CLOZAPINE A 3-IN-1 MEDICAL REFERENCE Medical Dictionary Bibliography & Annotated Research Guide TO I NTERNET
R EFERENCES
CLOZAPINE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Clozapine: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00274-4 1. Clozapine-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on clozapine. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CLOZAPINE ............................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Clozapine....................................................................................... 5 E-Journals: PubMed Central ....................................................................................................... 43 The National Library of Medicine: PubMed ................................................................................ 44 CHAPTER 2. NUTRITION AND CLOZAPINE ..................................................................................... 89 Overview...................................................................................................................................... 89 Finding Nutrition Studies on Clozapine ..................................................................................... 89 Federal Resources on Nutrition ................................................................................................... 92 Additional Web Resources ........................................................................................................... 92 CHAPTER 3. ALTERNATIVE MEDICINE AND CLOZAPINE ............................................................... 95 Overview...................................................................................................................................... 95 National Center for Complementary and Alternative Medicine.................................................. 95 Additional Web Resources ......................................................................................................... 102 General References ..................................................................................................................... 103 CHAPTER 4. PATENTS ON CLOZAPINE .......................................................................................... 105 Overview.................................................................................................................................... 105 Patents on Clozapine.................................................................................................................. 105 Patent Applications on Clozapine.............................................................................................. 109 Keeping Current ........................................................................................................................ 110 CHAPTER 5. BOOKS ON CLOZAPINE ............................................................................................. 111 Overview.................................................................................................................................... 111 The National Library of Medicine Book Index ........................................................................... 111 CHAPTER 6. PERIODICALS AND NEWS ON CLOZAPINE ................................................................ 113 Overview.................................................................................................................................... 113 News Services and Press Releases.............................................................................................. 113 Academic Periodicals covering Clozapine.................................................................................. 115 CHAPTER 7. RESEARCHING MEDICATIONS .................................................................................. 117 Overview.................................................................................................................................... 117 U.S. Pharmacopeia..................................................................................................................... 117 Commercial Databases ............................................................................................................... 118 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 121 Overview.................................................................................................................................... 121 NIH Guidelines.......................................................................................................................... 121 NIH Databases........................................................................................................................... 123 Other Commercial Databases..................................................................................................... 125 APPENDIX B. PATIENT RESOURCES ............................................................................................... 127 Overview.................................................................................................................................... 127 Patient Guideline Sources.......................................................................................................... 127 Finding Associations.................................................................................................................. 129 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 131 Overview.................................................................................................................................... 131 Preparation................................................................................................................................. 131 Finding a Local Medical Library................................................................................................ 131 Medical Libraries in the U.S. and Canada ................................................................................. 131 ONLINE GLOSSARIES................................................................................................................ 137 Online Dictionary Directories ................................................................................................... 137
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CLOZAPINE DICTIONARY ....................................................................................................... 139 INDEX .............................................................................................................................................. 197
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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with clozapine is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about clozapine, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to clozapine, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on clozapine. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to clozapine, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on clozapine. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON CLOZAPINE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on clozapine.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and clozapine, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “clozapine” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Oral Health Care for the Patient with Schizophrenia Source: SCD. Special Care in Dentistry. 11(5): 179-183. September-October 1991. Summary: This article outlines strategies for the oral health care of patients with schizophrenia. The authors note that conceptualizing the disorder as consisting of positive and negative symptoms has led to improved treatment modalities. Medications used in managing the positive symptoms have numerous adverse systemic and orofacial effects that must be recognized by the dentist. Dental treatment strategies for the identification and management of these side effects are described. Negative symptoms are responsible for chronicity of the disorder and frequently impede rehabilitation. These symptoms are potentially devastating to oral health, as they impair a patient's desire and ability to achieve preventive oral hygiene. The authors outline treatment strategies to improve compliance for oral hygiene. A medication, clozapine,
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Clozapine
that is specifically indicated for patients with treatment-resistant disease, has recently been approved for use in the U.S. The authors conclude by reviewing the adverse systemic and orofacial effects of this medication and its influence on dental management. 62 references. (AA-M). •
Conventional vs. Newer Antipsychotics in Elderly Patients Source: American Journal of Geriatric Psychiatry. 7(1): 70-76. Winter 1999. Summary: This article presents a research report on neuroleptics used in treating Alzheimer's disease and other dementing illnesses. The drugs discussed are classified as conventional/typical neuroleptics (haloperidol and thioridazine) or newer/atypical antipsychotics (clozapine, risperidone, olanzapine, and quetiapine). The authors discuss these classes of medications, switching from a conventional neuroleptic to a newer antipsychotic, the economics of using the more expensive atypical antipsychotics, dosing considerations, and polypharmacy. These researchers studied 439 outpatients with a mean age of 65 years in whom antipsychotic treatment was indicated. The authors conclude that the availability of the newer antipsychotic drugs offers clinicians an additional means of treating the symptoms of schizophrenia, other psychotic disorders, and severe behavioral disturbances in patients with dementia. They also conclude that a comprehensive treatment approach for psychotic and other severe behavioral disorders must combine drug therapy with appropriate psychosocial interventions. 2 figures, 1 table, 33 references.
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Criterion Validity: Do the Symptoms Respond to Treatment - Pharmacologic or Nonpharmacologic? Antipsychotic Treatment in Outpatients With Dementia Source: International Psychogeriatrics. 8(Supplement 3): 355-361. 1996. Summary: This journal article reviews the literature on antipsychotic treatment in patients with behavioral disturbances of dementia. First, it reviews results from the four randomized, double-blind, placebo-controlled trials of neuroleptics in dementia which were published in the past 20 years. Then it summarizes findings concerning the efficacy and safety of clozapine, risperidone, and benzodiazepines. Next, the article discusses the optimal dose of haloperidol, the optimal duration of antipsychotic treatment, and antipsychotic side effects. In 1 study of the course of psychopathology, conducted by the author and colleagues, 235 patients with early, probable Alzheimer's disease (AD) were followed at 6-month intervals for up to 5 years. Agitation was found to be the most persistent symptom, which suggests that prolonged treatment may be needed. Finally, the article suggests an approach to initiating and monitoring antipsychotic treatment in older patients with dementia. In the author's opinion, the available data, while limited, suggest that antipsychotic drugs may be effective in treating psychotic symptoms and behavioral problems in some patients with dementia. However, the relative efficacy of antipsychotics in different subtypes of dementia, such as AD and multiinfarct dementia, has not been adequately studied. 35 references.
