D2 and, being readily displaced by endogenous dopamine, do not give rise to extrapyramidal effects. Because the loosely bound antipsychotics dissociate from D2 more rapidly, clinical relapse may occur earlier than that found with the tightly bound traditional antipsychotics. 6. The dopamine hypothesis of schizophrenia is supported by the fact that D2 is the main target of antipsychotic action, that monomers of D2 appear elevated in schizophrenia, and the synaptic levels of dopamine in schizophrenia are at least twofold higher than in control subjects.

II. DO THE CLINICAL POTENCIES OF ANTIPSYCHOTICS CORRELATE WITH THE DISSOCIATION CONSTANTS AT D2? The clinical potencies of antipsychotic drugs correlate with their ability to block dopamine D2 receptors.1–4 This is shown in Figure 1 (left), where the average doses for controlling acute schizophrenia are graphed vs. the dissociation constants at the dopamine D2 receptor for antipsychotic drugs. The dissociation constants in Figure 1 were obtained using [3H]raclopride and human cloned dopamine D2 receptors,5–9 as listed in Table 1. Of the antipsychotic drugs shown in Figure 1 (left), only chlorpromazine and thioridazine deviate significantly from the overall correlation. The deviations for these two drugs, however, disappear when the spinal fluid concentrations (or the concentrations in the plasma water) of the various antipsychotic drugs are used5–9 (shown in Figure 1 right).

III. DO THERAPEUTIC CONCENTRATIONS OF ANTIPSYCHOTICS OCCUPY THE SAME LEVELS OF BRAIN D2 RECEPTORS? In order to determine whether dopamine D2 receptors are consistently occupied to the same extent for every antipsychotic drug, it is necessary either to calculate or to measure the proportion of D2 receptors occupied in the human brain. For example, it is possible to calculate the proportion, f, of brain dopamine D2 receptors occupied by an antipsychotic drug given the concentration, C, of the antipsychotic drug in the plasma water or the spinal fluid and the inhibition (or dissociation) constant, K, of the antipsychotic drug using the equation f = C/(C + K)


Antipsychotic Drugs, Dopamine D2 Receptors, and Schizophrenia

45

FIGURE 1 The clinical antipsychotic doses correlate with the antipsychotic dissociation constants, using the K values with [3H]raclopride (from Table 1). The deviations for chlorpromazine and thioridazine disappear when the spinal fluid concentrations of the antipsychotic drugs are considered (right side). The clinical dose for cis-flupentixol was taken as half the standard racemate dose used clinically.

The value for the dissociation constant, however, depends on the radioligand used, as shown in Table 1.6–8,10 This is because a higher concentration of antipsychotic drug must be used to compete with a ligand of high fat solubility, such as [3H]spiperone or [3H]nemonapride, compared to a ligand of low fat solutibility, such as [3H]raclopride. Because the lowest K values are closer to the true K values, the lowest K values* in Table 1 were used to calculate the antipsychotic drug occupancies of the D2, D3, and D4 receptors, the results of which are shown in Figure 2. Figure 2 indicates that dopamine D2 receptors are consistently occupied at 75% by therapeutic maintenance doses for all the antipsychotic drugs. This finding does not hold for either the D3 or D4 dopamine receptors. The therapeutic concentrations of antipsychotic drugs used to derive the receptor occupancies in Figure 2 have been summarized previously,6–10 with the exception of clozapine for which new data have appeared.11 The average concentration of clozapine in plasma found in patients taking clinically effective doses of clozapine is 292 ng/ml or 894 nM (see references in Reference 9). The concentration of clozapine in the spinal fluid is 20% of that in the plasma11 or 179 nM. In addition, the average ratio between norclozapine and clozapine is 0.59 (see references in Reference 9), resulting in a norclozapine concentration of 106 nM in the spinal fluid. However, because norclozapine has a dissociation constant of 100 nM at D2, compared to a value of 44 nM for clozapine (Table 1), the spinal fluid concentration of 106 nM norclozapine is equivalent to a “clozapine-like D2-blocking concentration” of 106 × 44 nM/100 nM or 47 nM. Hence, the average D2-blocking concentration of clozapine (including norclozapine in clozapine equivalents) in the spinal fluid is 179 + 47 nM or 226 nM.

* The lowest K values are the ligand-independent ones. These values exactly match the K values which were directly obtained using the [3H]antipsychotic drug.6–9

Antipsychotic drugs Amisulpride Amoxapine “Apomorphine, D2 low” Benperidol Bromocriptine Butaclamol-(+) Chlorpromazine [3H]Chlorpromazine Chlorprothixene Clebopride Clozapine [3H]Clozapine “Dopamine, D2 high” “Dopamine, D2 low” Droperidol Epidepride Flupentixol-cis Fluperlapine Fluphenazine Glaxo 1192U90 Haloperidol [3H]Haloperidol Iloperidone (HP873) Isoclozapine Isoloxapine Loxapine

[3H]ligand used:

Human clone:

2.1 30 70 0.06 2.8 0.14 1.3 — 0.7 82 — 2.8 2500 0.54 ~0.03 0.35 0.53 13 0.7 — 5.4 15 20 9.8

1.4 16 35 0.027 2 0.05 0.66 0.72 3.3

44 51 1.5 1000 0.25 ~0.01 0.14

0.32 ~4 0.35 0.4 3.5 6 6 5.2

1.9 45 9.5 — 20 130 310 45

385 — 50 23 µM 4.5 0.28 2.5

8 140 280 0.8 9 2.3 13 — 5

0.17 8.8 — 20 19 21

6.2 14 11.5 18

0.7

0.3 0.11

190 —

1.3 —

150 —

0.84

28

15 — 33 30

0.2

3

270 —

1.8 —

33

23 — 54 52

0.3

7

340 —

3 —

1.6 21 50 0.8 0.84 0.84 2.5 5.8 4.5 7.8

11 80 30 5 2 — 9 25 11 9

2

0.84

60 9.5 — 1

4.5 1.2 1.15 0.64

22 —

0.6

0.066

1.6 1.6

8

2

22 155 23 11 2.9 — 14 60 17 10

2.8

40 —

178 23 — 3.4

1.6

18

46 — 0.16 1.8 3.7 1.9

3.2

3.5 3.5

1.8 —

0.5

60 — 0.2 2.2 4 2

3.8

4 —

2 —

0.6

103 — 0.3 3.1 4.9 2.5

5.8

5.2 —

2.8 —

1.2

46

1.2 ~12 2.9 — 11 60 96 23

4.6 60 140 0.4 5 0.8 4.8 — 2.2 1.5 180 — 10 8000 2.1 ~0.07 0.8

D2 D2 D2 D2 D3 D3 D3 D3 D4 D4 D4 S2A S2A S2A nM nM nM nM nM nM nM nM nM nM nM nM nM nM None Raclopride Spiperone Nemonapride None Raclopride Spiperone Nemonapride None Spiperone Nemonapride None Ketanserin Spiperone

K values (Dissociation constants)

TABLE 1 Dissociation Constants for Antipsychotic Drugs at the Human Cloned Dopamine D2, D3, D4, and Serotonin-2A Receptors



“MDL 100,907” Melperone metabolite FG5155 [3H]Methylspiperone Molindone Moperone [3H]Nemonapride Norclozapine Olanzapine [3H]Olanzapine Perlapine Perospirone Perphenazine Pimozide Prochlorperazine Raclopride [3H]Raclopride Remoxipride Risperidone Ritanserin Seroquel Sertindole [3H]Sertindole SM 13496 [3H]Spiperone Sulpiride-S Thioridazine

[3H]ligand used:

Human clone:

9000 50 70 0.094 6 1.8 0.068 100 3 2.7 60 1.6 0.16 0.06 1.2 0.64 1.9 30 0.3 10 78 1.6 1.9 1.5 0.065 5 0.4 300 980 — 15 3.7 — 300 21 — 450 0.48 0.33 4 7.2 — 800 4 27 680 6.5 — 2 — 10 4

105 160 — 9.6 2.5 — 160 6.4 — 135 0.26 0.13 1.7 1.6 — 80 1 16 155 1.2 — 1.5 — 8 1.1

0.92 0.85 5.3 22 — 900 19 54 1400 8.2 — 3 — 20 18.5

520 2300 — 31 5.4 — 650 45 — 1300 — 14 — 150

0.097 7.8

0.23

2.9 — 960 3.5 240 3 — — 10 1.9

0.13

2 1.6 640 2.5 160 2.5 — 0.32 6.4 1.5

100

— 35

20

160

— 15 2.5

520 2 —

4.8 — 1600 3.6

0.58

23 — 180

—

— 38

— 30 3.5

780 3 —

7.9 — 2500 5.2

1.1

40 — 290

—

— 76

32 70 2400 — 2400 4.4 120 2000 9 — 90 — 1000 10.5

5.4 620 — 2800 0.25 30 3000 0.9 0.84 0.3 0.089 200 1.5

— 3500 7 — 120 14 — 190

700

2400 2 0.165 20 1.6 1.6 30 0.09 17

410

140 4100 — 2200 18 210 1600 16 — 200 — 2000 26

48

— 4300 14 — 260 30 — 430

800

4400 — 6600 0.2 0.54 135 0.28 — 8.4 — 1.3

1.1

3.4 — 22

—

— 5200

0.23 180

4000 — 5200 0.21 0.54 110 0.3 0.28 8.2 0.57

3 1.6 13 ~1.3*

—

— 5800

0.14 150


2.4

6500 — 10 µM 0.19 0.6 200 0.26 — 8.8 —

4.9 — 85

—

— 5000

0.57 290



TABLE 1 (continued) Dissociation Constants for Antipsychotic Drugs at the Human Cloned Dopamine D2, D3, D4, and Serotonin-2A Receptors


47


0.15 1.6 2

0.12 0.96

1.2

6

0.17 3.8 11

0.26 6.8 1.1

0.45 1.5

0.7 2.2

0.95 3.5

1.6

6.4 44 0.35 0.8

100 39 0.9 8

250 40 1.3 16

3.3

7.4

3

8.8

2.4

12


48

Note: Blank boxes indicate “not done”; dash indicates “not possible”; “None” indicates the ligand-independent K value obtained by extrapolating all the K values (see text). The binding of three different radioligands, [3H]raclopride, [3H]spiperone, and [3H]nemonapride, was inhibited by each antipsychotic drug. These three inhibition constants were then related to the membrane/buffer partition coefficients of the radioligands. By extrapolating to a partition coefficient of “zero or unity,” one obtained the true dissociation constant which was independent of the radioligands; this extrapolated K value is in the column identified by “none.” This extrapolated dissociation constant agreed with that determined directly using the radioactive form of the same antipsychotic drug.

Thiothixene-cis Trifluperazine Trifluperidol Ziprasidone

[3H]ligand used:

Human clone:

TABLE 1 (continued) Dissociation Constants for Antipsychotic Drugs at the Human Cloned Dopamine D2, D3, D4, and Serotonin-2A Receptors





49

% of Receptors Calculated to be Occupied at Clinical Antipsychotic Levels in CSF

90

100

D2

90

100

D3

90 80

70

70

60

60

60

50

50

50

40

40

40

30

30

30

20

20

20

10

10

10

0

0

0

CPZ Cloz. Halo. Molin. Olan. Raclo. Remox. Sulp.

80

70

CPZ Cloz. Halo. Molin. Olan. Raclo. Remox. Sulp. Thior. Flupen.

80

D4

CPZ Cloz. Halo. Molin. Olan. Raclo. Remox. Sulp. Thior. Flupen.

100

FIGURE 2 Antipsychotic drugs consistently occupy ~75% of dopamine D2 receptors, as calculated from the therapeutic concentration of the drug in plasma water (Figure 1) and using the ligand-independent K values at D2 (Table 1). Similar calculations for the dopamine D3 and dopamine D4 receptors did not reveal any constant percent occupancy for the antipsychotic drugs. CPZ, chlorpromazine; Cloz., clozapine; Halo., haloperidol; Molin., molindone; Olan., olanzapine; Raclo., raclopride; Remox., remoxipride; Sulp., S-Sulpiride; Thior., thioridazine; Flupen., cis-flupentixol; and Per., perphenazine.

The D2 receptors are 60 to 80% occupied by therapeutic doses of antipsychotics when directly measured by positron emission tomography (PET) or SPET (single photon emission tomography)12–20 in the human striatum (i.e., the caudate nucleus and/or the putamen) (Figure 3). The only antipsychotics with low D2 occupancy are clozapine and quetiapine, as discussed later.

IV. DOES ENDOGENOUS DOPAMINE RAISE THE ANTIPSYCHOTIC CONCENTRATION NEEDED FOR D2 BLOCK? Because the antipsychotic drug must compete with dopamine within the synaptic space, it should also be noted that the antipsychotic therapeutic concentration to block dopamine receptors in the presence of dopamine will be higher than that in the absence of dopamine, in accordance with the equation C50% = K × [1 + D/D2High] where D is the effective dopamine concentration in the synapse and where D2High is the dissociation constant of dopamine at the high-affinity state of the dopamine D2 receptor. The basal level of synaptic dopamine in the rat nucleus accumbens has been estimated to be 4 nM.21 At a firing frequency of five impulses per second, the synaptic dopamine in rat striatum has been estimated to be about 200 nM in the first few milliseconds and then rapidly falling to 1 to 4 nM within 200 msec.21 In addition, the dopamine D2 receptor can exist in either a high- or a low-affinity state for dopamine, wherein the high-affinity state, D2High, is the physiologically functional state.22 The


50


dissociation constant of dopamine at D2High has an average value of 7 to 7.5 nM when using [3H]spiperone. However, in the same way as the dissociation constant of an antipsychotic drug depends on the radioligand used (see earlier), the dissociation constant of dopamine at the D2 receptor also depends on the radioligand used. For example, the dissociation constants of antipsychotic drugs, as well as dopamine agonists, are consistently lower by a factor of 3 when using [3H]raclopride, compared to the values obtained when using [3H]spiperone. In fact, the radioligandindependent dissociation constant of dopamine at the high-affinity state of the D2 receptor is indeed one fifth that of 7.5 nM, or 1.5 nM. Hence, although the synaptic average concentration of dopamine, D, is not known, it appears that D is of the same order of magnitude as the dopamine K for D2High. Hence, with this single assumption that D ~ D2High, the previous equation of C50% = K × [1 + D/D2High] reduces to C50% ~ 2 × K In addition, the fraction, f, of D2 receptors occupied by an antipsychotic at a concentration C is C/(C + K). Using this formula, it may be shown that the concentration of antipsychotic drug needed to occupy 75% of the D2 receptors (i.e., C75%) is about three times higher than that required to occupy 50% of the receptors, C50%. In other words, C75% = 3 × C50%, or C75% = 6 × K Finally, using the radioligand-independent K values in Table 1, the antipsychotic C75% concentrations have been calculated according to the latter equation and found to be virtually identical to the therapeutic concentrations of the antipsychotic drugs in the cerebrospinal fluid or the plasma water (i.e., corrected for drug binding to the plasma proteins). These calculations, therefore, further confirm the D2 receptor as the main antipsychotic target and that D2 receptors are 75% occupied at therapeutic maintenance concentrations of antipsychotic drugs.

V. WHAT IS THE BASIS FOR THE APPARENTLY LOW D2 OCCUPANCY BY CLOZAPINE AND QUETIAPINE? As noted earlier, antipsychotic drugs, when given at clinically effective doses, generally occupy 60 to 80% of brain dopamine D2 receptors in patients, as measured by PET or SPET in the human striatum (Figure 3). Clozapine, however, has consistently been an apparent exception. For example, in patients taking therapeutically effective antipsychotic doses of clozapine, this drug only occupies between 0 and ~50% of brain dopamine D2 receptors, as measured by a variety of radioligands using either positron tomography12,13,16–19,40–44 or single photon tomography.32–37,45 Although the apparently low occupancy of D2 by clozapine might suggest that D2 is not the major antipsychotic target for clozapine,13,46 there are several factors, however, which may account for the apparently low occupancy of D2 by clozapine and quetiapine. First, the fraction of receptors occupied by a drug depends on the radioligand used to measure that receptor6–8,10,47 (Table 1). In fact, clozapine occupies ~50% of D2 receptors when using [11C]raclopride, but only 20 to 45% when using the more fat-soluble [123I]iodobenzamide (summarized in Figure 3). Quetiapine, moreover, occupies ~40 to 50% when using [11C]raclopride, but only ~4% when using the more fat-soluble [11C]methylspiperone (Figure 3).


% Occupancy of D2

Quetiapine

Clozapine

51

Remoxipride

Amoxapine

Sulpiride

Loxapine

Sertindole Olanzapine

Trifluoperazine Raclopride Ziprasidone

100

Haloperidol Chlorpromazine Pimozide

Flupentixol


PET SPECT

80 60 40

Dopamine K

20 0

No Extrapyramidal Signs

Extrapyramidal Signs

0.1

1 10 100 Antipsychotic Binding Constant, K (nM)

FIGURE 3 A summary of the reported ranges of dopamine D2 receptor occupancy by maintenance doses of antipsychotic drugs in schizophrenia patients, as measured by positron emission tomography or SPECT (single photon emission computed tomography). All antipsychotic drugs occupy 60 to 80% of the D2 population, with the exception of clozapine and quetiapine (Seroquel®) which occupy 20 to 50% when using [11C]raclopride, but lower when using [11C]methylspiperone. When it is considered that the injected [11C]raclopride or [123I]iodobenzamide, as well as low levels of endogenous dopamine, can displace some of the D2-bound clozapine or quetiapine, then both clozapine and quetiapine may occupy higher levels of the dopamine D2 receptors in humans under therapeutic conditions, as indicated by the arrow. The dissociation constant (K) for dopamine at the high-affinity state of the dopamine D2 receptor is 1.6 nM. Antipsychotic drugs with a K higher than 1.6 nM usually elicit fewer extrapyramidal signs, especially if a lower-than-average dose is used. The horizontal axis gives the ligand-independent dissociation constants of the antipsychotic drugs (Table 1). The references for the drugs are flupentixol,23 haloperidol,14,16,20,23–25 chlorpromazine,23 pimozide,23 trifluoperazine,23 raclopride,26 ziprasidone,27,28 sertindole,29,30 olanzapine,18,19 loxapine,17,31 sulpiride,23 remoxipride,23,32,33 clozapine,15,23–25,29,32–38 and quetiapine24,25,39 (Seroquel).

Second, we have found that low concentrations of raclopride and iodobenzamide can displace an appreciable amount of [3H]clozapine and [3H]quetiapine which are prebound to D2 receptors (see Figure 4), but do not displace the more tightly bound antipsychotic [3H] ligands such as [3 H]haloperidol, [3 H]chlorpromazine, [3 H]remoxipride, [3 H]olanzapine, [3 H]raclopride, or [3H]sertindole.48 This finding suggests that clozapine is loosely bound to the D2 receptor and that the injected radioactive ligand at its peak concentration may displace some of the D2-bound clozapine, resulting in an apparently low occupancy of D2 receptors. Therefore, under clinical brain imaging conditions with [11C]raclopride, the D2 occupancies by clozapine and quetiapine may be higher than currently estimated. The same applies for brain imaging with [123I]iodobenzamide. Third, an endogenous concentration of 100 nM of dopamine21 displaces D2-bound [3H]clozapine 3 or [ H]quetiapine at least 100 times faster than D2-bound [3H]haloperidol or [3H]chlorpromazine, (Figure 5). Thus, the rapid release of clozapine and quetiapine from dopamine D2 receptors by endogenous dopamine may contribute to low D2 receptor occupancy.


52


% of D2 occupied by [3H]Clozapine

80

C om pe tit io n

60 Peak raclopride concentration in plasma water of patients during PET

40 20

Displacement

80 0.02

0.05

0.1 0.2 0.5 1 2 Final concentration of Raclopride, nM

5

10

FIGURE 4 Raclopride concentrations between 0.07 and 0.15 nM displaced D2-bound [3H]clozapine (310 nM) within 10 min. Much higher concentrations of raclopride were needed to compete with [3H]clozapine when using the conventional competition method (where the tissue was added to tubes containing the ligand and the competing drug). The dashed vertical lines indicate the raclopride concentration range occuring in the plasma water of patients undergoing positron emission tomography (PET).

Rapid replacement of [3H]clozapine and [3H]quetiapine by dopamine at D2 [3H]Haloperidol

% of Binding at t = 0

100 Dopamine added (100 nM) [3H]Clozapine

50 [3H]Quetiapine

0 0

1

10

100 Sec

1,000

10,000

FIGURE 5 The addition of 100 nM of dopamine (which is the average physiological concentration of dopamine in the synaptic space) displaced [3H]clozapine (from human cloned dopamine D2 receptors) much more quickly than [3H]haloperidol.

VI. WHAT IS THE RECEPTOR BASIS OF ANTIPSYCHOTIC DRUGS WHICH ELICIT LITTLE OR NO PARKINSONISM? The D2-blocking action of antipsychotic drugs commonly elicits Parkinsonism and other extrapyramidal signs. Clozapine and quetiapine, however, cause little or no extrapyramidal signs. Other antipsychotics may also cause few extrapyramidal signs if the dose is kept low. A dominant factor in determining whether a particular antipsychotic drug elicits Parkinsonism is whether it binds more tightly or more loosely than dopamine at the high-affinity state of the dopamine D2 receptor. This is illustrated in Figure 6.



53

FIGURE 6 Antipsychotic drugs which bind more tightly than dopamine at the dopamine D2 receptor elicit Parkinsonism, while those which bind more loosely than dopamine elicit little or no Parkinsonism or other extrapyramidal clinical signs in patients. The radioligand-independent value for the dissociation constant of dopamine at the high-affinity state of the dopamine D2 receptor is 1.5 nM. Data from Table 1.

Thus, for those antipsychotic drugs which tend to elicit little or no extrapyramidal signs, it appears that the high endogenous dopamine in the human striatum outcompetes the loosely bound antipsychotic at the D2 receptor. The endogenous dopamine in the limbic brain regions (e.g., frontal cortex, cingulate gyrus), however, is of the order of one tenth that in the striatum, and so the lower synaptic endogenous dopamine in the limbic regions would not be as effective in outcompeting the administered antipsychotic drug. Thus, the D2 occupancy in the human limbic regions would be expected to be somewhat higher than that in the human striatum. That is, the higher output of endogenous dopamine in the striatum readily displaces more D2-bound clozapine in the striatum, compared to the lower output of dopamine in the cerebral cortex. In fact, it has been found that clozapine occupies more D2 receptors in the cerebral cortex of patients than in the striatum.49 The important element in avoiding extrapyramidal signs appears to be the rapid displacement of clozapine by dopamine, as noted in Figure 5. While dopamine can also displace other antipsychotic drugs50 such as raclopride51–53 or [3H]chlorpromazine (Figure 5), such action is not sufficiently rapid because these drugs are more tightly bound to D2, compared to clozapine. The separation of antipsychotic drugs into loose and tight binding to D2, relative to that for dopamine, is consistent with the findings by Kalkman et al.54 These authors were able to reverse catalepsy induced by olanzapine and loxapine (both more loosely bound than dopamine), but were not able to reverse that by haloperidol (Kalkman, H.O., Tricklebank, MD, 1997, personal communication).

VII. DOES BLOCKADE OF SEROTONIN RECEPTORS ALLEVIATE PARKINSONISM? Although it has often been suggested that the blockade of serotonin-2A receptors may alleviate the Parkinsonism caused by D2 blockade, most data do not support this principle.


54


BLOCK OF D2 AND S2 ENHANCES CATALEPSY

D2

40

blo ck

60

bloc k

80

S2

% Catalepsy

100

20 0 0.1 1 10 D2 block by raclopride, mg/kg FIGURE 7 The selective block of serotonin-2A receptors by MDL100,907 enhances the cataleptic potency of raclopride in rats (Wadenburg, M.-L.G., Hicks, P.B., and Young, K.D., 1997, personal communication, with permission).

1. Selective serotonin-2A receptor blockade markedly enhances the catalepsy of submaximal doses of raclopride (Figure 7). 2. There is no correlation between the cataleptic doses of neuroleptics and the ratio of the antipsychotic dissociation constants at D2 and serotonin-2A receptors, as shown in Figure 8, using the values in Table 1. 3. A high degree of serotonin-2A receptor occupancy (95%) by risperidone (6 mg/day) did not prevent extrapyramidal signs in six out of seven patients.55,56 4. Ritanserin (2 mg/kg s.c.) had no effect on raclopride-induced catalepsy, using either maximal (4 mg/kg s.c.) or submaximal (0.2 mg/kg s.c.) doses of raclopride.57 However, in apparent conflict with this latter negative result, Lucas et al.58 found that 1.25 mg/kg ritanserin i.p., given 15 min prior to haloperidol (1 mg/kg s.c.), reduced haloperidol-induced catalepsy. It is also clear that serotonin-2A receptors have little, if any, role in the antipsychotic process because the block of serotonin-2A receptors “is not a prerequisite for the antipsychotic effect.”55,56,59 In fact, full block of serotonin-2A receptors occurs at subtherapeutic doses of risperidone, olanzapine and clozapine, indicating that the serotonin-2A block has little or no antipsychotic action (Figure 9). In addition, because clozapine is 20- to 50-fold more potent in blocking muscarinic acetylcholine receptors than blocking dopamine D2 receptors, clozapine is an extremely potent anticholinergic drug. Clozapine blocks muscarinic receptors between 1.5 and 36 nM, possibly contributing to the absence of Parkinsonism by clozapine. Isoclozapine, however, is equally anticholinergic, yet elicits catalepsy in low doses in contrast to clozapine.

VIII. CLINICAL IMPLICATIONS A. IS D2 BLOCK

A

NECESSARY MINIMUM

FOR

ANTIPSYCHOTIC ACTION?

The consistent finding that all antipsychotic drugs, including clozapine, occupy high levels of D2 receptors suggests that the blockade of D2 is an essential minimal requirement for clinical antipsychotic action in those patients who respond to neuroleptics. Because many schizophrenia


Dose for Catalepsy, mg/kg (Corbett)


55

1192

100

Clozapine

Perlapine Melperone Iloperidone Olanzapine

10 Sertindole

Thioridazine

Risperidone Isoclozapine

CPZ Molindone

1

Haloperidol Trifluperazine Raclopride Loxapine

Fluphenazine

0.1

0.01 0.1 1 10 Selectivity for 5-HT2A (compared to D2)

FIGURE 8 There is no correlation between the antipsychotic doses for rat catalepsy7,8 and the ratio of the K values at the D2 and S2 receptors (data from Table 1). S2

S2

60 Average optimal dose

40 20 0

8 10 2 4 6 Risperidone dose (mg/day)

12

% of receptors occupied

D2

80

0

100

100



100

D2 80 60 Average optimal dose

40 20 0

0

10 20 30 40 50 Olanzapine dose (mg/day)

60

S2

80 D2

60 40 20

Average optimal dose

0 0 100 200 300 400 500 600 700 800 900

Clozapine dose (mg/day)

FIGURE 9 Full block of serotonin-2A receptors occurs at subtherapeutic doses of antipsychotic drugs. (Adapted from Kapur, S., et al., Am. J. Psychiatry, 156, 286, 1999. With permission.)

patients may not clinically improve despite high occupancy (>75%) of their D2 receptors, this may indicate that there are several types of schizophrenia.

B. DO “THERAPY-RESISTANT” PATIENTS RESPOND TO CLOZAPINE OR REMOXIPRIDE VIA D2 BLOCK? Although clozapine is selective for the dopamine D4 receptor (Table 1), the clinical antipsychotic action of clozapine appears to reside in its D2-blocking ability with its loose blockade of D2 at 44 nM, based primarily on the findings in Figures 1 and 2 that clozapine fits the rule of high levels of D2 block for clinical antipsychotic action. It has been stated that D2 block is inadequate to explain the antipsychotic action of clozapine because clozapine has a low occupancy of D2 and also because clozapine is effective in 30% of


56


TABLE 2 Features of Antipsychotics Tightly and Loosely Bound to D2

EPS Dose Offset Relapse Tardive

Tight

Loose

High Low (1–5 mg) Weeks, Months Low risk High risk

Low High (10–500 mg) Days Higher risk Lower risk

patients who are resistant to haloperidol and similar traditional D2-blocking drugs.60 Such treatmentresistant patients, however, also respond (often dramatically) to remoxipride,61–63 which is extremely selective for D2 (Table 1). In fact, remoxipride clinically improves at least 30% of treatmentresistant schizophenia patients.61–63 This experience with remoxipride indicates that treatmentresistant patients may still improve via D2 block when using a low potency drug such as clozapine (K = 44 to 51 nM at D2) or remoxipride (K = 30 nM at D2).

C. WHY DO MANY PATIENTS SUDDENLY RELAPSE WHEN STOPPING CLOZAPINE? Patients taking clozapine often relapse within days of stopping clozapine.64,65 Because clozapine is loosely bound to the dopamine D2 receptor (K = 44 to 51 nM), clozapine is readily displaced by any sudden pulse of endogenous dopamine arising from emotional or physical activity. In fact, both R. Conley (cited in Reference 64) and Pickar et al.66 observed that the D2 occupancy by clozapine readily decreased upon clozapine withdrawal, in contrast to the 2 weeks or more of residual occupancy of D2 by traditional neuroleptics.67 Any sudden surge of impulse-triggered release of endogenous dopamine will quickly displace any residual clozapine and may lead to a sudden clinical relapse. Table 2 summarizes this point that the relatively more rapid offset of drugs such as clozapine could result in a higher risk of earlier relapse when compared to the more traditional haloperidol and chlorpromazine drugs which are more tightly bound to the D2 receptor.

D. WHY ARE LOW DOSES OF CLOZAPINE TREATING L-DOPA PSYCHOSIS?

OR

REMOXIPRIDE EFFECTIVE

IN

The psychosis caused by L-DOPA or bromocriptine in Parkinson’s Disease can be readily treated by low doses of either clozapine68–72 or remoxipride.73 The average dose for clozapine is 55 mg/day, while that for remoxipride is 150 mg/day, much lower than that used in schizophrenia for either drug (Figure 1). These lower doses follow directly from the well-known fact that 90 to 99% of brain dopamine has been depleted in Parkinson’s disease. Hence, there is virtually no endogenous dopamine to compete against clozapine or remoxipride. The low dose of clozapine corresponds to a low spinal fluid concentration of clozapine and norclozapine, estimated to be of the order of 60 nM (given that the unbound clozapine is 20% of the total plasma clozapine11). Under these conditions, the fraction of D2 receptors occupied would be about 60%.* This D2 occupancy by clozapine may be even lower, possibly 20%, if the estimated free concentration of clozapine in plasma (~10 nM) is used from four Parkinson patients who developed psychosis.74 Because the D2 occupancy by * Where C/(C + K) is 60 nM/(60 + 44 nM) = 60% of D2.



Control

2 2

S

2

Psychosis

R R

R

57

S

2

R

S

2

R

S

2

R

D

FIGURE 10 Possible resolution of the findings that [11C]methylspiperone, but not [11C]raclopride reveals elevated densities of D2 in schizophrenia. [3H]Spiperone (S) preferentially labels D2 monomers, while [3H]nemonapride labels D2 monomers and dimers. If radioraclopride (R) behaves as [3H]nemonapride, then one may not expect a change in the density of the total population of D2 receptors in schizophrenia, but the density of D2 monomers may rise as a result of high release of dopamine.84

clozapine in Parkinson patients has not been directly examined, however, the D2 occupancy by clozapine in such patients remains uncertain. The treatment of L-DOPA psychosis by 150 mg/day of remoxipride would be expected to be associated with about 73%* occupancy of dopamine D2 receptors, in accord with the general rule of 60 to 80% of D2 block for antipsychotic action.

IX. THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA The dopamine hypothesis of schizophrenia is supported by several observations. First, the D2 receptor is the common target of antipsychotic drugs (Figures 1 and 2). Second, additional support for the dopamine hypothesis comes from the finding that the density of dopamine D2 receptors is elevated in postmortem schizophrenia tissues75 as well as in schizophrenia patients, as measured by [11C]methylspiperone,76,77 but not by [11C]raclopride.78 The discrepant findings with [11C]methylspiperone and [11C]raclopride suggest that the two radioligands may bind differently to the D2 receptor. A partial explanation of these apparently conflicting data is provided by the observation that D2 receptors can exist as either monomers or dimers in human and rat brain tissues79 with radiospiperone labeling the monomer, while radionemonapride labels both forms of D2, a situation similar to that for cloned D2 receptors which exist in monomer and dimer forms.80–82 Hence, if the two benzamides (nemonapride and raclopride) have similar properties, the findings of Wong et al.76,83 may suggest that the D2 monomers (labeled by [11C]methylspiperone) are elevated in schizophrenia, but that the total population of monomers and dimers of D2 (labeled by [11C]raclopride) are the same as in control subjects (Figure 10). The elevation of D2 monomers in schizophrenia75,76 may arise from the fact that the dopamine in the synaptic space in postmortem schizophrenia tissues is virtually absent,75 as indicated by the lack of effect of guanine nucleotide on the density of [3H]raclopride sites75 (summarized in Figure 11, left). Third, although the concentration of dopamine in the extracellular synaptic space in postmortem schizophrenia tissue is low, as just mentioned previously, the synaptic level of dopamine in schizophrenia in the presence of a resting level of neurone firing is at least twofold higher than in control

* Where C/(C + K) is 80 nM/(80 + 30 nM) = 73% of D2.


58


SYNAPTIC DOPAMINE IN SCHIZOPHRENIA

30

Low DA

High DA

High DA

No impulses (postmortem)

Impulses at "rest" (patients)

Amphetamine (patients)

Rise in Rise in [3H]raclo [123I]IBZM with G.N. after AMPT

Fall in [123I]IBZM after AMPT

20 % 10 0

C C

S

C

S

S

–10 FIGURE 11 Synaptic dopamine is low in postmortem schizophrenia striata, as indicated by an absence of any effect on the binding of [3H]raclopride by guanine nucleotide.75 In schizophrenia patients, the “resting” synaptic dopamine in the striatum is elevated, as indicated by a rise in [123I]iodobenzamide binding after alpha-methylpara-tyrosine administration.51,53,85 The impulse-associated release of dopamine is also higher in schizophrenia patients, as shown by the enhanced fall in the binding of [123I]iodobenzamide after amphetamine.52,83,86,87

subjects52,53,85 (summarized in Figure 11, center). Amphetamine, moreover, elicits about a twofold higher release of dopamine in schizophrenia, compared to control subjects52,87 (Figure 11, right). Fourth, although the dopamine D1 receptor influences the dopamine D2 receptor (apparently by reducing the proportion of high-affinity states of D2), this D1–D2 communication is reduced or absent in postmortem tissues from individuals who have died with psychosis in schizophrenia or in Huntington’s disease, but not in those who died with either Alzheimer’s disease or with nonneurological disorders88 (Figure 12). Thus, the reduced link between D1 and D2 would result in a higher proportion of D2 receptors in the high-affinity state and, subsequently, to mediate or enhance the psychotic state, because the high-affinity state of D2 is the physiological active state.22 Future research on the dopamine hypothesis of schizophrenia must examine the role that various genes have in expressing or influencing the dopamine system.

ACKNOWLEDGMENTS We thank Dr. S. Kapur for generously providing unpublished data. This work was supported by Mr. and Mrs. Robert Peterson of The Peterson Foundation (University Park, FL) and NARSAD



59

SCHIZOPHRENIA

HUNTINGTON

ALZHEIMER

100 90 80 70 60 50 40 30 20 10 0

CONTROLS

% Inhibition (of the Dopamine effect) by SCH 23390

DISRUPTED D1-D2 LINK IN PSYCHOSIS

FIGURE 12 Reduced D1–D2 link in psychosis, as measured in postmortem human brain striata.

(National Alliance for Research in Schizophrenia and Depression); the Ontario Mental Health Foundation; the Medical Research Council of Canada; the Medland family (J. Aubrey and Helen Medland, Pamela and Desmond O’Rorke, and Janet Marsh and David Medland); the National Institute on Drug Abuse, U.S.; the Stanley Foundation of the NAMI Research Institute, Bethesda; and the Schizophrenia Society of Canada, Don Mill, Canada.