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Treatment Strategies for Agitation and Psychosis in Dementia Source: Journal of Clinical Psychiatry. 57(Supplement 14): 21-29. 1996. Summary: This journal article reviews treatment strategies for agitation and psychosis in patients with dementia, specifically Alzheimer's disease. It describes types of behavioral disturbances that are associated with dementia and a systematic approach used in evaluating and managing these behavioral complications. It discusses the treatment of psychosis in dementia using traditional antipsychotic agents (haloperidol and
Studies
5
thioridazine), newer antipsychotic agents (clozapine and risperidone), and other drugs. It also discusses the benefits and side effects of treatment of agitation in dementia using antipsychotic agents; anticonvulsant agents (carbamazepine and valproic acid); anxiolytic agents (benzodiazepines and buspirone); antidepressants (trazodone and selegiline); serotonin selective reuptake inhibitors (alaproclate, citalopram, fluvoxamine, fluoxetine, and sertraline); cholinergic therapy; and other therapies such as electroconvulsive therapy, hormonal therapy, and phototherapy. 4 tables, 97 references. •
Drug-Induced Liver Disease Source: Current Opinion in Gastroenterology. 14(3): 208-214. May 1998. Contact: Available from Lippincott-Raven Publishers. 12017 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: This review article discusses the recent literature on drug-induced liver disease, a common and often underappreciated cause of liver injury. There continues to be very little insight into the pathogenesis of hepatotoxicity for most drugs. Acetaminophen is one of the few drugs for which the mechanisms of liver injury are reasonably well understood. With an understanding of these mechanisms, new reports have identified several factors that can increase the severity or risk of developing acetaminophen associated liver injury. These factors include depletion of glutathione stores (caused by fasting or alcohol use). Other studies have improved the understanding of the mechanisms by which halogenated anesthetics cause liver injury. This information has made it possible to correlate the pathway of metabolism of these agents with their incidence of hepatotoxicity and even to potentially predict the risk of liver injury with new anesthetics. Antibiotics continue to be one of the most commonly used medications and one of the more common causes of drug-induced liver disease. Recent reports stress the importance of these drugs as potential causes of liver injury and highlight the frequency with which some antibiotics cause hepatotoxicity. Finally, the author reviews several case reports of other drugs noted to cause liver disease: ketoconazole, octreotide, clozapine, and omeprazole. 84 references (9 annotated). (AAM).
Federally Funded Research on Clozapine The U.S. Government supports a variety of research studies relating to clozapine. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to clozapine. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use 2
Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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Clozapine
animals or simulated models to explore clozapine. The following is typical of the type of information found when searching the CRISP database for clozapine: •
Project Title: 5-HT MODULATION OF NA+ CURRENTS IN PFC PYRAMIDAL CELLS Principal Investigator & Institution: Carr, David B.; Physiology; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-SEP-2002 Summary: The prefrontal cortex (PFC) plays important roles in cognitive and affective function. Dysfunction within PFC circuitry is strongly implicated in the pathophysiology of schizophrenia, particularly in the expression of negative symptoms. The ability of atypical antipsychotics such as clozapine to ameliorate these negative symptoms has focused attention on the serotonin (5-HT) as well as dopamine (DA) modulatory systems within the PFC, as these drugs are potent antagonists at both 5-HT and DA receptors. Despite the importance of these two neuromodulatory systems in regulating PFC neuronal activity, very little is known as to how they affect the ionic conductances that shape information processing within PFC cells. Moreover, almost nothing is known as to how 5-HT and DA interact at the level of individual PFC neurons. To address these issues, a research and training plan is proposed utilizing a combination of electrophysiological, pharmacological and molecular biological techniques to achieve two specific aims. The first is to examine the effect of 5-HT2a/c receptor stimulation on Na+ currents in acutely isolated PFC neurons and to characterize the mediating signaling cascade. The second aim is to characterize the nature and mechanism of interaction of 5-HT2a/c and DA1/5 signaling pathways on Na+ currents will be examined. The achievement of these aims will provide vital information necessary to construct accurate, integrative models of PFC function as well as dysfunctional states such as schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: A PHARMACOGENETICS APPROACH TO DRUG INDUCED WEIGHT GAIN Principal Investigator & Institution: Coe, Natalie R.; Jackson Laboratory 600 Main St Bar Harbor, Me 04609 Timing: Fiscal Year 2002; Project Start 26-MAY-2002 Summary: (Scanned from the applicant?s description) Obesity, often the result of a person?s genetic predisposition, can lead to serious medical conditions, including noninsulin dependent diabetes, heart disease, stroke, high blood pressure, kidney failure, and depression. Clozapine is a highly prescribed anti-psychotic drug, but unfortunately, many patients become obese within several months after initiation of this drug therapy. Identification of the clozapine weight responsive genetic locus and subsequent gene identification will 1) further enhance our understanding of obesity, including genetic suscepibility and onset as well as the its underlying molecular basis, 2) allow psychiatric patients to be screened prior to clozapine treatment to avoid potential health risks brought on by obesity, 3) identify potential cross talk of neuronal and obesity-related metabolic pathways, and 4) help aid in the design of new anti-psychotic drugs that do not interfere with metabolic weight homeostasis. The potential correlation (positive or negative) between formation of the principal active metabolite of clozapine(N-desmethyl-clozapine) and the onset of obesity will be explored as a viable tool to screen psychiatric patients genetically predisposed to clozapine induced weight
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gain. The involvement of histamine (H1) receptors and the neuroleptic induced obesity phenotype has abeen eluded to but not formally addressed in the literature. The potential role of the H1 receptor will be examined directly by the proposed work. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AMPAKINES IN SCHIZOPHRENIA Principal Investigator & Institution: Johnson, Steven A.; Senior Scientist; Cortex Pharmaceuticals, Inc. 15231 Barranca Pkwy Irvine, Ca 926182201 Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 31-AUG-2004 Summary: (Adapted From the Applicant's Abstract) Currently available antipsychotics effectively control positive symptoms (hallucinations, delusions), but persistent negative symptoms (withdrawal, apathy) and cognitive deficits are little affected and can be quite disabling in most patients with schizophrenia. Recently, a new class of orallybioavailable molecule that specifically enhances AMPA-type glutamate receptor activity has been developed. AMPAKINES facilitate acquisition and retention of memory in rodents and humans, and synergistically interact with modern antipsychotics. We recently completed an exploratory safety trial of the AMPAKINE CX516 added to clozapine in 19 treatment-resistant patients. CX516 was well tolerated and produced consistent improvements in negative symptoms, attention, and memory. We now propose to conduct a larger, placebo-controlled trial of CX516 added to olanzapine in patients with schizophrenia. The primary hypothesis is that CX516 will improve negative symptoms, attention, and verbal memory. Secondary aims are: 1) to asses the safety and tolerability of CX516 compared to placebo in olanzapine-treated patients; 2) to assess CX516 effects on positive symptoms, anxiety, depressive symptoms, executive function, and verbal fluency; and 3) to assess effects on extrapyramidal symptoms, including parkinsonism, akathisia and tardive dyskinesia. Positive effects on clinical (negative, positive, extrapyramidal) and neuropsychological (cognition, memory, attention) symptoms in a larger trial will strongly suggest that AMPAKINES may be useful for treatment of schizophrenia. PROPOSED COMMERCIAL APPLICATION: This research may lead to the development of a new, improved class of antipsychotic drug for schizophrenia. These new drugs have the potential to treat the diverse symptoms of this complex disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANTIPSYCHOTIC DRUG INDUCED DYSKINESIAS Principal Investigator & Institution: Casey, Daniel E.; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002 Summary: Antipsychotic (neuroleptic) drug-induced neurological dysfunctions in the motor system are substantial limitations of therapy. These motor disorders include acute dystonic reactions and drug-induced parkinsonism. They occur at the initiation of neuroleptic treatment and may continue in many patients throughout the course of treatment. The underlying pharmacological basis of these disorders is poorly understood. A recently developed drug, Clozapine, appears to have very few of these neurological side effects yet maintains good clinical antipsychotic efficacy. Therefore, it is important to study Clozapine and other potentially new antipsychotic drugs to identify the possible mechanism of action that will lead to reduced neurological side effects. To better understand this issue, we have studied 31 Cebus monkeys in shortterm trials lasting a few days to a few months. Drugs which affect the receptor subtypes