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Neurotransmitter Receptors in Actions of Antipsychotic Medications 49. Pilowsky, L. S., Mulligan, R. S., Acton, P. D., Ell, P. J., Costa, D. C., and Kerwin, R. W., Limbic selectivity of clozapine, Lancet, 350, 490, 1997. 50. Seeman, P., Guan, H.-C., and Niznik, H. B., Endogenous dopamine lowers the dopamine D2 receptor density as measured by [3H]raclopride: implications for positron emission tomography of the human brain, Synapse, 3, 96, 1989. 51. Laruelle, M., De Souza, C., Baldwin, R. M., Abi-Dargham, A., Bowers, M., Seibyl, J. P., Charney, D. S., and Innis, R. B., SPECT measurement of human striatal synaptic dopamine concentration in the resting state, Soc. Neurosci. Abstr., 22 (Abstr.), 266, 1996. 52. Laruelle, M., Abi-Dargham, A., van Dyck, C. H., Gil, R., De Souza, C. D., Erdos, J., McCance, E., Rosenblatt, W., Fingado, C., Zoghbi, S. S., Baldwin, R. M., Seibyl, J. P., Krystal, J. H., Charney, D. S., and Innis, R. B., Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug free schizophrenic subjects, Proc. Natl. Acad. Sci. U.S.A., 93, 9235, 1996. 53. Laruelle, M., D’Souza, C. D., Baldwin, R. M., Abi-Dargham, A., Kanes, S. J., Fingado, C. L., Seibyl, J. P., Zoghbi, S. S., Bowers, M. B., Jatlow, P., Charney, D. S., and Innis, R. B., Imaging D2 receptor occupancy by endogenous dopamine in humans, Neuropsychopharmacology, 17, 162, 1997. 54. Kalkman, H. O., Neumann, V., and Tricklebank, M. D., Clozapine inhibits catalepsy induced by olanzapine and loxapine, but prolongs catalepsy induced by SCH 23390 in rats, Naunyn-Schmiedeberg’s Arch. Pharmakol., 355, 361, 1997. 55. Nyberg, S., Eriksson, B., Oxenstierna, G., Halldin, C., and Farde, L., PET study of D2- and 5-HT2 receptor occupancy induced by risperidone in schizophrenic patients, Am. Coll. Neuropsychopharmacol., 35 (Abstr.), 184, 1996. 56. Nyberg, S., Nakashima, Y., Nordström, A.-L., Halldin, C., and Farde, L., Positron emission tomography of in-vivo binding characteristics of atypical antipsychotic drugs. Review of D2 and 5-HT2 receptor occupancy studies and clinical response, Br. J. Psychiatry, 168, 40, 1996. 57. Wadenberg, M.-L., Salmi, P., Jimenez, P., Svensson, T., and Ahlenius, S., Enhancement of antipsychoticlike properties of the dopamine D2 receptor antagonist, raclopride, by the additional treatment with the 5-HT2 receptor blocking agent, ritanserin, in the rat, Eur. Neuropsychopharmacol., 6, 305, 1996. 58. Lucas, G., Bonhomme, N., De Deurwaerdère, P., Le Moal, M., and Spampinato, U., 8-OH-DPAT, a 5-HT1A agonist and ritanserin, a 5-HT2A/C antagonist, reverse haloperidol-induced catalepsy in rats independently of striatal dopamine release, Psychopharmacology, 131, 57, 1997. 59. Farde, L., Nyberg, S., Nordström, A.-L., Halldin, C., and Sedvall, G., Dopamine and serotonin receptor occupancy examined by PET in antipsychotic drug treated patients, Am. Coll. Neuropsychopharmacol., 32 (Abstr.), 38, 1993. 60. Kane, J., Honigfeld, G., Singer, J., Meltzer, H. Y., and the Clozaril Collaborative Study Group, Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine, Arch. Gen. Psychiatry, 45, 789, 1988. 61. Scurlock, H. J. and Robinson, P. H., Case report 2: remoxipride in resistant schizophrenia, J. Drug Dev., 6, 71, 1993. 62. Scurlock, H. J., Singh, A. N., and Catalan, J., Atypical antipsychotic drugs in the treatment of manic syndromes in patients with HIV-1 infection, J. Psychopharmacol., 9, 151, 1995. 63. Vartianen, H., Leinonen, E., Putkonen, A., Lang, S., Hagert, U., and Tolvanen, U., A long-term study of remoxipride in chronic schizophrenic patients, Acta Psychiatr. Scand., 87, 114, 1993. 64. Shore, D., Matthews, S., Cott, J., and Lieberman, J. A., Clinical implications of clozapine discontinuation: report of an NIMH workshop, Schizophr. Bull., 21, 333, 1995. 65. Meltzer, H. Y., Lee, M. A., Ranjan, R., Mason, E. A., and Cola, P. A., Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine, Psychopharmacology, 124, 176, 1996. 66. Pickar, D., Su, T.-P., Coppola, R., Lee, C. S., Hsiao, J. K., Breier, A., and Weinberger, D. R., D2 occupancy and dopamine release determined by 123I-IBZM SPECT following clozapine dose reduction, Schizophr. Res., 15 (Abstr.), 96, 1995. 67. Baron, J. C., Martinot, J. L., Cambon, H., Boulenger, J. P., Poirier, M. F., Caillard, V., Blin, J., Huret, J. D., Loc’h, C., and Maziere, B., Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels, Psychopharmacology, 99, 463, 1989. 68. Friedman, J. H. and Lannon, M. C., Clozapine in the treatment of psychosis in Parkinson’s disease, Neurology, 39, 1219, 1989.



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69. Pfeiffer, R. F., Kang, J., Graber, B., Hofman, R., and Wilson, J., Clozapine for psychosis in Parkinson’s disease, Movement Disord., 5, 239, 1990. 70. Kahn, N., Freeman, A., Juncos, J. L., Manning, D., and Watts, R. L., Clozapine is beneficial for psychosis in Parkinson’s disease, Neurology, 41, 1699, 1991. 71. Factor, S. A. and Brown, D., Clozapine prevents recurrence of psychosis in Parkinson’s disease, Movement Disord., 7, 125, 1992. 72. Rabey, J. M., Treves, T. A., Neufeld, M. Y., Orlov, E., and Korczyn, A. D., Low-dose clozapine in the treatment of levodopa-induced mental disturbances in Parkinson’s disease, Neurology, 45, 432, 1995. 73. Sandor, P., Lang, A. E., Singal, S., and Angus, C., Remoxipride in the treatment of levodopa-induced psychosis, J. Clin. Psychopharmacol., 16, 395, 1996. 74. Meltzer, H. Y., Kennedy, J., Dai, J., Parsa, M., and Riley, D., Plasma clozapine levels and the treatment of L-DOPA-induced psychosis in Parkinson’s disease. A high potency effect of clozapine, Neuropsychopharmacology, 12, 39, 1995. 75. Seeman, P., Guan, H.-C., and Van Tol, H. H. M., Dopamine D4 receptors elevated in schizophrenia, Nature, 365, 441, 1993. 76. Wong, D. F., Wagner, H. N., Jr., Tune, L. E., Dannals, R. F., Pearlson, G. D., Links, J. M., Tamminga, C. A., Broussolle, E. P., Ravert, H. T., Wilson, A. A., Toung, J. K. T., Malat, J., Williams, J. A., O’Tuama, L. A., Snyder, S. H., Kuhar, M. J., and Gjedde, A., Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics, Science, 234, 1558, 1986. 77. Nordström, A.-L., Farde, L., Eriksson, L., and Halldin, C., No elevated D2 dopamine receptors in neuroleptic-naive schizophrenic patients revealed by positron tomography and [11C]N-methylspiperone, Psychiatr. Res. Neuroimaging, 61, 67, 1995. 78. Farde, L., Wiesel, F.-A., Stone-Elander, S., Halldin, C., Nordström, A.-A., Hall, H., and Sedvall, G., D2 dopamine receptors in neuroleptic-naive schizophrenic patients, Arch. Gen. Psychiatry, 47, 213, 1990. 79. Zawarynski, P., Tallerico, T., Seeman, P., Lee, S. P., O’Dowd, B. F., and George, S. R., Dopamine D2 receptor dimers in human and rat brain, FEBS Letts., 441, 383, 1998. 80. Ng, G. Y. K., O’Dowd, B. F., Caron, M., Dennis, M., Brann, M. R., and George, S. R., Phosphorylation and palmitoylation of the human D2L dopamine receptor in Sf9 cells, J. Neurochem., 63, 1589, 1994. 81. Ng, G. Y. K., O’Dowd, B. F., Lee, S. P., Chung, H. T., Brann, M. R., Seeman, P., and George, S. R., Dopamine D2 receptor dimers and receptor-blocking peptides, Biochem. Biophys. Res. Commun., 227, 200, 1996. 82. Ng, G. Y. K., Varghese, G., Chung, H. T., Trogadis, J., Seeman, P., O’Dowd, B. F., and George, S. R., Resistance of the dopamine D2L receptor to desensitization accompanies the up-regulation of receptors on to the surface of Sf9 cells, Endocrinology, 138, 4199, 1997. 83. Wong, D. F., Gjedde, A., Reith, J., Grunder, G., Szymanski, S., Yokoi, F., Hong, C., Nestadt, G., Neufeld, K., Pearlson, G., Tune, L., and Angrist, B., Imaging intrasynaptic postsynaptic and presynaptic dopamine function in psychosis, Soc. Neurosci. Abstr., 23, 1405, 1997. 84. Bischoff, S., Krauss, J., Grunenwald, C., Gunst, F., Heinrich, M., Schaub, M., Stöcklin, K., Vassout, A., Waldmeier, P., and Maître, L., Endogenous dopamine (DA) modulates [3H]spiperone binding in vivo in rat brain, J. Receptor Res., 11, 163, 1991. 85. Abi-Dargham, A., Kegeles, L., Zea-Ponce, Y., Printz, D., Rodenhiser, J., Weiss, R., Mann, J., Gorman, J., Van Heertum, R., and Laruelle, M., Baseline dopamine synaptic concentration is increased in schizophrenia and related to treatment response, Soc. Neurosci. Abstr., 24, 525, 1998. 86. Breier, A., Su, T.-P., Saunders, R., Carson, R. E., Kolachana, B. S., De Bartolomeis, A., Weinberger, D. R., Weisenfeld, N., Malhotra, A. K., Eckelman, W. C., and Pickar, D., Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method, Proc. Natl. Acad. Sci. U.S.A., 94, 2569, 1997. 87. Abi-Dargham, A., Gil, R., Krystal, J., Baldwin, R. M., Seibyl, J. P., Bowers, M., van Dyck, C. H., Charney, D. S., Innis, R. B., and Laruelle, M., Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort, Am. J. Psychiatry, 155, 761, 1998. 88. Seeman, P., Niznik, H. B., Guan, H.-C., Booth, G., and Ulpian, C., Link between D1 and D2 dopamine receptors is reduced in schizophrenia and Huntington diseased brain, Proc. Natl. Acad. Sci. U.S.A., 86, 10156, 1989.



5

D1 Dopamine Receptors, Schizophrenia, and Antipsychotic Medications Akeo Kurumaji and Yoshiro Okubo


Introduction .............................................................................................................................65 General Aspect of Human D1 Receptors ...............................................................................66 Pathophysiology of Schizophrenia and D1 Receptors ...........................................................66 A. Cognitive Deficit and D1 Receptors...........................................................................66 B. Role of D1 Receptors in Amphetamine-Induced Behavioral Sensitization ..............67 C. Synergism between D1 and D2 Receptors.................................................................67 IV. Genetic Studies of D1 Receptors in Schizophrenia ...............................................................68 V. Postmortem Studies of D1 Receptors in Schizophrenia ........................................................70 VI. PET Studies of D1 Receptors in Schizophrenia ....................................................................71 VII. D1 Receptors and Antipsychotic Medications .......................................................................72 A. Clinical Studies of D1-Related Drugs in Schizophrenia ...........................................72 B. Common Action of D2 Receptor Antagonism on Cortical D1 Receptors ................73 VIII. Concluding Comments............................................................................................................73 Acknowledgments ............................................................................................................................74 References ........................................................................................................................................74

I. INTRODUCTION The original dopamine hypothesis postulated that schizophrenia is a manifestation of hyperdopaminergic activity in the central nervous system (CNS). Antipsychotic drugs bind to and block striatal D2-like receptors in a strong correlation with their clinically effective antipsychotic doses.1 An increase in D2-like receptor binding in the striatum of postmortem brains of schizophrenics was revealed by many studies in vitro.2 However, schizophrenia has been reconceptualized by abnormally low prefrontal dopamine activity (causing deficit symptoms) and excessive dopamine activity in mesolimbic dopamine neurons (causing positive symptoms).3 The former hypoactivity may lead to the latter hyperactivity. The deficit symptoms are far less responsive to treatment with D2 antagonists than the positive symptoms. Many investigations have recently been carried out to find evidence of changed activities in the dopamine receptor family in the cerebral cortex of schizophrenia. In particular, D1 receptors in the prefrontal cortex may play an important role in working memory which is defective in schizophrenic patients.4,5 Further, the decreased level of cortical D1 receptors in drug-naive schizophrenics has been revealed by a positron emission tomography (PET) study.6

0-8493-0744-9/00/$0.00+$.50 © 2000 by CRC Press LLC

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In this chapter, findings both supporting and refuting the role of D1 receptors in the pathophysiology of schizophrenia will be reviewed, including postmortem brain studies and genetic analyses of D1 receptors.

II. GENERAL ASPECT OF HUMAN D1 RECEPTORS Five distinct dopamine receptor subtypes in the CNS have been identified and classified into D1 and D2 subfamilies on the basis of homology of pharmacological properties and sequences of amino acids. The D1 subfamily consists of D1 and D5 subtypes, and the D2 subfamily is comprised of D2, D3, and D4 subtypes.1 The D1 and D5 dopamine receptors are guanine nucleotide-binding (G-protein coupled) receptors and are linked to stimulation of adenylate cyclase activity via the Gs protein. The human D17–9 and D510,11 dopamine receptor genes have been cloned and assigned to chromosome 5q35.1 and 4p15.1-15.3, respectively. The protein products were of average length, being 446 amino acid residues for D1 and 477 for D5. The coding regions of both genes were not interrupted.12 The amino acid sequence identity of D1 and D5 in their characteristic seven transmembrane domains was 80%, with an overall amino acid homology of 50%.10 Both D1 and D5 receptors expressed in COS-7 cells exhibited similar inhibitory constants (Ki) of various dopaminergic agonists and antagonists for [3H]SCH 23390 binding, although D5 displayed a tenfold higher affinity for dopamine than D1.10 High levels of D1 receptor mRNA were homogeneously distributed throughout the caudate, putamen, and nucleus accumbens.13 D1 mRNA was relatively abundant in the neocortex (prefrontal, temporal, and occipital cortices) and was sparse in the hippocampus.14 D5 receptors mRNA showed a strikingly dissimilar distribution pattern to D1 receptor in human brains,13,14 with levels being relatively high in the hippocampus, lower in the neocortex, and scarce in the striatum. Densities and distribution of D1 dopamine receptors were investigated using an autoradiographic receptor binding assay on human postmortem brain slices, in comparison with D2 dopamine receptors.15 Densities of both [3H]SCH 23390 (D1) and [3H]raclopride (D2) bindings were similarly high in the caudate nucleus and the putamen. In several limbic regions, e.g., the hippocampal and neocortical regions, there were four to seven times higher densities of the D1 than D2 dopamine receptors. The striatum showed a path/matrix organization of D1 receptors. The density of D1 in the D1-rich zone was 30% greater than in the D1-poor zone.16 The cortical D1 receptors were distributed more densely in the superficial and deep layers than in the intermediate layer.17

III. PATHOPHYSIOLOGY OF SCHIZOPHRENIA AND D1 RECEPTORS A. COGNITIVE DEFICIT

AND

D1 RECEPTORS

Negative symptoms and cognitive dysfunctions in schizophrenia may be associated with hypofunction of the prefrontal cortex. Hypometabolism and anatomical abnormalities have been demonstrated in the prefrontal cortex.4 The D1 dopamine receptors in the cortex, particularly the dorsolateral region, play an important role in working memory which is defective in schizophrenia. The receptors modulate the cortical output activities to subcortical regions such as nucleus accumbens and striatum.18 Depletion of dopamine in the prefrontal cortex of monkeys induced deficits in a delayed alteration spatial memory task.19 Local cerebral injection of selective D1 antagonists, but not of selective D2 antagonists, into the dorsolateral prefrontal cortex induced impairment in an oculomotor delayed-response task.20,21 On the other hand, low levels of D1 antagonists enhanced the task,22 and increased dopamine turnover in the cortex induced by anxiogenic drugs hindered spatial working memory performance (this effect can be blocked by dopamine receptor antagonists).23 Hence, it has been suggested that an optimal range of dopamine concentration and cortical D1 receptor activation is required for normal cognitive performance.


D1 Dopamine Receptors, Schizophrenia, and Antipsychotic Medications

67

TABLE 1 Synergistic Effects of D1 and D2 Agonists Changes in Behavioral, Physiological, and Neurochemical Parameters In normal condition Mashurano and Waddington (1986)27 Walter et al. (1987)28 Bertorello et al. (1990)29 Piomelli et al. (1991)30 LaHoste et al. (1993)31 Ruskin and Marshall (1995)32

Stereotyped behavior in rat Firing rates of globus pallidus of rat (Na+ + K+) ATPase activity in striatal neurons of guinea pig Arachidonic acid release from Chinese hamster ovary cells expressing D1 and D2 dopamine receptors Fos-like immunoreactivity in rat striatum Fos-like immunoreactivity in globus pallidus and subthalamic nucleus of rat

In the striatum of dopamine-depleted hemispheres Robertson and Robertson (1986)33 Turning behavior of rat Calabresi et al. (1992)34 Long-term depression in striatum of rat Paul et al. (1992)35 Fos-like immunoreactivity and c-fos mRNA in striatum of rat Keefe and Gerfen (1995)36 mRNA of zif 268 and c-fos in striatum of rat Fos-like immunoreactivity in globus pallidus of rat Ruskin and Marshall (1995)32 Kashihara et al. (1996)37 AP-1 DNA-binding activity in striatum and glubus pallidus of rat

B. ROLE OF D1 RECEPTORS IN AMPHETAMINE-INDUCED BEHAVIORAL SENSITIZATION Amphetamine psychosis exhibits symptoms closely resembling positive symptoms of schizophrenia and shows a good response to antipsychotic drugs. Chronic administration of amphetamines produces behavioral sensitization in rodents, which is characterized by a progressive augmentation of locomotor activity and stereotyped behavior. After discontinuation of the drugs, this enhanced behavior is reproduced by a relatively smaller dosage of the drug. Both selective D1 antagonists and selective D2 antagonists not only reversed methamphetamine (MAP)-induced motor effects, but also prevented the induction of behavioral sensitization produced by repeated MAP administration in rats.24 A lasting increase in D1 dopamine receptor density was found in the substantia nigra after subchronic MAP administration.25 Another study indicated that D1 receptors, but not D2 receptors, in the ventral tegmental area may play a critical role in the development of sensitized locomotor and nucleus accumbens dopamine response to amphetamine.26 An easy relapse to a psychotic state (vulnerability) is one of the characteristic features of chronic schizophrenia. Understanding the neurochemical mechanism underlying the vulnerability could provide information for a new drug design to prevent the chronic process of the disease. One of the candidates would be a drug modulating D1 receptor activity.

C. SYNERGISM

BETWEEN

D1

AND

D2 RECEPTORS

Animal experiments demonstrating synergism between D1 and D2 agonists are summarized in Table 1. Their results imply that endogenous dopamine may induce certain effects on behavior,27 electrophysiological response,28 signal transduction process,29,30 and regulatory action of gene expression31,32 by concurrent stimulation of both receptor subtypes in the basal ganglia. There was, however, a breakdown in D1/D2 synergism in stereotyped motor behavior38 and electrophysiological responses39 in the dopamine-depleted striatum. Submaximal doses of D1 and D2 agonists still exerted additive or synergistic effects in the striatum.32–37 The striatum receives two main inputs, the nigrostriatal dopaminergic pathway and the corticostriatal glutamtergic pathway. These two projections converge on the medium spiny GABAergic neurons projecting to the other structures of the basal ganglia, globus pallidus, and


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substantia nigra pars reticulata. The synergistic effect on rotation behavior could be explained by a convergent modulation on the substantia nigra. Both D1-mediated excitation of striatonigral neurons and D2-mediated inhibition of the striatopallidal–subthalamic nucleus–pars reticulata pathway would have a similar inhibitory effect on the firing rate of neurons in the pars reticulata.40 Moreover, the striatum receives glutamatergic innervations from the thalamus and projects to the thalamus and the mesencephalic reticular formation via globus pallidus. It is proposed that the cerebral cortex is capable of controlling its sensory input and arousal by means of a negative feedback loop involving the striatal complexes (caudate, putamen, nucleus accumbens, and globus pallidus), the thalamus, and the mesencephalic reticular formation.41 Hence, the synergistic effect between D1 and D2 in the striatum may provide important insights into the pathophysiology of Parkinson’s disease and the extrapyramidal side effects induced by antipsychotics, e.g., dystonia and tardive dyskinesia.35 Moreover, the striatal functions modulated by both D1 and D2 receptors also regulate the arousal and filter mechanisms of the thalamic relay nucleus, which might be disturbed in schizophrenia.41 Long-term depression (LTD), originally found in the cerebellum and considered to be the basis of several forms of motor learning, was also confirmed in the corticostriatal glutamatergic fibers.34 LTD was absent in dopamine-depleted striatal slices, which could be restored by applying exogenous dopamine as well as the co-administration of SKF 38393 (D1 agonist) and LY 171555 (D2 agonist). The activations of dopamine receptors may induce a long-term modulation of glutamatergic synaptic transmission via arachidonic acid release30 or stimulation responses of immediate-early genes coupled to long-term changes in gene function.38 Therefore, the modulation of long-term neuronal activity of the corticostriatal pathway is probably involved in the functional interaction between the cortex and subcortical areas. In schizophrenia, hypofunction in the prefrontal cortex may produce hyperfunction in the subcortical regions via the corticostriatal glutamatergic pathway.42 D1 and D2 are also co-expressed in a subset of striatal neurons, and their synergism was also demonstrated on isolated striatal neurons29 and at cellular levels.30 Abnormal D1–D2 interaction in homogenized striatal tissue has been demonstrated in schizophrenic patients. In control brains, pretreating the tissue with a D1 selective antagonist (SCH 23390) prevented a reduction in [3H]raclopride binding induced by a D2 agonist. Conversely, a dopamine-induced decrease in [3H]SCH 23390 binding to D1 receptors could be prevented by the D2 selective antagonist eticlopride. Interestingly, the link between D1 and D2 was missing in over half of the postmortem brains of schizophrenia. Consequently, these results support the notion that there is a disturbed interaction between D1 and D2 in the striatal cells in a subpopulation of schizophrenia.

IV. GENETIC STUDIES OF D1 RECEPTORS IN SCHIZOPHRENIA Polymorphisms in the human D1 dopamine receptor genes are summarized in Table 2. Two polymorphisms of restriction fragment length were recognized by Eco R1 and Taq I.49,50 There were 13 polymorphisms in the DNA sequence, including 4 silent mutations in the coding region observed only in patients with schizophrenia.45,46 (Table 2). However, neither linkage49–51 nor association43,44,52,53 studies using the two restriction fragment length polymorphisms or DNA variations in the promoter, 5′ UTR and 3′ UTR, revealed any positive findings of D1 receptors with schizophrenia (Table 3). Ten variations in the DNA sequence have been reported in the human D5 dopamine receptors.47,48 (Table 2). There were no statistically significant findings in the linkage54 or association study47 with schizophrenia (Table 3). Consequently, it is unlikely that genes of the D1 subfamily (D1 and D5) play a major role in the genetic predisposition of schizophrenia.



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TABLE 2 DNA Polymorphisms in Human D1 and D5 Dopamine Receptors Genes Location

DNA Polymorphism

D1 dopamine receptors Promotor –2218 T>C,43 –2102 C>A,43 –2030 T>C,43 –1992 G>A,43 –1251 G>A,43 –800 T>C43 5′ UTR –800 T>C,43 –94 G>A,44 –48 A>G45 Coding region 90 A>G (Leu30Leu),45 198 G>A (Leu66Leu),46 222 A>C (Ala74Ala),45 1263 G>A (Ser421Ser)44 3′ UTR 1403 T>C44 D5 dopamine receptors Coding region 66 G>A (Ala22Ala),47 262 C>T (Leu88Pro),48 806 C>T (Ala269Val),47 978 T>C (Pro326Pro),47 989 C>A (Pro330Gln),47 990 G>A (Pro330Pro),47 1005 C>A (Cys335X),47 1051 A>G (Asn351Asp),47 1358 C>G (Ser453Cys)47 3′ UTR 1481 C>T47 Note: UTR: untranslated region. Superscripts note Reference numbers.

TABLE 3 Schizophrenia and D1 and D5 Dopamine Receptors Gene Polymorphisms Authors (year) D1 dopamine receptors Jensen et al. (1993)49

Population Analyzed (Number of Subject)

European linkage: Eco R1

Coon et al. (1993)50

European linkage: Eco R1

Campion et al. (1994)51

France and the Island of la Reunion in the Indian Ocean German S (60) vs. C (60) German S (36) vs. C (45)

Nöthen et al. (1993)52 Cichon et al. (1994)44

Type of Study: Polymorphism

Results

Linkage excluded Linkage: Taq 1 Linkage excluded Linkage: Taq 1 Linkage: Eco R1

Linkage excluded Linkage excluded

Association: Eco R1

No association

Association: –94 G>A, –48 A>G, 1263 G>A, 1403 T>C

No associations

Linkage excluded

Cichon et al. (1996)43

German S (36) vs. C (45)

Association: –2218 T>C, –2102 C>A, –2030 T>C, –1992 G>A, –1251 G>A, –800 T>C

No associations

Kojima et al. (1999)53

Japanese S (148) vs. C (148)

Association: –48 A>G

No association

Icelandic and English pedigrees Caucasian S (131~400) vs. C (256~2036)

Linkage: VNTR Association: 806 C>T, 1005 C>A, 1051 A>G, 1358 C>G

Linkage excluded No associations

D5 dopamine receptors Kalsi et al. (1996)54 Sobell et al. (1995)47

Note: S: schizophrenia; C: controls; VNTR, see the Reference of Sherrington, R. et al., 1993. 11


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TABLE 4 D1 Receptors in Postmortem Brains of Schizophrenics Characters or Methods

Direction of Change

c-AMP formation Carenzi et al. (1975)55 Memo et al. (1983)56

Induction by dopamine (10 µM) Induction by SKF 38393

No change Increase

Caudate nucleus Caudate nucleus

[3H]Flupenthixol binding Cross et al. (1981)57

Specific binding (2 nM)

No change

Caudate nucleus

[3H]SCH 23390 binding Pimoule et al. (1985)58 Hess et al. (1987)59 Joyce et al. (1988)16

Specific binding (0.4 nM) Bmax and Kd Specific binding (1 nM)

No change Decrease No change

Knable et al. (1994)61

High-affinity Bmax Kd Low-affinity Bmax Kd Specific binding (2 nM)

No change Decrease No change No change No change

Putamen Caudate nucleus Caudate, putamen, nucleus accumbens Caudate nucleus

Knable et al. (1996)17 Domyo et al. (1998)62

Specific binding (2 nM) Specific binding (1 nM)

No change Increase

Authors

Mamelok et al. (1993)60

mRNA Harrington et al. (1995)64 Meador-Woodruff et al. (1997)65

Caudate nucleus

Specific binding (3n M)

No change

Caudate, putamen, nucleus accumbens Prefrontal cortex, cingluate cortex Superior parietal cortex, medial and inferior temporal cortex 14 areas of cerebral cortex, substantia nigra Prefrontal cortex (dorsolateral)

In situ hybridization In situ hybridization D1

No change

Caudate nucleus

No change

D5

No change

Caudate, putamen, nucleus accumbens, prefrontal cortex (BA 8,9,11,32,46), visual cortex (BA 17) Prefrontal cortex (BA 8,9,11,32,46), visual cortex (BA 17)

No change Dean et al. (1999)63

Brain Regions

Note: BA: Broadmann area.

V. POSTMORTEM STUDIES OF D1 RECEPTORS IN SCHIZOPHRENIA An increased formation of c-AMP induced by D1 agonist (SKF 38393) was observed in the caudate nucleus of postmortem brains of schizophrenics. Receptor binding studies, except for a report by Hess et al.,59 failed to find any changes in densities of D1 receptors in the basal ganglia (Table 4). There were also no alterations in the mRNA levels of D1 receptors.64,65 Hess et al.,59 however, demonstrated that D1 in the caudate nucleus was significantly reduced by 43%, and there was a marked increase in the D2 receptor density. They speculated that the alteration in the D2/D1 dopamine receptor ratio might reflect the imbalance between the receptors, which could be associated with the subsequent psychopathology of schizophrenia. Increased D2 receptors in the striatum



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TABLE 5 PET Studies on D1 Dopamine Receptors in Shizophrenia Authors

Radioligand

Brain Regions

Direction of Change

Karlsson et al. (1993)66 Sedvall and Farde (1995)67 Okubo et al. (1997)6

[11C]SCH 23390 [11C]SCH 23390 [11C]SCH 23390

Putamen (whole) Putamen (patch component) Striatum Prefrontal cortex Anterior cingulate gyrus Temporal cortex

No change Decrease No change Decrease Trend toward decrease Trend toward decrease

revealed by many postmortem studies2 may be partly responsible for imbalanced interaction between D1 and D2 receptors, irrespective of subtle changes in D1 receptors. There were no changes in [3H]SCH 23390 binding17,62,63 or mRNAs of D1 and D5 dopamine receptors in the prefrontal cortex of postmortem brains of schizophrenics.64,65 In our preliminary postmortem study,62 D1 receptors were increased in the superior parietal cortex and medial and inferior temporal cortex of postmortem brains of chronic schizophrenia patients who did not receive antipsychotic drug for more than 40 days before death. However, further investigation is required to confirm this finding and to clarify the functional role of D1 in the parieto-temporal cortex.

VI. PET STUDIES OF D1 RECEPTORS IN SCHIZOPHRENIA Results of PET studies of D1 receptors in schizophrenia are summarized in Table 5. The first in vivo measurements of D1 receptors in schizophrenia using PET and [11C]SCH 23390 were performed by Karlsson et al.66 They found no changes in the measurements of D1 receptors of the whole putamen. Subsequently, they measured D1 receptors in the patch component of the putamen using the values of the four pixels with the highest radioactivity and found it to be lower in drug-naive schizophrenics.67 They hypothesized that a low D1 density may result in reduced activity of the D1 receptor to D2 receptor regulated feedback system to limbic regions in schizophrenia. Recently, we examined the D1 and D2 receptors in 17 male schizophrenics and 18 healthy male volunteers.6 Ten of the patients were completely neuroleptic naive, and seven were previously treated with neuroleptics but were drug free for a minimum of 2 weeks prior to the PET examination. Two PET runs were performed on each subject on the same day using [11C]SCH 23390 and [11C]N-methylspiperone ([11C]NMSP), respectively, as tracers. The in vivo labeling of the striatum and cortex by [11C]SCH 23390 was thought to be due to the D1 receptor. [11C]NMSP bound predominantly to D2 receptors in the striatum. We found no statistically significant difference among the three groups either in the striatal D2 receptor or in the striatal D1 receptor. However, we observed that the D1 receptor binding decreased in the prefrontal cortex of schizophrenics and that this reduction was related to negative symptoms and poor performance in the Wisconsin Card Sorting Test by which the neuropsychological deficit most widely recognized as being associated with prefrontal function in human is revealed.5 Our findings suggest that the dysfunction in the D1 receptor modulation mechanism in the prefrontal cortex may contribute to negative symptoms such as alogia; affective blunting; avolition; anhedonia clearly related to cognition, motivation, and emotion; and cognitive deficits in schizophrenia. These mental functions are rather general functions of the brain. If these functions are really related to the cortical D1 receptor, it can be assumed that there is impairment of cortical D1 receptor function not only in schizophrenia, but also in other neuropsychiatric disorders. There have been two other PET studies on the cortical D1 receptor in neuropsychiatric disorders. Suhara et al.68 investigated patients with bipolar mood disorder and found decreased D1 receptor binding in the frontal cortex. Sedvall et al.69 found a decreasing trend of D1 receptor in the frontal cortex of


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TABLE 6 Open Clinical Trial of D1 Antagonists in Acute Psychotic States Drug and Author SCH 39166 Karlsson et al. (1995)72 Den Boer (1995)73

Style

Dosage (mg/day)

a b

Number of Subjectsa

Results and Comments

17 (7)

No change in BPRS or CGI

12 (5)

Improvement in negative symptomsb No change in positive symptoms Good responses in two schizoaffective disorders

Fixed dosage 10 (initial)–100 (final) 28 days schedule Fixed dosage 1.25 (initial)–200 (final) 28 days schedule

De Beaurepaire (1995)74 Fixed dosage 50 (initial)–600 (final) schedule NNC 01-0687 Karle et al. (1995)75

Period

Fixed dosage 30 or 100 schedule

28 days

6 (3)

35 days

14 (9)

A tendency to decrease in positive and negative subscales of PANSS

Number of subjects who completed the trial (in parentheses). There was a statistical significance between the baseline subscore and the subscore at 28 days assessed by PANSS.

patients with Huntington disease as well as about 75% reduction in the striatum. In mood disorders, hypodopaminergic activity has been suggested to underline the commonly observed features of depression, such as psychomotor retardation and diminished motivation.70 Furthermore, the findings from an animal study,71 that different selective D1 agonists showed the “antidepressant effect” in the behavioral despair model of depression and the antidepressant effect of imipramine was antagonized by SCH 23390, suggest an important role of the D1 receptor in depression. The psychiatric symptoms of Huntington disease are apathy and withdrawn behavior, and some patients show depressive symptoms. These findings suggest that the dysfunction in the prefrontal D1 receptor system is related to the commonly observed symptoms among these neuropsychiatric disorders.

VII. D1 RECEPTORS AND ANTIPSYCHOTIC MEDICATIONS A. CLINICAL STUDIES

OF

D1-RELATED DRUGS

IN

SCHIZOPHRENIA

Results of open clinical trials of selective D1 antagonists in acute psychotic states are summarized in Table 6. A selective D1 antagonist, SCH 39166, was withdrawn prematurely in half of the patients of each trial because of deterioration of psychotic symptoms and refusal to take the drug. The trials did not reveal any significant effects on positive symptoms of schizophrenia, while an effect on negative symptoms was observed in one study73 and an improvement in the brief psychiatric rating scale (BPRS) scores was observed in two schizoaffective disorders, but not in schizophrenics.74 The lack of apparent antipsychotic effects of D1 antagonists could not be attributed to inadequate dosage of the drug, as single oral doses of 100 mg SCH 39166 induced around 70% D1 receptor occupancy in the basal ganglia.76 Another selective D1 antagonist, NNC 01-0687, was given to 14 chronic schizophrenic patients, and 9 patients completed the clinical trial.75 Some improvement of psychotic symptoms as well as negative symptoms were noted in the scores of positive and negative syndrome scale (PANSS), although statistical analysis was not performed in this study. The D1 antagonists produced a low degree of extrapyramidal effects compared to typical antipsychotics, in agreement with the results of selective D1 antagonists in animal models of



73

extrapyramidal symptoms.76 Although data from animal studies have suggested that selective D1 antagonists possibly possess antipsychotic efficacy, potent antipsychotic activity with the compounds was not confirmed in the open trials on schizophrenia. Barnes and Gerlach had stressed that there is a need for the interaction between D1 and D2, which probably varies across species, to be clarified in a clinical neuropsychiatric context and that the tentative evidence of benefit for negative symptoms may be worth further investigation by combining the D1 and D2 blockades.76 Clinical effects of D1 agonist SKF 38393 (250 mg/day) combined with haloperidol (20 mg/day) in ten schizophrenic patients on their symptoms and involuntary movements were evaluated by a crossover double-blind trial.77 The combined treatment was associated with decreases in BPRS scores of approximately 20% in three patients and similar increases in scores in two other patients. Wisconsin Card Sorting Test preservative errors were reduced in three patients and increased in six patients. Haloperidol with SKF 38393, however, produced reductions in tardive dyskinesia in seven patients.

B. COMMON ACTION OF D2 RECEPTOR ANTAGONISM CORTICAL D1 RECEPTORS

ON

The observation that the therapeutic potency of antipsychotic drugs directly correlates with their affinity for dopamine D2 receptors is a keystone of the dopamine hypothesis of schizophrenia.1 However, it still remains unclear where the D2 receptors are located to modulate most critically the symptoms of schizophrenia. It has recently been demonstrated that upregulation of the cortical D2 receptors after chronic treatment with antipsychotic drugs is accompanied by downregulation of the cortical D1 receptors in nonhuman primates.78,79 It appears that an appropriate interaction and balance between D1 and D2 activity is associated with clinical effects of antipsychotic drugs. Considering the finding that the activation of prefrontal D1 receptors in a narrow range of occupancy optimizes physiological signaling in prefrontal neurones engaged by working memory in nonhuman primates,22 it was suggested that the adjustment of cortical D1 receptor levels in combination with D2 receptor antagonism may be an important goal of future antipsychotic treatments for schizophrenia.80

VIII. CONCLUDING COMMENTS The dopamine hypothesis for schizophrenia has been supported mainly by the antipsychotic effect of D2 dopamine receptor antagonists.1 However, recent PET studies81–84 cast doubt on a variant of the dopamine hypothesis that schizophrenia is related to increased striatal D2 densities. The dopamine D1 receptor, which is highly expressed in the prefrontal cortex,15 has been implicated in the control of working memory,20–22 and working memory dysfunction is a prominent feature of schizophrenia.4,5 Although several postmortem studies have failed to produce a consistent finding of abnormal D1 receptor density, two recent PET studies have found decreased D1 receptors in schizophrenia.6,67 This inconsistency between in vitro postmortem studies and in vivo PET studies has been observed in the studies of D2 and 5-HT2 receptors in schizophrenia. In spite of postmortem studies reporting increased striatal D2 receptor density or decreased cortical 5-HT2 receptor density, PET studies of schizophrenia have revealed no changes in either D2 receptors81–84 or 5-HT2 receptors.85,86 PET studies have several advantages over postmortem studies. Postmortem studies examine patients who have been treated with neuroleptics for a long time, while PET studies investigate neuroleptic-naive patients. It may be difficult for postmortem studies to exclude the possible effect of antipsychotics on the alteration in neural transmission. The older age of subjects, usually over 50 to 60 years of age, and the longer duration of illness, usually 20 to 30 years, must also be taken into consideration, since a dramatic decline in D1 receptors with age has been confirmed.87 Furthermore, it is impossible for postmortem studies to set a true normal control group because all subjects have died through some disease which could affect D1 receptors. A distinct advantage of PET is that studying neuroreceptors in living patients makes it possible to investigate the association between neuroreceptor function and clinical symptom. We observed that the reduction in D1 receptor binding in the prefrontal


74


cortex of schizophrenic patients was related to negative symptoms and poor performance in the Wisconsin Sorting Card Test.6 These findings support the notion that dysfunction in the D1 receptor modulation mechanism in the prefrontal cortex may contribute to the negative symptoms and cognitive deficit in schizophrenia. However, it should be noted that PET studies also have revealed decreased D1 receptor binding in patients with other neuropsychiatric disorders.68,69 Considering these findings together with the results of genetic investigations that neither linkage nor association studies have revealed any positive finding of D1 receptors with schizophrenia, it is possible that dysfunction in the prefrontal D1 receptor system is not specific to schizophrenia, but is related to the commonly observed symptoms among these neuropsychiatric disorders. In vivo receptor imaging techniques in combination with careful and sophisticated clinical assessment provide promising research strategies for determining the role of the D1 receptor in schizophrenia. The results of clinical studies regarding the therapeutic potential of selective D1 antagonists have proved to be disappointing. Possible hypodopaminergic activity in the prefrontal cortex of schizophrenic patients and our PET finding of the relationship between decreased prefrontal D1 receptor binding and negative symptoms suggest that selective agonists may be helpful in treating the negative symptoms of schizophrenia.6 Otherwise, as suggested in the study of working memory of nonhuman primates,22 optimization of D1 stimulation in a narrow range of occupancy may have a therapeutic effect.80 The role of the D1 receptor system must be understood in the context of existing theories involving other receptor types and other neurotransmitters which may act independently and interact with D1 receptor. The finding of the downregulation of cortical D1 receptors induced by chronic treatment with different D2 antagonistic drugs78–80 suggests that further studies of the interaction between D1 and D2 receptors may be helpful for elucidating the role of D1 receptor in the pathophysiology of schizophrenia and for developing new strategies for antipsychotic medications of schizophrenia.