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Clozapine
of dopamine D1 and D2 and serotonin 5HT1A and 5HT2 have been studied. All these drugs produce typical signs of dystonia and parkinsonism, with the exception of Clozapine and 5HT1A agonists. These findings suggest that the mechanism of Clozapine is as yet unknown. Combinations of receptor antagonists of dopamine and serotonin subtypes have not yet identified a clear line of drug development to pursue for creating new antipsychotic drugs that free of neurological side effects. FUNDING NIH MH36657 PUBLICATIONS Casey DE. Effects of clozapine (Clozaril) therapy in schizophrenic individuals at risk for tardive dyskinesia. J Clin Psychiatry 59(Suppl 3):3137, 1998. Casey DE, Garver DC, Lasagna L, Marder SR, Masand PS, Miller D, Pickar D, Tandon R. Clinical trial evaluations and outcome measures in psychiatry. J Clin Psychiatry 59(Suppl 12):1-52, 1998. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTIPSYCHOTIC MEDICATION Principal Investigator & Institution: Newcomer, John W.; Associate Professor; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 20-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant) Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Type 2 diabetes mellitus is characterized by disturbances in insulin action on skeletal muscle, liver and adipose tissue. Diabetes causes increased morbidity and mortality due to acute (e.g., diabetic ketoacidosis) and long-tenn (e.g., cardiovascular disease) complications. The combination of hyperglycemia, dyslipidemia and abdominal adiposity is even more strongly associated with increased cardiovascular morbidity and mortality. The association of type 2 diabetes and hyperglycemia with schizophrenia was first noted prior to the introduction of antipsychotic medications, suggesting that these patients may be at increased risk. Since then, however, additional glucoregulatory abnormalities (e.g., new Onset diabetes), dyslipidemia, and increased weight and adiposity have all been associated with antipsychotic medications. Concern about antipsychotic effects on glucose, lipids and adiposity has increased recently, focusing on the widely-used newer medications, clozapine and olanzapine. Increased abdominal adiposity can secondarily decrease insulin sensitivity and antipsychotics can increase adiposity. However, medication effects on glucose control and insulin action may also occur independent of differences in adiposity. This project aims to a) evaluate the effects of selected antipsychotic medications on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (whole-body lipolysis), b) evaluate the effects of selected antipsychotic medications on abdominal adipose tissue mass, total body fat and total fat-free mass, and c) explore the longitudinal effects of treatment with selected ant:ipsychotics on glucose tolerance, lipid profiles, abdominal adipose tissue mass, total body fat and total fat-free mass. These hypotheses will be evaluated by measuring 1) whole-body glucose and lipid kinetics with the use of gold-standard stable isotopetracer methodology, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, and 3) longitudinal changes in glucose tolerance and lipid profiles. The aims will be addressed in non-diabetic schizophrenia patients chronically treated with risperidone, olanzapine, clozapine, or haloperidol, and untreated healthy controls. Re-evaluations will also be performed in patients treated with olanzapine and risperidone (from groups above), crossed over to treatment with the other agent for 6 months. Relevant data is critically needed to target basic research, identify long-term cardiovascular consequences, and plan therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANTIPSYCHOTIC TREATMENT RESPONSE Principal Investigator & Institution: Miller, Del D.; Psychiatry; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-MAY-2000; Project End 30-APR-2005 Summary: (Adapted from the Applicant's Abstract): In this application for a Mentored Patient-Oriented Research Career Development Award, Del D. Miller will obtain expertise in clinical trials methodology with the intent of studying the biological aspects of antipsychotic response with the goal of improving outcome in persons suffering from schizophrenia. Despite the use of newer atypical agents, many patients with schizophrenia continue to suffer from chronic symptoms and never return to baseline functioning. Dr. Miller will examine plasma concentrations and the presence of mutations of genes that code for neurotransmitter receptors to determine their roles in the clinical response of treatment-refractory persons with schizophrenia receiving clozapine. The candidate proposes a training and research program using the resources of a preventive medicine department devoted to training clinical investigators in the intricacies of treatment trials, a psychiatry department with a long history of research, and a Mental Health Clinical Research Center devoted to the neurobiology of schizophrenia. While Dr. Miller has training in schizophrenia research, he requires additional training in the design of large scale clinical investigations to study the role of biological factors on antipsychotic response. This training will be integrated with a research project seeking: 1) To examine the influence of receptor of polymorphism of the genes that code for neurotransmitter receptors and transporters predicts response to treatment with clozapine 2) To determine whether the combination of clozapine plasma concentrations and presence or absence of genetic polymorphism of neurotransmitter receptors and transporters allows for prediction of response to treatment with clozapine and 3) To develop a model for understanding the relationship between these biological factors and known predictors of clinical outcome. These findings will lead to a therapeutic model for guiding clinicians in choosing treatments for persons with schizophrenia. This award would provide the candidate with the necessary background for further studies of factors influencing antipsychotic response and may yield important algorithms for the pharmacological treatment of schizophrenia. This award will also serve as a mechanism by which the candidate can establish professional collaborative relationships with his mentors and provide him with the background for ongoing research leading to an independent research career. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MACHINERY
ANTIPSYCHOTICS
AND
RECEPTOR
DESENSITIZATION
Principal Investigator & Institution: Gurevich, Eugenia V.; Pharmacology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 05-DEC-2000; Project End 30-NOV-2003 Summary: (Adapted from applicant's abstract) Arrestins and G protein-coupled receptor kinases (GRKs) participate in homologous desensitization of hundreds of G proteincoupled receptors (GPCRs). The rate and extent of desensitization of GPCRs is sensitive to the concentration of arrestins and GRKS in the cells. In its turn, the amount of arrestins and/or GRKs can be modulated by activity of GPCRs. Typical antipsychotic drugs are potent antagonists of the D2 dopamine receptor, whereas atypical drugs interact with several GPCRs. Plasticity of several GPCRs is implicated in schizophrenia pathology and actions of antipsychotic drugs. The a[[;ocamts hypothesize that treatment
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Clozapine
with antipsychotics induces alterations in the concentration of specific arrestins and/or GRKs in selected brain regions, thereby modifying signal transduction via GPCRs in these regions. Exploration of this hypothesis is clinically relevant because molecular mechanisms of the beneficial actions of antipsychotic drugs remain elusive. Mechanism of action of atypical antipsychotics with their higher efficacy against negative symptoms and cognitive deficits is of particular interest. The specific aims designed to test this hypothesis include determination of the repertoire of arrestin and GRK proteins in specific subtypes of output neurons in the striatum and nucleus accumbens, the brain regions that are prime targets of antipsychotics. The second specific aim focuses on comparison of the effects of acute and subchronic treatment with typical antipsychotic haloperidol and atypical drug clozapine on the expression of arrestin and GRK mRNAs and proteins in various brain areas implicated in schizophrenia pathology and action of antipsychotics. The third specific aim is to determine whether alterations in the arrestin and GRK expression are associated with development of tardive dyskinesia induced by chronic treatment with haloperidol. Plasticity of neuronal receptor trafficking system produced by antipsychotic treatment may lead to changes in the concentrations of specific GPCRs and, ultimately, to long-term modulations of neuronal responses to endogenous stimuli and exogenous drugs. Specific modifications in the arrestin/GRK expression may thus be essential for the beneficial or side effects of antipsychotic drugs. We expect that the information gained by examining the response of the key components of the receptor trafficking machinery to antipsychotics will be helpful for targeted design of drugs with improved clinical profile. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTION
ANTIPSYCHOTICS:
TEMPORAL
EFFECTS
ON
COGNITIVE
Principal Investigator & Institution: Terry, Alvin V.; Clinical & Administrative Pharmacy; University of Georgia 617 Boyd, Gsrc Athens, Ga 306027411 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2007 Summary: (provided by applicant): Schizophrenia is a debilitating illness that affects up to 1% of the world's population. While the use of antipsychotic (neuroleptic) drugs is the standard of care for treating the psychotic symptoms of the illness, little is known regarding which neuroleptics are best for extended use in those with cognitive impairment. This consistent feature of schizophrenia is now believed to have the most substantial impact on the longterm outcome of the disease. Accordingly, a major longterm goal of this laboratory is to develop mechanistically-based therapeutic strategies for patients suffering from psychotic symptoms and cognitive dysfunction. The objective of this application is to establish potential relationships between the cellular and biochemical effects of chronic neuroleptic exposure and cognitive function in an experimental animal model. We have compelling preliminary evidence from rat studies that chronic exposure to conventional neuroleptics such as haloperidol (in a temporally dependent fashion), but not atypical agents such as clozapine, leads to cognitive impairment and that a reduction in a key marker for cholinergic neurons, choline acetyltransferase, precedes the cognitive symptoms. Due to the pattern of reduced cholinergic enzyme staining and the fact that many of the cholinergic neurons involved in learning and memory are functionally dependent on the neurotrophin, nerve growth factor (NGF), we have developed the hypothesis that chronic exposure to conventional, but not atypical, neuroleptics in rats decreases neurotrophic support to cholinergic neurons, resulting in decreased cholinergic activity in the brain and impairment of cognitive function. The rationale for the proposed animal studies is that a better
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understanding of the differential (chronic) effects of neuroleptics on memory function will facilitate future (clinical) efforts to identify optimal drugs for cognitively impaired psychiatric patients. To test the hypothesis we propose two specific aims: 1): To evaluate differential temporal effects of different classes of neuroleptic drugs on cognitive function in an experimental animal model. 2): To define potential correlative relationships between neuroleptic-induced cognitive changes and temporal changes in biochemical and cellular parameters of cholinergic function in the brain, NGF release, and NGF receptor expression. We will use a water maze task to measure spatial learning, an 8-arm radial arm maze task to assess working memory, and in situ hybridization, western blots, ELISA experiments, immunofluorescence staining, and receptor autoradiography to measure the expression of NGF and key cholinergic markers. We expect that chronic exposure to conventional, but not atypical neuroleptics will negatively affect both spatial learning and working memory and that neurolepticinduced alterations in CNS cholinergic activity will both precede and correlate with detectable manifestations of cognitive dysfunction. These studies, designed to mechanistically define neuroleptics based on their chronic effects on specific biological substrates of memory are significant because they will contribute to the identification of therapeutic agents with optimal effects on cognitive function, and thus potentially benefit many psychiatric patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APOMORPHINE CHALLENGE IN SCHIZOPHRENIA & NORMALS Principal Investigator & Institution: Lee, Myung A.; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ATYPICAL CONCENTRATION
ANTIPSYCHOTICS:
DETERMINANTS
OF
Principal Investigator & Institution: Pollock, Bruce G.; Professor of Psychiatry and Pharmacology; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2005 Summary: (provided by applicant): The primary goal of this revised application (MH64173), which is ancillary to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), is to reliably capture the concentration exposure of the antipsychotics (risperidone, olanzapine, ziprasidone, fluphenazine, perphenazine, and clozapine) using mixed effect population pharmacokinetic methodologies. The population pharmacokinetic approach is ideally suited for analyzing drug concentration data from large clinical intervention trials because patient-specific as well as overall population pharmacokinetic parameters can be determined using only a few plasma samples per patient. An understanding of pharmacokinetic variability is essential to rational drug prescribing. The population pharmacokinetic approach will permit determination of the extent of variability in drug exposure associated with the use of atypical antipsychotics in large populations under conditions that mirror clinical practice. In addition, the ability of population pharmacokinetic models to capture subjects' drug exposure utilizing single concentration measurements will be assessed in this study. Population pharmacokinetics has also been successfully used to identify
12
Clozapine
sources of variability in drug concentration exposure. Therefore, this ancillary study will provide an innovative way to make optimal use of plasma samples that are being obtained in the CATIE trials. The CATIE trials will recruit up to 2,250 patients providing from 1 to 6 plasma concentration samples per subject for each medication. A separate population pharmacokinetic model will be constructed for each drug incorporating covariate effects. Specific covariates will be then be evaluated as potential contributors to drug exposure variability. Demographic covariates to be examined are age, sex, race/minority status, and body mass index. The potential impact of additional covariates such as prior medication exposure, concomitant medications, smoking status, estimated renal clearance, and treatment adherence will also be assessed. By providing pharmacokinetic data on the atypical antipsychotics under "real world" conditions, this study has broad public health implications, leading to greater awareness of the need to individualize antipsychotics pharmacotherapy for patients suffering from either schizophrenia or Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BEHAVIORAL & PHARMACOLOGICAL ANALYSIS OF DRUGS OF ABUSE Principal Investigator & Institution: Winter, Jerrold C.; Professor; Pharmacology and Toxicology; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2002; Project Start 01-JAN-1985; Project End 30-JUN-2006 Summary: The discovery by Albert Hofmann more than fifty years ago of the hallucinogenic effects of LSD irreversibly altered the course of both biological psychiatry and popular culture. Hallucinogens of all types are subject to widespread and increasing abuse by adolescents and young adults in this country. For example, in 1998 use of hallucinogens exceeded that of cocaine in the age groups 12-17 and 18-25. Indeed, hallucinogens were more commonly ingested than tranquilizers, inhalants, and sedatives combined. Furthermore, LSD was identified in 1999 as a "club drug" in the campaign by the National Institute on Drug Abuse to alert the public to the hazards of these agents. In addition to the well recognized abuse liability of these drugs, hallucinogens are perhaps unique in that an understanding of their mechanisms of action would contribute not only to an amelioration of the burdens of illicit use but might also provide a key to solving the puzzle of psychosis, another major human