ACKNOWLEDGMENTS We thank Emeritus Prof. M. Toru of our department; Dr. T. Suhara of the National Institute of Radiological Sciences, Japan; and M. Shimizu for their help. This work was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Grant 11B-3 from the Ministry of Health and Welfare of Japan.

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Neurotransmitter Receptors in Actions of Antipsychotic Medications 69. Sedvall, G., Karlsson, P., Lundin, A., Anvret, M., Suhara, T., Halldin, C., and Farde, L., Dopamine D1 receptor number — a sensitive PET marker for early brain degeneration in Huntington’s disease, Eur. Arch. Psychiatry Clin. Neurosci., 243, 249, 1994. 70. Brown, A. and Gershon, S., Dopamine and depression, J. Neural Transm. Gen. Sect., 91, 75, 1993. 71. D’Aquila, P. S., Collu, M., Pani, L., Gessa, G. L., and Serra, G., Antidepressant-like effect of selective dopamine D1 receptor agonists in the behavioural despair animal model of depression, Eur. J. Pharmacol., 262, 107, 1994. 72. Karlsson, P., Smith, L., Farde, L., Haernryd, C., Sedvall, G., and Wiesel, F. A., Lack of apparent antipsychotic effect of the D1-dopamine receptor antagonist in acutely ill schizophrenic patients, Psychopharmacology, 121, 309, 1995. 73. Den Boer, J. A., van Megen, H. J. G. M., Fleischhacker, W. W., Louwerens, J. W., Slaap, B. R., Westenberg, H. G., Burrows, G. D., and Srivastava, O. N., Differential effects of the D1-DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia, Psychopharmacology, 121, 317, 1995. 74. De Beaurepaire, R., Labelle, A., Naber, D., Jones, B. D., and Barnes, T. R., An open trial of the D1 antagonist SCH 39166 in six cases of acute psychotic states, Psychopharmacology, 121, 323, 1995. 75. Karle, J., Clemmesen, L., Hansen, L., Andersen, M., Andersen, J., Fensbo, C., Sloth, N. M., Skrumsager, B. K., Lublin, H., and Gerlach, J., NNC 01-0687, a selective dopamine D1 receptor antagonist, in the treatment of schizophrenia, Psychopharmacology, 121, 328, 1995. 76. Barnes, T. R. and Gerlach, J., D1 receptor antagonists in schizophrenia, Psychopharmacology, 121, 287, 1995. 77. Davidson, M., Harvey, P. D., Bergman, R. L., Powchik, P., Kaminsky, R., Losonczy, M. F., and Davis, K. L., Effects of the D-1 agonist SKF-38393 combined with haloperidol in schizophrenic patients, Arch. Gen. Psychiatry, 47, 190, 1990. 78. Lidow, M. S. and Goldman, R. P., A common action of clozapine, haloperidol, and remoxipride on D1- and D2-dopaminergic receptors in the primate cerebral cortex, Proc. Natl. Acad. Sci. U.S.A., 91, 4353, 1994. 79. Lidow, M. S., Elsworth, J. D., and Goldman, R. P., Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs, J. Pharmacol. Exp. Ther., 281, 597, 1997. 80. Lidow, M. S., Williams, G. V., and Goldman-Rakic, P. S., The cerebral cortex: a case for a common site of action of antipsychotics, Trends Pharmacol. Sci., 19, 136, 1998. 81. Farde, L., Wiesel, F. A., Stone, E. S., Halldin, C., Nordstrom, A. L., Hall, H., and Sedvall, G., D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride, Arch. Gen. Psychiatry, 47, 213, 1990. 82. Nödstrom, A. L., Farde, L., Eriksson, L., and Halldin, C., No elevated D2-dopamine receptor in neuroleptic-naive schizophrenic patients revealed by positron emission tomography and [11C]N-methylspiperone, Psychiatr. Res. Neuroimaging, 61, 67, 1995. 83. Hietala, J., Syvalahti, E., Vuorio, K., Nagren, K., Lehikoinen, P., Ruotsalainen, U., Rakkolainen, V., Lehtinen, V., and Wegelius, U., Striatal D2 dopamine receptor characteristics in neuroleptic-naive schizophrenic patients studied with positron emission tomography, Arch. Gen. Psychiatry, 51, 116, 1994. 84. Martinot, J. L., Person-Magnan, P., Huret, J. D., and Mazoyer, B., Striatal D2 dopaminergic receptors assessed with positron emission tomography and [76Br]bromospiperone in untreated schizophrenia, Am. J. Psychiatry, 147, 44, 1990. 85. Lewis, R., Kapur, S., Jones, C., DaSilvs, J., Brown, G. M., Wilson, A. A., Houle, S., and Zipursky, R. B., Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neurolepticnaive patients and normal subjects, Am. J. Psychiatry, 156, 72, 1999. 86. Trichard, C., Paillere, M. M., Attar, L. D., Blin, J., Feline, A., and Martinot, J. L., No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET, Schizophr. Res., 31, 13, 1998. 87. Suhara, T., Fukuda, H., Inoue, O., Itoh, T., Suzuki, K., Yamasaki, T., and Tateno, Y., Age-related changes in human D1 dopamine receptors measured by positron emission tomography, Psychopharmacology, 103, 41, 1991.


6

Serotonin Receptors as Targets of Antipsychotic Medications Anissa Abi-Dargham and John Krystal


Introduction .............................................................................................................................79 5-HT Receptor Subtypes.........................................................................................................80 Alteration of 5-HT Receptors in Schizophrenia ....................................................................81 A. 5-HT Transporters.......................................................................................................82 B. 5-HT1 Receptors..........................................................................................................83 C. 5-HT2 Receptors..........................................................................................................83 D. Other Serotonin Receptors..........................................................................................84 IV. Pharmacological Manipulation of 5-HT Transmission in Schizophrenia..............................84 A. 5-HT Precursors ..........................................................................................................84 B. 5-HT-Depleting Agents ...............................................................................................85 C. 5-HT2A Agonism: LSD and “Model” Psychosis ........................................................85 1. Neuropharmacological Effects of Hallucinogens........................................85 2. Anatomical Substrates of Hallucinogens.....................................................86 D. 5-HT2A Antagonism, Clozapine and Atypicality ........................................................87 E. Action of Antipsychotic Drugs at Other Serotonergic Receptors..............................88 V. Serotonin–Dopamine Interactions ..........................................................................................90 A. Inhibitory Influence of 5-HT on DA Function...........................................................90 1. Spontaneous Locomotor Activity ................................................................90 2. Amphetamine-Induced Locomotor Activity................................................91 3. Amphetamine-Induced Stereotypies............................................................91 4. Turning Behavior .........................................................................................91 5. Neuroleptic-Induced Catalepsy....................................................................92 6. VTA DA Neuron Activity............................................................................92 B. Stimulatory Influence of 5-HT on DA Function........................................................93 VI. Discussion ...............................................................................................................................93 References ........................................................................................................................................95

I. INTRODUCTION A dysfunction of the 5-hydroxytryptamine (5-HT) function in schizophrenia was first postulated because of the structural similarity between 5-HT and the hallucinogenic drug lysergic acid diethylamide (LSD).1,2 However, the recognition that LSD-induced psychosis differed clinically from the schizophrenic psychotic episodes3 contributed to the eclipse of 5-HT-related hypotheses of schizophrenia by dopaminergic theories during the 1970s and early 1980s. The interest in the role of 5-HT in schizophrenia was renewed after the introduction of clozapine in the U.S., a drug with negligible liability for extrapyramidal side effects (EPS) and superior antipsychotic properties compared to 0-8493-0744-9/00/$0.00+$.50 © 2000 by CRC Press LLC

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typical antipsychotics.4 Clozapine is associated with moderate potency as a dopamine D2 receptor antagonist, but it displays higher affinity than most typical neuroleptics for multiple other receptors such as D1 and D4 receptors; 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors; muscarinic cholinergic receptors; adrenergic alpha1 receptors; and histaminic H1 receptors.5–8 The superior efficacy of clozapine has been attributed to its relatively potent 5-HT2 receptor antagonism,5 prompting the development of pure 5-HT2 antagonists or “balanced” 5-HT2-D2 antagonists as potential antipsychotics. So far, available data indicates acceptable antipsychotic efficacy for combined 5-HT2-D2 antagonists, but not for pure 5-HT2 antagonists. At the same time, we have learned more about the potential role of other serotonergic receptors in the action of atypical antipsychotics. In addition, postmortem studies, cerebrospinal fluid (CSF) studies, and clinical challenge studies performed over the last decade have reinforced the suggestion of a serotonergic dysfunction in the brains of patients with schizophrenia. In this chapter, we will first review the multilpe serotonin receptor subtypes, with a particular emphasis on those implicated in schizophrenia, reviewing the evidence for alterations of these receptors in schizophrenia and their involvement in the therapeutic effects of antipsychotics. The putative role of 5-HT transmission in schizophrenia will then be discussed in the context of preclinical studies demonstrating interactions between the dopaminergic and the serotonergic systems and of recent advances in the conceptualization of the DA hypothesis of schizophrenia.

II. 5-HT RECEPTOR SUBTYPES Serotonin projections innervate virtually all regions of the brain. Ascending serotonergic fibers arise principally from two midbrain nuclei, the dorsal raphe (DR, B7) and the median raphe (MR, B8), and project to virtually all forebrain regions, including the thalamus, hypothalamus, caudateputamen, hippocampus, and neocortex.9–11 Several brain regions, including the frontal cortex and hypothalamus, receive innervation from both nuclei. However, the caudate-putamen receive their main input from the DR, while the hippocampus is mainly innervated by the MR.12, 13 The substantia nigra and the ventral tegmental area (VTA) receive innervation from both MR and DR nuclei.12,14–18 Since the classification of the different serotonin receptor subtypes by an international committee in 1986,19,20 several new receptors have been described, mostly due to the advances in molecular biology techniques and the development of selective ligands. To date, seven classes of serotonin receptors have been described in the brain, distinguishable by three criteria: structural (amino acid sequence), operational (drug related), or transductional (receptor coupling). These criteria have been developed and adopted by the International Union of Pharmacology Committee for Receptor Nomenclature and Drug Classification (IUPHAR) to avoid confusion in the nomenclature created by the rapid discovery of new receptors. Receptors belonging to the 5-HT1 family are G-protein coupled receptors negatively linked to adenylate cyclase, sharing 40% homology in their amino acid sequence. These receptors are characterized by a high affinity for serotonin in the nanomolar range. 5-HT1A is a somatodendritic autoreceptor in the raphe nucleus; is postsynaptic in the cortex, hippocampus, and other limbic structures;21,22 and plays a role in feeding and sexual behavior in rodents. 5-HT1A agonists are beneficial in the treatment of anxiety disorders, while antagonists may be effective in enhancing and accelerating the response to selective serotonin reuptake inhibitors (SSRIs) in depression.23 The human 5-HT1B receptors are autoreceptors that regulate the release of 5-HT from the 5-HT terminals.24 Historically, the human versions of these receptors were included in the class of 5-HT1D receptors because it had not been clear that the animal form of the 5-HT1B receptor could be found in the human brain. The class of 5-HT1D receptors has been divided into 5-HT1Dα and 5-HT1Dβ receptors,25 which were recently renamed as human 5-HT1D and 5-HT1B receptors, respectively.26 The 5-HT1B is the predominant form of the 5-HT1D/B family in the human brain.27 5-HT1B receptors are


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present in highest concentration in the globus pallidus, as well as in caudate, putamen, nucleus accumbens, and hippocampal formation, with lower levels in the neocortical regions. 5-HT1B receptors act as terminal autoreceptors or heteroreceptors, modulating the release of 5-HT and other transmitters such as glutamate and acethylcholine. The knockout mouse lacking the 5-HT1B receptors displays enhanced impulsive aggressive behavior28 and vulnerability to develop alcoholism.29 In addition, recent electrophysiological studies revealed that regulation of 5-HT1B receptors plays a key role in the delayed therapeutic response to SSRIs, further establishing the importance of this receptor in mood disorders.30 5-HT1E and 5-HT1F are closely related receptors. 5-HT1E is localized in the cortex, caudate, putamen, and amygdala. 5-HT1F is located on the pyramidal cells of the cortex, in the hippocampus, and the dorsal raphe. No selective ligands are available for these two receptors, and their functions remain to be clarified. Previously named the D receptors by Gaddum and Picarelli,31 5-HT2 receptors are coupled to G-proteins, linked to phospholipase C, and stimulate phosphoinositol turnover. They share 60% homology in their amino acid sequence and a low affinity for serotonin. These receptors are involved in regulation of the hypothalamus-pituitary-adrenal axis and plasma glucose levels. 5-HT2A is often referred to as the classical 5-HT2 receptor and is present in high concentrations in the olfactory bulb, hippocampus, frontal cortex, and piriform and entorhinal cortices.21,32 The 5-HT2A receptor is located on apical dendrites of most pyramidal cells in the primate cerebral cortex,33 in addition to its presence on axon terminals, and on large and medium size gamma-aminobutyric acid (GABA)ergic interneurons. It is believed to be a main target for the psychotogenic action of hallucinogens and some of the therapeutic effects of atypical antipsychotics. The relevance of its apical localization to its role in psychosis is supported by a study showing that clozapine and other atypical antipsychotics induce a redistribution of this receptor from the apical dendrites to the intracellular compartment.34 The human 5-HT2B was recently described. Its mRNA is widely spread in the human brain in very low levels.35 Little is known about its functional significance. The 5-HT2C, previously known as a 5-HT1C, has been reclassified based on its amino acid sequence and second messenger characteristics. It is present in its highest density in choroid plexus, anterior olfactory nucleus, piriform and entorhinal cortices, striatum, amygdala, and SN.21 The location of these receptors in the SN may be of particular interest as they may play a role in regulating the function of dopaminergic cell bodies of the A9 neurons in the SN. 5-HT2C is involved in the regulation of eating, sexual, and locomotive behaviors. Activation of 5-HT2C receptors decreases feeding. 5-HT2C knockout mice are obese and have a decrease in seizure threshold, the latter suggesting a role in regulation of GABA and glutamate transmission. Previously named the M receptors by Gaddum and Picarelli in the periphery,31 5-HT3 receptors were first described in the central nervous system (CNS) in 1987.36 These receptors are ligand-gated cation channels. They are present in low density in limbic and striatal structures.37 They facilitate the release of serotonin, dopamine, and GABA and inhibit acethylcholine and noradrenaline release. Recently described, the 5-HT4 receptor is a G-protein coupled receptor, positively coupled to adenylate cyclase. Present in humans in the hippocampus, striatum, cortex, and substantia nigra, it may play a role in cognition38 and dopamine transmission.39 The 5-HT5 receptors include 5-HT5A and 5-HT5B. No second messenger system has been identified. 5-HT6 and 5-HT7, like 5-HT4 receptors, are positively coupled to adenylate cyclase and may play a role in the therapeutic action of atypical antipsychotics, as some of the new compounds exhibit affinity for these two sites.8

III. ALTERATION OF 5-HT RECEPTORS IN SCHIZOPHRENIA The involvement of alteration of 5-HT transmission in the pathophysiology of schizophrenia is supported by numerous postmortem studies, which have been reviewed elsewhere40–43 (Table 1). The most consistent abnormalities of 5-HT markers in schizophrenia are a reduction in cortical 5-HT


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TABLE 1 Alterations in 5-HT Receptors in Schizophrenia: Postmortem Studies Author

Year

Site

Ohuaha et al.47

1993

5-HT uptake site

Laruelle et al.44 Joyce et al.45 Dean et al.48 Hashimoto et al.51

1993 1993 1995 1991

Joyce et al.45

1993

[3H]8-OH-DPAT

Simpson et al.54 Sumiyoshi et al.55 Burnet et al.53,56 Burnet et al.52 Gurevich et al.49

1996 1996 1996 1997 1997

[3H]8-OH-DPAT [3H]8-OH-DPAT [3H]8-OH-DPAT [3H]8-OH-DPAT [3H]WAY-100635

Dean et al.50,79 Benett et al.73 Whitaker et al.74 Mita et al.77 Arora and Meltzer78 Reynolds et al.80 Laruelle et al.44 Joyce et al.45 Dean et al.50,79 Abi-Dargham et al.97 Dean et al.50,79

1999 1979 1981 1986 1991 1983 1993 1993 1999 1993 1999

[3H]8-OH-DPAT [3H]LSD [3H]LSD [3H]ketanserin [3H]spiperone [3H]ketanserin [3H]ketanserin [3H]ketanserin [3H]ketanserin [3H]LY278584 [3H]GR113808

5-HT1A

5-HT2

5-HT3 5-HT4

Ligand

Bmax

[3H]citalopram

Decrease

[3H]citalopram [3H]cyanoimipramine [3H]citalopram [3H]8-OH-DPAT

Decrease Decrease No change Increase

KD

Brain Region

No change Frontal cortex

No change Frontal cortex No change Frontal cortex Increase Hippocampus Frontal cortex, BA 10 Temporal cortex Not significant Frontal cortex BA 9, cinguate cortex Increase Motor cortex, Hippocampus Increase Frontal cortex BA 12 and 11 Increase PFC Increase Frontal cortex BA 46 Increase Frontal cortex BA 46 Increase Frontal cortex BA 9, 44, 6, cinguate cortex No change Frontal cortex BA 9, 8, 10 Decrease No change Frontal cortex No change No change Frontal cortex Decrease No change Frontal cortex Decrease No change Frontal cortex No change No change Frontal cortex No change No change Frontal cortex No change No change Frontal cortex Decrease Frontal cortex BA 9 No change No change Amygdala No change Frontal cortex BA 9, 8,10

transporter density and an increase in cortical 5-HT1A receptor binding. A decrease in 5-HT2A density has also been frequently noted, but this observation might be secondary to previous neuroleptic exposure.

A. 5-HT TRANSPORTERS 5-HT transporters are located on presynaptic serotonergic terminals and are believed to provide an index of serotonergic innervation. Three studies reported decreased density of 5-HT transporters in the frontal cortex of patients with schizophrenia.44–47 Laruelle et al.44 reported decreased density of 5-HT transporters labeled with [3H]paroxetine in the frontal cortex of schizophrenic patients as compared to controls, while no changes were observed in the occipital cortex of the same subjects.44 Joyce et al.45 reported decreased 5-HT transporter density labeled with [3H]cyanoimipramine in the frontal and cingulate cortices in patients with schizophrenia, while no changes were observed in the motor cortex, temporal cortex, and hippocampus. In the same schizophrenic patients, increased 5-HT transporter density was observed in the striatum. Ohuoha et al.47 reported decreased density of 5-HT transporters labeled with [3H]citalopram in the frontal cortex of schizophrenic patients as compared to controls. Dean et al.48 reported decreased affinity of the transporters in the hippocampus, but did not replicate the findings of decreased 5-HT transporters in the frontal cortex in schizophrenia, possibly due to methodological differences, as they examined a different area of the frontal cortex than did the other investigators. Similarly, negative findings were reported by Gurevich and



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Joyce.49 Thus, additional studies are needed to resolve this discrepancy. Unfortunately, no PET radiotracer is presently available to image the 5-HT transporter in the cortex.

B. 5-HT1 RECEPTORS As noted by Gurevich and Joyce, “Postmortem studies of the concentration of 5-HT1A receptors in schizophrenic patients represent a rare consensus in schizophrenia: all studies published to date found an elevation of this receptor subtype in schizophrenic patients.”49 With the exception of one recent negative study,50 seven out of eight studies reported elevations of 5-HT1A receptors in the frontal cortex of patients with schizophrenia.45,49,51–55 All studies were performed with the 5-HT1A receptor agonist [3H]8-hydroxy-2-[di-n-propyl-amino]tetralin ([3H]8-OH-DPAT), except for the study of Burnet et al.52 which used [3H]WAY-100635. Two studies were performed with homogenate binding and five with autoradiography. All studies included samples from the prefrontal cortex (PFC); a significant increase has been reported in all prefrontal Brodmann areas (BA) studied, including the dorso-lateral prefrontal cortex (DLPFC) (areas 8, 9, 45, 46), the frontal pole (BA 10), the orbito-frontal cortex (OFC) (BA 11 and 12), and some premotor areas (BA 6, 44). The effect size (difference in the means divided by SD) varied considerably from small (0.24) to large (1.13), with an average effect size of 0.85 ± 0.34. A similar effect size was obtained when the average was weighted by the number of cases included per study. Combined, these studies reach a significance level of p = 0.0006. Other regions were evaluated. In the cingulate, two studies reported an increase and two found no change. An increase was also reported in the temporal cortex, motor cortex, and hippocampus, but none of these findings were confirmed by the other studies. The finding of increased 5-HT1A receptors was reported in patients on and off drugs at the time of death. Moreover, subchronic (21 days) treatment with haloperidol or clozapine does not affect the density of prefrontal 5-HT1A receptors.56–58 However, as most patients received antipsychotics and other psychotropic medications for years, the possibility that this increase may be a long-term effect of treatment cannot be excluded. An increase in 5-HT1A receptors in the OFC (but not the DLPFC) has also been reported in suicide victims,59 raising questions about the disease specificity of this alteration in patients with schizophrenia. However, four studies failed to detect abnormalities in [3H]8-OH-DPAT binding in the frontal cortex of suicide victims.60–63 In the PFC, 5-HT1A receptors are concentrated in layers I to II, with lower densities in layers III to IV.22,45,61,64 At the ultrastructural level, prefrontal neuronal 5-HT1A receptors are mostly present on the axon hillock of pyramidal cells.65,66 Striatal lesions which induce a degeneration of cortico-striatal projections decrease 5-HT1A receptors in the deep cortical layers, indicating that 5-HT1A receptors are located on pyramidal cells projecting to the striatum.65 In primate pyramidal cortical neurons, 5-HT1A receptors are observed in high levels in the initial segment of the axons (axon hillock).66 This localization is consistent with inhibition of action potential by 5-HT1A agonists.66 Given the postmortem and clinical suggestion of reduced 5-HT innervation in the PFC in schizophrenia, one could propose that the increase in 5-HT1A receptors observed in this region may be due to a functional upregulation of these receptors. This hypothesis is not supported by a majority of studies in rodents, which failed to observe an upregulation of 5-HT1A receptors following 5,7-dihydroxytryptamine lesions of the 5-HT system.67–70 Nevertheless, if the alteration of the 5-HT system in the PFC in schizophrenia is neurodevelopmental, the relevance of lesions in adult rodents is limited. A neurodevelopmental alteration is suggested by the study of Slater et al.,71 showing a lack of regression of vermal 5-HT1A receptors in the cerebellum of patients with schizophrenia compared to controls.

C. 5-HT2 RECEPTORS Studies of 5-HT2 receptors in the frontal cortex of patients with schizophrenia have generated conflicting results. Early studies were performed with [3H]LSD, a ligand which labels both 5-HT1 and 5-HT2 families.72 Bennett et al.73 reported decreased [3H]LSD binding in the frontal cortex of patients with schizophrenia as compared to controls. Because [3H]5-HT binding was not reduced


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in these samples, the decreased [3H]LSD binding was attributed to the 5-HT2A sites, which display relatively low affinity for 5-HT. A second study performed with [3H]LSD showed no differences in the frontal cortex between schizophrenic and control samples.74 The more selective 5-HT2 ligands, [3H]ketanserin and [3H]spiperone, were used in five studies to evaluate frontal density of 5-HT2 receptors. Since both ligands are relatively more selective for 5-HT2A than 5-HT2C,75,76 these studies can be viewed as measuring the 5-HT2A rather than the 5-HT2C. Three studies demonstrated a significant decrease in 5-HT2 density in the frontal cortex of schizophrenic patients,77–79 while no changes were reported in the other three studies.44,45,80 Given that 5-HT2 antagonists downregulate 5-HT2 receptors81–83 and that most antipsychotic drugs display 5-HT2 antagonism,84–86 these differences may reflect differences in the antemortem medication. Supporting this interpretation, a recent PET study with [18F]setoperone failed to detect any significant changes in 5-HT2 density in drug-naive patients with schizophrenia.87 Alternatively, these differences in the density of 5-HT2 receptors in the frontal cortex in schizophrenia may be related to the heterogeneity of the disease. Laruelle et al.44 observed that while schizophrenic patients who committed suicide had 5-HT2 levels comparable to controls, schizophrenic patients who died from natural causes had significantly lower 5-HT2 levels than controls. Interestingly, none of the patients in the series of Mita et al.77 and Arora and Meltzer78 committed suicide. Thus, three studies suggest decreased frontal 5-HT2 density in nonsuicide schizophrenic patients. The cause of death was not reported by Reynolds et al.80 and the series of Joyce et al.45 included both suicide and nonsuicide victims. The significance of this finding is unclear. Suicide per se has been associated with increased frontal 5-HT2 receptor density in some,88–91 but not all44,92–96 postmortem studies. Therefore, this factor has to be controlled in studies of 5-HT2 density in schizophrenia as it may account for some of the discrepancies in the findings. Decreased 5-HT2 density may be associated with predominantly negative symptoms and a lower incidence of suicide.

D. OTHER SEROTONIN RECEPTORS No change in the density of 5-HT3 receptors was observed in the amygdala of patients with schizophrenia.97 A recent study found no change in the density of 5-HT4 receptors in the frontal cortex of patients with schizophrenia.79

IV. PHARMACOLOGICAL MANIPULATION OF 5-HT TRANSMISSION IN SCHIZOPHRENIA In addition to the direct evidence reviewed earlier that 5-HT transmission might be affected in schizophrenia, pharmacological interventions modifying 5-HT transmission provided data implicating 5-HT transmission in the mediation of schizophrenia symptomatology. This evidence is especially compeling regarding interventions modifying 5-HT2A receptor function.

A. 5-HT PRECURSORS The amino acid l-tryptophan is the dietary precursor of 5-HT. Administration of large doses of l-tryptophan increases the synthesis of 5-HT in the brain.98 During the 1960s and 1970s, numerous studies examined the effects of 5-HT precursors on the clinical symptoms of schizophrenia. Lauer et al.99 and Pollin et al.100 administered tryptophan with iproniazid to schizophrenic patients and reported mood elevation, increased involvement, and motor activity. Given the concomitant use of monoamine oxidase inhibitors (MAOI), these data are difficult to interpret. Bowers101 reported mild improvement in the Brief Psychiatric Rating Scale (BPRS) in schizophrenic patients treated with L-tryptophan at doses of 2 to 4 g/day in combination with vitamin B6. Gillin et al.102 observed that tryptophan administration (20 g/day) had no effect in schizophrenia. Chouinard et al.103 tested the



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clinical efficacy of tryptophan (2 to 6 g/day) and benserazide co-administration against chlorpromazine and concluded that the antipsychotic action of the tryptophan-benserazide combination was inferior to that of chlorpromazine. Morand et al.104 described a decrease in aggressivity in schizophrenic patients treated by tryptophan (4 g/day). In summary, tryptophan administration may produce a limited improvement in negative symptoms. Of interest is the fact that worsening of psychosis was not reported. Similar results were reported during the administration of the immediate 5-HT precursor L-5-hydroxytryptophan, although some patients presented exacerbation of psychotic symptoms, maybe related to the fact that l-5-hydroxytryptamine administration also increases catecholaminergic function.105–107

B. 5-HT-DEPLETING AGENTS Two studies with a limited number of patients investigated the effects of the tryptophan hydroxylase inhibitor p-chlorophenylalanine (pCPA). Casacchia et al.108 reported improvement in three out of four acute schizophrenics during pCPA treatment (1250 mg/day), while DeLisi et al.109 reported no significant changes in chronic schizophrenic patients (n = 7, 3000 mg/day). Fenfluramine, a halogenated amphetamine derivative, is believed to cause depletion of the serotonergic system when administered chronically. Shore et al.110 and Stahl et al.111 failed to show significant changes during fenfluramine treatment in placebo-controlled studies (8 to 12 weeks). Soper et al.112 demonstrated that fenfluramine treatment produced worsening of communication competence and thought disorder in treatment-resistant schizophrenic patients. In summary, these studies suggest that 5-HT-depleting agents are not useful in the treatment of schizophrenia and may even further impair cognitive functioning.

C. 5-HT2A AGONISM: LSD

AND

“MODEL” PSYCHOSIS

The observation of an LSD-induced psychosis in healthy subjects was the first indication of a potential relationship between serotonin function and schizophrenia. The early reports in the 1950s emphasized the clinical similarities between LSD-induced psychosis and schizophrenia.113 These were followed by numerous studies which carefully examined the differences, such as the prevalence of visual as opposed to auditory hallucinations, the absence of thought disorder, and the preservation of affect and insight.114 However, these differences were lessened when the comparison involved early as opposed to chronic schizophrenics115 and when cross-cultural differences in schizophrenic symptomatology were examined.116 One study117 attempted to compare LSD effects to the different subtypes of schizophrenia and found similarities between the drug group and the paranoid but not the undifferentiated patients. Interestingly enough, the authors described a higher rate of overlap of symptoms for those drug subjects with poorly integrated premorbid personality. Overall, LSD-induced psychosis seemed to be a potential model for some (i.e., hallucinations and paranoid delusions), but not all aspects of schizophrenia (such as disorganization and negative symptoms).118 Administration of mescaline (3,4,5-trimethoxy-phenethylamine), a phenethylamine hallucinogen, to healthy volunteers resulted, similarly, in symptoms of dissolution of ego boundaries, visual hallucinations, “oceanic boundlessness,” and passivity experiences.119 Similar findings were described in humans with psilocybin.120 Disturbances in performance on neuropsychological tasks and alterations of cerebral blood flow measured with single photon emission tomography and 99Tm-HMPAO have also been described.119 1. Neuropharmacological Effects of Hallucinogens The first observation of an effect of LSD on serotonergic transmission was made in 1961 by Freedman.121 With the discovery of more than 15 subtypes of 5-HT receptors, much more is known about the effects of LSD on central serotonergic receptors. LSD inhibits serotonergic cells in raphe nuclei through a direct agonism on the presynaptic 5-HT1A site, thus reducing the firing of these


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neurons and the release of serotonin.122 It also acts as a weak agonist on the postsynaptic 5-HT1A site. LSD has high affinity for all other 5-HT1 subtypes123,124 and for 5-HT5A, 5-HT5B,125 5-HT6,126 and 5-HT7 receptors.127 However, the hallucinogenic effect of LSD has been linked to its affinity for the 5-HT2 receptor, as this property is shared by substituted phenethylamine hallucinogens such as mescaline, DOI (1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane), DOB (4-bromo-2,5-dimethoxyphenylisopropylamine), and DOM (2,5-dimethoxy-4-methylamphetamine)128 and other indoleamine hallucinogens such as DMT (N,N-dimethyltryptamine) and psilocybin. In general, phenethylamine hallucinogens are more selective for the 5-HT2 receptor than LSD.129–131 A strong correlation was described between effective doses of indoleamines (LSD) and phenethylamine hallucinogens and their respective potency at the 5-HT2 receptor,129,132 suggesting that 5-HT2 receptors mediate the hallucinogenic effects of these drugs. Most data indicates a specific 5-HT2A mechanism, although a 5-HT2C effect cannot be ruled out. LSD has been reported to be an antagonist at the 5-HT2 site by some investigators133 and a full or partial agonist134 by others. However, more recent data demonstrates clearly a partial agonist effect of LSD and DOI on the 5-HT2A receptors in the piriform cortex in the rat.135 This partial agonism effect may explain why LSD can appear as an antagonist, since it can decrease the effect of the agonist, when co-administered at high doses. Its dual effect on 5-HT2 (stimulatory) and 5-HT1A (inhibitory) can also explain how it may appear as an antagonist, since it can modulte its own effect. Psilocybin’s psychotomometic effects in humans were blocked by ketanserin, a pure 5-HT2A antagonist, and risperidone.120 As psilocybin is a potent 5-HT2A and weak 5-HT1A agonist, this study demonstrates, in humans, that 5-HT2A activation is psychotogenic. Another study by the same group showed that this psychosis may be, at least partly, mediated by an increased release of dopamine, as evidenced by a 20% decrease of [11C]racploride binding after psilocybin administration in the striatum of human subjects.136 2. Anatomical Substrates of Hallucinogens 5-HT2A receptors are present in high concentration in the olfactory bulb, hippocampus, frontal cortex, and piriform and entorhinal cortices, while 5-HT2C receptors are present in highest density in choroid plexus, anterior olfactory nucleus, piriform and entorhinal cortices, striatum, amygdala, and SN.137–139 Hallucinogens have been shown to interact with 5-HT2 receptors in the locus coeruleus (LC) and the cortex in rats. In the LC, their effects were reversed by 5-HT2 antagonists140 and by various antipsychotics.141 The reversal of effect was correlated with the 5-HT2 binding affinity of the antipsychotic medications. In the piriform cortex in the rat it has been shown that serotonin induces activation of GABAergic interneurons through the 5-HT2A receptor, resulting in an enhancement of spontaneous inhibitory postsynaptic potentials in the pyramidal cells (IPSPs).142–144 In agreement with the data of Jakab et al. mentioned earlier,33 Aghajanian et al.145,146 have shown that 5-HT, through 5-HT2A receptors, enhances spontaneous excitatory post synaptic potentials (EPSPs) in pyramidal cells of layer V of the neocortex through a focal action on apical dendrites, the main targets for excitatory corticocortical and thalamocortical inputs. This activation leads to an increase in asynchronous release of glutamate by pyramidal cells. This suggests a facilitation of glutamatergic transmission in the cortex via 5-HT2A agonism and may be consistent with the data of Farber and Olney147 showing that 5-HT2A agonism can prevent the vacuolization related to N-methyl-D-asparate (NMDA) neurotoxicity in rodent brain. However, this increase in glutamate release can lead to an alteration in cortico-cortical and cortico-subcortical transmission. In summary, overall these studies suggest a strong relationship between 5-HT2A stimulation and hallucinogen-induced psychosis. More similarities have been described between hallucinogeninduced psychosis and positive symptoms of schizophrenia as opposed to negative symptoms. Thus, one can conclude that alterations in 5-HT2A function may mediate positive symptoms of schizophrenia, possibly by affecting directly or indirectly other transmitter systems such as DA and glutamate. This is consistent with the therapeutic efficacy of the new atypical neuroleptics known to have a strong 5-HT2 antagonism.