affliction. The present investigations seek to characterize indoleamine hallucinogens such as LSD and phenethylamine hallucinogens as exemplified by DOM in combined behavioral, biochemical, and analytical [GC-MS] studies. Specifically, studies will also examine the neuroanatomical sites involved in hallucinogen- induced stimulus control. In addition, experiments will further characterize interactions between the serotonergic and glutamatergic systems in the brain. Finally, the mechanisms responsible for the potentiation of LSD and other hallucinogens by fluoxetine and related selective serotonin reuptake inhibitors will be examined. Taken together, the correlational use of powerful methods for the assessment of in vivo and in vitro efficacy and of brain levels of DOM and of neurotransmitters will provide new understanding of the mode of action of hallucinogens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOPHYSICAL STUDY OF ANTIPSYCHOTICS BEHAVIORAL EFFECTS Principal Investigator & Institution: Fowler, Stephen C.; Professor; Human Develmt and Family Life; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-MAR-2004 Summary: (Adapted from the Investigator's Abstract) The atypical antipsychotic drugs are a major advance over the older drugs that frequently induced extrapyramidal side effects (EPS). These newer drugs, except for clozapine, continue to induce EPS at higher doses. Despite its superior efficacy in the treatment of refractory schizophrenic patients, clozapine produces measurable cognitive side effects as well as distinctive, but not EPSlike, motor effects in both humans and rats. The over arching purpose of this proposal is to quantify, in rats and in inbred strains of mice, the motor and cognitive side effects of clozapine and other atypical antipsychotic drugs as well as to continue efforts to quantitate low-dose EPS in rodents. Three, primary behavioral measurement procedures will be used: 1) the food-anticipation-operant-microcatalepsy (FAOM) task that models low dose EPS (bouts of immobility that interrupt behavior) and bradykinesia (slowing of movements) in both rats and mice; 2) the sustained attention task (SAT) that concurrently measures reaction time and cognitive performance and closely resembles the continuous performance task that reveals deficits characteristic of schizophrenia; 3) the forelimb tremor task (FT) that uses force-transducer technology and Fourier analysis to quantify drug-induced tremor and detects the hypotonia and antitremor effects of clozapine. In the FAOM procedure, the EPS liability of atypical antipsychotics clozapine, risperidone, sertindole, quetiapine, and olanzapine will be evaluated in haloperidol-sensitized rats. When haloperidol-treated inbred strains of mice were compared in the FAOM task, the C57bl/6 mice showed striking EPS-like effects while the Balb/c mice did not-a result suggesting genetic causes. Several inbred strains of mice will be compared to identify strains likely to express EPS-like effects of atypical antipsychotic drugs. The SAT procedure will be used with rats to assess deleterious cognitive effects of chronic clozapine. The FT task will be used with rats to explore clozapine's recently discovered withdrawal effect (tremor rebound), to evaluate other atypical antipsychotics for clozapine-like motor effects, and to assess clozapine's ability to dampen tremor induced by harmaline or physostigmine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BRAIN ERPS AND COGNITIVE DEMAND IN SCHIZOPHRENIA Principal Investigator & Institution: Bruder, Gerard E.; Professor; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 100321098 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 28-FEB-2004 Summary: (Adapted from applicant's abstract): Schizophrenic patients have shown a reduction in amplitude of the P3 brain ERP to tones, which was maximal over left temporal lobe sites. In the initial project period, the investigator replicated this finding in a dichotic complex tone task and found reduced N2 amplitude and asymmetry in schizophrenic patients in a dichotic syllable task. This suggests that left hemisphere dysfunction in schizophrenia for verbal processing occurs as early as 200 ms after stimulus onset. N2 abnormalities in schizophrenic patients were present in both auditory and visual tasks, whereas P3 abnormalities appear to be modality specific. The investigator proposes to conduct four studies to determine the task and patient characteristics necessary for producing these ERP abnormalities and to further resolve their neurophysiologic mechanisms. Study 1 will record ERPs in a large sample of
14
Clozapine
schizophrenic patients (n=120) and normal controls (n=40) on verbal and nonverbal binaural oddball tasks, and will assess the influence of response mode (silent counting, right hand or left hand). These large samples will enable the investigator to examine the relation of ERP abnormalities in schizophrenia to symptom features, outcome of treatment with neuroleptics, familial history of schizophrenia, and neuroimaging measures. Study 2 will develop and apply new verbal and nonverbal tasks that incorporate advantages of dichotic listening procedures, but utilize a simple oddball paradigm. Study 3 compares ERPs of schizophrenic patients and controls in auditory and visual continuous word recognition tasks, which are thought to reflect left medial temporal lobe function. Study 4 continues the investigator's study of visuospatial processing in schizophrenia using a revised paradigm designed to disentangle effects of selective attention and later cognitive processing. Patients will be tested while off medication and again after six weeks of treatment with haloperidol or an atypical neuroleptic (clozapine or risperidone). A more long range clinical goal is to contribute toward the development of tests that could predict response to treatment with conventional or atypical neuroleptic medications for schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BUILDING SCHIZOPHRENIA
A
MOUSE
MODEL
WITH
RELEVANCE
TO
Principal Investigator & Institution: Fish, Kenneth N.; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The career development and research program described in this proposal supports the application for a Mentored Research Scientist Development Award for Dr. Kenneth N. Fish, and is intended to provide the candidate with the background knowledge, research experience, and research management skills that will prepare him for an independent research career in schizophrenia. Training will take place at the Harold L. Dorris Neurological Research Center in the Department of Neuropharmacology (Dr. Floyd E. Bloom, Chair) of the Scripps Research Institute, under the direct supervision of Dr. Tamas Bartfai. Dr. Bartfai is highly qualified to serve as Preceptor for the Candidate, because of his experience with the methodologies to be used, his active research program in depression and schizophrenia, and his commitment to the development of junior research scientists. The Department of Neuropharmacology emphasizes a multi-disciplinary approach to problems of mental disorders. Thus, this is an ideal environment for the Candidate to materialize his goal of developing a multidisciplinary research approach to the neurobiology of schizophrenia. The overall objective of the research plan is to perform a thorough analysis of the reeler and scrambler mice to define test parameters that will be used to study new mouse models and to determine their applicability as models to study schizophrenia. Tests will include a morphological analysis of the neocortex, cerebellum, and hippocampus using three-dimensional reconstruction with NeuroZoom, immunocytochemical analysis of DA, GLU, and GABA expression, quantitative behavioral measurements [prepulse inhibition (PPI) of the startle response], and their responsiveness to clinically effective antipsychotics (haloperidol, risperidone, and clozapine). In addition, to further characterize the reeler phenotype we will generate a transgenic mouse in which reelin expression is temporally regulated and generate a mouse model that has a conditional block of reelin function to induce specific changes in brain morphology that are required to alter prepulse inhibition and/or induce ataxia. These studies will advance our understanding of how neurodevelopmental abnormalities relate to behavioral changes
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and will assist in the development of new antipsychotic drugs with relevance to schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CAMP/PKA SCHIZOPHRENIA
SIGNALING
&
ENDOPHENOTYPES
OF