D. 5-HT2A ANTAGONISM, CLOZAPINE

AND

87

ATYPICALITY

Almost all antipsychotic drugs have appreciable affinity for the 5-HT2 receptors. 5-HT2 receptors were initially termed “serotonergic component of neuroleptic receptors,” and it was proposed as early as 1978 that this component may play an important role in the antipsychotic properties of neuroleptics.84 Nevertheless, as average clinical doses correlated better with D2 affinity rather than 5-HT2 affinity, D2 receptor blockade was proposed to be the principal mechanism of action of neuroleptic drugs.148–150 Drugs such as clozapine, chlorpromazine, thioridazine, and pipamperone had significantly higher affinity for 5-HT2 than for D2 receptors. However, they were usually prescribed at high doses which induced D2 blockade, suggesting that 5-HT2 blockade was not the principal mechanism of their antipsychotic action. The inverse was true for haloperidol and fluphenazine, which did not significantly block 5-HT2 receptors at average clinical doses.150 More recently, the demonstration of the superior efficacy of clozapine for treatment of schizophrenia and of its low incidence of EPS has promoted a renewed interest in the role of 5-HT2 antagonism in schizophrenia. Given the lack of pharmacological specificity of clozapine, many theories have been proposed to account for its particular clinical profile and have been extensively reviewed elsewhere.5,151–154 Most prominent hypotheses include a higher in vivo selectivity of clozapine as compared to typical neuroleptics for (1) “corticolimbic” D2 receptors, as compared to “striatal” D2 receptors,155,156 possibly as an effect of lower competition with endogenous dopamine in corticolimbic regions than in striatal regions; (2) D4 receptors;153,157 and (3) 5-HT2 receptors.156,158–160 While a host of preclinical and clinical data support each of these assumptions, the introduction of new compounds with a more narrow pharmacological profile is indispensable to identify which of these putative mechanisms are critical for a clozapine-like atypical profile. For example, supporting the first hypothesis is the relative corticolimbic selectivity of benzamides with atypical profiles such as sulpiride or remoxipride, compounds which are otherwise devoid of D4 and 5-HT2 selectivity as compared to D2. Compounds with high D4/D2 selectivity other than clozapine or pure D4 receptor antagonists have not been shown to be effective antipsychotics.161–163 Many new compounds support the hypothesis that a relative 5-HT2 to D2 selectivity provides “atypical” properties, the most extensively tested being risperidone. Following an extensive study of the in vitro receptor affinity profile of typical and putative atypical compounds, Meltzer et al.160 proposed that a ratio of 5-HT2 pKi to D2 pKi > 1.19 (corresponding to a 25-fold selectivity for 5-HT2 as compared to D2) was desirable to achieve an atypical profile. Risperidone, a compound not included in the original study of Meltzer et al.,160 provides a 19-fold selectivity, slightly lower than the cutoff point originally proposed, but still more selective than the typical chlorpromazine (seven-fold selectivity). Placebo-controlled studies have demonstrated the antipsychotic efficacy of risperidone,164,165 and comparison studies with haloperidol or perphenazine have shown superior antipsychotic properties of risperidone.166,167 The U.S.–Canadian collaboration study included 388 schizophrenic patients divided into six groups: placebo, 2, 6, 10, or 16 mg daily risperidone and haloperidol 20 mg daily for 8 weeks.168 Positive symptoms were significantly reduced as compared to placebo in the 6-, 10-, 16-mg risperidone groups and in the 20-mg haloperidol group. Negative symptoms were significantly reduced only in the 6- and 16-mg risperidone group, but not in the 20-mg haloperidol group. EPS were significantly higher than placebo in the 16-mg risperidone group and in the 20-mg haloperidol group. Because haloperidol is significantly more selective toward D2 than 5-HT2 and because neither haloperidol nor risperidone have prominent antimuscarinic properties, this study provided the best data to date to evaluate the impact of the addition of a preferential 5-HT2 blockade to D2 blockade in the treatment of schizophrenia. This study supports the hypothesis that a balanced 5-HT2/D2 blockade has superior efficacy in the treatment of negative symptoms and a lower EPS liability. However, EPS and negative symptoms can be correlated and difficult to distinguish clinically. The observation of a significant improvement in negative symptoms despite a similar incidence of EPS in the 16-mg risperidone group as compared to the 20-mg haloperidol group


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suggests that improvement in negative symptoms is unrelated to decreased EPS. This study also indicates that a pronounced selectivity (20-fold or more) for 5-HT2 blockade as opposed to D2 blockade reduces EPS incidence within a certain dose range only. At higher doses of risperidone, EPS were comparable to the haloperidol group. Thus, 5-HT2 blockade may not be efficient at reducing EPS in the presence of complete or near complete D2 blockade. In other terms, the beneficial effect of 5-HT2 blockade on EPS may only be manifest when D2 receptors are not completely saturated. More recently, other atypical agents have been introduced: olanzapine,169 quetiapine,170 and ziprasidone.171–173 These have been demonstrated to be effective in the treatment of positive and negative symptoms in schizophrenia with fewer side effects than typical neuroleptics. Efficacy in treatment-resistant schizophrenia has been demonstrated for clozapine4 and risperidone,174 while the evidence for olanzapine is mixed.175,176 Most studies have shown a preferential response of negative symptoms to atypical antipsychotics vs. typicals.4,177 This, however, was attributed by some investigators to an improvement in secondary negative symptoms, i.e., those related to positive symptoms, depression, EPS, or environmental deprivation, vs. the primary negative symptoms otherwise characterized by the deficit syndrome,178,179 resulting in controversial debates.180 Meta-analyses of available studies have been published showing generally slight advantages of atypical antipsychotics in the treatment of negative symptoms.181,182 Despite the traditional resistance to treatment of cognitive impairments in schizophrenia, recent data related to atypical neuroleptics suggest that these drugs may have relatively greater efficacy than typical neuroleptics for treating these deficits.183,184 The improvement in negative symptoms and cognition is generally attributed to increased dopaminergic tone in the frontal cortex induced by 5-HT2A antagonism and possibly 5-HT1A agonism for some compounds (see later). While these treatment studies clarify the therapeutic effect of a combined 5-HT2 and D2 antagonism, they do not inform us about the potential benefit of “pure” 5-HT2 antagonists in the treatment of schizophrenia. Ritanserin, a potent 5-HT2A/2C antagonist, is not devoid of activity at the D2 receptor, but its 5-HT2/D2 selectivity is three times higher than risperidone. In predominantly type II schizophrenic patients, ritanserin augmentation of classical antipsychotics, as compared to placebo augmentation, was found to induce a significant reduction in BPRS, mainly due to a decrease in negative symptoms such as anergia and anxiety/depression.185 In this trial, ritanserin was more potent than placebo in reducing EPS, a finding which has been replicated.186,187 However, therapeutic effects of ritanserin administered alone remain controversial and need further study.188,189 Pipamperone, a highly selective 5-HT2/D2 drug, has been characterized by a low EPS profile and antiautistic, disinhibiting, and resocializing effects.84,185 MDL 100,907, a compound with high affinity for 5-HT2A receptors and negligible affinity for D2 receptors, has shown promising properties in preclinical studies predictive of atypical antipsychotic properties.190 However, MDL 100,907 alone was not found to be as effective as haloperidol, and its development as an antipsychotic was recently discontinued, suggesting that pure 5-HT2A antagonism alone may not be sufficient to have a clinically effective antipsychotic agent. So far, D2 blockade remains a necessary component for a therapeutic antipsychotic effect, as demonstrated by the fact that no known effective antipsychotic lacks D2 antagonism. Clinical trials with fananserin, an antagonist at D4 and 5-HT2A receptors, show a lack of efficacy, illustrating the notion that neither D4 or 5-HT2A antagonism in the absence of D2 antagonism seem to be associated with clinical improvement.191 In conclusion, antagonism at 5-HT2A when added to D2 antagonism may contribute to the atypical profile of an antipsychotic, i.e., to better tolerability, fewer motor side effects, and better efficacy on negative symptoms, but alone may not confer antipsychotic properties.

E. ACTION

OF

ANTIPSYCHOTIC DRUGS

AT

OTHER SEROTONERGIC RECEPTORS

Most atypical antipsychotics have affinities for multiple serotonergic receptors (Table 2). The 5-HT1A, 5-HT2C, 5-HT6, and 5-HT7 receptors deserve further discussion, as 5-HT3 antagonists have been shown to lack antipsychotic property.192 The actions of 17 antipsychotic agents at the 5-HT1A were explored by Newman-Tancredi et al.7 Clozapine, ziprasidone, and quetiapine exhibited partial



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TABLE 2 Affinities of Selected Antipsychotic Drugs for 5-HT Receptors Drug

5-HT1A

Clozapine Olanzapine Risperidone Quetiapine Sertindole Ziprasidone Amperozide Remoxipride Haloperidol

132 (a)* 1,637 (a)* 292 (a) 250 (a)* 433 (a) 1.24 (a)* 3,100 (b) 11,000 (b) 1,910 (a)

5-HT1B 1,200 1,355 1,325 5,400

(c) (c) (c) (c)

5-HT1D 980 800 100 6,220

(c) (c) (c) (c)

6,950 (c)

5-HT2A

5-HT2C

4 (b) 1.9 (b) 0.39 (b) 82 (b) 0.2 (b) 0.25 (b) 20 (b) 23,000 (b) 28 (b)

5 (b) 2.8 (b) 6.4 (b) 1,500 (b) 0.51 (b) 0.55 (b) 440 (b) 5,500 (b) 1,500 (b)

5-HT3 69 (c) 57 (c) 170 (c)

>1000 (c)

5-HT6 9.5 10 2,400 33

5-HT7

(d) (d) (d) (d)

6.3 (e) 104 (e) 1.39 (e)

1,600 (d)

549 (e) >5,000 (e) 263 (e)

6,600 (d)

Note: a: Values taken from Newman-Tancredi et al., measured in cloned human receptors; * indicates an agonist effect at this receptor.7 b: Values reported in Arnt and Skarsfeldt, available from Lunbeck Pharmacological screening system. 274 c: Bymaster et al., in rat brain.275 d: Kohen et al., values obtained in human cloned receptors. 276 e: Roth et al., in cloned rat receptors.8

agonist activity and marked affinity at the human 5-HT1A receptors, similar to their affinity at D2 receptors. In contrast, risperidone and sertindole displayed low affinity at 5-HT1A receptors and behaved as “neutral” antagonists. Likewise the “typical” neuroleptics, haloperidol, pimozide, raclopride, and chlorpromazine, exhibited relatively low affinity and “neutral” antagonist activity. This study suggests that agonist activity at 5-HT1A receptors may be beneficial, although it is clear from clinical experience with drugs such as buspirone that 5-HT1A agonism without D2 blockade does not confer antipsychotic properties. Recent data has indicated that DA release in the frontal cortex induced by clozapine and other atypical antipsychotics is mediated by 5-HT1A agonism.193 This provides a mechanism for a potential role of this receptor in alleviating negative symptoms and cognitive impairment, an important property of atypical antipsychotics. Currently, new compounds with strong affinity for this receptor are under development and may shed further light on its contribution to the treatment of schizophrenia. Clozapine and olanzapine have high affinities for the newly discovered 5-HT6 receptor (Ki < 20 nM), while clozapine and risperidone but not olanzapine displayed affinities for the 5-HT7 receptor lower than 15 nM in cloned rat cells.8 In addition, this study showed that several typical antipsychotic agents (chlorpromazine and fluphenazine) had high affinities for both the 5-HT6 and 5-HT7 receptors with pimozide displaying the highest affinity of all the typical antipsychotic agents tested for the 5-HT7 receptor (Ki = 0.5 nM). This study seems to indicate that a high affinity for 5-HT6 or 5-HT7 does not relate to the atypical properties of antipsychotics, as it is shared by some typical antipsychotics, and is present in a minority of atypical antipsychotics, unlike 5-HT2A antagonism. Recent studies have shown that serotonin has opposing effects via different serotonergic receptor subtypes. A study by Martin et al.194 showed that ritanserin, a mixed 5-HT2A/2C antagonist, counteracts the inhibitory effect of MDL 100,907 on the hyperlocomotion induced by MK801 in a mouse model of schizophrenia. In another elegant series of experiments,195 the same group showed that the effect of MDL 100907 was abolished by serotonin depletion achieved by pCPA treatment and restored by restitution of endogenous serotonin. This finding suggests that activation of 5-HT2A receptors is stimulatory, while activation of 5-HT2C receptors is inhibitory. A first conclusion from this study is that agonism at the 5-HT2C receptor may be antipsychotic. Another conclusion is that 5-HT2A antagonists effects may depend on increased serotonergic tone. This would suggest that a response to atypical antipsychotics may be observed in patients with high serotonergic transmission.


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This conclusion is in agreement with clinical studies showing that a high serotonin tone, reflected by a low pretreatment CSF HVA/5HIAA ratio, predicts preferential response to clozapine (see references in Reference 195). According to this line of thinking, agonism at the presynaptic 5-HT1A receptor would result in a decreased serotonergic tone and would diminish the beneficial effects of 5-HT2A antagonists, while therapeutic strategies aimed at increasing serotonergic tone would be expected to enhance the efficacy of 5-HT2A antagonists. An alternative interpretation of this data is that atypical antipsychotics may benefit most those patients without serotonergic deficits. Severe deficits in serotonergic function may underlie treatment resistance.

V. SEROTONIN–DOPAMINE INTERACTIONS The “classical” dopaminergic hypothesis of schizophrenia proposes that hyperactivity of dopaminergic (DA) transmission is responsible for at least some of the symptoms of the disorder.196,197 This hypothesis was supported by two observations: (1) the psychotogenic effects of amphetamine and other DA-enhancing drugs such as methylphenidate and L-DOPA and (2) the correlation between the antipsychotic potency of neuroleptics and their potency to block DA D2 receptors.148,149 Because Parkinsonian symptoms can be associated with degeneration of DA neurons in the substantia nigra,198 it is believed that EPS related to antipsychotic treatments are due to blockade of the DA system in the nigrostriatal pathway. Antipsychotic properties are postulated to be a consequence of blockade of an excessive DA activity in the mesolimbic system.3,199 Since negative symptoms are usually not improved, but worsened by typical antipsychotic drugs, it has been proposed that these symptoms are associated with a deficit of DA function.200–202 Given the importance of DA systems in schizophrenia, the putative role of 5-HT in schizophrenia cannot be assessed without examining how alterations of the 5-HT system might affect DA activity. DA–5-HT interactions in the brain are present at different anatomical levels, are mediated by different 5-HT receptor subtypes, and affect different aspects of DA function. The most frequent observations are consistent with the general rule that 5-HT function opposes DA function, i.e., that reduction of 5-HT activity is associated with an enhancement of DA function. This interaction might account for some of the beneficial effects of 5-HT2 antagonism in schizophrenia, such as reduction in EPS liability and improvement in negative symptoms.

A. INHIBITORY INFLUENCE

OF

5-HT

ON

DA FUNCTION

Inhibitory influence of 5-HT has been observed on several DA functions, such as spontaneous locomotor activity, amphetamine-induced locomotor activity and stereotypies, turning behavior, and extrapyramidal functions. 1. Spontaneous Locomotor Activity The antagonistic action of 5-HT activity on DA-mediated behaviors is well documented in many preclinical studies. Electrolytic lesions of the midbrain raphe203 and pCPA administration204 increase spontaneous locomotor activity in rodents. This effect is observed with MR, but not DR lesions.205 Although both lesions induce significant decreases in 5-HT in the cortex, hypothalamus, and striatum, only MR lesions lower hippocampal 5-HT levels, suggesting that 5-HT regulation of spontaneous locomotor activity may be mediated by projections from the MR to the hippocampus.205 This was confirmed by the observation that ablation of the hippocampus abolished the hyperactivity induced by pCPA or raphe lesions206 and by the finding that lesions of MR, but not DR, induced hyperlocomotion, hyperactivity in a novel environment, and a larger startle response. Increased startle is a measure of increased arousal, reflecting a loss of prepulse inhibition as a model of schizophrenia.207 The increase in locomotor activity following 5-HT depletion in neonate rats was manifest at only 15 days of age, suggesting that this inhibitory hippocampal serotonergic system becomes functional as the brain matures.208



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2. Amphetamine-Induced Locomotor Activity Locomotor stimulation following amphetamine is believed to be mediated by DA activity in the accumbens, since DA depletion in the accumbens, but not in the striatum, abolishes locomotor response to d-amphetamine.209 An inhibitory control of DA activity by 5-HT was suggested by the observation that lesions of the raphe nuclei210–212 and the medial forebrain bundle,213 pCPA administration,208,214 5,6-dihydroxytryptamine administration,215 and tryptophan-free diet216 enhance d-amphetamine-mediated hyperlocomotion. 5-HT depletion and amphetamine act synergistically as the increase in locomotion following 5-HT depletion and amphetamine is greater than the sum of both effects alone.208,214 Again, potentiation of amphetamine activity was induced by MR, but not DR lesions.207,217 pCPA also potentiated locomotor activation induced by l-dopa administration218 and by the DA agonist apomorphine.219,220 This suggests that the 5-HT projection which controls locomotion response to DA acts at the postsynaptic level, since the effects of both indirect (amphetamine) and direct (apomorphine) stimulation of DA receptors are enhanced by 5-HT depletion. Direct infusion of 5-HT into the nucleus accumbens reduced hyperactivity induced by intraaccumbens DA infusion or systemic amphetamine administration, suggesting that this nucleus is one site of the inhibitory effect of 5-HT on DA-induced locomotion.221 In parallel, microinfusion of 5-HT in the MR, an operation decreasing 5-HT release in the projection territory via activation of 5-HT somatodendritic receptors, increases apomorphine-induced hypermobility.222 Thus, there is considerable evidence that MR 5-HT neurons modulate DA activity in the nucleus accumbens, at a postsynaptic level, both via direct projection in the accumbens and via the cortical projection. A possible defect in this inhibitory MR-cortical-accumbens circuit in schizophrenia is suggested by some postmortem studies reporting decreased density of 5-HT transporters in the cortex. Such a lesion could result in a disinhibition of mesolimbic DA systems. 3. Amphetamine-Induced Stereotypies While amphetamine- and apomorphine-induced hyperlocomotion are mediated by the mesolimbic system, increased stereotyped behavior such as gnawing, biting, or licking observed after higher doses of amphetamine are mediated by the nigrostriatal DA system.209 Both intrastriatal DA and 5-HT infusions induce stereotyped behavior.223,224 In contrast to the clear effects of 5-HT manipulation on locomotion, the effect of 5-HT on amphetamine- or apomorphine-induced stereotypies is unclear. While several investigators reported that manipulation of the 5-HT system does not affect apomorphine- or amphetamine-induced stereotypies,215,220,225,226 others observed a decrease in amphetamine or apomorphine stereotyped behavior following pCPA or raphe lesions.212,214 Yet, this decrease in stereotypy after pCPA may result from the potentiation of the locomotor response.214 Thus, it is unclear if 5-HT projections directly inhibit stereotyped behavior. 4. Turning Behavior Turning behavior is another paradigm that was used to investigate 5-HT control on the DA nigrostriatal system. Unilateral stimulation of DA activity induces a controlateral turning behavior.227 Unilateral lesions of MR or unilateral intranigral infusion of 5,7-dihydroxytryptamine (DHT) or pCPA induce a controlateral turning behavior, an observation supporting an inhibitory role of 5-HT systems originating from the MR on the activity of nigrostriatal DA neurons.228–233 In contrast, unilateral 5,7-DHT infusion into the DR or the striatum induces ipsilateral turning behavior, and this effect is blocked by neuroleptics, suggesting a facilitatory role of the DR 5-HT systems on striatal DA transmission.212,229,234–236 Stimulation of DR has been shown to increase release of DA in the striatum.237 Thus, while MR 5-HT neurons inhibit DA activity in the substantia nigra, DR 5-HT may facilitate this activity by local action in the striatum.


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5. Neuroleptic-Induced Catalepsy The observation that serotonergic antagonism inhibits neuroleptic-induced catalepsy provides robust behavioral evidence supporting a 5-HT modulation of the DA nigrostriatal system. Blockade of D2 receptors in the striatum by drugs such as haloperidol and chlorpromazine induces catalepsy in rats, a phenomenon generally considered to be an equivalent of EPS in humans.238 p-Chlorophenylalanine (PCPA) or electrolytic lesions of the raphe decreases neuroleptic-induced catalepsy.239,240 5-HT antagonists such as methysergide reduces haloperidol-induced catalepsy, while agonists such as quipazine, the 5-HT precursor 5-hydroxytryptamine, and the 5-HT uptake blockers femoxetine, citalopram, and clomipramine increase haloperidol-induced catalepsy.241,242 These data support an opposing action of 5-HT on DA in the nigrostriatal system. This effect may be mediated by an excitatory action of 5-HT on striatal cholinergic neurons which are inhibited by DA.242 Thus, antiserotonergic drugs may act similarly to the anticholinergic drugs which reduce cholinergic disinhibition following DA blockade. However, striatal infusion of 5,7-DHT does not affect fluphenazine-induced catalepsy, while intranigral infusion decreases fluphenazine-induced catalepsy.243 Thus, the substantia nigra appears to be an important site of action of the 5-HT modulation of neuroleptic-induced catalepsy. Both 5-HT1A agonists (at the autoreceptor sites on the raphe neurons) and 5-HT2 antagonists reduced haloperidol-induced catalepsy.244 6. VTA DA Neuron Activity Activity of DA neurons is inhibited by raphe stimulation, and this effect is prevented by pCPA.16,17 The inhibitory action of 5-HT on SN and VTA neurons appears to be mediated by the local dendritic release of DA245,246 which promotes D2 autoreceptor activation. This inhibitory effect of serotonin on VTA and SN neurons may be mediated by 5-HT2 receptors; acute systemic administration of the 5-HT2 antagonist ritanserin increased the burst firing and firing rate of VTA and SN neurons.247 This effect required the presence of intact endogenous 5-HT, as it was not observed after pCPA treatment. Thus, VTA and SN are under tonic inhibition by 5-HT neurons, possibly via DA dendritic release mediated by 5-HT2 receptors. Acute administration of ritanserin increased DA concentration in the extracellullar fluid in the accumbens measured with microdialysis.248 Since extracellullar DA concentration is thought to depend more on the tonic than the phasic release of DA,202 this observation suggests that 5-HT2 antagonism increases the tonic release of DA in the terminal fields. Furthermore, VTA neurons are more sensitive than SN neurons to the disinhibiting effect of 5-HT2 antagonists. Low doses of ritanserin or ICS 169,369, a highly selective and potent 5-HT2 antagonist, increase A10 firing rate, but do not affect A9 cells. At higher doses, this selective effect of 5-HT2 antagonists on VTA neurons is lost.249 In addition to interactions at the level of the VTA, 5-HT2 receptor antagonism promotes DA release in the terminal fields of the VTA projection. In the prefrontal cortex, local administration of the 5-HT2A antagonists clozapine, ritanserin, ICS 205,930, amperozide, and MDL 100,907 increases DA efflux measured with microdialysis.250–254 Together, these observations suggest that 5-HT2 blockade might enhance DA activity at the level of the VTA and DA terminals. Activation of VTA DA systems by 5-HT2 blockade also prevents dysregulation of VTA DA functions observed following reductions in prefrontal cortex glutamatergic input. Local and reversible cooling of the prefrontal cortex alters the pattern of activity of VTA cells from their normal, burst firing activity to a regular “pacemaker” pattern.255 This alteration of firing activity has been proposed to mediate some of the negative symptoms associated with hypofrontality in schizophrenia such as poor drive and reward. Administration of the NMDA antagonist phencyclidine, known to induce both positive and negative symptoms in humans,256,257 produces the same effects as hypofrontality on VTA neurons, i.e., a reduction in burst activity.258 Ritanserin and amperozide, both potent 5-HT2 blockers, protect VTA DA cells from deactivation induced by cooling of prefrontal



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cortex or phencyclidine administration.254,258–260 These observations are also compatible with a stimulating effect of 5-HT2 antagonists on DA neuronal activity. Together, these data suggest that 5-HT2 antagonists might reduce negative symptoms in schizophrenia through activation of midbrain DA projections to the limbic system and cerebral cortex. Since VTA DA neurons projecting to the accumbens are involved in drive and reward,261 it has been proposed that activation of VTA neurons by 5-HT2 antagonists might provide a basis for their thymosthenic action and the improvement in negative symptoms.247

B. STIMULATORY INFLUENCE

OF

5-HT

ON

DA FUNCTION

Behavioral studies performed with raphe lesions or pCPA treatment have consistently demonstrated an enhancement of amphetamine effects after 5-HT depletion. However, more recently, electrophysiological and microdialysis studies have demonstrated that selective 5-HT2 blockade decreases amphetamine effects on locomotion. MDL 100,907, a selective 5-HT2A antagonist, blocks amphetamine-stimulated locomotion at a dose that does not affect spontaneous locomotion.190 While having no effect on basal DA extracellular concentration, 5-HT2 antagonists such as MDL 100,907, amperozide, and ketanserin decrease methylenedioxymethamphetamine (MDMA)-mediated DA release measured by microdialysis.262,263 Electrophysiological data support the fact that 5-HT2 blockade decreases DA-mediated amphetamine effects by interfering with regulation of DA synthesis. D-Amphetamine produces a marked inhibition of DA activity as recorded by single cell recording. This inhibition is due to neural feedback loops in the SN and to stimulation of somatodendritic receptors following DA release in VTA.264,265 α-Methyl-paratyrosine (αMPT), an inhibitor of tyrosine hydroxylase, the rate-limiting step in DA synthesis, attenuates amphetamine-induced DA release266 and blocks amphetamine-induced slowing of cell firing.264 Thus, DA synthesis plays a major role in the effect of amphetamine on DA neurons. Interestingly, the selective 5-HT2 antagonists ritanserin and MDL 28,133A also significantly suppress the effect of amphetamine on VTA neurons. However, this effect was restored when L-DOPA was co-administered with a 5-HT2 antagonist. Since L-DOPA enters the DA synthetic pathway beyond the point of synthesis regulation (tyrosine hydroxylase), it was proposed that 5-HT regulates tyrosine hydroxylase activity via 5-HT2 receptors. While the 5-HT2 agonist DOI does not appear to increase DA synthesis when given alone, it greatly potentiates amphetamine-induced increase in DA synthesis267 and amphetamine-induced DA release.268 These data suggest that 5-HT2 stimulation may be needed to maintain the increase in phasic DA neuronal activity, as observed after administration of stimulants or during stress. Thus, in this model, 5-HT2 blockade would decrease DA phasic activity (a tyrosine hydroxylase-dependent process) without affecting tonic basal DA activity.269 Since positive symptoms are associated with increased DA release in schizophrenia,270 these preclinical observations suggest that 5-HT2 antagonism might have a beneficial effect on positive symptoms.

VI. DISCUSSION The hypothesis that schizophrenia may be associated with decreased tonic DA activity and increased phasic activity271 provides a framework in which the effects of a balanced 5-HT2/D2 antagonism could be conceptualized. The tonic mode, or baseline mode, plays a role in motivation and drive and appears to be regulated by a corticostriatal and cortico-VTA glutamatergic input. In contrast, the phasic mode is responsible for a rapid increase of DA in the synapse in response to emotions or stress. One function of the tonic baseline activity is to regulate the sensitivity of the system to the phasic release of DA. A decrease in the tonic activity would result in an increased sensitivity of the phasic activity. In schizophrenia, cortical lesions may induce a hypoactivity of the corticostriatal and corticolimbic glutamatergic projections, leading to a decrease in the tonic release of DA, which may be associated with negative symptoms such as lack of drive and motivation. This


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decreased tonic activity, in turn, induces a state of hypersensitivity of the DA system to the phasic release, which can be the substrate of positive symptoms.271 Examination of 5-HT/DA interactions mediated by the 5-HT2A receptors lead to the following suggestion regarding the mechanism of action of balanced 5-HT2A/D2 agents. It is suggested that 5-HT2A blockade acts as a buffer to narrow the range of DA activity in the VTA projection territories, elevating the baseline activity (thus reducing negative symptoms) and decreasing the amplitude of the phasic reactivity (thus reducing positive symptoms). Decreased tonic activity of VTA is observed after inactivation of the frontal cortex or administration of NMDA antagonists. 5-HT2A antagonists restore normal VTA DA activity after inactivation of the frontal cortex, and this might account for improvement in negative symptoms. Obviously, if stimulation of mesocorticolimbic DA baseline activity is the mechanism mediating the improvement in negative symptoms attributed to 5-HT2A antagonism, this effect would be lost in the presence of a complete blockade of D2 receptors.272 Thus, a moderate rather than a complete D2 receptors occupancy might be desirable to permit 5-HT2A antagonism to exert its therapeutic action on the negative symptoms. On the other hand, positive symptoms could be reduced by attenuation of DA phasic activity via blockade of 5-HT2A-stimulated tyrosine hydroxylase activity. If increased DA phasic activity is at least partially dependent on 5-HT2A-stimulated tyrosine hydroxylase activity, 5-HT2 blockade might reduce the tyrosine hydroxylase-dependent DA phasic release responsible for the positive symptoms of schizophrenia. One study seems to contradict this hypothesis so far, where clozapine and risperidone treatment did not normalize the amphetamine-induced DA release in patients with schizophrenia compared to controls.273 However, the effect of D2 blockade may have counfounded the interpretation of the effect of the 5-HT2 antagonism in this study. Revisiting this issue after treatment with a pure 5-HT2 antagonist such as MDL 100,907 is warranted. In addition, a balanced 5-HT2/D2 blockade would alleviate or prevent EPS. Supporting this suggestion is the observation that 5-HT2A blockade added to partial D2 blockade prevents the longterm effects of partial D2 blockade on nigrostriatal systems such as (1) upregulation of D2 receptors in the striatum (but not in the accumbens), (2) initial increase and delayed blockade of the firing rate of DA nigrostriatal neurons, and (3) haloperidol-induced catalepsy. These actions may explain the lower incidence of EPS and the relative protection against tardive dyskinesia observed with balanced D2/5-HT2A antagonism. In addition, this protection against EPS might contribute to the improvement noted on negative symptoms scales. So far, 5-HT2A antagonists show modest efficacy as stand-alone treatments for schizophrenia. However, they do not appear to be as effective in treating schizophrenia as haloperidol. The combination of 5-HT2A antagonism with a partial D2 blockade may be beneficial for the following three reasons. (1) 5-HT2A antagonism increases DA release in the cortex, this effect might lead to an improvement in negative symptoms and cognition, possibly through an increased stimulation of the D1 receptor. This effect may be potentiated by agonism at the 5-HT1A receptor. (2) 5-HT2A antagonists may decrease the tyrosine hydroxylase-dependent or phasic DA release in subcortical areas and improve positive symptoms. (3) 5-HT2A antagonists may increase the D2 receptor blocking threshold associated with emergence of EPS. 5-HT2A antagonists may be even more beneficial in the presence of high serotonergic tone, since increased stimulation of the 5-HT2A receptors, because of their location on apical dendrites of most pyramidal cells in the cortex, may lead to a dysregulation of glutamatergic transmission and cortico-cortical as well as cortico-subcortical transmission. As we better understand the role of the 5-HT2A receptors in the treatment of schizophrenia, much remains to be learned about the other receptors, although the evidence so far does not suggest they play a role as prominent as the 5-HT2A. More research is needed to further clarify the role of these receptors. In conclusion, results of postmortem studies indicate possible alteration of 5-HT transmission in the prefrontal cortex of patients with schizophrenia. Decreased 5-HT transporter density might indicate a deficit in 5-HT innervation. Increased 5-HT1A receptors and decreased 5-HT2A receptors might also contribute to perturbation of 5-HT function in schizophrenia, although the relationship



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between these abnormalities and previous antipsychotic exposure remains to be clarified. On the other hand, stimulation of 5-HT2A receptors is psychototogenic, although LSD-induced psychosis is an imperfect model of the illness. 5-HT2A receptor blockade is a useful augmentation or modulation of the D2 receptor blockade, but 5-HT2A antagonism alone has not yet demonstrated incisive antipsychotic properties. If a 5-HT2A blockade per se does not produce antipsychotic effects in patients with schizophrenia, it would support the argument that these symptoms are not primarly due to hyperstimulation of 5-HT2A receptors. The potential of pharmacological interventions targeted at other 5-HT receptors (such as 5-HT1A agonism) remains to be clarified. A comprehensive model of alterations of 5-HT transmission in schizophrenia has not yet emerged. Additional research is needed, not only to clarify possible alterations of 5-HT systems in schizophrenia, but also to establish their significance in terms of modulation of other transmitters systems (dopamine and glutamate), role in symptomatology, and treatment opportunity.

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245. Williams, J. and Davies, J. A., The involvement of 5-hydroxytryptamine in the release of dendritic dopamine from slices of substancia nigra, J. Pharm. Pharmacol., 35, 734, 1983. 246. Nedergaard, S., Bolam, J. P., and Greenfield, S. A., Facilitation of a dendritic calcium conductance by 5-hydroxytryptamine in the substancia nigra, Nature, 333, 174, 1988. 247. Ugedo, L., Genhoff, J., and Svensson, T. H., Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition, Psychopharmacology, 98, 45, 1989. 248. Devaud, L. L. and Hollingsworth, E. B., Effect of the 5-HT2 antagonist, ritanserin, on biogenic amines in the rat nucleus accumbens, Eur. J. Pharmacol., 192, 427, 1991. 249. Goldstein, J. M., Litwin, L. C., Sutton, E. B., and Malick, J. B., Effects of ICI 169,369, a selective serotonin2 antagonist, in electrophysiological tests predictive of antipsychotic activity, J. Pharmacol. Exp. Therap., 249, 673, 1989. 250. Schmidt, C. J. and Fadayel, G. M., The selective 5HT2A receptor antagonist, MDL 100,907, increases dopamine efflux in the prefrontal cortex of the rat, Eur. J. Pharmacol., 273, 273, 1995. 251. Pehek, E. A., Meltzer, H. Y., and Yamamoto, B. K., The atypical antipsychotic drug amperozide enhances rat cortical and striatal dopamine efflux, Eur. J. Pharmacol., 240, 107, 1983. 252. Pehek, E. A., Meltzer, H. Y., and Yamamoto, B. K., Local administration of ritanserin or ICS 205,930 enhances dopamine and serotonin efflux in rat prefrontal cortex, Soc. Neurosci. Abstr., 19, 302, 1993. 253. Moghaddam, B. and Bunney, B. S., Acute Effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study, J. Neurochem., 54, 1755, 1990. 254. Svensson, T. H., Mathe, J. M., Andersson, J. L., Nomikos, G. G., Hildebrand, B. E., and Marcus, M., Mode of action of atypical neuroleptics in relation to the phencyclidine model of schizophrenia: role of 5-HT2 receptor and alpha 1-adrenoceptor antagonism, J. Clin. Psychopharmacol., 15, 11S, 1995. 255. Svensson, T. H. and Tung, C. S., Local cooling of pre-frontal cortex induces pace-maker-like firing of dopamine neurons in rat ventral tegumental area in vivo, Acta Physiol. Scand., 136, 135, 1989. 256. Allen, R. M. and Young, S. J., Phencyclidine-induced psychosis, Am. J. Psychiatry, 135, 1081, 1978. 257. Snyder, S., Phencyclidine, Nature, 285, 355, 1980. 258. Svensson, T. H., Mode of action of atypical neuroleptic drug: role of 5HT2 receptor antagonism, Schizophr. Res., 11, 115P, 1993. 259. Svensson, T. H., Tung, C. S., and Grenhof, F. J., The 5-HT2 antagonist ritanserin blocks the effect of prefrontal cortex inactivation on rat A10 dopamine neurons in vivo, Acta Physiol. Scand., 136, 497, 1989. 260. Grenhoff, J., Tung, C. S., Ugedo, L., and Svensson, T. H., Effects of amperozide, a putative antipsychotic drug, on rat midbrain dopamine neurons recorded in vivo, Pharmacol. Toxicol., Suppl. 1, 29, 1990. 261. Bozarth, M. A., Neural basis of psychomotor stimulant and opiate reward: evidence suggesting an involvement of a common dopaminergic system, Behav. Brain Res., 22, 107, 1986. 262. Nash, J. F., Ketanserin pretreatment attenuates MDMA-induced dopamine release in the striatum as measured by in vivo microdialysis, Life Sci., 47, 2401, 1990. 263. Schmidt, C. J., Sullivan, C. K., and Fadayel, G. M., Blockade of striatal 5-hydroxytryptamine(2) receptors reduces the increase in extracellular concentrations of dopamine produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine, J. Neurochem., 62, 1382, 1994. 264. Bunney, B. S. and Aghajanian, G. K., d-Amphetamine-induced inhibition of central dopaminergic neurons: mediation by a striato-nigral feedback pathway, Science, 192, 391, 1976. 265. Wang, R. Y., Dopaminergic neurons in the rat ventral tegmental area. III. Effects of D- and L-amphetamine, Brain Research Reviews, 3, 153, 1981. 266. Butcher, S. P., Fairbrother, I. S., Kelly, J. S., and Arbuthnott, G. W., Amphetamine-induced dopamine release in rat striatum: an in vivo microdialysis study, J. Neurochem., 50, 346, 1988. 267. Huang, X. and Nichols, D. E., 5HT2 mediated potentiation of dopamine synthesis and central serotonergic deficits, Eur. J. Pharmacol., 238, 291, 1993. 268. Ichikawa, J. and Meltzer, H. Y., DOI, a 5-HT2A/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat striatum, Brain Res., 698, 204, 1995. 269. Schmidt, C. J., Kehne, J. H., Carr, A. A., Fadayel, G. M., Humphreys, T. M., Kettler, H. J., McCloskey, T. C., Padich, R. A., Taylor, V. L., and Sorensen, S. M., Contribution of serotonin neurotoxins to understanding psychiatric disorders: the role of 5-HT2 receptors in schizophrenia and antipsychotic activity, Int. Clin. Psychopharmacol., 8, 25, 1993.



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7

Role of Adrenergic Receptors in Effects of Antipsychotic Medications on Prefrontal Cortical Function Amy F. T. Arnsten

CONTENTS I. Introduction ...........................................................................................................................109 II. Postsynaptic, α-2-Adrenoceptor Stimulation Improves PFC Function ...............................110 III. α-1-Adrenoceptor Stimulation Impairs PFC Function ........................................................111 IV. Relevance to Neuropsychiatric Disorders ............................................................................115 Acknowledgment............................................................................................................................116 References ......................................................................................................................................116

I. INTRODUCTION How do neuroleptics achieve their antipsychotic effects? The vast majority of research on antipsychotic medications has focused on the contribution of dopamine (DA) receptor actions, with particular emphasis on the role of the D2 DA receptor family. However, a few researchers have noted that all effective antipsychotic medications also have α-1-adrenoceptor blocking activity and that norepinephrine (NE) activity is altered in psychotic disorders.1,2 Indeed, the atypical antipsychotics share a triad of receptor blocking activities: DA D2/D4, serotonin (5HT) 5HT2A, and α-1-adrenergic receptor blockade. Although most recognize the importance of DA D2/D4 and 5HT2A receptor actions, many have considered that α-1-adrenoceptor blocking actions may only contribute to the sedative side effects of antipsychotic medications.3 This perspective is consistent with the known excitatory effects of α-1 receptor stimulation on thalamic4 and cortical activity.5 However, recent research suggests that α-1-adrenoceptor blockade may also confer therapeutic actions to antipsychotic medications, as α-1-adrenoceptor stimulation can markedly impair the cognitive functions of the prefrontal cortex (PFC).6–8 The cognitive functions subserved by the PFC are fundamental to many symptoms of mental illness.9 The PFC allows working memory to guide behavior, inhibiting inappropriate motor responses and reducing processing of distracting stimuli. Thus, the disruption of these processes by high levels of NE α-1-adrenoceptor stimulation in PFC could produce such common symptoms as working memory deficits, poor concentration, impaired sensory gating, and impulsivity. PFC dysfunction also likely contributes to thought disorder (concrete or perseverative thinking, loose associations) and negative symptoms such as social withdrawal. This chapter will briefly review the evidence that NE has powerful modulatory effects on PFC functions.