Principal Investigator & Institution: Druhan, Jonathan P.; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002 Summary: (provided by applicant): Recent evidence suggests that disturbances in intracellular signaling may underlie some of the cognitive and neurobehavioral dysfunctions observed in schizophrenia. Studies in humans suggest that the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway is upregulated within the central nervous systems of schizophrenic patients. Our preliminary studies indicate that transgenic mice overexpressing a constitutively active form of the signaling protein Gs(Gs-*) in forebrain neurons exhibit deficits in two neurobehavioral processes known to be disrupted in schizophrenics, inhibitory gating and explicit learning. Studies in this proposal will examine the effects of increased cAMP/PKA signaling on inhibitory gating and learning in mice to determine whether signaling disturbances could contribute to these endophenotypes of schizophrenia. Studies in Aim 1 will test transgenic mice that overexpress constituents of the cAMP/PKA signaling pathway (i.e. Gs-*, the catalytic subunits of PKA, or a nuclear target of PKA, CREB) in animal models of inhibitory gating and learning to determine whether such mice show deficits in these paradigms (prepulse inhibition, P20/N40 gating, and Morris water maze). Offspring of Gs-* mice crossbred with mice having reduced PKA or CREB activity also will be tested in these behavioral paradigms to determine whether reductions in PKA or CREB can normalize the behavioral deficits produced by the overexpression of Gs-*. Studies in Aim 2 will measure inhibitory gating and learning after localized stimulation of cAMP/PKA activity in forebrain regions of wild-type mice, or after localized inhibition of cAMP/PKA in forebrain regions of Gs-* mice, to determine whether localized pharmacological manipulation of cAMP/PKA activity modifies gating and learning processes. Studies in Aim 3 will determine whether drugs effective at treating symptoms of schizophrenia will normalize gating and learning deficits in mice with upregulated cAMP/PKA activity. These studies will provide important new information about the role that intracellular signaling in cAMP/PKA pathways plays in the expression of gating and learning endophenotypes of schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CANNABIS AND SCHIZOPHRENIA: CLOZAPINE VS RISPERIDONE Principal Investigator & Institution: Green, Alan I.; Professor; Psychiatry; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 30-NOV-2002 Summary: (Applicant's Abstract) Cannabis use disorder contributes to the morbidity of schizophrenia, leading to, poorer overall functioning. The typical antipsychotic drugs are of limited value in controlling cannabis use in these "dual diagnosis" patients. This study will assess whether new antipsychotic medications, introduced into clinical practice in the past decade, are of value for this purpose. Preliminary data suggest that the atypical antipsychotic drug clozapine (CLOZ), currently used primarily for treatment resistant patients, may limit cannabis use in "dual diagnosis" patients with
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Clozapine
schizophrenia much more effectively than do either typical antipsychotics or the "novel" (post-CLOZ) antipsychotic risperidone (RISP). In a recently published paper, we have hypothesized (a) that CLOZ will lessen substance use in such "dual diagnosis" patients in part because of its mechanism of action that includes release of dopamine (DA) in the prefrontal cortex (PFC), and (b) that the CLOZ-induced release of DA in the PFC will decrease negative symptoms (an effect shared especially by the novel antipsychotic RISP). Moreover, we have further hypothesized, (c) that through its diverse effects on both dopaminergic and noradrenergic systems, CLOZ (but not RISP or typical antipsychotics) will help to normalize dysfunctional brain reward circuits that may underlie the comorbid substance use in patients with schizophrenia. In the proposed study, patients comorbid for both schizophrenia and a cannabis use disorder will be randomly assigned to double-blind treatment (for 12 weeks) with either CLOZ or RISP. The primary aim of this study is to launch a carefully controlled pharmacological trial of the short-term effects of CLOZ and RISP on cannabis use in this population to test the hypothesis that patients treated with CLOZ will have decreases in cannabis use as compared to patients treated with RISP. A secondary aim is to begin to investigate the process by which CLOZ produces its effects on cannabis use through study of negative symptoms. A subsidiary aim is to begin to address key auxiliary measures of the effects of CLOZ in this "dual diagnosis" population: psychiatric symptoms, quality of life, and measures of neuropsychological functions. If the results of this study confirm the preliminary data, they could suggest a new use for CLOZ, one that could have important public health implications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CLOZAPINE IMPROVEMENT
&
SENSORY
INHIBITION:
MECHANISM
OF
Principal Investigator & Institution: Simosky, Johanna K.; Pharmacology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-APR-2002 Summary: (provided by applicant): Although control subjects will inhibit the evoked electrophysiological response to the second of paired auditory stimuli, schizophrenics are unable to do so. Inhibitory pathways in the hippocampus, which can be modulated through alpha7 nicotinic cholinergic receptors, are insufficiently activated in schizophrenia patients. This results in an inability to appropriately inhibit the response to repetitive sensory stimuli. Clozapine, unlike typical antipsychotics, is able to normalize this deficit in sensory inhibition. The mechanism of this normalization is unknown, but its elucidation would allow better understanding of clozapine?s efficacy. We propose that clozapine-induced increases in cholinergic neurotransmission are responsible for the increased inhibition of response. This hypothesis will be tested in DBA/2 mice, a mouse model of the deficit which shares both phenotypic and genotypic attributes with the deficit observed in schizophrenia. After construction of a dose response curve for the effects of clozapine on sensory inhibition we will carry out mechanistic studies. The first of these will determine how the normalizing effects of clozapine on sensory inhibition are affected by pretreatment of the mice with various nicotinic antagonists, to infer if (and which) nicotinic receptors are involved in mediating the effects of clozapine. In the final aim, the techniques of hippocampal in vivo microdialysis and single unit recording will be used to determine if clozapine increases the release of acetylcholine and/or increases the activity of septohippocampal cholinergic neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CLOZAPINE AND OLANZAPINE IN VIOLENT SCHIZOPHRENICS Principal Investigator & Institution: Krakowski, Menahem I.; Senior Research Scientist; Nathan S. Kline Institute for Psych Res Psychiatric Research Orangeburg, Ny 10962 Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 31-JAN-2004 Summary: Chronic violence and hostility in schizophrenic patients represent a serious problem which impacts on the perpetrators, other patients and caregivers. In preliminary studies, we have identified a group of schizophrenic patients who evidence persistent violence and hostility linked to specific schizophrenic symptoms. These patients are responsible for a high percentage of all inpatient assaults. The literature suggests that clozapine (CLO) has specific anti- aggressive effects and it improves psychotic symptoms and cognitive impairments similar to those which we identified in these patients. Olanzapine's (OLZ) without the latter's potentially serious side effects suggests that it may have an important place in the treatment of these patients. We will examine the examine the comparative efficacy of CLO, OLZ and standard agent haloperidol (HAL) in the treatment of persistent. We will also how underlying symptoms and deficits are associated with persistent violence and how they improve with each of these three treatments. Violent patients (N=212) will enter a 12-week clinical trial in which they will be randomized to either CLO, OLZ or HAL under double-bind conditions. Outcomes measures include the Modified Overt Aggression Scale, the Buss-HAL under double-blind conditions. Outcomes measured include the Modified Overt Aggression Scale, the Buss-Durkee Hostility inventory, and the NOSIE. Patients' reduction in psychotic symptoms will be assessed by PANSS and CGI. Reduction in cognitive impairment will be assessed by the Wisconsin Card Sorting Test, in impulsivity by the Barrat Impulsiveness scale. It is hypothesized that: 1) the effects of CLO on physical assaults, hostility and social functioning will be superior to those of OLZ, which, in turn, will be superior to HAL's. 2) Improvement in the outcome variables-violence, hostility and social functioning-will be related to improvement in underlying symptoms, i.e. ability to utilize environmental feedback, impulsivity, and psychosis. Similar to the outcome measures, these symptoms will improve more with CLO than OLZ and more with OLZ than HAL. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CLOZAPINE DRUG DISCRIMINATION IN C57BL/6J MICE Principal Investigator & Institution: Philibin, Scott Commonwealth University Richmond, Va 232980568