0-8493-0744-9/00/$0.00+$.50 © 2000 by CRC Press LLC

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II. POSTSYNAPTIC, α-2-ADRENOCEPTOR STIMULATION IMPROVES PFC FUNCTION There is now extensive evidence that NE improves PFC functions through actions at postsynaptic α-2A adrenoceptors.10,11 α-2-Adrenoceptor agonists such as clonidine, guanfacine, or meditomidine administered systemically12–16 or directly into the PFC8,17,18 improve working memory performance in monkeys and rats. These effects are blocked by co-administration of α-2 antagonists such as yohimbine, which by themselves impair working memory performance.13,19 α-2 Agonists are more potent and more efficacious in animals with catecholamine depletion, consistent with actions at postsynaptic receptors.13,20 Evidence suggests that the α-2A receptor subtype is likely the receptor underlying beneficial effects on working memory, based on pharmacological profiles12,16,21 and preliminary results from mice with genetically altered α-2 receptors.22 The cognitive-enhancing effects of α-2 agonists can be completely dissociated from their sedating and hypotensive actions,12 which likely occur in different brain regions. The importance of drug actions in the PFC for working memory enhancement has recently been confirmed in electrophysiological studies of monkeys performing working memory tasks. In these studies, iontophoresis of the α-2 antagonist yohimbine onto PFC neurons reduced delay-related firing.23,24 Delay-related firing, i.e., an increased rate of firing during the delay period relative to spontaneous activity, is thought to be the cellular basis of working memory function.25 Conversely, systemic administration of the α-2 agonist clonidine increased delay-related activity, and this enhancement was reversed by iontophoresis of yohimbine onto the PFC neuron.23 Taken together, these results at the cellular and behavior level indicate that NE actions at α-2 receptors in PFC play an important role in facilitating working memory function. α-2 Agonist-enhancing effects are particularly prominent under conditions of high interference or distraction, conditions that require PFC function for optimal performance.26,27 In contrast, performance of tasks that do not depend on the PFC is not improved by α-2 agonist treatment,28,29 suggesting that these mechanisms may be unique to the PFC. Accumulating evidence indicates that the beneficial effects of α-2 agonists on PFC function in animals extend to humans as well. An older literature showed that the α-2 agonist clonidine could improve PFC deficits in patients with Korsakoff’s amnesia30 or attention deficit hyperactivity disorder (ADHD),31 but the side effects of this agent have limited its clinical use. Interestingly, clonidine improved memory and Trails B performance in schizophrenic patients,32 suggesting that the PFC deficits in this disorder may respond to α-2 agonist stimulation. The drug had no effect on psychotic symptoms or on non-PFC functions, consistent with the animal studies showing preferential effects on PFC function. Similarly, a recent study has shown that clonidine can improve word fluency and working memory in Alzheimer’s patients,33 and researchers have suggested that α-2 agonists may provide an important adjunctive therapy in Alzheimer’s disease.34 Clonidine’s effects in healthy young adults have been more complex. Higher doses that are thought to improve PFC function were often not given to normal individuals due to problematic side effects, and studies using lower clonidine doses have shown mixed effects on cognitive function.29,35–37 Imaging studies with clonidine showed enhanced frontal function in Korsakoff’s patients,38 but studies of normal individuals with lower clonidine doses generally showed changes in thalamus likely related to clonidine’s sedating actions.39 Recent studies of the more selective α-2A agonist guanfacine have been more successful in enhancing PFC function with fewer side effects, similar to studies in animals. Guanfacine improves working memory and other PFC functions in young adults,29,37 and enhances PFC metabolic activity in healthy adults as measured by positron emission tomography (PET) imaging (B. Swartz, personal communication, 2000). Guanfacine has been shown to improve ADHD symptoms and PFC task performance in both open label40–42 and controlled trials (F. Taylor, personal communication, 2000; L. Scahill, personal communication, 2000) and is now being tested in other PFC cognitive disorders. Thus, α-2A receptor stimulation may have therapeutic effects in disorders with PFC cognitive deficits.


Role of Adrenergic Receptors in Effects of Antipsychotic Medications on Prefrontal Cortical Function

111

InsP phosphatase

Inositol

Li+

InsP Phosphotidyl inositol pathway

Gi ENHANCED PFC FUNCTION

Gq

-1

-2A

Ki NE: 56 nM basal levels NE release

NE

-2

IMPAIRED PFC FUNCTION

Ki NE: 330 nM high levels NE release (e.g., during stress, psychotic disorders)

FIGURE 1 Highly schematized summary of NE actions at α-1 vs. α-2 receptors in the PFC. NE has a higher affinity for α-2A receptors (56 nM)67 than for α-1 receptors (330 nM).68 Thus, lower basal levels of NE release may engage α-2A receptors and facilitate PFC function, while high levels of NE release during stress may be needed to engage α-1 receptors and impair PFC function. α-1 Receptors are generally coupled to the phosphotidyl inositol pathway, which is disrupted by lithium administration as indicated.

III. α-1-ADRENOCEPTOR STIMULATION IMPAIRS PFC FUNCTION In contrast to NE actions at α-2A receptors, recent evidence indicates that activation of α-1 receptors impairs PFC cognitive function (Figure 1). NE has a higher affinity for α-2A than α-1 receptors (see legend to Figure 1). Thus, it is likely that low levels of NE (e.g., under basal or nonstress conditions) preferentially engage α-2 receptors and improve PFC function, while during conditions of high NE release, α-1 receptors would become engaged and override the effects of α-2 receptor stimulation. It is well established that high levels of NE are released in the PFC during stress exposure,43 and recent evidence suggests that these high NE levels stimulate α-1 receptors and impair PFC function.7 Thus, rats exposed to a pharmacological stressor, FG7142 (30 mg/kg, i.p.), were markedly impaired on performing a delayed alternation task (Figure 2A),7 a test of working memory dependent on the medial PFC region in rats. This same stressor had little effect on a nonPFC task, spatial discrimination, with the same motor and motivational demands, indicating that stress exposure specifically impairs the cognitive functions of the PFC.44 Stress-induced cognitive deficits were blocked by infusion of the α-1 receptor antagonist urapidil into the PFC prior to cognitive testing (Figure 2A).7 These results indicate that NE stimulation of α-1 receptors contributes to stress-induced PFC cognitive deficits. Infusions of urapidil had no effect under nonstress conditions,7 presumably due to little endogenous NE α-1 receptor stimulation during nonstressful conditions. The effects of stress on working memory performance can be mimicked by infusion of an α-1 receptor agonist into the PFC. Infusions of the α-1 agonist phenylephrine into the PFC in rats markedly impaired working memory performance (Figure 2B).6 This impairment was reversed by co-infusion of the α-1 antagonist urapidil,6 consistent with actions at α-1 receptors. Similar effects have been observed in monkeys performing the delayed-response task, a test of spatial working memory dependent on the dorsolateral PFC surrounding the principal sulcus.8 Infusions of phenylephrine produced a delay-related impairment in working memory performance (Figure 3).8 Infusions were most effective in the caudal two thirds of the principal sulcal cortex,8 the cortical region most tightly associated with spatial working memory performance.45 α-1 Receptors are commonly coupled to the phosphotidyl inositol/protein kinase C intracellular pathway via Gq proteins (see Figure 1).46 Evidence to date suggests that α-1 receptor stimulation


112


A. STRESS VS. URAPIDIL % CORRECT

100 80 60

*

40

VEH VEH VEH STRESS

URA URA VEH STRESS

B. PHENYLEPHRINE VS. URAPIDIL % CORRECT

100 80 60

*

40 VEH VEH

VEH PE

URA VEH

URA PE

C. PHENYLEPHRINE VS. LITHIUM % CORRECT

100 80

*

60 40 VEH VEH

VEH PE

Li+ VEH

Li+ PE

FIGURE 2 Evidence that α-1 receptor stimulation in the PFC impairs working memory function in rats exposed to stress or α-1 agonist infusions. (A) Intra-PFC infusion of the α-1 antagonist urapidil reverses the working memory deficits induced by stress exposure (FG7142 30 mg/kg, i.p.). Results represent mean ± S.E.M. percent correct on the delayed alternation task. VEH = vehicle; URA = urapidil (0.1 µg/0.5 µL); * significantly different from vehicle + vehicle; and † significantly different from stress + vehicle. (B) IntraPFC infusion of the α-1 agonist phenylephrine induces working memory deficits which are reversed by coinfusion of the α-1 antagonist, urapidil. Results represent mean ± S.E.M. percent correct on the delayed alternation task. VEH = vehicle; PE = phenylephrine (0.1 µg/0.5 µL); URA = urapidil (0.01 µg/0.5 µL); * significantly different from vehicle + vehicle; and † significantly different from phenylephrine + vehicle. (C) A dose regimen of lithium (4 mequiv/kg, 18 hr pretreatment) which suppresses phosphotidyl inositol turnover in the brain reverses the working memory deficits induced by intra-PFC infusions of the α-1 agonist phenylephrine. Results represent mean ± S.E.M. percent correct on the delayed alternation task. VEH = vehicle; PE = phenylephrine (0.1 µg/0.5 µL); Li+ = lithium chloride; * significantly different from vehicle + vehicle; and † significantly different from phenylephrine + vehicle.



113

SPATIAL WORKING MEMORY

INFUSION SITES IN MONKEY PFC

Principal Sulcus Arcuate Sulcus

% CORRECT

100

90

80

70 3.0 mm

*

effective sites ineffective sites

2

4 6 8 DELAY (sec)

FIGURE 3 Evidence that α-1-adrenoceptor stimulation in the PFC impairs working memory function in monkeys. (Left panel) Effective infusion sites in the monkey PFC are indicated by the solid circles. This area of the principal sulcus (PS) is the region most associated with spatial working memory function in monkeys.45 (Right panel) Infusion of the α-1 agonist phenylephrine (closed circles) into the monkey PFC produces a highly significant, delay-related impairment in working memory performance. Results represent mean ± S.E.M. percent correct; * significantly different from baseline performance.

impairs PFC function through activation of this second messenger pathway. For example, the cognitive impairment induced by phenylephrine infusions into the rat PFC can be completely reversed by pretreatment with a dose of lithium known to suppress phosphotidyl inositol turnover (Figure 2C).6 These data may have special relevance to bipolar disorder, a disorder commonly treated with lithium and associated with increased NE turnover (see later). However, lithium can alter other second messenger pathways; thus, current studies in animals are focusing on agents which selectively target molecules in the phosphotidyl inositol/protein kinase C cascade. For example, intra-PFC infusion of the protein kinase C inhibitor chelerythrine appears to block the detrimental effects of α-1 agonists.7 These results are consistent with activation of the phosphotidyl inositol/protein kinase C pathway underlying α-1 receptor-mediated impairment of PFC cognitive function. Figure 4 presents a model of how high levels of NE acting at α-1 receptors might impair PFC function at a neuronal level. This model is based on the intracellular recordings of PFC pyramidal neurons by Marek and Aghajanian47 from rat PFC slices. Under basal conditions, signals are conveyed from the distal dendritic tree to the soma by way of high threshold calcium currents. Figure 4A depicts a hypothetical intracellular recording of a calcium-mediated signal. During stress, high levels of NE are released in the PFC, engaging α-1 receptors. The work of Marek and Aghajanian47 suggests that α-1 receptor stimulation may erode signal transfer by increasing noise in the dendritic stem. These studies have shown that NE acts at α-1 adrenoceptors to increase glutamate release, which in turn increases excitatory postsynaptic sodium currents in the proximal stem. This increase in background noise (Figure 4B) would obscure signal transmission by decreasing the signal-to-noise ratio of cell response. Thus, this erosion in signal transfer would prevent the normal increase in delay-related activity of the soma needed to guide behavior during working memory tasks (Figure 4C). Serotonin mechanisms may also contribute to this response. Marek and Aghajanian48 have shown that 5HT2A receptor stimulation in the PFC, like α-1-adrenoceptor stimulation, can increase glutamate release and excitatory postsynaptic potentials in the dendritic stem. This is of particular interest given that most effective antipsychotic medications have both α-1 and 5HT2A receptor blocking properties.


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PREFRONTAL CORTEX

2

A.

Ca++ Ca++ Ca++

Na+ Na+ Na+ Na+

B.

NE NE NE

NE

NE AXON FROM LC

1 GLU

5HT2A

C. cue delay response

FIGURE 4 Hypothetical mechanism by which high levels of α-1-adrenoceptor stimulation in the PFC could impair working memory function. Under optimal conditions, signals are conveyed from the dendritic tree to the soma via calcium currents along the dendritic stem (A). During stress exposure, catecholamine release is increased in the PFC. High levels of NE may engage α-1 adrenoceptors, inducing glutamate release and sodium entry into the dendritic stem.47 This increase in “noise” would obscure signal transfer to the cell body (B). Loss of information would weaken delay-related firing (C); thus, there would be little new information to effectively guide behavioral responses. (See text for a more complete description.)

DA mechanisms also contribute to stress-induced PFC deficits. Stress-induced PFC cognitive deficits can be reversed by DA antagonists, including the D1/D5/5HT2A antagonist SCH23390.44 Furthermore, infusions of a selective D1/D5 agonist into the PFC impairs working memory performance.49 In their intracellular recordings from PFC neurons, Yang and Seamans50 have shown that DA acting at D1/D5 receptors can decrease the high threshold calcium currents that normally convey signals to the soma by closing n and p calcium channels. We have proposed that high levels of DA D1 receptor stimulation during stress might contribute to stress-induced PFC dysfunction by reducing the calcium currents that convey the signals along the dendritic stem.49 Thus, DA D1 receptor stimulation would decrease “signal,” while NE α-1 stimulation may increase noise. It is likely that these NE and DA actions may be additive or synergistic and that the signal may be able to survive either modest reduction by DA or modest noise by NE, but could not survive both. This hypothesis is supported by the finding that either a D1/D544,51 or an α-1-adrenoceptor antagonist7 can protect performance from the detrimental effects of stress. High levels of NE release in PFC may also shift control to subcortical regulation of behavior. Recent evidence from rat studies suggests that α-1 receptor stimulation in the PFC augments DA-mediated processes in the nucleus accumbens, i.e., amphetamine-induced locomotor activation.52 Furthermore, α-1 receptor stimulation appears to enhance β-adrenergic facilitation of amygdala function, i.e., long-term memory consolidation of emotionally charged material.53 Thus, high levels of α-1 receptor stimulation may take the PFC “off-line” but facilitate subcortical regulation of behavior.



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IV. RELEVANCE TO NEUROPSYCHIATRIC DISORDERS The data reviewed earlier suggest that excessive α-1-adrenoceptor stimulation may contribute to PFC dysfunction in mental disorders associated with elevated NE turnover. PFC dysfunction may manifest as impaired working memory, increased distractibility and/or impulsivity, poor stimulus filtering, aggressive outbursts, or other forms of inappropriate behavioral regulation. There are several important neuropsychiatric disorders associated with high levels of NE turnover and PFC dysfunction. Affective disorders have long been thought to involve altered NE activity. The manic phase of bipolar disorder is affiliated with increased brain NE turnover and is commonly treated with lithium.54–56 As mentioned earlier, the finding that phenylephrine’s detrimental effects can be blocked by lithium pretreatment may have particular relevance to mania. These findings suggest that excessive NE stimulation of α-1 adrenoceptors coupled to phosphotidyl inositol/protein kinase C pathways in the PFC may contribute to manic symptoms (e.g., distractibility, impulsivity). Indeed, converging evidence indicates that overactivity of protein kinase C contributes to biploar disorder.57 Although most schizophrenia research has focused on DA, indices of NE overactivity are also found in schizophrenic patients.1 In this regard, it is of interest that clonidine can improve memory and Trails B performance32 and that the atypical neuroleptics may be more effective than typical neuroleptics in normalizing cognitive deficits in schizophrenic patients.58 Recent evidence suggests that the α-2A adrenergic agonist, guanfacine, may further improve PFC cognitive function in patients treated with atypical neuroleptics (J. Friedman, D. Adler, and K. Davis, personal communication, 2000). Most research on patients with Alzheimer’s disease has focused on acetylcholine and the memory functions of the medial temporal lobe. However, there are also marked changes in the NE system. Although the NE cells of the locus coeruleus markedly degenerate in Alzheimer’s disease, brain NE turnover actually appears to increase in patients with advanced dementia.59–61 The appearance of agitated, inappropriate behaviors correlated with elevated plasma NE turnover.61 These behavioral symptoms are often more problematic than memory deficits and frequently lead to institutionalization. Thus, effective pharmacological treatment for these symptoms is critical. Current treatment of behavioral symptoms often involves neuroleptics with potent α-1-adrenoceptor blocking activity. Although the sedative effects of these agents may be considered helpful in these patients, it is also possible that α-1 receptor blockade may actually help to normalize PFC function and inhibit the expression of inappropriate behaviors. Anxiety-related syndromes such as panic62 and post-traumatic stress disorders (PTSD)63–65 are also associated with elevated NE activity. Administration of the α-2 adrenergic antagonist yohimbine to patients with PTSD can increase NE release, exacerbate symptoms such as intrusive memories and flashbacks, and reduce metabolism in the PFC.63 The model proposed in Figure 1 may provide a rationale for these findings. Yohimbine may produce an imbalance between α-1/α-2 actions in the PFC, whereby detrimental NE actions at α-1 adrenoceptors would be increased, while beneficial actions at postsynaptic α-2 adrenoceptors would be blocked. Southwick et al.66 have proposed that loss of PFC function may contribute to the flashbacks and intrusive memories experienced by PTSD patients during yohimbine administration or stress exposure. Southwick et al. argues that the PFC in humans is important for reality testing and that loss of this PFC function may impede a patient’s ability to discriminate between a vivid memory and current experience. It is noteworthy that neuroleptics with α-1-adrenoceptor blocking properties have been used to treat behavioral disinhibition in patients with mania, dementia, and PTSD, as well as schizophrenia. More recently, it has become common to treat the disruptive symptoms of these disorders with atypical neuroleptics which have 5HT2A receptor blocking activity in addition to their α-1-adrenoceptor and dopaminergic actions. As stated earlier, both α-1-adrenoceptor and 5HT2A receptor stimulation in the PFC can increase noise (excitatory postsynaptic potentials) in the dendritic stem


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of pyramidal cells.48 Thus, blockade of both receptors with atypical neuroleptic administration may be particularly helpful in restoring PFC function. It is hoped that continued research in this area will provide a strong rationale for the potential therapeutic contribution of α-1-adrenoceptor blockade.

ACKNOWLEDGMENT This work was supported by PHS MERIT Award AG06037 to AFTA.

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8

Glutamate Receptors in Schizophrenia and Antipsychotic Drugs Donald C. Goff

CONTENTS I. Introduction: Relevance of Glutamate to Schizophrenia .....................................................121 II. Glutamate Receptors .............................................................................................................122 III. Amino Acid Concentrations in Schizophrenia .....................................................................123 IV. Amino Acid Receptors in Schizophrenia .............................................................................123 V. Phencyclidine and Ketamine.................................................................................................124 VI. Antipsychotic Agents Modulate NMDA Antagonist Effects ...............................................126 VII. Antipsychotic Drugs and Amino Acid Concentrations in Serum, Brain, and CSF ............127 VIII. Clinical Trials with Glutamatergic Agents ...........................................................................129 A. Glycine ......................................................................................................................129 B. D-Cycloserine ............................................................................................................129 C. Ampakines.................................................................................................................130 IX. Conclusion.............................................................................................................................130 References ......................................................................................................................................131

I. INTRODUCTION: RELEVANCE OF GLUTAMATE TO SCHIZOPHRENIA Converging lines of evidence suggest that glutamatergic receptors play an important role in the pathophysiology of schizophrenia and may contribute to the unique efficacy of atypical antipsychotic drugs.1–3 In this chapter, evidence will be reviewed linking glutamatergic receptor dysfunction to schizophrenia. In addition, actions of typical and atypical antipsychotic agents at glutamatergic receptors will be discussed, as well as promising new findings of therapeutic strategies targeting glutamateric receptors in schizophrenia. Glutamate and aspartate are the primary excitatory neurotransmitters in the human brain and are involved in aspects of brain development and function implicated in the pathophysiology of schizophrenia. Glutamatergic receptors stimulate neuritic outgrowth, synaptogenesis, and maturation of synapses in the developing brain.4–6 Abnormalities in these processes could result in the abnormal neuronal migration7,8 or reduced neuropil9 recently identified in the postmortem schizophrenia brain. The excitatory amino acids also mediate apoptotic cell death, both as part of programmed neuronal “pruning” during brain development and in response to insults such as hypoxia or excessive activation.10–12 Hippocampal structures are particularly vulnerable to the cascade of hypoxic injury initiated by glutamatergic receptors, hence potentially playing a role in mediating perinatal hypoxia as a risk factor for schizophrenia. Lipska and colleagues13,14 have demonstrated that excitotoxic lesions of the ventral hippocampus of neonatal rats remain silent 0-8493-0744-9/00/$0.00+$.50 © 2000 by CRC Press LLC

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TABLE 1 Glutamate Receptor Subunits Ionotropic AMPA GluR1–4

Kainate

NMDA

GluR5–7 GluRKA1–2 βKA1–2

NMDAR1A–G NMDAR2A–D

α α

Metabotropic mGluR1–8

Note: α is low affinity, and β is high affinity.

until adulthood, at which time the lesioned animals display behavioral hyperactivity in response to stress and dopamine agonists, thus modeling a syndrome suggestive of schizophrenia.13,14 Consistent with postmortem studies in schizophrenia, glutamatergic neurotoxicity can produce cell death without gliotic changes. Additionally, glutamatergic receptors comprise the primary excitatory synaptic links in corticostriatal, thalmocortical, and corticocortical association fibers. Abnormal neurotransmission along these tracts could result in a functional “disconnection” consistent with recent findings in schizophrenia.15 Finally, glutamatergic and dopaminergic systems are highly integrated in the human brain; dopamine D2 receptors mediate release of glutamate and glutamatergic receptors modulate activity of dopamine neurons. This reciprocal relationship between glutamate and dopamine systems implies that a “glutamate model” and “dopamine model” for schizophrenia are complementary.16

II. GLUTAMATE RECEPTORS Glutamate and aspartate are the primary excitatory neurotransmitters in the mammalian brain. Three distinct subtypes of glutamatergic ionotropic receptors (which gate ion channels) have been identified and named according to exogenous ligands that bind selectively to the three receptor subtypes: NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid), and KA (kainic acid) (Table 1).17 NMDA receptors differ from non-NMDA receptors (AMPA and KA) in displaying slower kinetics, increased permeability to calcium influx, and voltage dependency. Only the NMDA-gated ion channel has a binding site for magnesium which occludes the channel at resting membrane potential.18,19 After partial depolarization, the magnesium is displaced and depolarization can be accelerated via the NMDA-gated channel. An additional class of metabotropic glutamatergic receptors are coupled by G-proteins to the inositol signal transduction pathway. NMDA receptors are found in particularly high density in the hippocampus and cerebral cortex and play an important role in long-term potentiation (LTP) which is believed to underlie aspects of memory and learning.20 Because the functional excitatory role of NMDA receptors must be balanced against the potential risk of neurotoxicity associated with excessive activation, the NMDA receptor has a complex assortment of modulatory sites which “fine tune” activation. In addition to the primary recognition site for glutamate and aspartate, there is a second obligatory co-agonist site known as the “strychnine-insensitive glycine recognition site” which must be occupied by glycine, D-serine, or D-alanine in order for glutamate or aspartate to produce opening of the ion channel. Kynurenic acid, a metabolite of tryptophan, acts as an endogenous antagonist at the glycine recognition site. Although saturating concentrations of glycine have been reported in the central nervous system (CNS), localized transporters probably maintain glycine concentrations below saturating levels in the vicinity of NMDA receptors. Additional modulatory sites for zinc and polyamines (spermine and spermidine) have been identified, as well as a redox-sensitive modulatory site. Glutamatergic receptors recently have been cloned and discrete subunits of these receptors have been identified. The receptor complex is formed by subunits which transverse the cell membrane


Glutamate Receptors in Schizophrenia and Antipsychotic Drugs

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in loops forming the ion channel. Specific subunits differ in important pharmacodynamic properties, including affinity for glutamate, threshold for channel opening, and permeability to calcium influx. The GluR-2 subunit reduces calcium permeability of AMPA-gated channels; this effect is dependent upon posttranscriptional editing of the GluR-2 gene. AMPA receptors which lack the GluR-2 subunit or a failure of posttranscriptional editing could produce channels permeable to calcium and place neurons at risk for dysfunction or degeneration. NMDA, AMPA, and KA receptors may differ by region or functional role according to subunit composition; for example, NMDA receptors on inhibitory interneurons may preferentially express NMDAR2C and NMDAR2D subunits, which are more sensitive to activation by glutamate due to a lower threshold for magnesium blockade.21 Pharmacodynamic properties of glutamatergic receptors may be modified by alterations in relative subunit composition. Some evidence suggests that exposure to alcohol, nicotine, and antipsychotic drugs may alter subunit composition.22,23

III. AMINO ACID CONCENTRATIONS IN SCHIZOPHRENIA Kim and colleagues24 first reported diminished concentrations of glutamate in cerebrospinal fluid (CSF) of patients with schizophrenia and proposed decreased glutamatergic activity as an etiologic factor. This finding was replicated by some,25,26 but not all subsequent investigators.27–29 More recent research has suggested that glutamate concentrations in CSF may correspond with specific symptoms or may identify clinically relevant subgroups of patients with schizophrenia. Faustman and colleagues30 assayed CSF from 19 medication-free patients and found a significant inverse correlation between glutamate concentrations and ratings of positive symptoms (r = –0.46). Correlations with CSF glutamate were strongest for ratings of hallucinatory behavior (r = –0.62). Lumbar punctures were repeated in 11 patients 2 to 4 weeks after initiating treatment with haloperidol and revealed no change in glutamate concentrations with treatment, nor did CSF glutamate concentrations correlate with symptom ratings after treatment. Tsai and colleagues29 reported that CSF amino acid concentrations did not differ between a sample of 61 medication-free male patients with schizophrenia or schizoaffective disorder and an age-matched sample of 23 normal controls. However, low CSF concentrations of glutamate, aspartate, and glycine in schizophrenia patients were associated with cortical atrophy (r = –0.31 to –0.33), and low glutamate was associated with more severe thought disorder (r = –0.34). Tsai and colleagues31 also compared 8 brain regions in the post-mortem brains of 12 patients with schizophrenia, 11 unmedicated normal controls, and 6 nonschizophrenic controls medicated with conventional antipsychotic agents. Concentrations of glutamate and aspartate were decreased in the prefrontal cortex and glutamate was decreased in the hippocampus of patients with schizophrenia compared to controls. In addition, concentrations of N-acetylaspartyl glutamate (NAAG), an acidic dipeptide which acts as an antagonist at NMDA receptors, were increased in the hippocampus, and the activity of N-acetylated alpha-linked acidic dipeptidase (NAALADase), the enzyme which cleaves NAAG to produce glutamate and N-acetyl aspartate (NAA), was reduced in the prefrontal cortex and hippocampus. Concentrations of glutamate were increased in the hippocampus and prefrontal cortex of control subjects treated with conventional antipsychotics. In summary, although early findings of low CSF glutamate concentrations have not consistently been replicated, subsequent work suggests that this finding may be relevant to subgroups of patients. In the postmortem brain, regional differences in glutamate and NAAG concentrations may provide more consistent evidence of diminished glutamatergic activity and of compensatory increased glutamate release in response to antipsychotic pharmacotherapy.

IV. AMINO ACID RECEPTORS IN SCHIZOPHRENIA Early autoradiographic binding studies in postmortem brains of individuals with schizophrenia using NMDA, KA, and AMPA or quisqualate revealed consistent increases in non-NMDA receptor


124


TABLE 2 Glutamate Receptors in the Postmortem Schizophrenia Brain Quantitative Autoradiography KA Frontal cortex Hippocampus Striatum Sensory cortex and association fields

AMPA

NMDA

↑ [32, 33] ↓ [34, 35]

Aspartate (Uptake Sites) ↑ Aspartate [32]

↑ [144]

↑ [145] ↑ [38]

↓ Aspartate [146]

Messenger RNA Expression KA Frontal cortex Hippocampus

↓ GluR7 ↓ KA1 [36]

AMPA ↓ ↓ ↓ ↓

Edited GluR2 [41] GluR1 [146] GluR1 and 2 [40] GluR1 [39]

NMDA ↑ NMDAR2D [42] ↓ NMDAR1 [36]

Striatum Note: Numbers shown in brackets are Reference numbers.

binding in the prefrontal cortex32,33 and decreases in the hippocampus.34,35 Binding of aspartate, which reflects density of glutamate uptake sites, was increased in the frontal cortex and decreased in the striatum.36 In addition, Ishimaru and colleagues37,38 found significant increases in strychnineinsensitive glycine binding throughout the primary sensory cortex and related association fields. Ishimaru and colleagues further demonstrated in rats that subchronic (21-day) administration of haloperidol did not affect the density of glycine binding. Cloning of glutamate receptor subunits has allowed more specific regional measurement of receptor expression. Most consistent have been findings of a reduction in subunits comprising AMPA receptors in the hippocampus and parahippocampus.39,40 The AMPA subunit GluR-2, which confers reduced calcium permeability, has been found to be selectively reduced in the hippocampus and parahippocampus, suggesting increased vulnerability to neurotoxicity or neuronal dysfunction.40 Similarly, Akabarian and colleagues41 found an increased proportion (1 vs. 0.1%) of unedited GluR-2 RNA molecules in the prefrontal cortex of patients with schizophrenia and Alzheimer’s disease compared to normal controls, but similar densities of total mGluR-2. This finding is also consistent with a higher risk for neurodegeneration or dysfunction in the schizophrenia brain. The relative subunit composition of NMDA receptors was also found to be altered in the prefrontal cortex of patients with schizophrenia despite normal total density of NMDA receptors.42 Brains of patients with schizophrenia exhibited a mean 53% increase in NMDAR2D, a subunit associated with increased pharmacodynamic response to glutamate — possibly reflecting a compensatory increase in receptor sensitivity. Finally, Sokolov36 found reductions in mRNAs in the frontal cortex for certain subunits associated with AMPA, KA, and NMDA receptors in schizophrenia patients who had been free of neuroleptics for 6 months prior to death. Levels of these subunits (NMDAR1, GluR-1, GluR-7, and KA1) inversely correlated with the time elapsed since discontinuation of antipsychotic medication (see Table 2).

V. PHENCYCLIDINE AND KETAMINE It has been recognized since 1959 that phencyclidine (PCP) produces a syndrome in normal individuals which closely resembles schizophrenia43–45 and exacerbates symptoms of patients with



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chronic schizophrenia.43,46 At subanesthetic doses, PCP is a selective, noncompetitive antagonist of the NMDA receptor which binds to a site within the ion channel and blocks the influx of calcium. Because of reports of protracted psychosis, liability for abuse, and neurotoxicity at high doses in rodents,12 PCP was abandoned as an anesthetic agent and a tool for psychiatric investigation in favor of ketamine, another cyclohexylamine anesthetic which is approximately 10 to 50 times less potent and has a shorter half-life than PCP. Ketamine’s affinity for the PCP binding site is severalfold higher than for other relevant receptors.47 Byrd and colleagues48 demonstrated that the behavioral effects of ketamine and PCP are not affected by co-administration with naloxone, atropine, or chlorpromazine. Ketamine is used commonly as a dissociative anesthetic in veterinarian medicine and less commonly in humans, due to concerns about psychotic symptoms experienced as patients are emerging from anesthesia. Interestingly, psychotic reactions are reported to occur less frequently in children, suggesting that vulnerability to the psychotomimetic effects of ketamine may develop with age in parallel to the typical age of onset for psychotic symptoms in schizophrenia. The psychotomimetic and perceptual effects of PCP are diminished under conditions of sensory deprivation, suggesting that processing of sensory information, rather than perception, is disrupted.49 It has also been reported that frontal lobotomy protects patients with schizophrenia from PCP-induced psychotic exacerbation.46 When infused intravenously, ketamine produces psychotic symptoms, negative symptoms, and cognitive deficits suggestive of, but not identical to, those found in schizophrenia.44 While neurotoxicity has been reported with ketamine in rodents, these lesions occurred at blood concentrations 50 to 100 times higher than levels which produce a schizophrenia-like syndrome in humans.50 Ketamine produces an amotivational state in normal subjects, characterized by blunted affect, withdrawal, and psychomotor retardation.51 Psychotic symptoms tend to take the form of suspiciousness, disorganization, and visual or auditory illusions rather than true hallucinations. Dissociative symptoms, in excess of those found in schizophrenia, also are observed. Cognitive effects of ketamine include impaired performance on the Wisconsin Card Sorting Test, delayed word recall, verbal declarative memory tests, and verbal fluency without evidence of global impairment on the Mini-Mental State Exam.50–52 When administered to medication-free patients with schizophrenia, ketamine produces worsening of delusions, hallucinations, and thought disorder — described as duplicating a patient’s typical pattern of psychotic relapse.53,54 In contrast to studies with normal subjects, worsening of negative symptoms was not consistently observed in schizophrenia patients.53,54 Cognitive functioning, particularly recall and recognition memory, were further impaired by ketamine in schizophrenia subjects.53,54 Chronic treatment with clozapine, but not with haloperidol, blunted ketamine’s exacerbation of clinical symptoms.53,55 Jentsch and Roth45 have argued that chronic administration of NMDA antagonists provides a more valid model for schizophrenia than acute administration. Whereas single-dose infusion studies with ketamine have produced mild and somewhat inconsistent positive symptoms in normal subjects, prolonged exposure in abusers is associated with chronic, severe psychotic symptoms more typical of schizophrenia.44 Monkeys repeatedly exposed to PCP display more perseveration, cognitive impulsiveness, and fewer nonspecific cognitive deficits than monkeys administered a single dose.45 Repeated daily dosing of PCP in vervet monkeys over a 2-week period resulted in impaired performance on a memory task sensitive to prefrontal cortical function which persisted after PCP exposure was stopped.56 This effect was blocked by clozapine. Acute administration of ketamine in normal subjects produced increased prefrontal cortical perfusion bilaterally,57 whereas chronic exposure to PCP is associated with classical “hypofrontality.”58,59 Single-dose administration of ketamine to patients with schizophrenia increased perfusion in the anterior cingulate cortex and decreased perfusion in the hippocampus and visual cortex.53 In rodents, acute administration of NMDA antagonists markedly increases release of dopamine and glutamate in the prefrontal cortex and subcortical structures.60–62 Whereas this increase in dopamine concentrations was previously thought to reflect impaired reuptake, more recent work indicates that increased dopamine release may be mediated by blockade of NMDA receptors


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on inhibitory GABAergic interneurons secondarily disinhibiting glutamatergic transmission via non-NMDA receptors.21,63 Moghaddam and colleagues64 demonstrated that the acute ketamineinduced increase in prefrontal cortical dopamine release and impaired performance on a prefrontal cortical-sensitive memory task in rats could be ameliorated by LY293558, an AMPA/KA receptor blocker. In contrast, administration of a metabotropic glutamate receptor agonist blocked PCPinduced glutamate release without affecting dopamine release.65 Svensson and colleagues66 have demonstrated, by the use of single-cell recordings from ventral tegmental area (VTA) dopamine neurons in rats, that administration of NMDA antagonists increases the firing rate, but decreases the variability of firing, thereby impairing the signal-to-noise ratio. Burst firing was increased in the ventral tegmental area (VTA) dopamine neuron cells projecting to limbic regions and was decreased in cells projecting to the prefrontal cortex. Whereas acute administration of NMDA antagonists releases prefrontal dopamine, subchronic administration of NMDA antagonists is associated with decreased basal and evoked dopamine release in the frontal cortex,56,67 reflecting compensatory effects which may persist after the NMDA antagonist has been discontinued. Medial prefrontal dopamine utilization (DOPAC-to-dopamine ratio) is reduced by approximately 75% in rats following repeated exposure to PCP.67 Total dopamine concentrations are preserved, suggesting that neurotoxicty does not account for this finding. In contrast, Lindefors and colleagues68 recently reported increased dopamine release in the rat prefrontal cortex following repeated administration of ketamine — the reason for this different finding is not clear. Of interest, subchronic administration of NMDA antagonists results in decreased expression of D1 receptor mRNA in the prefrontal cortex of rats and monkeys.45,69,70 The D1 receptor has been shown to be critical to working memory function.71 Consistent with recent revisions of the dopamine model for schizophrenia which posit diminished dopamine activity in the prefrontal cortex and reciprocal dopaminergic hyperactivity in mesolimbic pathways,72 subchronic PCP administration also increases subcortical dopamine release, particularly in the nucleus accumbens.60,73 Increased mesolimbic dopamine activity associated with long-term administration of PCP produces sensitization to the behavioral effects of NMDA antagonists (PCP, ketamine, and MK-801),74–76 dopamine agonists,77,78 and stress.78 Subchronic administration of PCP also leads to an increased mesolimbic dopamine response to haloperidol.78 These findings emphasize the reciprocal modulation of glutamate and dopamine systems and are consistent with a “sensitization model” of schizophrenia, which accounts for the progressive course and reactivity to stress.79

VI. ANTIPSYCHOTIC AGENTS MODULATE NMDA ANTAGONIST EFFECTS As noted previously, psychotic relapse triggered by ketamine in patients with schizophrenia is blunted by pretreatment with clozapine, but is unaffected by haloperidol.53,55 Svensson and colleagues66 demonstrated that clozapine and ritanserin enhance mesocortical dopamine neuron firing after disruption by NMDA antagonists. Prazosin (alpha-1 adrenergic antagonist) inhibited the NMDA-induced increase in mesolimbic dopamine neuron firing.80 Raclopride did not improve mesocortical dopaminergic signaling, but, at high doses, raclopride and prazosin antagonized hyperlocomotion. In mice, PCP-induced hyperlocomotion was blocked by haloperidol only at doses which decreased spontaneous locomotion in untreated mice (0.3 mg/kg).81 In contrast, olanzapine (0.03 mg/kg) and clozapine (0.3 mg/kg) blocked PCP-induced hyperlocomotion at doses 30- and 10-fold, respectively, below those that decreased spontaneous motor activity. These investigators81 further demonstrated similar blockade of PCP-induced hyperlocomotion with 5HT2 antagonists (ritanserin, kitanserin) and found no effect with a 5HT3 antagonist (zatosetron) or 5HT1A antagonist (WAY 100,635).81 Freed and colleagues82 reported that PCP-induced behavioral stimulation in mice was blocked by chlorpromazine, clozapine, GABA receptor agonists (imidazole acetic acid and muscimol), yohimbine, and methylsergide. Haloperidol, diazepam, baclofen, cholinergic and



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anticholinergic drugs, opiate antagonists, and beta-noradrenergic antagonists were ineffective in this model.82 Studying PCP-induced social isolation in rats, Sams-Dodd83 found that SCH 23391 (D1 antagonist) blocked social isolation short term (3 days), but tolerance developed to this effect by day 21. The D2 receptor blocker sulpiride alleviated PCP-induced social isolation and stereotyped behaviors, whereas the D2 receptor agonist quinpirole mimicked and potentiated these behaviors. A D4 antagonist, L-745,870, had no effect. In contrast, Corbett and colleagues84 reported that olanzapine (0.25 mg/kg) and clozapine (2.5 mg/kg) reversed PCP-induced social withdrawal in rats, whereas SCH 23390, raclopride, chlorpromazine, haloperidol, and risperidone failed to reverse social withdrawal. The atypical antipsychotic agents clozapine, olanzapine, and quetiapine have all been found to restore ketamine-induced deficits in sensorimotor gating of the startle reflex, measured by prepulse inhibition.85–87 Haloperidol, raclopride, SCH 23390, ritanserin, and ketanserin did not improve the deficit in sensory gating, whereas chlorpromazine and remoxipride did.85,88,89 Finally, Olney and Farber90 have performed a series of experiments comparing the efficacy of antipsychotic drugs in preventing NMDA antagonist-induced neurotoxicity of the posterior cingulate and retrosplenial cortex in rats. Olanzapine, clozapine, and fluperlapine strongly prevent neurotoxicity, whereas haloperidol and thioridazine display intermediate effectiveness in this model and sulpiride has no significant effect.90–92 Similar to ketamine’s induction of psychosis in humans, neurotoxicity is age related, with relative sparing of young rats.93

VII. ANTIPSYCHOTIC DRUGS AND AMINO ACID CONCENTRATIONS IN SERUM, BRAIN, AND CSF No consistent effect of conventional antipsychotics on serum concentrations of amino acids has been reported94 in clinical trials. However, Alfredsson and Wiesel95 observed that nonresponders to sulpiride had elevated serum concentrations of glutamate at baseline and an increase in serum glutamate concentrations with treatment correlated with response. In a preliminary study, Evins and colleagues96 found that clozapine treatment was associated with an increase in serum glutamate concentrations and baseline serum glycine concentrations correlated inversely with clinical response. In contrast, Labarca and colleagues97 reported that haloperidol treatment decreased glutamate concentrations in CSF and found no correlation with clinical response. In rats, clozapine acutely increases glutamate and dopamine in the prefrontal cortex.98,99 Chronic treatment with clozapine increases dopamine and serotonin in the prefrontal cortex, without affecting glutamate.98–100 In contrast, chronic administration of haloperidol increased glutamate concentrations in the striatum fivefold.98,99 See and Lynch found significant elevation of glutamate in the ventrolateral caudate putamen of rats after 32 days of treatment with fluphenazine.101 The release of glutamate by conventional antipsychotics in the striatum is believed to be mediated by D2 inhibitory axoaxonic receptors on glutamatergic corticostriatal terminals.101 Of possible clinical relevance, CSF concentrations of aspartate and glutamate have been reported to correlate with ratings of tardive dyskinesia in neuroleptic-treated patients, suggesting that elevated striatal glutamate may place patients at risk for neurotoxic injury and irreversible neurological side effects.102,103 In addition, perforated synapses in the caudate, which have been associated with haloperidol-induced extrapyramidal side effects, have been shown to occur in glutamatergic synapses and to be mediated by NMDA receptors.104 In addition to affecting striatal glutamate release via D2 receptor blockade, antipsychotic drugs may affect excitatory amino acid transmission directly by binding at glutamate receptors or by altering the density or subunit composition of glutamate receptors. Lidsky and colleagues105 measured haloperidol and clozapine displacement of [3H]MK-801 binding in rat striatum and cortex and found pKi values for both drugs ranging between 6.2 and 6.7. Based on the binding data, the investigators calculated that haloperidol does not significantly act at NMDA receptors at typical


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clinical doses, but clozapine may produce clinically relevant NMDA receptor blockade, albeit less than 50%. Using intracellular recording and single-electrode voltage clamp, Arvanov and colleagues106 found that haloperidol produced a concentration-dependent inhibition of AMPA receptor-induced current in rat medial prefrontal cortex slices, whereas clozapine produced an enhancement of NMDA receptor-mediated transmission. Ossowska and colleagues107 reported a significant reduction in AMPA receptor binding in the caudate following chronic administration of haloperidol in rats, but no effect on MK-801 binding. Tarazi and colleagues108 found that subchronic (28 days) treatment with SCH 23390 elevated [3H]MK-801 binding in the hippocampus, suggesting an important role for D1 receptors in regulation of hippocampal NMDA receptors. Subchronic, but not chronic (8 months) treatment with haloperidol and clozapine reduced [3H]MK-801 binding in the medial prefrontal cortex and both subchronic and chronic clozapine treatment decreased [3H]MK-801 binding in the caudate putamen.108 In contrast, Ulas and Cotman109 found an increase in NMDA receptor binding in the rat parietal cortex after 21 days of treatment with haloperidol. NMDA receptor binding was measured by [3H]glutamate incubated with AMPA and KA, a method designed to identify the glutamate receptor of the NMDA receptor complex, whereas [3H]MK-801 binds to the PCP binding site and its accessibility to the ligand is determined by channel opening. For example, [3H]MK-801 binding is increased two- to threefold by the addition of glutamate or glycine.110 Banerjee and colleagues110 found that the addition of low-dose haloperidol or clozapine further increased [3H]MK-801 binding; glycine-stimulated binding was particularly enhanced. Both drugs increased levels of depolarization at low dose and inhibited depolarization at high dose, suggesting partial agonist activity mediated via the glycine recognition site. Similar effects were demonstrated for chlorpromazine and thioridazine.111 Fletcher and MacDonald112 also demonstrated that potentiation of NMDA-evoked response by haloperidol was attenuated by an increase in extracellular concentrations of glycine, again suggesting partial agonist activity at the glycine recognition site. McCoy and Richfield113 treated rats for 21 days with haloperidol, pimozide, clozapine, or risperidone and found that all four antipsychotic agents reduced [3H]MK-801 binding. Furthermore, chronic treatment with antipsychotics selectively inhibited glycine-stimulated binding, consistent with desensitization of the glycine recognition site with subchronic exposure.113 Whereas McCoy and Richfield found no effect on spermine-stimulated binding, several groups have recently reported that haloperidol binds to the polyamine spermidine binding site of the NMDA receptor NR2B subunit.114,115 The variability in antipsychotic effects upon glutamatergic receptors is further illustrated by a report by Reynolds and Miller116 that chlorpromazine and phenothiazine derivatives act at the zinc binding site of the NMDA receptor complex to produce an acute inhibitory effect in a functional neurochemical assay. Several investigators studying mRNA expression in the rat brain have reported differential effects of chronic antipsychotic treatment upon densities of glutamatergic receptor subunits which are highly variable depending upon drug class, particular subunit, and brain region (Table 3).22,117–119 Several striking differences have been demonstrated between effects of clozapine and conventional agents. In general, typical antipsychotics increase mRNA expression for NMDA receptors (NMDAR1 and 2) in the striatum, whereas clozapine produces no change.118 This difference may reflect differential liability for extrapyramidal symptoms (EPS). Parallel changes have been found for certain AMPA receptor subunits;119 GluR-1 is increased and GluR-3 is decreased by both haloperidol and clozapine. Other AMPA subunits display differential effects, with haloperidol decreasing GluR-2 and GluR-4, whereas clozapine increases GluR-2 and, in the entorhinal cortex, dramatically increases GluR-4. Similar dissimilarities have been found for KA receptors, with only clozapine reported to elevate expression of mRNA for GluR-6, GluR-7, and KA2.119 Finally, Schneider and colleagues120 demonstrated that administration for 30 days of haloperidol significantly decreased expression of GLT-1, the glial glutamate transporter in rat striatum. Clozapine produced significantly less decrease in mRNA GLT-1. In summary, extensive and complex interactions have been demonstrated between antipsychotic drugs and glutamatergic receptors; several of these relationships consistently differ



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TABLE 3 Antipsychotic Effects on Brain Glutamate Receptors Cortex Clozapine

NMDA ↓ NMDA2C [118]

Typicals

AMPA ↑ ↓ ↑ ↓

GluR1,2&4 GluR3 [22, 119] GluR1 GluR2-3 [22, 119]

Striatum

NMDA

AMPA

Clozapine

No effect [22, 118]

↓ GluR3 [117, 119]

Typicals

↑ All subunits [118] ↑ NMDAR1 [22]

↓ GluR2&4 [117, 119]

Kainate ↑ GluR6–7 ↑ KA2 [119] ↑ GluR5 [119]

Kainate ↓ GluR5 ↑ GluR7 and KA2 [117] ↑ KA2 [117]

Note: Numbers shown in brackets are Reference numbers.

between conventional and atypical agents. In contrast to clozapine, conventional agents increase levels of glutamate in the striatum, the result of blockade of inhibitory D2 receptors on corticostrial glutamatergic tracts120 and downregulation of glutamate transporters. Unlike clozapine, conventional agents also increase mRNA for NMDA receptors in striatum. Growing evidence suggests that increased glutamatergic activity mediated by NMDA receptors in the striatum may play a role in perforated synapses, EPS, and tardive dyskinesia.

VIII. CLINICAL TRIALS WITH GLUTAMATERGIC AGENTS A. GLYCINE Two approaches to clinical trials have shed some light on the relationship between glutamatergic receptors and symptom response in schizophrenia. The evidence for hypoactivity of NMDA receptors associated with a wide range of symptoms characteristic of schizophrenia led to the therapeutic use of agents which activate this receptor complex. Direct agonists at the NMDA receptor are not practical because of the risk of excessive activation and neurotoxicity.121 More promising is the targeting of modulatory sites of the NMDA receptor, particularly the strychnine-insensitive glycine recognition site. Early trials with glycine, 5 to 15 g/day, produced inconsistent results, probably because glycine poorly crosses the blood–brain barrier.122–125 More recently, Javitt, Heresco-Levy, and colleagues have performed a series of trials adding high-dose glycine (30 to 60 g/day) to antipsychotic agents and have demonstrated improvement in negative symptoms.126–128 Glycine did not significantly affect psychotic symptoms or EPS. In one 6-week trial, glycine significantly improved the cognitive subscale of the positive and negative syndrome scale (PANSS). Serum glycine concentrations at baseline significantly predicted (r = 0.9) the response of negative symptoms to adjunctive glycine. Tsai and colleagues129 recently administered D-serine, another full agonist at the glycine recognition site, and reported improvements in negative symptoms, psychosis, and cognitive function as measured by the cognitive subscale of the PANSS and performance on the Wisconsin Card Sorting Test.

B.

D-CYCLOSERINE

In a related approach, several groups have administered D-cycloserine, an antimicrobial agent which acts as a relatively selective partial agonist over a narrow range of concentrations. D-Cycloserine produces approximately 60% activation compared to glycine, so it can be expected to act as an agonist in the presence of low concentrations of glycine and as an antagonist in the presence of


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high concentrations130 — similar to the hypothesized partial agonist characteristics of certain antipsychotic agents at this binding site.110,112 Van Berckel et al.131 observed improvement of negative symptoms in a preliminary study of medication-free patients with a D-cycloserine dose of 100 mg/day. In a preliminary dose-finding trial and a fixed-dose, 8-week, parallel group trial in 46 patients with schizophrenia, Goff and colleagues132,133 also found significant improvement of negative symptoms when D-cycloserine 50 mg/day was added to conventional antipsychotics. However, D-cycloserine did not produce cognitive improvement after 8 weeks of treatment. Rosse and colleagues134 found no improvement in negative symptoms when D-cycloserine 15 and 30 mg/day was added to molindone. In contrast, Goff and colleagues135,136 demonstrated relative worsening of negative symptoms in two placebo-controlled trials in which D-cycloserine 50 mg/day was added to clozapine. This striking dissociation between D-cycloserine effects when added to clozapine compared to conventional agents further supports evidence presented earlier that antipsychotic agents may be acting at the glycine site and that clozapine may differ from conventional agents, possibly by producing sufficient activation to cause D-cycloserine to act as an antagonist.

C. AMPAKINES A final and as yet quite preliminary area of investigation involves the study of drugs acting at the AMPA receptor. A family of drugs, known as “ampakines” which act as positive modulators at the AMPA receptor complex, has recently become available for clinical trials. CX516, the first drug of this class to be studied, has been shown to increase the peak and duration of AMPA receptor-gated currents.137 In rat studies, CX516 increased hippocampal activity in response to stimulation pulses and increased long-term potentiation.138,139 CX516 also improved acquisition and retention in radial arm maze, water maze, and olfactory cue tasks in rats.140 These effects persisted for up to 8 days.140 When added to clozapine and to conventional antipsychotic agents, CX516 synergistically blocked methamphetamine-induced rearing behavior, an effect believed to predict antipsychotic efficacy.141 CX516 was added to clozapine in a small, placebo-controlled, 4-week, escalating-dose trial in six patients with schizophrenia and was well-tolerated without significant adverse effects.142 An additional 13 patients have been studied, adding CX516 at a fixed dose of 900 mg tid to clozapine, again without evidence of serious adverse effects. Safety and efficacy data from the first two trials were combined,143 and none of the 12 patients who received active drug displayed clinical worsening or reported adverse events. Electroencephalographs (EEGs) and electrocardiograms (ECGs) showed no change. CX516 was associated with a consistent pattern of improvement in performance on tests of attention, memory, and distractability. A composite, normalized cognitive score was derived from all cognitive tests, and comparison between groups revealed a statistically significant improvement in cognitive functioning with CX516 (p = 0.002) compared to placebo. While these preliminary data suggest a consistent pattern of response, this work requires replication in a larger sample of patients.

IX. CONCLUSION Multiple lines of evidence have linked abnormalities in glutamatergic receptor density, composition, and function in schizophrenia. Similarities between behavioral effects of NMDA antagonists and clinical symptoms of schizophrenia have focused attention on treatment trials targeting “NMDA receptor hypoactivity.” However, currently available antipsychotic agents alter glutamatergic activity in multiple ways, including enhancing release of glutamate in the striatum, direct binding to NMDA receptors, altering glutamatergic receptor density, and altering the subunit composition of glutamatergic receptors. Many of these effects are regionally selective and differ between antipsychotic agents, with important differences emerging between atypical and conventional agents. Finally, clinical trials in which NMDA receptor activity is enhanced via the strychnine-sensitive glycine recognition site have demonstrated selective improvement in negative symptoms and have



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presented evidence that clozapine may be acting similarly by enhancing NMDA receptor activity. Although quite preliminary, recent work with an ampakine indicate that positive modulation of the AMPA receptor holds promise as selectively improving cognitive deficits in schizophrenia.

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9

The Antipsychotic Effects of Sigma Drugs Ralf-Michael Frieboes and Axel Steiger

CONTENTS I. II.

Introduction ...........................................................................................................................137 Characterization of the Sigma Binding Site.........................................................................138 A. Historic Perspective ..................................................................................................138 B. Sigma Binding Sites in the Brain and in the Periphery ..........................................138 C. Influences of Sigma Ligands on EEG Activity........................................................139 1. EEG Activity and Sigma Ligands in Animals ..........................................139 2. Sleep EEG Investigations in Humans .......................................................139 III. Relationship between Sigma Ligands and Psychosis ..........................................................141 A. Animal Models..........................................................................................................141 B. Sigma Binding Site and Psychosis in Humans ........................................................141 IV. The Role of Sigma Binding in the Efficacy of Classical Neuroleptics...............................141 V. Antipsychotic Efficacy of Antagonistic Sigma Ligands ......................................................142 A. Rimcazole..................................................................................................................142 B. Tiosperone .................................................................................................................142 C. DuP 734 ....................................................................................................................143 D. Panamesine................................................................................................................143 E. Eliprodil.....................................................................................................................147 F. E 5842 .......................................................................................................................147 VI. Conclusions ...........................................................................................................................147 A. Treatment Efficacy of Sigma Ligands ......................................................................147 B. Treatment Safety and Side Effects of Antagonistic Sigma Ligands........................147 References ......................................................................................................................................148

I. INTRODUCTION Three major observations in humans led to the hypothesis that new developed antagonistic sigma (σ) receptor ligands could be useful in the treatment of schizophrenia: (1) there are psychotomimetic effects of σ receptor agonists (benzomorphans and cocaine); (2) most, though not all, of the neuroleptics have (probable) antagonistic affinities for σ receptors, e.g., haloperidol has a high affinity, even exceeding that for dopaminergic receptors; and (3) σ receptors were identified in brain structures, which are possibly involved in the pathogenesis of schizophrenic symptoms. Therefore, since the 70 σ receptor ligands have been developed by different companies, the substances were studied in animal models testing possible antipsychotic properties and were investigated partially in clinical studies on the efficacy in patients with schizophrenia.

0-8493-0744-9/00/$0.00+$.50 © 2000 by CRC Press LLC

137


138


II. CHARACTERIZATION OF THE SIGMA BINDING SITE A. HISTORIC PERSPECTIVE In 1976, Martin et al.1 proposed the first classification of opiate structures. The three subtypes were denoted from their prototypal agonists: µ for morphine, κ for ketocyclazocine, and σ for SKF 10047 (N-allyl-normetazocine). Based on its analgesic property, SKF 10047 was found to induce delusions, hallucinations, depressions, and dysphoria.2,3 This pharmalological profile prompted numerous studies which, due to the absence of selective ligands, resulted in much confusion for several years. Indeed, it was later established that the racemic form of SKF 10047 binds to several receptors;4 (–)SKF 10047, responsible for the analgetic effect, acts on the classical µ and κ opiate receptors,4,5 whereas the σ and phencyclidine (PCP) binding, which correspond, respectively, to the high and low affinity sites for (+)SKF 10047, were assumed to mediate the psychotomimetic effects of the drug.5,6 These latter effects, however, are not reversed by the opiate antagonists naloxone and naltrexone, providing definite evidence that σ sites do not belong to the opiate family.5–8 The distinction between σ and PCP sites took longer to be established. For several years, these two sites were believed to be more or less identical.9 It was only in 1987 that the existence of distinct sites were demonstrated.10

B. SIGMA BINDING SITES

IN THE

BRAIN

AND IN THE

PERIPHERY

σ Receptors, initially identified with [3H]SKF 10047 as a prototypic ligand, are widely distributed in the organism. In vitro autoradiography of σ receptors was done in guinea pig and rat central nervous system (CNS). High levels of σ receptors were found in the hippocampal pyramid cell layer, hypothalamus, pontine and cranial nerve nuclei, and cerebellum.11 C-fos gene expression by the selective σ ligand panamesine (EMD 57445) was detected in the piriform cortex; in the hippocampal areas CA1, 2, 3; the gyrus dentatus, the caudate putamen, the nucleus accumbens, amygdala, and the mamillary bodies.12 In addition, in the brain of the rhesus macaque, the distribution provides support for a functional role of σ binding sites in the limbic system. The highest densities of σ receptors were seen in the amygdala and were widely distributed within the hippocampal formation,13 brain structure involved in emotion and cognition. Several radioligands, for example, NE 100, labeled with 11C in different positions have been used for mapping σ receptors in the living brain, but they have limited potential in positron emission tomography (PET) techniques because of nonspecific binding.14 Probably the high affinity σ1 receptor mediates effects in the CNS (e.g., N-methyl-D-aspartate [NMDA] response in the CA3 region) as well as some in the gastrointestinal tract (GI) (e.g., bicarbonate secretion from the duodenal wall). Low affinity σ2 receptors have been proposed to mediate effects different from σ1 receptors without enantioselectivity and are associated with different signal transduction mechanisms (i.e., guanosine triphosphate [GTP] sensitivity, phosphoinositide response) and/or enzyme function.15,16 In addition to their possible role in the CNS and GI, it has been suggested that σ receptors modulate the immune system.15,16 σ Receptors are present in high concentrations in rat spleen and human blood leukocytes, and there is evidence that signaling mechanisms in immune cells are affected by σ agonists.17 In addition to the interaction with the dopaminergic system, evidence exists for a relationship of σ receptors with neuropeptide Y (NPY) and the NMDA/glutamate system18–22 and with endocrine organs.16,23–25 Wolfe and De Souza26 have demonstrated the presence of σ receptors in rat pituitary, adrenal, testis, and ovary that have kinetic and pharmacologic characteristics comparable with the σ receptor found in the CNS. The physiologic significance of the σ receptors in the various lymphoid and endocrine tissues remains to be determined, but their presence in such high densities suggests that endogenous σ ligands may play an important role in regulating and integrating endocrine and immune responses. Thus, in addition to their central actions, σ agonists including PCP and SKF 10047 may exert their immunosuppressive and endocrine effects directly through actions in the pituitary and target organs. On the other hand, the effects of selective PCP agonists on endocrine function appear to be mediated


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139

primarily through actions in the brain. Furthermore, the immunologic and endocrine effects of neuroleptics such as haloperidol, which have previously been attributed primarily to actions at D2 dopamine receptors, may also be mediated via σ receptors in brain, lymphoid, and endocrine organs. Finally, the immune and neuroendocrine systems may represent useful “windows to the brain” to assess the role of σ and PCP receptors in the CNS.26 In summary, an important role of σ receptors in different regulation systems of the body can be suggested.

C. INFLUENCES

OF

SIGMA LIGANDS

ON

EEG ACTIVITY

A powerful tool for the characterization of neuroactive drugs is the recording of electroencephalographic (EEG) activity after the administration of the substances in animals, healthy controls, or patients with psychiatric diseases. Human EEG recordings can be done either during the daytime in awake subjects or during sleep as polygraphy integrating EEG, electrooculogram, and electromyogram in order to differentiate the various sleep stages. One problem of sleep EEG study designs in patients with psychiatric disorders is that there are alterations of polysomnography due to the disorders themselves, though effects of neuroactive substances on sleep in patients can be compared intraindividually with baseline conditions. Until then, there is little knowledge about the effects of σ receptor ligands on EEG during wakefulness and sleep. 1. EEG Activity and Sigma Ligands in Animals In rats, the behavioral arousal increased and the EEG power spectrum desynchronized after the administration of the σ receptor agonist dextromethorphan through a chronically implanted cannula into the locus coeruleus (LC).27 Rat LC was chosen for microinfusion because it is known that LC neurones are involved in sleep–wake cycle regulation.28 Intravenous administration of a κ opioid agonist after i.v. saline pretreatment produced occasional high-voltage EEG slow-wave bursts that were associated with relatively small increases in spectral power in the 2.5 to 7.5 Hz band as a spectral peak. After pretreatment with the σ antagonists rimcazole and S-7389-4, the κ agonist administration produced significantly larger increases in absolute EEG spectral power, both over the 1 to 50 Hz range and in the 2.5 to 5.0 and 5.0 to 7.5 Hz bands, than after saline. In summary, effects of the κ agonistic substance and the σ ligand on EEG, EEG power spectra, and behavior may reflect interactions between the κ opioid and σ receptor-effector systems.29 In another animal model, cortical and hippocampal power spectra were measured after the administration of metamphetamine, PCP, and cocaine. PCP induced a shift of θ waves to higher frequencies, but cocaine produced no significant change in the hippocampal spectra.30 In conclusion, the three publications were able to describe spectral analytic EEG changes under σ receptor agonists and antagonists and to discriminate influences of σ receptor ligands on EEG power spectrum vs. effects of the κ opioid receptor and vs. effects of the PCP receptor. 2. Sleep EEG Investigations in Humans To our knowledge, in humans pharmaco-EEG studies are not available after the administration of σ receptor ligands. Recently, we performed a randomized placebo-controlled sleep EEG protocol in healthy controls. A single dose of the σ ligand panamesine (EMD 57445) was administered at bedtime to ten young male normal controls.25 Sleep efficiency index increased significantly, whereas time spent awake decreased significantly after the drug. Total sleep time, sleep efficiency index, and sleep onset latency under panamesine in ten probands are depicted in Figure 1. No significant changes in rapid eye movement (REM) sleep or non-REM parameters occurred. The sleep EEG investigation showed sleep-consolidating effects of the drug, comparable to those of classical neuroleptics. Interestingly, panamesine, like haloperidol,31 lacks the prominent effect of the atypical neuroleptic clozapine in increasing stage 2 sleep that has been suggested to be related to clozapineinduced cytokine release.32 Therefore, the immune system, which has been suggested to be involved


140


TST (min)

500 480

SEI (%)

SOL (min)

100

50 45 40 35 30 25 20

95

460 440 420

90 85

15 10 5

400 80 380 360 Placebo

75 Verum Placebo

Verum

0 Placebo

Verum

FIGURE 1 Changes of sleep-continuity parameters after the σ ligand panamesine vs. placebo in ten young controls. Abbreviations: TST, total sleep time; SEI, sleep efficiency index; and SOL, sleep onset latency. (From Frieboes, R. M. et al., Psychopharmacology, 141, 107, 1999. With permission.)

in the pathophysiology of schizophrenia,33 and in the regulation of sleep34,35 is unlikely to be involved in panamesine effects on the CNS. In the young controls, the substance exerted sedative effects, as evidenced by an increase in total sleep time and sleep efficiency and a decrease in intermittent time awake. Beside these sleep-consolidating effects, no significant alterations in sleep architecture, especially in REM sleep parameters, were observed, and the probands did not feel tired in the morning after active treatment, as measured by a sleep questionnaire. There were no changes in the power spectrum of non-REM sleep; however, there have not been any similar investigations on other antipsychotic drugs using sleep EEG spectral analysis yet. Under the assumption that neuroleptics, including panamesine, have σ-antagonistic properties, the results are in accordance with the changes in spectral EEG power after administration of the σ receptor agonist dextromethorphan in the LC of the rat. The σ-agonistic substance increased the behavioral arousal and desynchronized the electrocortical power spectrum, interpreted as sleep-deteriorating effects,27 whereas the probable antagonistic σ receptor ligand panamesine showed sleep-consolidating properties. Similarly, we found sleep-promoting effects of panamesine in a pilot study in patients with schizophrenia.36 In five patients with acute schizophrenia, sleep EEGs were investigated in the course of the third or fourth week of panamesine administration. Sleep EEGs showed shallow and fragmented sleep. In contrast to the sleep EEG variables of matched untreated patients, sleep time under panamesine medication was enhanced; and in sleep stages 1 and 2 the amount of REM sleep and REM density was increased, whereas slow-wave sleep (SWS) was decreased. One patient had a sleep onset REM period with a latency of 1.5 min from sleep onset to the first episode of REM sleep. The exploratory sleep EEG investigation during panamesine treatment showed a wide range of sleep patterns. In the descriptive analysis, sleep period time, sleep onset latency, and amount of SWS, REM sleep, and REM density were different from the same variables in drug-naive patients with schizophrenia.37 There were some similarities to sleep characteristics during treatment of patients with acute schizophrenia with other neuroleptics, e.g., clozapine and haloperidol.31 In a sleep EEG investigation, under these neuroleptic drugs, trends toward a shortened sleep onset latency and an extended sleep period time were found. This is in accordance with the sleep EEG alterations after panamesine in healthy controls mentioned earlier.


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III. RELATIONSHIP BETWEEN SIGMA LIGANDS AND PSYCHOSIS A. ANIMAL MODELS The administration of benzomorphans, e.g., SKF 10047, as well as PCP is followed by psychotomimetic effects with similar behavioral supersensitivity responses in monkeys and rats.38 The σ receptor was proposed to account for that. Ogawa and co-workers39 investigated PCP-induced cognitive dysfunction in rats in a water maze task. PCP-treated rats were significantly slower to find the platform in the water throughout the training; in several trials their swimming latency decreased less than that of the control group.39 Although PCP binding sites on the NMDA/ion channel complex are different from σ receptors, the σ receptor ligand NE 10040 significantly shortened the PCP-induced prolonged swimming latency until the platform was found. Other σ receptor ligands such as BMY 14802 and rimcazole had the same effect, but animals that received the D2 receptor antagonist sulpiride did not differ from PCP-psychotic animal groups that received placebo.39 As there are effects of σ ligands against the PCP-induced behavior, it was suggested that σ receptor ligands would be effective in the treatment of different types of psychosis, including schizophrenia. In another animal model, amphetamine- and dizocilpine-induced enhancement of locomotion and sniffing in rats was decreased by the highly potent and selective σ ligand 1,3-di-(2-tolyl)guanidine (DTG). These results characterize DTG as an antagonist at σ binding sites. In the latent inhibition investigation in rats measuring the retarded conditioning to a previously presented nonreinforced stimulus, the σ ligand BMY 14802 was found to antagonize amphetamine-induced disruption of latent inhibition and to enhance it when low numbers of preexposures and two conditioning trials were given.42

B. SIGMA BINDING SITE

AND

PSYCHOSIS

IN

HUMANS

In normal human controls, severe psychodysleptic symptoms resembling those in schizophrenia, such as hallucinations and depersonalization, developed after PCP and SKF 10047 administration.43 Although there is evidence that these substances exert their effects by acting at two distinct binding sites, psychotomimetic effects of the two ligands are equal. The PCP binding site is located in the ion channel of the NMDA receptor, while the SKF 10047 binds the σ receptor,44 suggesting a functional interaction where σ ligands may modulate the NMDA/glutamatergic system. It had previously been supposed that in schizophrenia the relationship between a decrease of glutamatergic function, including NMDA, AMPA, and kainate receptor sites, and the increased dopaminergic system contributes to pathophysiology,45,46 although the σ binding site may be a superordinate modulating system. Besides the psychotomimetic effects of the σ ligand SKF 10047, we know that even cocaine, which induces acute psychotic episodes, has high affinity for σ receptors. Furthermore, an association between polymorphins in the σ1 receptor gene and schizophrenia was found recently in a sample of 308 patients with schizophrenia compared with 433 controls (odds ratio: 1.27, p = 0.04).47

IV. THE ROLE OF SIGMA BINDING IN THE EFFICACY OF CLASSICAL NEUROLEPTICS In addition to binding to D2 dopamine receptors, many typical and atypical antipsychotic drugs act also on serotonin receptors and on σ binding sites, and it was hypothesized that these receptors are also targets of antipsychotic drugs. It should be noted that the prima vista evidence that antipsychotic drugs act at dopamine and serotonin receptors does not rule out the role of the σ receptor for the antipsychotic efficacy of neuroleptics. Some, but not all of them have very high affinity for σ binding sites, e.g., haloperidol has a σ binding affinity (σ1: 50% BPRS) improvement in out of 12 acute patients who CGI, BPRS, completed the study PANSS in intent-to-treat analysis totally n = 12, 4 responders Significant (improvement >50% BPRS) improvement in out of 7 acute patients who CGI, BPRS, completed the study PANSS in intent-to-treat analysis 4 patients improved in Improvement in negative symptons out of CGI, BPRS, 10 patients with chronic PANSS schizophrenia ? ?

Note: CGI, Clinical Global Impressions; BPRS, Brief Psychiatric Rating Scale; and PANSS, Positive and Negative Syndrome Scale.

this hypothesis.64 In the second clinical trial, tiosperone improved the total BPRS score in only 6 out of 28 patients by more than 20% from baseline. The substance was well tolerated.65

C. DUP 734 DuP 734 is a potent ligand for σ1 and 5HT2, but not for other receptors.66 It preferentially increased dopamine turnover in the cerebral frontal cortex of rats67 and showed antipsychotic-like activities in behavioral experiments. Although it was suggested that a combined pharmacotherapy of classical neuroleptics, for example, of haloperidol and DuP 734, may have beneficial effects on the outcome of patients,68 the authors do not know any results of clinical investigations in patients with schizophrenia.

D. PANAMESINE Panamesine (EMD 57445) is a substance of the 3-aryl-2-oxazolidinone group. In in vitro receptor binding studies, the substance shows a high affinity to σ1 binding sites (σ1: 830 82 1,500 4,060 56 4.5 1,100 21

48 1 6.7 16 21 0.5 11 >10,000 >3,000 1.4 2.4 122

Ziprasidone 10 2.8 7.5 28 37 0.25 0.55 2,830 >10,000 1.9 390 510

Note: Ki values, nmol/L; values derived from several sources. 1–4

include specific 5-hydroxytryptamine (5-HT) subtypes, DA D4, muscarinic acetylcholine (ACh), and α-noradrenergic receptors. Other examples of novel APDs currently in use or in development include risperidone, olanzapine, quetiapine, and ziprasidone. As seen in Table 2, all of these drugs have a mixed affinity profile. The improved clinical profile of the novel APDs over older drugs such as haloperidol is widely held to be due to these mixed receptor profiles. It is still far from clear how the receptor profiles of the novel APDs confer advantages for clinical efficacy, such as the alleviation of negative symptoms or improvement in patients who are treatment resistant to typical APDs. However, some of the specific side effects of all APDs (e.g., certain motor syndromes) can now be related to discrete receptor populations. Until such time as the action of APDs on schizophrenic symptoms is better understood, it is the adverse side effect profile of a drug which will continue to best define the advantages or disadvantages of its clinical application.