D.;
Psychology;
Virginia
Timing: Fiscal Year 2003; Project Start 18-AUG-2003; Project End 17-AUG-2006 Summary: (provided by applicant): Clozapine is the prototypical atypical antipsychotic drug and represents a tremendous improvement over conventional antipsychotics in terms of therapeutic efficacy and reduced side effect liability for the treatment of schizophrenia. Understanding the pharmacological properties that are important for clozapine's unique profile can help lead to the discovery of improved and safer antipsychotic drugs for the treatment of schizophrenia. One approach for investigating the molecular bases underlying the relationship of pharmacological agents and behavior has been the use of gene-targeted knockout or transgenic animals. This technique allows for the manipulation of receptors for which selective pharmacological ligands do not exist. One restriction of this approach is that most of the knockout mutations that have been developed are available only in mice - not rats. Therefore, it is necessary to have preclinical assays for mice in order to utilize these new and potentially powerful new techniques. The current proposal represents an important first step in this process. Two-
18
Clozapine
lever drug discrimination is a valuable preclinical behavioral model that has been used to investigate the discriminative stimulus properties of clozapine in rats and has helped identify neurotransmitter receptor targets for putative atypical antipsychotics. Wildtype mice (C57BL/6J) will be trained to discriminate clozapine from vehicle and then a series of atypical and typical antipsychotic drugs will be tested to determine which drugs generalize to clozapine's discriminative cue. Establishing this procedure in wildtype mice will allow for the future use of knockout and transgenic mice and will expand the tools available to molecular geneticists and behavioral pharmacologists. This will help to increase our understanding of the perplexing pharmacology of schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CLOZAPINE EFFECTS ON GLUTAMATE TRANSMISSION AND DOPAMINE Principal Investigator & Institution: Hasenkamp, Wendy; Biology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-OCT-2002; Project End 31-JUL-2005 Summary: (provided by applicant): The broad objective of the proposed research is to elucidate the effects of clozapine treatment on subpopulations of midbrain dopaminergic neurons. Specifically, the molecular and neurochemical changes in NMDA-mediated glutamate transmission induced by acute (1d) versus chronic (21d) treatment of clozapine will be evaluated through two aims. In the first aim, the prefrontal cortex and nucleus accumbens of rats will be injected with retrograde tracer prior to acute or chronic clozapine (or vehicle) treatment. Following drug administration, mRNA from retrogradely-labeled mesolimbic or mesocortical dopaminergic neurons will be amplified and hybridized to a custom cDNA microarray for determination of global changes in gene expression. In the second aim, microdialysis will be used to evaluate changes in extracellular dopamine in the prefrontal cortex and nucleus accumbens, as well as glutamate in the midbrain, after acute and chronic clozapine. In addition, the functional response of midbrain dopaminergic neurons to NMDA and AMPA antagonists will be analyzed based on changes in dopamine release in response to these compounds. These studies will further our understanding of atypical neuroleptic action, and in doing so, may help elucidate the underlying neuropathology of schizophrenia, in addition to identifying ways of improving current pharmacotherapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CLOZAPINE TREATMENT OF SCHIZOPHRENIC PATIENTS Principal Investigator & Institution: Buchanan, Robert W.; Professor; Psychiatry; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-APR-1990; Project End 31-DEC-2006 Summary: This is a submission of a competitive renewal application, MH 45074: "Clozapine Treatment of Schizophrenic Outpatients". Over the last ten years, the new generation antipsychotics clozapine, risperidone, olanzapine, quetiapine, and ziprasidone have been approved and introduced for the treatment of schizophrenia. Of these agents, only clozapine has been shown to have superior efficacy to conventional antipsychotics, and is FDA approved for treatment-resistant patients with schizophrenia. However, up to 50 percent of patients adequately treated with clozapine will fail to respond, and will continue to exhibit clinically significant residual positive and negative symptoms and cognitive impairments. These patients represent a major
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therapeutic challenge and raise the question: What treatment options are available for these patients? The major emerging treatment trend is to use a second antipsychotic medication. This clinical practice has become relatively widespread, but there is little empirical evidence to support the validity of this approach. We will conduct a 16-week randomized, parallel group, double-blind comparison of adjunctive risperidone and placebo in clozapine-treated patients with schizophrenia to address two primary aims: is adjunctive risperidone superior to placebo for the treatment of persistent positive symptoms and cognitive impairments in clozapine-treated patients with schizophrenia, and three secondary aims: is adjunctive risperidone superior to placebo for the treatment of persistent negative symptoms and functional impairments, and is adjunctive risperidone associated with increased incidence of side effects as compared to placebo in clozapine-treated patients with schizophrenia. We will perform biweekly positive and negative symptom and side effect assessments, and baseline and end of study neuropsychological and functional assessments. The study will provide new information on the clinical utility of adjunctive risperidone in treatment-resistant patients who fail to adequately respond to clozapine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONSTITUTIVELY ACTIVE SEROTONIN RECEPTORS Principal Investigator & Institution: Teitler, Milt; Professor; Pharmacology & Neuroscience; Albany Medical College of Union Univ Albany, Ny 12208 Timing: Fiscal Year 2002; Project Start 01-JUL-1997; Project End 31-MAR-2006 Summary: (provided by applicant): We have shown that clozapine and risperidone, atypical antipsychotic drugs, have potent inverse agonist properties at constitutively activated mutant (CAM) forms of the rat 5SHT2A and 5HT2C receptors. Inverse agonist activity may be a significant property of antipsychotic drugs, given the revised ternary complex model of G-protein coupled receptors (GPCR), which predicts a steady-state level of activation of receptors in the absence of ligand stimulation. Further studies of antipsychotic drug actions at CAM forms of clozapine-sensitive human SHT receptors are necessary to determine if inverse agonist activity is a key property of atypical antipsychotic drugs. In order to expand the studies to the human 5HT6 and 5HT7 receptors we have attempted to make CAM forms of these receptors by mutating two well-documented regions of GPCR constitutive activity. Initial experiments involving mutations in these areas have produced forms of the receptor either lacking robust constitutive activity or producing apparently null mutant forms of the receptor (5HT6). While these results have slowed progress on determining the inverse agonist activity of antipsychotic drugs on these receptors they open up interesting avenues of research on the variability in structure within the GPCR family and within 5HT receptors in particular. Therefore we propose to pursue three specific aims: 1) we will continue to test typical and atypical antipsychotic drugs at human CAM forms of the 5HT2A and 5HT2C receptors; 2) we will continue to mutate the human 5HT6 and 5HT7 receptors to produce CAM forms of these receptors and test antipsychotic drugs for inverse agonist activity at these receptors; 3) we will examine effects of constitutive activation on clozapine-sensitive 5HT receptor cellular trafficking, and the effects of inverse agonists on the trafficking of the mutated receptors. The results of these studies should reveal the role inverse agonist activity of antipsychotic drugs plays in the atypical properties of clozapine, and may indicate a major role for one or more of the clozapine-sensitive receptors in the atypical properties of clozapine. This information should be very helpful in designing a new generation of atypical antipsychotic drugs sharing clozapine's unique antipsychotic properties, but lacking its deleterious hematological