III. MOTOR SIDE EFFECTS A. ACUTE MOTOR SIDE EFFECTS Several forms of acute motor side effects can manifest during treatment with APDs.5,6 Extrapyramidal side effects (EPS) generally occur early in treatment and may persist for prolonged time periods if left untreated. Neuroleptic-induced Parkinsonism is a fairly common form of EPS and resembles idiopathic Parkinson’s disease (rigidity, bradykinesia, and tremor). While the symptoms may improve with continued APD treatment or with co-administration of anti-Parkinsonian medication (e.g., benztropine),6,7 Parkinsonism constitutes a major side effect complication. Acute dystonia occurs less frequently than Parkinsonism, but is a severe motor side effect characterized by strong muscle spasms which produce contorting movements and abnormal postures.8 Akathisia is the least recognized form of acute EPS and the most difficult to diagnose. However, by some accounts, it is as common or even more prevalent than Parkinsonism, with prevalency rates ranging from 25 to 75%.9 The symptoms consist of self-descriptions of “inner restlessness,” compulsion to move, and discomfort of the limbs. Overt signs of the motor restlessness include constant shifting of posture and pacing.10 Clozapine is the one APD that is uniformly agreed upon as lacking the high incidence of EPS seen with typical APDs.11 Other novel APDs (e.g., risperidone and olanzapine) have also been found to have a lower incidence of EPS.12,13 However, in contrast to clozapine, some of these drugs show


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a clear dose-dependent occurrence of EPS. This is particularly true for risperidone, which begins to exhibit a typical APD profile at doses exceeding 6 mg/day.12,13 The advantage of the atypical over the typical APDs lies in the fact that therapeutic doses of the novel APDs can generally be maintained at levels below the threshold for EPS. Possible receptor mechanisms which may account for the lower incidence of EPS seen with novel APDs will be considered in turn. 1. Dopamine Receptors Although APDs of different chemical classes vary markedly in their molecular structure and receptor affinity profiles, they all act to some degree as DA receptor antagonists (Table 2). The alleviation of psychotic symptoms has been speculated to come about due to the effects of APDs on mesocortical and mesolimbic DA projections,14,15 while blockade of DA receptors in the nigrostriatal DA pathway has long been suggested as playing a major factor in the various motor side effects produced by APDs.16 Behavioral tests in animals for the acute EPS liability of APDs have relied on the induction of catalepsy, a measure of motor dysfunction in rats which models Parkinsonian effects.17 It is generally assumed that catalepsy is a direct result of DA receptor blockade and that the relative degree of dopaminergic blockade determines the incidence or degree of catalepsy. Another test for EPS liability is the comparison of APD blockade of DA agonist-induced oral stereotypy (mediated primarily by nigrostriatal DA) vs. DA agonist-induced hyperactivity (mediated primarily by mesolimbic DA).18,19 APDs which show a relatively more potent effect at blocking DA agonist induced hyperactivity are deemed to have an atypical profile. These behavioral models in rodents have generally supported a primary role of DA receptors (particularly D2 receptors) in the induction of acute motor side effects.20 Likewise, primate models of EPS have lent support to the role of DA receptor antagonism in the production of various motor side effects.21 However, animal models are limited in their reproduction of the full spectrum of EPS experienced in humans. In clinical studies, positron emission tomography (PET) and single photon emission computed tomography (SPECT) brain imaging have been used over the last decade to study the role of in vivo receptor occupancy in relationship to EPS. Convincing evidence that functional blockade of DA receptors underlies acute EPS has come from PET studies in which patients treated with typical APDs and simultaneously exhibiting acute EPS show high striatal DA D2 receptor occupancy relative to patients showing no EPS.22,23 In addition, patients treated with clozapine showed the lowest D2 receptor occupancy and the lowest incidence of EPS. Further studies have shown that clozapine consistently produces a lower occupancy of D2 receptors at clinically relevant doses (range of 20 to 67%).24,25 As a rule, high occupancy of striatal D2 receptors (>80%) is associated with a high incidence of EPS. Such data fits well with the classic interpretation of D2 receptor antagonism as a causal factor in EPS, especially Parkinsonian side effects. Subsequent studies with a variety of APDs have replicated the finding of a relationship between D2 receptor occupancy and EPS incidence.26 As for some of the novel APDs, risperidone and ziprasidone have been found to show dose-dependent D2 blockade at levels comparable to typical APDs.23,27 Olanzapine has been reported to exhibit D2 occupancy at comparable28 or higher29 levels than clozapine. Of the currently available novel APDs, quetiapine appears to have a D2 occupancy most similar to clozapine.30 Soon after the discovery of multiple DA receptors,31 researchers began looking at the effects of APDs on the different DA receptor subtypes. Of these, the D1 site has been most extensively studied in relation to EPS. Some studies have suggested that a higher ratio of D1 binding may provide a more atypical profile.32 However, selective D1 receptor antagonism produces catalepsy in rodent models33 and EPS in monkeys.21 In addition, clinical trials with D1 receptor antagonists have been disappointing. Thus, it seems that D1 receptor antagonism not only fails to contribute to an atypical profile, but it may actually play a role in the production of acute motor side effects. Two of the other “D2-like” receptors, the D3 and D4 receptors, have received attention as potential targets for antipsychotic efficacy based on the premise that the differences between typical


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and atypical APDs may be explained, in part, by activation of regionally distinct DA receptor subtypes.34,35 Clozapine and other novel APDs (notably quetiapine) have a preferential effect on mesolimbic DA pathways, with a relatively weaker action on nigrostriatal DA pathways.36,37 A high distribution of DA D3 and/or D4 receptors in limbic regions relative to neostriatal regions38 may account for mesolimbic selectivity. However, the contribution of D3 and/or D4 blockade to antipsychotic benefits remains unclear.1,39 As for acute motor side effect liability, it has recently been suggested that a higher D4/D2 ratio may improve the EPS profile of certain novel APDs.40,41 However, the D4/5-HT2A antagonist fananserin was recently reported to produce an increase in akathisia. Further studies are needed to clarify the role of multiple DA receptor subtypes in the production of EPS. The cumulative evidence based on animal studies and clinical data supports the idea that acute dystonic reactions are related to some form of dopaminergic system dysfunction.8,21 One plausible suggestion is that dystonic reactions may be the result of increased DA release occurring on supersensitized striatal DA receptors.43 As the concentration of a recently administered APD decreases, a heightened dopaminergic response occurs, leading to an emergence of dystonic reactions.44 Such a mechanism may also occur in conjunction with altered cholinergic function (see later). DA receptor blockade has also been suggested to play a role in the manifestation of akathisia symptoms. Akathisia was the specified EPS syndrome exhibited by a number of subjects showing concurrently high DA D2 receptor occupancy as determined by PET scans.25 In contrast to the striatal DA receptor blockade responsible for symptoms of drug-induced Parkinsonism, it has been suggested that akathisia may also be linked to blockade of cortical DA receptors by APDs.16,45 Furthermore, interaction of dopaminergic blockade with noradrenergic function may be a contributing factor to the symptoms of akathisia (see later). 2. Serotonin Receptors In recent years, the effects of APDs on various 5-HT receptor subtypes has generated great interest as a possible means of explaining differential motor side effect profiles. It has been proposed that APDs may be broadly separated into typical and atypical groups based on the ratios of their affinities for 5-HT2/D2 receptors.46 Specifically, atypical APDs, such as those listed in Table 2, have a higher 5-HT2/D2 receptor affinity ratio than typical APDs. This preferential serotonergic component has been suggested to contribute to both the superior therapeutic effects of atypical APDs, as well as a lower incidence of EPS.26,46 The major exception is the class of substituted benzamides (e.g., remoxipride), which are highly selective to DA D2/D3 receptors and are thus clearly distinguished from other novel APDs.47 While of interest for receptor affinity comparisons, most benzamide compounds are currently unavailable for clinical use. Evidence for the contribution of 5-HT2 receptor antagonism to a lower incidence of EPS has come from several directions. Some reports indicate that selective 5-HT2 receptor antagonists, such as ritanserin, do not induce EPS48 and may serve as effective treatments for neuroleptic-induced EPS.32,49,50 5-HT2 receptor antagonism has also been found to attenuate haloperidol-induced catalepsy.51 However, there are a number of preclinical and clinical studies which conflict with the hypothesis that 5-HT2 blockade ameliorates EPS,40,52 thus bringing into question the importance of 5-HT2 antagonism. As with DA receptors, PET/SPECT studies have been conducted in order to assess the in vivo 5-HT2 receptor occupancy after acute administration of various APDs. Several atypical APDs (clozapine, risperidone, and ziprasidone) with high affinity for the 5-HT2 receptor show high occupancy at doses below standard clinical doses.23,53,54 Goyer et al.55 found that relative receptor occupancy as determined by [11C]N-methylspiperone clearly differentiated between subjects given clozapine, typical APDs, or no drug. The 5-HT2A index separated clozapine subjects from the other two groups, and the D2 index separated typical APD subjects from the no drug subjects. Although these results suggest a possible contribution of 5-HT2 antagonism to a lower EPS profile, they are


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not conclusive. Several weaknesses of the hypothesized 5-HT2 contribution to a low EPS profile have been recently discussed. For example, correlational analysis of cataleptic potential and selectivity for the 5-HT2A receptor failed to support the contention that the 5-HT2A contribution by itself is critical for a lower EPS profile. Recent arguments on the contribution of 5-HT2 receptors to lowering EPS liability have emphasized the importance of the ratio of 5-HT2 to D2 binding rather than the absolute degree of 5-HT2 antagonism per se.1,26 The affinity of APDs to other 5-HT receptor subtypes may also contribute to the degree of EPS liability, although none have been studied as extensively as the 5-HT2 site in regard to the etiology of EPS. It is worth noting that clozapine has been shown to have greater affinity for the 5-HT1C and 5-HT3 sites when compared with typical APDs such as haloperidol, fluphenazine, and chlorpromazine.57 An intriguing possibility has been put forward that 5-HT1A agonist properties may play a role in an atypical APD profile.58 Both clozapine and ziprasidone have been characterized as showing agonist properties at the 5-HT1A site.59 These 5-HT1A agonist properties may contribute to a lower EPS profile, since selective 5-HT1A agonists can alleviate neuroleptic-induced catalepsy.60 3. Other Receptors The anticholinergic properties of APDs have generated interest for many years,61 primarily since administration of anticholinergic drugs is the standard treatment approach in the management of EPS.6 Excessive muscarinic cholinergic receptor stimulation can lead to dystonic reactions and may contribute to the acute dystonia produced by APDs with low anticholinergic properties.8 For typical APDs, the greater the degree of antimuscarinic activity, the lower the incidence of EPS.7 In fact, the earliest hypotheses on the atypicality of clozapine focused primarily on its significant anticholinergic properties.61 However, the degree of muscarinic receptor affinity cannot fully explain EPS liability, since clozapine (a noncataleptic drug) and isoclozapine (a cataleptic drug) have very similar affinity for muscarinic receptors.62 Furthermore, some of the novel APDs with a lower incidence of EPS (e.g., ziprasidone) have only weak affinity at muscarinic sites (Table 2). Adrenergic receptors have received less attention in regard to their role in EPS. Akathisia has been hypothesized to relate to adrenergic dysfunction, specifically excess activation of β-adrenergic receptors.63 Administration of β blockers, such as propranalol, has had some success in the alleviation of akathisia and is a currently preferred treatment.10 While the effects of adrenergic blockade may be of direct benefit for alleviation of akathisia, a receptor mechanism has been suggested whereby β-adrenergic antagonists enhance the firing rate of DA neurons, resulting in increased release of cortical dopamine. It is of interest to note that novel APDs (e.g., clozapine and risperidone) with significant α-adrenergic receptor affinity have been found to elevate plasma norepinephrine (NE) levels after several weeks of treatment, an effect not seen with typical APDs.64,65 Thus, adrenergic receptor affinity may contribute to the lower EPS profile of some novel APDs.

B. LATE ONSET MOTOR SIDE EFFECTS Chronic (months to years) APD administration can lead to late onset movement disorders, of which tardive dyskinesia (TD) is the most prevalent. TD most commonly presents as orofacial dyskinesia, but can also involve choreiform movements of the trunk and limbs. The disorder is generally accepted to be mainly the result of chronic APD exposure and is estimated to affect 15 to 25% of those receiving such drugs.5,11 TD often manifests more clearly during periods of reduced drug dosing or drug withdrawal. Among the risk factors associated with TD, age has been the most clearly established.66 Other late onset motor syndromes include tardive forms of dystonia and akathisia, which generally present in the same manner as the acute forms, but show a persisting course.67 Given the widespread incidence of late onset motor syndromes, there has been a great deal of interest in understanding the receptor mechanisms of prolonged APD exposure on basal ganglia motor pathways. In addition, an understanding of receptor mechanisms of chronic APD



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exposure may shed light on the atypical APD features which contribute to the lower incidence of such late onset side effects. Clozapine is the one APD for which there is strong evidence that it does not induce TD.11 As noted earlier, other novel APDs have a lower incidence of EPS at clinically relevant doses. Of these drugs, risperidone and olanzapine have been examined for their risk of associated TD. For risperidone, there is evidence for both an ameliorative effect on TD symptoms68 as well as case reports of TD developing after risperidone treatment.69 It has also been reported that olanzapine produces significantly less TD than haloperidol.70 Given the chronic nature of TD onset and duration, the full impact of the novel APDs on the incidence of TD remains to be fully determined. 1. Dopamine Receptors The majority of studies that have examined chronic APD-induced receptor changes have focused on DA receptor binding. Early reports71 on DA receptor changes after subchronic (2 to 4 weeks) drug administration in animals showed an increase in striatal DA receptor number (BMAX); this finding has been consistently replicated under a number of experimental conditions.72–74 Although initially attributed to postsynaptic DA D2 receptor changes, later evidence suggested that the alterations in DA receptors also reflect sensitivity changes in presynaptic DA receptors.75 As for type of drug, all of the typical APDs have been shown to increase DA receptors. However, most studies indicate that subchronic and chronic administration of clozapine and some other putative atypical APDs do not produce an increase in striatal D2 receptor numbers.76–78 In addition to increased DA receptor density, the phenomenon of receptor-mediated supersensitivity following prolonged APD treatment incorporates possible alterations in DA receptor-linked signal transduction mechanisms. The upregulation of striatal DA receptors following prolonged APD administration has been a pivotal argument for a DA receptor-mediated supersensitivity theory of TD, which holds that the disorder results from a form of receptor upregulation analogous to that seen after selective denervation.16 This theory postulates that over a prolonged period of APD treatment, adaptive processes create a functional hyperactivity in DA receptors, with a concomitant hypoactivity of striatal ACh function. In addition to the animal studies on receptor upregulation, several lines of clinical evidence have been relied on for support of the DA supersensitivity theory, including the following: 1. APD withdrawal (which would uncover receptors) often leads to an initial aggravation of symptoms.79 2. Acute administration of DA receptor antagonists can temporarily ameliorate TD.80 3. DA agonists can exacerbate the syndrome.81 The DA receptor-mediated theory of TD has been challenged by preclinical and clinical evidence.66,82,83 The major criticisms have focused on the temporal discrepancies between the development of receptor changes and the time course of TD. Symptoms often become apparent only after months or years of drug treatment, whereas maximal increases in DA receptors have been found within days to weeks of APD treatment.72 Thus, increased DA receptor sensitivity may actually underlie acute, rather than tardive, dyskinesia.83 A related problem concerns the temporal sequence following drug withdrawal. DA receptor supersensitivity returns to control levels within weeks73 or at most months,84 while TD is sometimes irreversible even after drug discontinuation.85 Additional evidence against the DA receptor theory comes from reports of a lack of correlation between increased DA receptors and the presence of dyskinesias in neuroleptic-treated schizophrenics86,87 or in animal models of TD.88 Although the DA receptor-mediated supersensitivity theory as originally proposed appears inadequate as an explanatory mechanism for TD, it is still likely that DA receptor-mediated supersensitivity plays some role as a causal factor in chronic motor side effects. Modifications of the DA receptor hypothesis have speculated that TD may involve a discrete subset of striatal DA


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receptors, particularly in regions controlling oral motor function.89,90 In addition, certain forms of dyskinesia are primarily manifested during withdrawal from APD treatment and are nonpermanent, in contrast to more continuous and persisting dyskinesia. Since increased D2 receptors occur relatively early in APD treatment and are most pronounced after withdrawal, it has been proposed that DA receptor supersensitivity is limited to withdrawal dyskinesia.83 The existence of multiple DA receptor subtypes other than the D2 receptor has led to further reformulations of possible DA receptor changes in the pathology of TD. The importance of DA D1 receptor alterations has been suggested to play a role in late onset motor syndromes. Typical APD administration studies generally indicate no increase in D1 binding following subchronic treatment,78,91 although there is some evidence that repeated clozapine treatment produces an increase in D1 binding in the nucleus accumbens78 or in the striatum.76,77 One modified version of the DA receptor sensitivity theory argues that the balance of D1 and D2 receptor function is altered with chronic treatment, such that overstimulation of D1 receptors occurs with prolonged D2 blockade, giving rise to dyskinetic movements.89 Evidence of enhanced oral movements and other forms of dyskinesias after D1 agonist administration in animal models of TD lends support to a role of the D1 receptor.92 DA receptor subtypes other than the D1 and D2 sites (e.g., D3 and D4) have not been explored in regard to their role in late onset motor syndromes. However, as discussed for acute EPS, the regional distribution of these subtypes (i.e., a preferential distribution outside of the neostriatum) may be a critical factor in accounting for a lower incidence of late onset motor side effects with atypical APDs. Although the long-term effects of APDs have primarily been studied by examining alterations in DA receptor number, functional alterations in DA receptor-linked second messenger systems may also play a significant role in the chronic action of these drugs. Chronic haloperidol produces an enhancement of D1 stimulation and D2 inhibition of adenylyl cyclase activity.93,94 In contrast, Rupniak et al.95,96 found that 1 or 12 months of haloperidol had no effect on DA-stimulated adenylyl cyclase activity, although the selective D2 antagonist sulpiride did produce a significant increase after 12 months. A study by Murugaiah et al.97 found that 18 months of cis-flupenthixol administration led to persisting increases (6 months after drug withdrawal) in cAMP activity, even in the absence of DA receptor binding changes. Ashby et al.98 reported an interactive effect, whereby 12 months of chronic haloperidol had no effect on striatal cAMP levels when a specific D1 or D2 agonist was applied alone; however, combined D1 and D2 agonist application produced a significant increase in cAMP levels. Further study of signal transduction pathways may provide more comprehensive answers on the effects of prolonged APD exposure which relate to delayed side effects and may serve as critical predictors for atypical compounds. 2. Amino Acid Receptors Several lines of evidence suggest that functional alterations in amino acid neurotransmitters, particularly γ-aminobutyric acid (GABA) and glutamate, play a significant role in late onset motor side effects. GABA is the major neurotransmitter for multiple striatal efferent projections and is a key modulator of dopaminergic function in the basal ganglia and the limbic system.99 Glutamatergic projections from the cortex form a major afferent input to basal ganglia nuclei.100 Thus, changes in both GABA and glutamate receptor-mediated function are likely to play a role in adverse motor side effects. Although APDs have little direct binding affinity for GABA receptors,101 adaptive changes in trans-synaptic amino acid neural circuitry following chronic APD treatment have been suggested to play a significant role in mediating late onset motor side effects.102 Subchronic and chronic APD administration increases [3H]muscimol and [3H]GABA binding in the substantia nigra reticulata, while clozapine has no effect.74,103,104 The increased GABA receptor binding in the substantia nigra may relate to decreases in the spontaneous activity of nigral neurons and increased neural responsiveness to GABA seen in haloperidol-treated rats.105 In contrast to the findings of increased nigral



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GABA receptor binding, chronic APDs have no effect on binding to the benzodiazepine site of the GABA receptor complex.104 APD-induced alterations in receptor binding and several other parameters of GABAergic function led to the hypothesis that GABA dysfunction underlies TD.89,99,102 Behavioral evidence that supports this hypothesis includes the finding that dyskinetic, but not nondyskinetic, monkeys chronically treated with APDs show decreased glutamic acid decarboxylase (GAD) activity in the substantia nigra, medial globus pallidus, and subthalamic nucleus.102 A further refinement of this theory has been presented that incorporates non-GABAergic mechanisms.106 In addition to GABA, several studies have examined the possible role of altered glutamatergic function in APD-induced late onset motor side effects. Microdialysis studies in rats have demonstrated that subchronic and chronic treatment with haloperidol, but not clozapine, increases extracellular striatal glutamate levels. This increase in glutamate contrasts with the lack of effect of acute APD injections on extracellular glutamate levels. The enhancement of extracellular glutamate by typical APD administration occurs to a lesser extent in the nucleus accumbens, but is not found in the cortex. At a behavioral level, activation of the corticostriatal pathways by direct chemical stimulation of the motor cortex produces oral dyskinesias in chronic haloperidol-treated animals, but not vehicle-treated animals.112 The overall evidence indicates that drugs with high motor side effect liability (e.g. haloperidol) increase striatal glutamate in a time-dependent fashion, presumably arising from corticostriatal glutamate projections. At the receptor level, chronic administration of haloperidol has been reported to increase N-methyl-D-aspartate (NMDA) receptor binding, while subchronic administration of haloperidol, but not clozapine, increases immunolabeling of striatal NMDAR1 and mRNA. A number of years ago, Benes et al.116 reported that chronic haloperidol administration increased the size of certain striatal terminals, which they suggested might represent nondopaminergic endings, including those of cortical origin. More recently, a series of studies by Meshul and colleagues have used immunogold electron microscopy to gather evidence that chronic haloperidol, but not clozapine, treatment results in an increase in striatal glutamatergic synaptic activity.117,118 Furthermore, it was found that rats with a high incidence of orofacial movements after chronic haloperidol showed an increase in glutamate synaptic function relative to animals with a low incidence.119 In conjunction with the findings of increased glutamate release,108,109 these findings support an excessive activation of glutamate function in TD. One of the possible consequences of continued overactivity of glutamatergic pathways following typical APD treatment is glutamate-mediated excitotoxicity. Such excitotoxicity may lead to structural damage or cell death, which may be the ultimate causal factor in irreversible cases of TD.120 The fact that clozapine shows a consistently different profile in its effects on glutamate release and glutamate receptor binding may explain its success as a drug with no reported incidence of TD. It will be worthwhile to test the chronic effects of other novel APDs for their effects on glutamatergic function in relationship to late onset motor side effects. 3. Other Receptors Although of obvious interest given the recent findings on acute motor side effects, the changes produced by long-term APD treatment on 5-HT function has received relatively limited attention. Recently, olanzapine has been reported to have a low TD incidence,70 and it has been reported that a relatively selective 5-HT2 receptor antagonist (trazodone) has a beneficial effect in treating TD. In terms of serotonergic alterations, subchronic typical APD treatment does not affect 5-HT levels, metabolism, or synthesis.122,123 Although an early report found an increase in striatal [3H]5-HT binding after subchronic haloperidol treatment,124 the use of selective 5-HT2 receptor ligands have indicated no effect of subchronic typical APD treatment.76,125 However, subchronic clozapine has been shown to decrease 5-HT2 receptor binding in the ventral striatum and cortex.76,125 Ishikane et al.126 have presented recent evidence that high occupation of 5-HT2 receptors can attenuate upregulation of D2 receptors, lending support to the role of 5HT2 receptors in contributing to an atypical profile of a lower incidence of TD. Further study of novel APD effects on multiple 5-HT


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receptors after chronic treatment is warranted in light of the importance attached to serotonergic receptor affinity in an atypical profile. Most studies report that subchronic or chronic APD treatment does not affect striatal muscarinic receptor binding,104,124,127,128 although a few studies have reported decreased muscarinic receptor number following subchronic or chronic APD exposure.129,130 Striatal muscarinic receptors have been shown to be unaffected by subchronic clozapine131 and either unaffected104 or increased129 by chronic clozapine treatment. At the behavioral level, co-treatment with an anticholinergic attenuates the development of behavioral hypersensitivity to haloperidol. Given the strong antimuscarinic properties of clozapine (but note agonist properties at the M4 site133), further investigation of chronic APD-induced changes in multiple cholinergic receptors may advance our understanding of the lack of TD seen with clozapine or “clozapine-like” drugs. In addition, there is currently renewed interest in muscarinic function in the pathophysiology of schizophrenia.134 Neurotensin (NT) exerts many of the same behavioral effects as APDs135 and studies have consistently demonstrated that acute, subchronic, and chronic APD administration increases NT-like immunoreactivity in the caudate-putamen and nucleus accumbens of rats.136–138 Repeated administration of haloperidol increases the number of NT binding sites in the substantia nigra, caudateputamen, and nucleus accumbens.139,140 Clozapine, in contrast, selectively decreases NT binding in ventral regions of the caudate-putamen.139 Recent evidence shows that chronic typical and atypical APDs can be distinguished by their regional specificity of NT mRNA regulation. Using an animal model of TD, administration of an NT antagonist (SR 48692) was found to suppress orofacial movements in chronic fluphenazine-treated rats. Thus, there is solid precedent for further determination of the relationship of NT changes produced by chronic APD treatment and late onset motor side effects.

IV. RECEPTOR MEDIATION OF OTHER ADVERSE SIDE EFFECTS A. SEDATION

AND

COGNITIVE IMPAIRMENT

Sedation is commonly experienced with APDs and may negatively impact attentive processing and psychomotor performance in patients.143 Even in healthy adults (nonpsychiatric sample), drugs such as haloperidol can decrease performance on psychomotor tests.144 Blockade of α1 adrenergic receptors and histaminergic receptors is likely to play the major role in the sedative effects of APDs. Impairments across a wide range of cognitive functions have long been recognized as a feature of schizophrenia.145 Improved cognitive performance in schizophrenics as seen by increased accuracy in perceptual judgment and enhanced concentration has been found with APD treatment when compared to placebo control.146 Atypical APDs may exhibit greater efficacy than typical APDs at improving cognitive function. For example, chronic clozapine can improve semantic memory,147 while risperidone can enhance verbal working memory.148 Thus, APDs may be viewed in some regards as cognition-enhancing agents, either by alleviation of core symptoms (e.g., hallucinations and thought disorders) or by directly reversing certain aspects of cognitive dysfunction in schizophrenia. On the other hand, there are concerns that APD treatment may also result in adverse effects on some measures of cognitive performance. It is difficult to ascertain possible cognitive side effects of APDs, given the endogenous cognitive deficits occurring in the treatment populations. In addition, methodological limitations have hindered the ability to gain clear information on the role of pharmacotherapy in cognitive deficits.149 In a review of studies which utilized a variety of neuropsychological tests in normal volunteers and schizophrenic patients, it was clear that certain cognitive functions can be impaired with APD treatment, most prominently sensory threshold detection and digit symbol substitution.144 However, the majority of studies seem to indicate that APD effects on cognitive performance in schizophrenics are often of minimal adverse consequence (i.e., no effects) or produce positive benefits.145



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Research on possible causal factors of cognitive impairments in patients treated with APDs is sparse. It is likely that a combination of receptor blockade (e.g. histaminergic and cholinergic) plays a role in producing performance impairments.150 Anticholinergic drugs are well known for impairing memory performance,151 and the anticholinergic properties of many APDs may contribute to cognitive disruption.152 However, the widely used anticholinergic drugs (e.g., benztropine) given for EPS are more likely contributors to any deficits observed.149 DA D2 receptor blockade per se may not be a critical component, as substituted benzamides (e.g., sulpiride or remoxipride) seem to have little or no noticeable detrimental effects on cognitive performance.144,153 On the other hand, it has been suggested that cortical DA D1 blockade may contribute to impaired performance on tasks such as the Wisconsin Card Sort Test.154 Recent evidence that 5-HT3 or α-1 adrenergic receptor antagonists can enhance cognitive function supports a possible role of APD affinity at these sites in preventing cognitive side effects or reversing endogenous cognitive deficits. Both the lower incidence of cognitive impairment and the cognitive improvements seen with atypical APDs157 may relate to receptor antagonism at these sites. There has also been some interest in the relationship of motor side effects and cognitive side effects. In fact, certain aspects of cognitive impairment, such as poor concentration, have been described under the general term of “mental parkinsonism.”158 EPS produced by typical APDs, in addition to the common use of adjunctive anticholinergic medications, may contribute to cognitive impairment.159 Patients with TD show impaired performance on learning tests, suggesting that chronic neuroleptic toxicity may contribute to cognitive deficits. However, given the role of aging and preexisting neurological deficits in TD,66 it is difficult to attribute the decreases in function solely to neuroleptic exposure. On a final note, recent conceptualizations of a “neuroleptic-induced deficit syndrome” have attempted to combine a variety of psychological side effects across a wide spectrum of emotional, social, and cognitive functions.162 While this broadly defined syndrome may involve DA D2 receptor blockade, the diverse nature of the symptoms makes it unlikely to be due simply to the antidopaminergic properties of APDs.

B. HORMONAL SIDE EFFECTS Several types of adverse neuroendocrine side effects have been reported with APD treatment. The most well-characterized hormonal change seen with APD administration is an increase in plasma prolactin levels.163,164 Hyperprolactinemia in women can produce breast swelling, amenorrhea, and loss of libido. The effects in men can include gynecomastia, impotence, loss of libido, and hypospermatogenesis. Prolactin release is under the tonic regulation of DA D2 receptors in the pituitary, and the blockade of these receptors by APDs is the cause of increased prolactin.164 In males, some drugs (e.g., thioridazine) show a greater propensity in producing difficulty in achieving erection and ejaculatory dysfunction. While such sexual dysfunctions are likely related to increased prolactin, a suppression of gonadal hormones has been suggested to play a role in the decreased sexual drive reported by some patients receiving APDs.165 Assumedly, certain adverse side effects of sexual dysfunction may also relate to the monoaminergic receptor blockade of APDs, particularly α-adrenergic receptor antagonism. Excessive appetite and weight gain are frequent complaints with APD treatment and can be a major reason for premature discontinuation of pharmacotherapy. Among the various APDs, chlorpromazine, thioridazine, clozapine, and olanzapine are most likely to produce weight gain.166–168 APD affinity for serotonin and/or noradrenergic α-1 receptors may contribute to weight gain, since blockade of these receptors is known to stimulate appetite and lead to weight gain. In addition, increased levels of reproductive hormones by APDs may play a role in weight gain. Recent evidence has implicated increased leptin levels as being associated with weight gain during clozapine and olanzapine treatment.167 As leptin (a hormone released from fat cells) is known to regulate body weight, the direct effects of APDs on adipose tissue may be an important factor in weight gain.


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C. NEUROLEPTIC MALIGNANT SYNDROME Neuroleptic malignant syndrome (NMS) is a rare, but extremely dangerous side effect of APD exposure. It is characterized by hyperthermia, muscle rigidity, fluctuating consciousness, and elevated serum creatine kinase levels. Recently, the term “hypodopaminergic, hyperpyrexia syndrome” has been applied as a more appropriate name for NMS. The most common pharmacological treatment for NMS is administration of a muscle relaxant (e.g., dantrolene) and/or DA agonists such as bromocriptine or amantadine. Hypotheses on receptor mechanisms of NMS have primarily centered on APD-mediated DA receptor antagonism of striatal and hypothalamic pathways,171,172 and a recent SPECT study directly implicated in vivo D2 receptor occupancy with the motor symptoms of NMS.173 Enhanced excitatory amino acid neurotransmission may also play a role in the etiology of NMS.174 Recently, a model of dysregulated sympathetic nervous system activity was put forward to explain the multiple symptoms of NMS.175 This model hypothesizes that tonic inhibition of sympathetic pathways is disrupted during NMS, leading to hyperactive function across multiple sympathetic endpoints. APD administration may act to trigger such a response in predisposed individuals.

D. AGRANULOCYTOSIS Agranulocytosis is a rare side effect of certain APDs, but, given its high mortality rate, it is of particular concern during treatment. While agranulocytosis has been associated with phenothiazines, clozapine-induced agranulocytosis has received the most attention. Early reports of agranulocytosis cases176 were so serious that they effectively blocked the further extension of clozapine in treatment until the late 1980s when it became clear that clozapine was a valuable pharmacotherapy option in treatment-resistant patients.177 The causes of agranulocytosis remain obscure, particularly due to the highly individualistic patterns of occurrence, making it difficult to discern causal factors.178 Current theories hold that it is due to a toxic drug effect of the drug on bone marrow or an immune-mediated response.178 There is no evidence for a particular receptor profile playing a role in the incidence of agranulocytosis, but nonphenothiazines show a very low incidence. Newer atypical APDs (e.g., risperidone), unlike clozapine, also show a very low or nonexistent risk for agranulocytosis.

E. CARDIOVASCULAR SIDE EFFECTS Cardiovascular side effects of APDs include arrhythmias, abnormal electrocardiogram (ECG) (e.g., QT interval prolongation), and orthostatic hypotension. While cardiovascular complications are not considered a common adverse side effect with APDs, they can pose a serious problem, as witnessed by the recent withdrawal of the novel APD sertindole as a result of higher than expected rates of QT interval prolongation and cardiac arrhythmias. Many of the cardiovascular disturbances which occur are related to the α-adrenergic receptor affinity of various APDs. For example, hypotension is more frequent with risperidone or clozapine, both of which possess significant α-1 adrenergic affinity.179 There have been reports of some cardiovascular side effects resulting in sudden deaths, especially with high doses in those patients with preexisting conditions or disability.180 However, given the very rare incidence of sudden death and the difficulty in ruling out other causal factors, it should not be considered a significant problem with APDs. Perhaps the only APD of concern in this regard is thioridazine, which has been most clearly implicated.181

F. OTHER SIDE EFFECTS Although a much less common side effect, some APDs have been associated with an increase in seizure activity, particularly at high doses.182 It has been suggested that the propensity for an APD to induce seizure may be related to the anticholinergic properties of the drug.183,184 This possibility may explain the greater rate of seizure seen with high doses of clozapine than other APDs,182 since clozapine has relatively high muscarinic binding.



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Since some APDs possess high affinity for ACh receptors, anticholinergic side effects such as dry mouth, constipation, blurred vision, and urinary retention can often occur, particularly early in treatment. APDs with significant anticholinergic effects include thioridazine, clozapine, olanzapine, and chlorpromazine. Clozapine can also lead to hypersalivation in a significant number of patients, an unexpected side effect of a drug with strong anticholinergic properties. However, there is evidence that clozapine also exhibits agonist properties at the M4 site,133 which may contribute to the hypersalivation effect.

V. CONCLUSIONS Receptor affinity profiles of APDs determine the multiple adverse side effects which may arise with their use. Although many complex issues remain, evidence for specific receptor mechanisms underlying adverse side effects continues to grow. It is vital to continue such work, since minimizing side effect liability is still a major requirement for improved drug treatment. Gaining a greater understanding of one side effect may benefit our ability to predict and understand other side effects. For example, knowing the receptor mechanisms which account for a low liability of EPS will ultimately benefit understanding and preventing TD, particularly as it has been shown that EPS liability can predict TD liability.185 Given the current knowledge in the field, the studies of interest have largely focused on APD actions on specific subtypes of cell-surface receptors. However, many of the physiological changes induced by APDs occur via postreceptor mechanisms.186 As the tools for studying these processes are readily available, future studies should aim to understand multiple transduction changes in relationship to adverse side effects. Furthermore, a number of receptor systems have yet to be examined in regard to APD-induced side effects, including recently characterized serotonin and glutamate receptor subtypes. The past decade has seen tremendous advances in the development and introduction of novel pharmacotherapies for schizophrenia. As novel APDs continue to grow in number and use, understanding the complex interaction of multiple receptor effects promises to further our understanding of the causes and prevention of adverse side effects. Such a goal will eventually benefit treatment of psychosis, the ultimate target of psychopharmacological intervention.

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15

Future Perspectives in Antipsychotic Drug Development W. Wolfgang Fleischhacker and Josef Marksteiner

As outlined in the previous chapters, a benefit/risk analysis of novel antipsychotics such as amisulpride, clozapine, olanzapine, quetiapine, risperidone, ziprasidone and zotepine, emphasizes that these compounds have many advantages over traditional neuroleptics.1 On the efficacy side, next to being at least as potent against the positive symptoms as their traditional counterparts, the new drugs have also been shown to have advantages with regard to negative and depressive symptoms as well as cognitive dysfunctions in patients with schizophrenia. First reports concerning suicide preventive effects and an enhancement of quality of life are very encouraging. Concerning safety, all the new antipsychotics have been convincingly shown to have a considerably lower risk for extrapyramidal motor side effects both in acute and long-term studies. Therefore, it is very likely that novel antipsychotics will help to improve outcomes in patients with schizophrenia. Although these prospects are very promising, the new drugs are still far from being perfect. Treatment with these compounds does not seem to substantially decrease the number of nonresponding or partially responding patients, and relapse prevention studies still indicate that around 20% of patients relapse despite continuing treatment with novel antipsychotics. Although better tolerated than the older drugs, the new compounds still present with a remaining potential to induce EPS, and new side effects such as weight gain are creating clinical problems. Therefore, the search for the “ideal antipsychotic” and the “ideal study” to test its benefit/risk profile must continue. Various different routes are currently being explored. They will be outlined in the following paragraphs. New drugs with alternative pharmacologic actions are currently being tested. Many of these have been covered in previous chapters of this book. They include drugs which act on specific receptor subtypes of the classical neurotransmitters, as well as compounds that target biological systems that are less well explored in schizophrenia research such as phospholipid membranes or neuropeptides. Clinically efficacious antipsychotic drugs have been found to increase neurotensin concentrations in the nucleus accumbens; “typical” antipsychotic drugs increase neurotensin concentrations in both the nucleus accumbens and the caudate nucleus, whereas “atypical” antipsychotics increase neurotensin concentrations only in the nucleus accumbens.2 Agonists of the neuropeptide neurotensin have been proposed as potential novel antipsychotics based on their ability to modulate neurotransmission in brain regions associated with schizophrenia.3 Phospholipid abnormalities have been found in patients with schizophrenia and particular symptom clusters.4,5 The phospholipid concept of schizophrenia suggests that abnormality in phospholipid metabolism alters the function of membrane-associated proteins,6 leading to altered neuronal membrane structure and cell signaling. There is some evidence that therapies based on this concept are beneficial in treating schizophrenia when used as an adjunct to neuroleptics.7 In the future it may be useful to combine antipsychotic drugs with compounds influencing phospholipid biochemistry.

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Concerning classical systems of neurotransmission, the pharmacologically promising concept of partial dopamine agonism is still being tested. First results in this respect have been reported for aripiprazole.8 After many of us have advocated monotherapy for years, we are now experiencing a renaissance of research into add-on medications. A supplementation of clozapine with the classical D2 antagonist sulpiride has been shown to produce favorable results in patients with treatment-resistant schizophrenia.9 An addition of the specific 5HT2 antagonist ritanserin to classical neuroleptics has been found to improve negative symptoms.10 More recently, similar findings have been reported for a combination of drugs which act on the glutamatergic system, such as serine and D-cycloserine.11 Clearly, an increasing understanding of the neurochemical pathophysiology of schizophrenia catalyzes new interesting leads into the treatment of this disorder. Treatment trials with new formulations of some of the novel antipsychotics are also underway. These include short acting intramuscular olanzapine and ziprasidone, as well as a depot formulation for risperidone. If proven to be effective and safe, these new routes of administration will certainly enhance the usefulness of the drugs in question. We also expect additional information on the combination of pharmacologic and psychosocial treatment measures. Such studies will hopefully show that such treatment strategies have additive beneficial effects. The finding that psychoeducation increases compliance also needs to be replicated in larger samples, especially with respect to long-term treatment outcome and relapse rates. At this point in time, we are still facing the disturbing fact that 20% of all patients with schizophrenia suffer a relapse despite antipsychotic treatment. Challenges for the future also include studies in special populations such as children, adolescents, and the elderly and during pregnancy and in patients with schizophrenia and comorbid substance abuse. Although we do have encouraging preliminary findings for both younger13 and older patients14 with some of the novel antipsychotics such as olanzapine and risperidone, there is still a need for more information on the benefit/risk profile of these drugs in such patients. Treatment of older patients with antipsychotic drugs also needs to take into consideration age-related changes in pharmacokinetics and the risks of drug–drug interactions. Current evidence of their efficacy in late-life psychoses is derived largely from studies and from the extrapolation of results obtained in studies of younger patients with schizophrenia. More controlled clinical studies of novel antipsychotics in elderly patients are urgently needed. There are few data regarding the use of novel agents such as clozapine in pregnancy.15,16 Therefore, the use of traditional high-potency agents appears to be preferable for first-line management. However, given the favorable side effect profile of the newer drugs, these may turn out to be safe and well tolerated also during pregnancy. With restrictive mental health budgets all over the world, an economical justification of treatment of patients with schizophrenia is becoming increasingly important. This has become an issue, as all of the novel antipsychotics are considerably more expensive than the traditional neuroleptics. Most of the available pharmacoeconomical studies rely on a determination of direct treatment costs. Such reports have convincingly demonstrated that the novel drugs are certainly worth their price. More sophisticated evaluations that include a determination of indirect costs are eagerly awaited to convince mental health providers to lift budgetary restrictions on the prescription of novel antipsychotics. A new therapeutic strategy has to consider the patients’ willingness to cooperate with treatment. Type and duration of treatment, patient- and illness-related variables, and other psychosocial features, as well as side effects are known to exert a significant influence on the compliance with antipsychotic treatment.19 Finally, clinical trial methodology will most likely need to be modified in the future. One of the issues of concern is the requirement of placebo control groups by many regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Committee for Proprietary Medicinal Products (CPMP). As the number of centers that are able and willing to perform placebo-controlled trials in patients with schizophrenia decreases practically daily,


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alternative methods will need to be discussed and tested. Since many of the novel compounds have now been available for a number of years and have been shown to be both reasonably safe and effective, it needs to be questioned whether drugs like risperidone or olanzapine should replace traditional reference compounds like chlorpromazine or haloperidol in clinical trials. As phase III studies, given increasing bureaucratic burdens, tend to include a very select population of patients, which in turn leads to problems with the generalizability of the data obtained in such studies, we need to refocus on phase IV research in patients that more accurately reflect the requirements of day-to-day clinical care. We also predict the return of the early phase II open exploratory clinical trial in which experienced clinician researchers provide initial judgements about the feasibility of the further development of experimental drugs. All in all, we foresee exciting developments in the next two decades in which it will be up to clinical psychopharmacologists to prudently follow their preclinical colleagues in evaluating treatment hypotheses derived from many sources of basic biological research of (the) schizophrenia(s).

REFERENCES 1. Fleischhacker, W. W. and Hummer, M., Drug treatment of schizophrenia in the 1990s. Achievements and future possibilities in optimising outcomes, Drugs, 53, 915, 1997. 2. Kinkead, B. and Nemeroff, C. B., The effects of typical and atypical antipsychotic drugs on neurotensin-containing neurons in the central nervous system, J. Clin. Psychiatry, 55 (Suppl. B), 30, 1994. 3. Sharma, R.P., Janicak, P.G., Bissette, G., and Nemeroff, C.B., CSF neurotensin concentrations and antipsychotic treatment in schizophrenia and schizoaffective disorder, Am. J. Psychiatry, 154, 1019, 1997. 4. Doris, A.B., Wahle, K., MacDonald, A., Morris, S., Coffey, I., Muir, W., and Blackwood, D., Red cell membrane fatty acids, cytosolic phospholipase-A2 and schizophrenia, Schizophr. Res., 31, 185, 1998. 5. Ross, B.M., Turenne, S., Moszczynska, A., Warsh, J.J., and Kish, S.J., Differential alteration of phospholipase A2 activities in brain of patients with schizophrenia, Brain Res., 821, 407, 1999. 6. Horrobin, D.F., Glen, A.I., and Vaddadi, K., The membrane hypothesis of schizophrenia, Schizophr. Res., 13, 195, 1994. 7. Shah, S., Vankar, G.K., Telang, S.D., Ramchand, C.N., and Peet, M., Eicosapentaeonic acid (EPA) as an adjunct in the treatment of schizophrenia, Schizophr. Res., 29, 158, 1998. 8. Petrie, J. L., Saha, A. R., and Ali, M.W., Safety and efficacy profile of apripiprazole, a novel antipsychotic, in Annual Meeting of the American College of Neuropsychopharmacology, Los Croabas, Puerto Rico, 1998. 9. Shiloh, R., Zemishlany, Z., Aizenberg, D., Radwan, M., Schwartz, B., Dorfman, E.P., Modai, I., Khaikin, M., and Weizman, A., Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study, Br. J. Psychiatry, 171, 569, 1997. 10. Duinkerke, S.J., Botter, P.A., Jansen, A.A., van Dougen, P. A., van Hoaften, A. J., Boom, A.J., van Loorhoven, J. H., and Busard, H.L., Ritanserin, a selective 5-HT2/1C antagonist, and negative symptoms in schizophrenia. A placebo-controlled double-blind trial, Br. J. Psychiatry, 163, 451, 1993. 11. Goff, D.C., Tsai, G., Levitt, J., Amico, E., Manoach, D., Schoenfeld, D.A., Hayden, D.L., McCarley, R., and Coyle, J.T., A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia [see comments], Arch. Gen. Psychiatry, 56, 21, 1999. 12. Penn, D.L. and Mueser, K.T., Research update on the psychosocial treatment of schizophrenia, Am. J. Psychiatry, 153, 607, 1996. 13. Toren, P., Laor, N., and Weizman, A., Use of atypical neuroleptics in child and adolescent psychiatry, J. Clin. Psychiatry, 59, 644, 1998. 14. Collaborative Working Group on Clinical Trial Evaluations, Treatment of special populations with the atypical antipsychotics, J. Clin. Psychiatry, 59 (Suppl. 12), 46, 1998. 15. Barnas, C., Bergant, A., Hummer, M., Saria, A., and Fleischhacker, W.W., Clozapine concentrations in maternal and fetal plasma, amniotic fluid, and breast milk, Am. J. Psychiatry, 151, 945, 1994. 16. Trixler, M. and Tenyi, T., Antipsychotic use in pregnancy. What are the best treatment options? Drug Saf., 16, 403, 1997.


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17. Aitchison, K.J. and Kerwin, R.W., Cost-effectiveness of clozapine. A UK clinic-based study, Br. J. Psychiatry, 171, 125, 1997. 18. Glazer, W.M. and Johnstone, B.M., Pharmacoeconomic evaluation of antipsychotic therapy for schizophrenia, J. Clin. Psychiatry, 58 (Suppl. 10), 50, 1997. 19. Fleischhacker, W.W., Meise, U., Gunther, V., and Kurz, M., Compliance with antipsychotic drug treatment: influence of side effects, Acta Psychiatr. Scand. Suppl., 382, 11, 1994.

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Index A Aberrant regional cerebral activity 3 Abilit, See Sulpiride Adenylate cyclase activity 202 signal transduction and antipsychotic drugs 204 ADHD, guanfacine 110 Adolescence, preschizophrenia 9, 244 Adrenoceptors, See Adrenergic receptors Adrenergic receptor antipsychotic drug motor effects 226 α-1-adrenergic receptor 27 norepinephrine system changes 115 blockers 115 clonidine 110 cognitive function 111 cognitive function, prefrontal cortex 109, 115 phosphotidyl inositol/protein kinase C pathways 115 treatment of behavioral disinhibition 115 α-2-adrenergic receptor ligands 110 β-adrenergic receptor amygdala function 114 NMDA antagonist modulation of agonist effect 127 Affective disorders and norepinephrine 115 Agranulocytosis 232 Akathisia 225, 226 Amine group, receptor-site-drug interaction 17 α-amino-3-hydroxy-methylisoxazole-4-propionic acid, See AMPA Amisulpiride (Socian, Solian) 18, 23 chemical structure 20 potency and side effects 26 Amoxapine 46 cAMP, caudate nucleus 70 AMPA 122 Ampakines, clinical trials 129 Amperozide, VTA dopaminergic neuronal activity 92 Amphetamine disregulation of monoamine neurotransmission 10 locomotor activity, 5-HT 91 protein kinases 202 psychosis, and D1 receptors 67 serotonin depletion synergism 91 stereotypies and 5-HT 91 d-amphetamine 91 dopaminergic activity 93 Amygdala function, β-adrenergic facilitation 114 Anticholinergic drugs 24 antiserotonergic drugs 92 NMDA antagonist effect modulation 127

Anticonvulsants 158 Antipsychotic drugs σ receptor binding and efficacy 141 α-1-adrenergic receptor blocking 109 serotonin receptor affinity 88, 89 5-HT1a serotonin receptor 88, 89 5-HT2 serotonin receptor antagonism 27, 84 animal models 35–37 benzisoxazoles 22 benzodiazepines 156 butyrophenones 18 cardiovascular effects 232 cell signaling changes 203 cellular signaling pathways 199–219 chemical classes 17 chlorpromazine 18 cisapride, classification basis and receptor occupancy 167 classification schemes 17 clinical potencies and dissociation constants at D2 dopamine receptor 44 clozapine 20 cognitive abilities 24, 88, 230–231 cortical catecholamine release 34 D1 dopamine receptor 72–73 D2 dopamine receptor 43, 49, 73, 166–167 D3, D4 dopamine receptors 43 defined 17 depolarization blockade 35 dibenzepins 20, 22 dibenzodiazepines 20, 22 diphenylbutylpiperidines 18 dopamine receptor mRNA regulation 186, 188 dopamine transmission interference 31 dosages and side effects 24 effectiveness 23, 26 endogenous dopamine 49 excitatory amino acid transmission 127 flupentixol 18 fluphenazine 18 gene expression modulation 204 glutamate concentrations 127 glutamatergic receptor subunit densities 128 haloperidol 18 hormonal side effects 231 imidazolines 22 immunology and endocrine effects 139 indoles 19 kainate receptors 128 limitations of classifications 22

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lorazepam 157 loxapine 22 mesorandile 18 metoclopramide 18 modulation of gene expression 20 molecular structure 17 molindone 19 motor side effects 223–230 negative symptoms 24 neuroleptic malignant syndrome 232 neuronal architecture and synaptic connectivity 205 NMDA receptor antagonist effect modulation 126 Parkinsonism 52, 53, 223 PCP-induced hyperlocomotion 126 perphenazine 18 phenothiazines 18 phenylbutylpiperidines 18 pimozide 18 potency 25 prochlorperazine 18 prolactin level 23 protein phosphorylation 204 rapid offset and relapse 56 receptor binding profile 26–27 receptor occupancy 163–176 regulation of neurotransmitter receptors 177–198 remoxipride 18 reserpine 19 sedative effects 109, 230 seizure 232 serotonin affinity 231 serotonin receptor mRNA regulation 190 serotonin receptor regulation 190 Sulpiride 18 tardive dyskinesia 185 therapy-resistant patients and clozapine 55 thioridazine 18 thiothixene 18 thioxanthenes 18 transient receptor occupancy 172 trifluoperazine 18 typical and atypical 23 mesotelencephalic dopamine system effects 33 receptor affinity 222 tyrosine hydroxylation 33 weight gain 231 Antiserontonergic drugs 92 Apomorphone 46 Arachidonic acid release 68 phospholipase A pathways 204 Aspartate pathophysiology of schizophrenia 121 tardive dyskinesia 127 Atropine, co-administration with ketamine and PCP 125 Atypical antipsychotic drugs, defined 23

B Baclofen 155 NMDA antagonist effect modulation 126

Basal ganglia, D1 dopamine receptors 70 Behavioral disinhibition, α-1-adrenergic receptors 115 Benperidol 46 σ binding affinity 141 Benserazide 18 chemical structure 20 compared to chlorpromazine 85 corticolimbic selectivity 87 Benzamides 20 Benzisothiazoyls 17, 21 Benzisoxazoles 21, 22 Benzodiazepines clinical trials 156 dopaminergic activity 154 Benzohazoles 17 Benzomorphans 137 Bipolar affective illness 3 Bipolar disorder D1 dopamine receptor binding 71 lithium and cognitive impairment 113 manic phase and norepinephrine 115 Bradykinesia 24 Brain development, abnormal 10 Bromocriptine 46 Parkinson’s disease 56 Buspirone, 5HT1a serotonin receptor 89 Butyrophenones 18

C Calcium 201 Cardiovascular effects of antipsychotic drugs 232 Catalepsy raclopride 54 reversing in olanzapine, loxapine, haloperidol 53 Catecholamine depletion, and α-2-adrenergic agonists 110 Caudate nucleus, c-AMP increase 70 Cell signaling gene expression modulation 204 protein phosphorylation 204 changes mediated by antipsychotic drugs 203 schizophrenia association 200 Cellular proteins, gene expression 201 Cerebral activity, patterns associated with schizophrenia syndromes 5 Cerebral cortex changes, haloperidol 180–181 Cerebral function, developmental disregulation 10 Chelerythrine, α-1-adrenergic agonists 113 Chlorpromazine 18 σ receptor affinity 141 5-HT2 and D2 receptor affinities 27, 87 5-HT6 and 5-HT7 serotonin receptors 89 and mesotelencephalic dopamine system effects 33 chemical structure 19 [3H]chlorpromazine 53 co-administration with ketamine and PCP 125 compared to tryptophan and benserazide 85 dissociation constants, table 46 dose and side effects 24 NMDA antagonist effect modulation 126


Index

potencies and dissociation constants at D2 44 receptor binding profile 27 Thorazine 19 weight gain 231 Chlorpromazine equivalencies 25 Chlorprothixene, dissociation constants 46 Cholinergic drugs, NMDA antagonist effect modulation 126 p-chlorophenylalanine (pCPA) 85 cis-Thiothixene, receptor binding profile 27 Citalopram, haloperidol-induced catalepsy 92 Clebopride, dissociation constants 46 Clomipramine, haloperidol-induced catalepsy 92 Clonidine 110 Clopenthixol, σ receptor affinity 141 Clozapine (Clozaril) 20, 23, 87 AMPA subunits 128 chemical structure 21 chronic treatment in striatum 180 cognitive deficits 35 cortical D2 dopamine receptor binding 181–182 D1 receptor levels 183 D1 receptor mRNA regulation 189 D2 and 5-HT2 receptor occupancy 168 D2 receptor antagonism and antipsychotic activity 26 D2 receptor occupancy 50–52 5-HT2 D2 receptor affinities 87 D3 receptor mRNA 188 D4 receptor regulation 183 density of prefrontal 5-HT1A receptor 83 dissociation constants 46 dopamine regulation 179 L-DOPA psychosis 56 dose and side effects 24 effects on cortical D2 receptor mRNA 186 efficacy 80, 88 extrapyramidal side effects 169, 223 gene expression 205 in amphetamine-induced dopaminergic release 94 in therapy-resistant patients 55 increased cortical dopamine efflux 35 mesocortical dopamine neuron firing 126 mesolimbic dopaminergic pathways 225 MK-801 128 motor side effects, striatal muscarinic receptor binding 230 muscarine acetylcholine receptor antagonists 25 neuronal architecture changes 205 NMDA antagonist effect modulation 126 norclozapine 45 Parkinsonism 52 potency 25 raclopride clozapine displacement 44 receptor binding profile 27 refractive schizophrenia 26 relapse after 56 seizure activity 232 serotonin receptor mRNA regulation 191 serotonin, role in schizophrenia 79 side effects 22 σ receptor binding affinity 142

249

5-HT6 serotonin receptor 89 striatal D2 dopamine receptor 184 VTA dopaminergic neuronal activity 92 weight gain 231 with ketamine 125 Clozaril 21, See also Clozapine Cocaine 137 Cognitive deficits 3 antipsychotic drugs 88, 230–231 cortical dopamine transmission 37 D1 receptors 66 monoamine disregulation 11 preschizophrenic children 9 Cognitive function 115 α-1 adrenergic receptors 111 prefrontal cortex, α-1-adrenergic receptors 109 Compazine 19, See also Prochlorperazine Cortical atrophy, amino acid concentrations 123 catecholamine release, atypical antipsychotic drugs 34 D2 dopamine receptor mRNA 186 receptors 184 CX516 130 Cyclohexylamine anesthetics 125 d-Cycloserine, clinical trials 129–130

D Deficit symptoms, See Negative symptoms 23 Delay-related firing 110 Depolarization blockade 33 extrapyramidal side effects 34 Depression, hypodopaminergic activity 72 Developmental disregulation hypothesis 9, 11 Diazepam, NMDA antagonist effect modulation 126 Dibenzapines, chemical structure 21 Dibenzazepines 17 Dibenzepins 20, 22 Dibenzodiazepines 20 Dibenzothiazepines 21, 22 Dibenzoxazepines 20 Dimensional models of schizophrenia 1 Diphenylbutylpiperidines 17, 18, 20 Disorganization 4, 5 Divalproex sodium, clinical studies 156–158 Dogmatil, See Sulpiride Dopamine agonists 32 disregulation, structural deficits 10 endogenous and antipsychotic drugs 49 extrapyramidal side effects 90 GABA receptor effects 153 glutamatergic system integration 122 in increased efflux, clozapine 35 mesocortical, neuron firing and clozapine, ritanserin 126 mesotelencephalic systems, antipsychotic drug effects 33 3-methoxytyramine (3-MT) 32 rapid increase in synaptic levels 32 release in schizophrenia 58


250


release pattern, typical antipsychotic drugs 34 serotonin interactions 90 synthesis 32, 93 system hypersensitivity 94 terminals in cerebral cortex vs. striatum 33 transmission, cortical and cognitive deficits 37 Dopamine blockade 2 GABAergic agents 155 prolactin elevation 167 Dopamine dissociation constants 49–50 Dopamine hypothesis of schizophrenia 31, 44, 65, 90 antipsychotic drugs and D2 receptor affinity 73 support for 57 Dopamine neurons, pharmacology 32 Dopamine receptors antipsychotic drugs motor effects 224, 227 gene polymorphisms 68 glutamatergic synaptic transmission 68 mRNA 178, 201 subtypes 178 tardive dyskinesia 227 D1 dopamine receptor 178 Alzheimer’s 58 amphetamine-induced psychosis 67 antagonists 72 antipsychotic drugs 65–78 binding 71, 72 cognitive deficits 66 cortex 71 D2/D1 receptor ratio 70 described 66 genes, polymorphisms 68 genetic studies in schizophrenia 68–70 Hungtington’s disease 58 interaction with D2 dopamine receptors 67, 68, 73 mRNA 66, 70, 71 postmortem studies 70 regulation 183, 188 whole putamen 71 working memory 65 D2 dopamine receptor 43, 178 Alzheimer’s 58 antagonism, clinical improvement 88 antagonists 33 antagonists, selective 26 binding, loose and tight 53, 56 blockade 87 clozapine, and quetiapine 50–52 D2/D1 receptor ratio 70 density across individuals 170–171 density, postmortem study 70 dimers 57 GABA-containing neurons 33 Hungtington’s disease 58 interaction with D1 receptors 67, 68, 73 monomers, elevated 57 motor side effects of antipsychotic drugs 224 mRNA regulation186–187 radioligands used to quantify 179

striatum, 70 occupancy antipsychotic response 166 atypical antipsychotic drugs 168 extrapyramidal side effects 167, 169 prolactin elevation 167 D2 receptor blockade extrapyramidal side effects 88 Parkinsonism 53 therapy-resistant patients 55 D3 dopamine receptor 43 effects of chronic antipsychotic treatment 185 mRNA regulating 188 regulation 182 D4 dopamine receptor 43 antagonism, clinical improvement 88 effects of chronic antipsychotic treatment 185 mRNA regulation 188 regulation 182 D5 dopamine receptor DNA sequences 68 mRNA, prefrontal cortex 71 Dopamine release, NMDA receptor antagonists, prefrontal cortex and subcortical regions 125 Dopaminergic activity, GABA regulation of 154 Dopaminergic innervation, frontal cortex vs. subcortical regions 32 Dopaminergic mechanisms, stress-induced prefrontal cortex deficits 114 Dopaminergic neuron activity, VTA 92 Dopaminergic overactivity, type 1 schizophrenia 2 Dopamine-serotonin interactions 90 Down regulation, dopamine, by GABA 154 Droperidol, dissociation constants 46 DuP 734, antipsychotic efficacy 143 Dystonia 225, 226

E E 5843, antipsychotic efficacy 147 EEG activity, σ ligand influences on 139 Eliprodil antipsychotic efficacy 147 possible antipsychotic σ ligand 143 EMD 57445, sleep EEG in humans 139 Epidepride, dissociation constants 46 Excitatory amino acid see glutamate Extrapyramidal side effects 23, See also Motor side effects clozapine 223 depolarization blockade 34 dopamine displacement 53 dopamine receptors 224, 227 mRNA expression 128 negative symptoms 24 risperidone 54 5-HT2 and D2 receptor blockade 88, 94 5-HT2 and D2 receptor occupancy 167, 169 Extrastriatal receptor occupancy 169


Index

251

F Fananserin 88 Femoxetine 92 Fenfluramine 85 Flupenthixol 18 D1 and D2 receptor regulation 184 Flupentixol-cis, dissociation constants 46 Fluperlapine, dissociation constants 46 Fluphenazine (Permitil, Prolixin) 18 chemical structure 19 dissociation constants 46 dose and side effects 24 -induced catalepsy 92 potency 25 receptor binding profile 27 σ receptor binding affinity 141 5HT6 an d5HT7 serotonin receptors 89 Frontal lobe volume, schizophrenia patients 10

G G protein coupling, antipsychotic drugs 204 postmortem levels 200 GABA down regulation of dopamine 154 motor side effects of antipsychotic drugs 228 pathophysiology in schizophrenia 154 GABAa receptor 159 GABAergic drugs 155 anticonvulsants 159 haloperidol effects on 154 Gamma-acetylenic acid 156 Gamma-vinyl GABA 156 GAP-43 201 Gene expression cellular proteins 201 modulation and cell signaling 204 Glaxo 1192U90 46 GluR-1 subunit of glutamate receptor, haloperidol 128 GluR-2 subunit of glutamate receptor 123 mRNA, prefrontal cortex 124 GluR-3 subunit of glutamate receptor and haloperidol 128 Glutamate motor side effects of antipsychotic drugs 228 concentrations, antipsychotic drugs 123, 127 in schizophrenia 123-124 receptors in postmortem schizophrenia brain 124 tardive dyskinesia 127 Glutamate ionotropic receptors 122 Glutamate model of schizophrenia 122 Glutamate receptor 122, 127–128, 191 antipsychotic drugs 121–136, 178 Glutamate release NMDA receptor antagonists, prefrontal cortex and subcortical 125 5-HT2A receptor stimulation 113 Glutamatergic agents, clinical trials 129–130 Glutamatergic neurotoxicity 122

Glutamatergic system 122 Glutamic acid decarboxylase 201 Glycine antipsychotic drugs 127 clinical trials 129 Guanfacine cognitive function 115 working memory 110

H Haldol, See Haloperidol Hallucinations, See also Reality distortion glutamate concentrations 123 severity 5 Hallucinogens anatomical substrates 86 -induced psychosis, schizophrenia positive symptoms 86 neuropharmacological effects on 85 Haloperidol (Haldol, Halperon) 18 AMPA receptor subunits 128 antipsychotic properties, compared to risperidone 87 catalepsy 92 cerebral cortex changes 180 chemical structure 19 cognitive deficits 35 D1 receptor levels 183 D1 receptor mRNA D2 receptor 166, 172, 180 D3 receptor 182, 188 D4 receptor 183 density of prefrontal 5-HT1A receptors 83 dissociation constants 46 dopamine upregulation 179 dose and side effects 24 effects on cortical D2 receptor mRNA 186 effects on striatal D2 receptor mRNA 187 extrapyramidal side effects compared to risperidone 88 GABAergic drugs 154 gene expression 205 glutamate concentrations 123, 127 immunologic and endocrine effects 139 mesotelencephalic dopamine system effects 33 [3H] MK-801 binding 128 motor side effects and GABA 228 neuronal changes 205–206 NMDA receptor antagonist effect modulation 126 potency 25 receptor binding profile 27 regulation 188 reversing catalepsy caused by 53 serotonin receptor mRNA regulation 191 5-HT2 receptor binding 190 σ receptor affinity 137, 141 striatal D2 receptor 184 treatment-resistant patients 55 valproate augmentation 157, 158 with ketamine 125 with SKF 38393 73 Halperon 20, See also Haloperidol


252


High potency drugs 25 Hippocampal structures, glutamatergic receptors and hypoxia 121 Histaminergic receptor binding 27 Homovanillic acid (HVA) 182 Huntington’s disease and dopamine D1 and D2 receptors 58, 72 l-5-hydroxytryptophan 85 Hypodopaminergic activity, mood disorders 72

I ICS 205,930 92 Iloperidone (HP873) 46 Imidazolines 17, 22 Indoles 17, 19, 20 Iodobenzamine, D2 occupancy effects 51, 52 Isoclozapine, dissociation constants 46

K KA, See Kainic acid Kainic acid, 122, 128 Ketamine 125 Ketanserin, blocking psilocybin psychotomimetic effects 86 Korsakoff’s amnesia 110

L L-745, 870 Leptin, antipsychotic drugs 231 Lithium, reversing cognitive impairment 113 Lorazepam 157 Loxapine (Loxitane) 21, 22 extrapyramidal side effects 23 dissociation constants 46 potency 25 receptor binding profile 27 reversing catalepsy caused by 53 Loxitane 21, See also Loxapine LSD 79 hallucinogenic effect and 5-HT2 receptor 86 -induced psychosis, compared to schizophrenia 85 serotonergic transmission effect 85 LY293558 126 Lysergic acid diethylamine, See LSD

M Mania, norepinephrine 115 MAOI 84 MDL 100,907 88 amphetamine-stimulated locomotion 93 VTA dopaminergic neuronal activity 92 dissociation constants 47 MDL 28,133A, amphetamine effect on VTA neurons 93 Medial and inferior temporal cortex, D1 receptor 71 Meditomidine, working memory 110 Medium potency drugs 25

Mellaril 19, See also Thioridazine Melperone, dissociation constants table 47 Mescaline psychosis 85 5-HT2 receptor 86 Mesorandile 18 Mesoridazine (Serentil) 19 Mesotelencephalic dopamine systems 34 3-methoxytyramine (3-MT) 32 Methylsergide haloperidol-induced catalepsy 92 NMDA antagonist effect modulation 126 Metoclopramide 18 Millazine 19, See also Thioridazine Miradol, See Sulpiride MK-801 clozapine 128 haloperidol 128 Moban 20, See also Molindone Molindone (Moban) 19 chemical structure 20 dissociation constants 47 potency 25 Monoamine 10, 11 Monoamine oxidase inhibitors 84 Monotherapy 244 Mood disorders, hypodopaminergic activity 72 Moperone, dissociation constants, table 47 Motor learning, long-term depression in cerebellum 68 Motor side effects 223–230, See also Extrapyramidal side effects acute 223 dopamine receptors 227 glutamate receptors 228 late onset 226 neurotensin 230 receptor mediation 230–233 5-HT receptor 225, 229 striatal muscarinic receptor mRNA extrapyramidal side effects 128 D1 receptor, postmortem study 70 α-methyl-paratyrosine, See αMPT αMPT 93

N Naloxone, co-administration with ketamine and PCP 125 Navane 19, See also Thiothixene Negative symptoms 2, 23 5-HT2 receptor blockade 93 5-HT2A receptor 94 alleviation 9 benzodiazepines 156 D1 receptor binding in prefrontal cortex 71 GABAergic drugs 154 Neural activity, regional, techniques for functional imaging 5 Neuroactive steroids 159 Neuroleptic malignant syndrome 232 Neuroleptics, See Antipsychotic drugs: Typical


Index

Neuronal architecture, long-term antipsychotic drug treatment 205 Neuropil formation, as signaling abnormality 201 Neuropsychological impairments 3–5 Neurotensin 230 NMDA receptor antagonist 125 motor side effects of antipsychotic drugs 229 working memory 126 NMDAR2C subunit of NMDA receptor 123 NMDAR2D subunit of NMDA receptor 123 N-methyl-D-aspartate, See NMDA NNC 01-0687, clinical trial 72 Nondopaminergic receptor binding 27 Norclozapine 47 Norepinephrine (noradrenalin) actions 110 affective disorders 115 prefrontal cortex 110, 113 psychotic disorders 109 stress exposure 111

O [3H]7-OH-DPAT 182 Olanzapine (Zyprexia) 22, 23 chemical structure 21 D2 and 5-HT2 receptor occupancy 168 dissociation constants 47 dose and side effects 24 efficacy in therapy-resistant schizophrenia 88 extrapyramidal side effects, 5-HT2 and D2 occupancy 169 motor side effects and serotonin 229 muscarine acetylcholine receptor antagonists 25 NMDA receptor antagonists 126 potency 26 receptor binding profile 27 reversing catalepsy caused by 53 5-HT2 receptor binding 27 5-HT6 receptor 89 weight gain 231 Opiate antagonists 127 Orap 20, See also Pimozide Orofacial dyskinesia 226

P Panamesine (EMD 57445) antipsychotic efficacy 143–146 possible antipsychotic σ receptor ligand 143 sleep EEG in humans 139 Panic disorder, norepinephrine activity 115 Parkinsonism 223 antipsychotic drugs 52 dopaminergic neuron degeneration 90 serotonin receptors blockade 53 Pathological process 10 Pathophysiology of schizophrenia 11 GABA 154 glutamate and aspartate 121

253

serotonin 81 PCP 35, 124 σ receptor agonist 138 diminished effects with sensory deprivation 125 increased mesolimbic dopamine activity 126 -induced hyperlocomotion, antipsychotic drug effects 126 -induced psychosis, cell signaling 202 NMDA 125 studies in monkeys 125 VTA dopaminergic neuronal activity 92 Perlapine 47 Permitil 19, See also Fluphenazine Perospirone# 47 Perphenazine (Trilafon) 18 antipsychotic properties, compared to risperidone 87 chemical structure 19 dissociation constants 47 potency 25 receptor binding profile 27 σ receptor binding affinity 141 Phencyclidine, See PCP Phenethylamine hallucinogens 86 Phenothiazines 17, 19 Phenylbutylpiperidines 17, 18, 19 Phenylephrine cognitive impairment and lithium 113 working memory 111 Phospolipase C 204 Phospholipids 200, 243 Phosphotidyl inositol/protein kinase C pathways 115 Pimozide (Orap) 18, 20 dissociation constants 47 dose and side effects 24 potency 25 receptor binding profile 27 5HT7 receptor 89 Pipamperone 88 5-HT2 and D2 receptor affinities 87 Piperazine 22 Pleiotropic genomic changes 205 Positive symptoms 2 dopaminergic system 94 GABAergic drugs 154 glutamate concentrations 12 5-HT2A receptor 94 Post-traumatic stress disorder, norepinephrine activity 115 Potency, dissociation constants at D2 44 Prazosin 126 Prefrontal cortex α-1-adrenergic receptor stimulation 115 cognitive deficits reversal, SCH23390 114 cognitive function, α-1-adrenergic receptors 109 D1 receptor binding and negative symptoms 71 function at neuronal level 113 hypofunction 66, 68 Korsakoff’s amnesia 110 regulation of mRNAs of D1 and D5 receptors 71 Preschizophrenia, cognitive and social deficits 9 Prochlorperazine (Compazine) 18, 19


254


Prolactin levels antipsychotic drug effects 231 D2 receptor occupancy 167 Prolixin 19, See also Fluphenazine Protein kinases 201, 202 Protein phosphorylation 204 Psilocybin psychosis 85 5-HT2 receptor 86

Q Quetiapine (Seroquel) 22, 23 chemical structure 21 D2 receptor 44, 50-52, 172 dose and side effects 24 haloperidol-induced catalepsy 92 mesolimbic dopaminergic pathways 225 Parkinsonism 52 potency 25 receptor binding profile 27 5HT1a receptor 88, 89

R Raclopride catalepsy 54 D2 receptor occupancy effects 51, 52 D2 receptor bound clozapine displacement 44 dissociation constants 47 dopamine displacement and extrapyramidal side effects 53 -induced catalepsy and ritanserin 54 neuronal changes 205–206 NMDA receptor antagonist effect modulation 126 Receptor occupancy 163–176 binding potential 165 described 164–166 determination 165 regional169 transient vs. sustained 172 underestimating 171 upregulation 171 vs. unoccupancy 170 Receptor-site-drug interaction 17 Refractive schizophrenia, clozapine 26 Remodipride 18, 23 σ receptor binding affinity 142 chemical structure 20 corticolimbic selectivity 87 dissociation constants 47 L-DOPA psychosis 56 haloperidol-resistant patients 56 therapy-resistant patients 55 Reserpine 19 Rimcazole EEG activity in animals 139 possible antipsychotic σ ligand 142, 143 Remoxipride (Roxiam) 20 Risperdal 21, See also Resperidone

Risperidone (Risperdal) 21, 22, 23 5HT1a receptor 89 5HT2 receptor binding 27 5-HT2 and D2 receptor selectivity and occupancy 87, 168, 172 amphetamine-induced dopaminergic release 94 antipsychotic efficacy 87 chemical structure 21 dissociation constants 47 dose and side effects 24 efficacy in therapy-resistant schizophrenia 88 extrapyramidal side effects 54, 88 potency 26 receptor binding profile 27 Ritanserin amphetamine effect on VTA neurons 93 D2 receptor 88 dissociation constants 47 firing rate of VTA and SN neurons 92 MDL 100907 89 mesocortical dopamine neuron firing 126 motor side effects and 5-HT receptors 225 raclopride-induced catalepsy 54 type 2 schizophrenia 88 VTA dopaminergic neuronal activity 92 Roxiam see Remoxipride 20

S S-7389-4, EEG activity in animals 139 SCH 23390 glutamate 128 prefrontal cortex cognitive deficits reversal 114 [3H]SCH 23390, D1 and D5 receptor affinity 183 SCH 23391 127 SCH 39166, clinical trials 72 Schizophrenia 3-dimensional model 3 compared to LSD-induced psychosis 85 development disregulation model 9, 11 developmental anomalies 10 dimensional models 1 negative and positive symptoms 2 pathological process 10 refractive 26 subtypes 1 symptoms 1 symptoms, segregation 3 time course 10 Schizophrenic syndromes 1–14 Second messenger generation 201 cell signaling and antipsychotic drugs 203 Seizure, antipsychotic drugs effects 232 Sensory gating deficit 127 Serentil 19, See also Mesoridazine Serlect 22, See also Sertindole Seroquel 21, See also Quetiapine dissociation constants 47 extrapyramidal side effects, 5-HT2 and D2 receptor occupancy 169


Index

Serotonin dopamine interactions 90 projections 80 tone 90 Serotonin receptors affinity 231 antipsychotic drugs 178 atypical antipsychotic drugs 80 classification and distribution 190–191 messenger RNA levels 201 atypical antipsychotic drugs 80 messenger RNA levels 201 5-HT1 serotonin receptor described 80 subtypes and LSD 86 5-HT1A serotonin receptor antipsychotic drugs 88 described 80 LSD 85 prefrontal neuronal 83 5-HT1B serotonin receptor 80 5-HT1C serotonin receptor 81 5-HT1Dα serotonin receptor80 5-HT1D serotonin receptor 80 5-HT1E serotonin receptor 81 5-HT1F serotonin receptor 81 5-HT2 serotonin receptor amphetamine locomotor effects 93 antipsychotic drug affinity for 84 binding 27 blockade and extrapyramidal side effects 88, 168, 169, 225 glutamatergic input of the prefrontal cortex 92 LSD hallucinogenic effect 86 negative symptoms 93 neuronal sensitivity in VTA and SN 92 5-HT2/D2 receptor blockade 87, 94 5-HT2A serotonin receptor activation 86 antagonism, clinical improvement 88 antagonists and serotonergic tone 89 antagonists, efficacy 94 blockade activity 94 description 81 hallucinogen-induced psychosis 86 mediation of schizophrenia symptomatology 84 negative symptoms 94 positive symptoms 94 receptor stimulation and glutamate release 113 5-HT2B serotonin receptor 81 5-HT2C serotonin receptor 81 5-HT3 serotonin receptor 81, 84 5-HT4 serotonin receptor 81, 84 5-HT5 serotonin receptor 81 5-HT5B serotonin receptor 81 5-HT6 serotonin receptor clozapine and olanzapine 89 description 81 5-HT7 serotonin receptor 81 description 89 haloperidol-induced catalepsy 92

255

Sertindole (Serlect) 22, 23 5-HT1a receptor 89 5-HT2 receptor binding 27 dissociation constants 47 dose and side effects 24 potency 26 receptor binding profile 27 Servenin, See Sulpiride Sigma receptor (σ) agonists 138 binding sites 138 drugs, antipsychotic effects 137–152 ligands 141, 142, 131, 147 Signal transduction antipsychotic drugs 204 processes 200 Signaling abnormality, europil formation 201 SKF 10047 138 SKF 38393 73 SL 76 002 156 Sleep, σ ligands 139–140 SM13496 47 SN neuronal firing rate, ritanserin 92 Social deficits, preschizophrenic children 9 Socian 20, See also Amisulpiride Solian 20, See also Amisulpiride Stelazine 19, See also Trifluoperazine Stimulant drug abuse 10 Stress 111 Striatal inputs 67 Striatal receptors 184 occupancy 169 Striatonigral neurons 68 Stroop task 4 Strychnine-insensitive glycine recognition site 122 Subcortical regions 68 Substituted benzamines 17 Sulpiride 18, 23, 127 chemical structure 20 corticolimbic selectivity 87 dose and side effects 24 potency and side effects 26 receptor binding profile 27 Superior parietal cortex, D1 receptors 71 Suprazine 19, See also Trifluoperazine Synaptic connectivity, long-term antipsychotic drug treatment 205 Synedil, See Sulpiride

T Tardive dyskinesia 226 antipsychotic drugs 185 aspartate and glutamate concentrations 127 gamma-vinyl GABA 156 olanzapine 229 trazodone 229 Temporal lobe volume, schizophrenia patients 10 Theoridazine, extrapyramidal side effects 23 Therapy-resistant schizophrenia patients divalproex sodium 157


256


fenfluramine 85 olanzapine 88 Thienobenzodiazepines 21, 22 Thioridazine (Mellaril, Millazine) 18, 19 5-HT2 and D2 receptor affinity 87 dissociation constants 47 dose and side effects 24 potency 25, 44 receptor binding profile 27 weight gain 231 Thiothixene (Navane) 18, 19 Thiothixene-cis 48 Thioxanthenes 17, 19 Thioxene, dose and side effects 24 Thorazine 19, See also Chlorpromazine Thought disorder and glutamate concentrations 123 Three-dimensional model of schizophrenia 3 Tiosperone, possible antipsychotic σ ligand 142, 143 Tourette’s syndrome, pimozide 18 Trails B task 4 Transmembrane signal mediators 202 Trazodone 229 Trifluoperazine (Stelazine, Suprazine) 18, 19 dissociation constants 48 Trifluperidol 48 Trilan, See Sulpiride Trilafon 19, See also Perphenazine Tryptophan compared to chlorpromazine 85 serotonin precursors and clinical symptoms 84 Tryptophan hydroxylase inhibitors 85 l-tryptophan 84 Turning behavior, serotonin and amphetamine 91 Type 1 schizophrenia 2 Type 2 schizophrenia 2 ritanserin 88 Tyrosine hydroxylation, typical antipsychotic drugs 33

U Urapidil 111

V Valproate and haloperidol augmentation 157, 158 clinical studies 156–158 safety 158 Valproic acid 155 clinical studies 156–158 Ventricular enlargement, negative symptoms 2 Verbal fluency task 4 Vitamin B6, with l-tryptophan 84 VTA neuronal firing rate, ritanserin 92

W Working memory α-2-adrenergic receptor 110 D1 receptor 65 guanfacine 110 NMDA receptor antagonist

Y Yohimbine delay-related firing 110 NMDA receptor antagonist effect modulation 126 post-traumatic stress disorder 115 working memory 110

Z Zeldox 21, See also Ziprazidone Ziprazidone (Zeldox) 21, 22 dissociation constants 48 5HT2 receptor binding 27 5HT1a receptor 88, 89 Ziprazidone 21 receptor binding profile 27 Zyprexia 21, See also Olanzapine

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Pharmacogenomics and Personalized Medicine (Methods in Pharmacology and Toxicology) (Methods in Pharmacology and Toxicology)

Apoptosis Methods in Pharmacology and Toxicology: Approaches to Measurement and Quantification (Methods in Pharmacology and Toxicology)

The Evidence-based Guide to Antipsychotic Medications

Dermal Absorption Models in Toxicology and Pharmacology

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Neurotransmitter Receptors in Actions of Antipsychotic Medications (Handbooks in Pharmacology and Toxicology)