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effects. Information concerning alterations in cellular processing of CAM receptors should also be forthcoming, including information on the molecular domains involved in directing cellular compartmentalization, believed to play a key role in cellular receptor sensitivity states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--KNOWLEDGE TRANSFER Principal Investigator & Institution: Mendelowitz, Alan; Long Island Jewish Medical Center New Hyde Park, Ny 11040 Timing: Fiscal Year 2002 Summary: The overall goal of this new Knowledge Transfer Unit (KTU) is to better inform the medical community, patients, and their families about schizophrenia. There are 4 aims of the KTU. First is to improve the recognition of prodromal and early signs of schizophrenia and stress the importance of early intervention. Second is to improve knowledge and utilization of best treatments for schizophrenia. Third is to improve knowledge about the size effects of anti-schizophrenia medications. Finally, the KTU aims to increase the knowledge concerning poor treatment response and the role of clozapine in the method of "academic detailing" seems to be a worthy intellectual centerpiece for this unit. The leaders of the KTU are both junior, and there are examples of issues that seem internalized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENTAL ANTIPSYCHOTICS
PSYCHOPHARMACOLOGY
OF
Principal Investigator & Institution: Wiley, Jenny L.; Associate Professor; Pharmacology and Toxicology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Antipsychotics are administered to children and adolescents for a number of disorders with chronic use often continuing into adulthood. Yet, little is known about short- and long-term effects of these agents on the developing brain and behavior. Research on the effects of atypical antipsychotics (e.g., clozapine) that do not produce extrapyramidal motor effects is particularly lacking. The major hypotheses of this grant proposal are that (1) developing animals are more sensitive to the effects of dopamine antagonists, including antipsychotics, on motor processes than are adult animals and (2) chronic dosing with antipsychotics during development produces long-term changes in response to challenges with dopaminergic agents in later life such that animals are more sensitive to the effects of dopamine agonists and less sensitive to those of dopamine antagonists. In order to test the first hypothesis, rats of different ages (postnatal day 22 to adult) will be administered acute doses of selected antipsychotics; subsequently, they will be evaluated in behavioral procedures designed to measure motor activity (locomotion and catalepsy). In order to test the second hypothesis, rats will be chronically injected with selected antipsychotics during development. After reaching adulthood, these rats will be evaluated in behavioral procedures to evaluate motor activity (locomotion and catalepsy), cognition (sensorimotor gating, acquisition of a response, short-term memory), and the reinforcing efficacy of food. In addition to baseline activity in these procedures, the effects of challenges with antipsychotics and dopamine agonists will also be assessed in these rats. In order to determine possible underlying changes in dopamine receptor binding and distribution, autoradiography of the brains of rats that received identical chronic
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injection regimens will be performed using radioligands selective for dopamine D1 and D2 receptors. The proposed studies will provide empirical information on acute and long-term effects of traditional and atypical antipsychotics on the developing brain and behavior. This information will help to provide a more rational basis for making treatment decisions concerning children and adolescents who may benefit from treatment with an antipsychotic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOPAMINE DEFICIT AND SCHIZOPHRENIA Principal Investigator & Institution: Roth, Robert H.; Professor; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 25-SEP-1997; Project End 31-DEC-2005 Summary: (Adapted from applicant's abstract) The cognitive deficits that occur in schizophrenia are arguably the most debilitating of the symptoms, and the most resistant to pharmacological treatment. While the atypical antipsychotic drug, clozapine, is the one of the few drugs with any success in treating the negative and cognitive symptoms of schizophrenia, its mechanism of action is not fully understood and this has hindered development of other agents that are more effective than clozapine and lack its dangerous side effects. In man, repeated use of phencyclidine (PCP) can often induce an enduring schizophrenic-like syndrome. In the monkey, we have found that subchronic exposure to PCP induces a decrease in doparnine function in the prefrontal cortex (PFC), which persists for more than a month. Demonstrates, neurochemical and anatomical specificity. This PCP-induced PFC dopamine deficiency correlates with cognitive impairments in the monkey, which resemble those occurring in schizophrenia Furthermore, these cognitive deficits are partially ameliorated by administration of clozapine Using in vivo and ex vivo techniques in rats and monkeys, this project will examine the mechanisms responsible for the neurobiological changes induced by repeated PCP administration on the anatomical integrity, neurotransmitter regulation and behavioral functions associated with the PFC. In addition, the mechanisms involved in the pharmacological reversal of the cognitive deficits produced by subchronic exposure to PCP will be evaluated. The research plan will address the following four specific aims: (1) What neurobiological changes; responsible for the reduction in dopamine function in the PFC following repeated PCP administration, (2) clozapine's ability to reverse the PCP-induced cognitive impairment mediated by a preferential increase dopamine turnover in the PFC, and what receptors are essential for this action? (3) Determine if atypical antipsychotic drugs (or receptor specific agents) that reverse the PFC dopamine deficit in PCP-treated monkey attenuate the cognitive impairments, and (4) Determine whether there are regionally specific adaptive changes the parvalbumin GABAergic interneurons of the PFC in the monkey repeatedly treated with PCP. The generation of critical neurochemical and behavioral data in this monkey model of PFC dopamine deficiency and impaired cognition will provide important new insights concerning the neural systems relevant the frontal cortical cognitive dysfunction in schizophrenia. These data will aid in the development of novel strategies for ameliorating the neurochemical and behavioral deficits in this potential animal model, and in the cognitive dysfunctions associated with schizophrenia and other psychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Clozapine
Project Title: DOPAMINE SYSTEM INTERACTIONS AND SCHIZOPHRENIA Principal Investigator & Institution: Deutch, Ariel Y.; Professor; Psychiatry; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-MAY-1989; Project End 30-NOV-2004 Summary: The thalamic paraventricular nucleus (PVT) has generally been considered as one of the non-specific thalamic nuclei. More recent data indicate there is a high degree of specificity in the efferent projections of the PVT and argue against a non-specific role for the PVT. The PVT projects to several key sites linked to the pathophysiology of schizophrenia and drug abuse, including the prefrontal cortex (PFC), the shell of the nucleus accumbens (NAS), and the central and basolateral nuclei of the amygdala. The PVT also receives a dopamine (DA) innervation and PVT neurons express the D3 (but not other) DA receptor transcripts. We hypothesize that the PVT is both regulated by DA afferents and coordinately regulates DA function in mesocorticolimbic regions, including the NAS and PFC. Three related specific aims will explore the anatomical and functional organization of the PVT and test our hypotheses. 1)Tract-tracing-immunohistochemistry studies will determine the origins of the DA innervation of the PVT, examine the relationship of efferent projections to the extended amygdala and NAS, and characterize the phenotype of PVT neurons that innervate the NAS and other corticolimbic areas. 2)A series of studies will examine the regulation of the dopamine system of the PVT. These studies will determine the efferent targets of PVT neurons that are activated by clozapine and psychostimulants, determine if the Fos response of PVT neurons occurs in D3 receptor-expressing cells, and assess the regulation of D3 gene expression by chronic clozapine and psychostimulants. 3)The ability of the PVT to functionally regulate the DA innervations of mesocorticolimbic terminal fields, including the NAS and PFC, will be examined using in vivo microdialysis. These studies will assess the responsiveness of the NAS and PFC DA innervations to agents that evoke DA release (KC1 and amphetamine) and to excitatory amino acid agonists (NMDA and AMPA). These studies should reveal new aspects of thalamic regulation of mesocorticolimbic DA function that may be deranged in schizophrenia and drug abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ECT IN CLOZAPINE REFRACTORY SCHIZOPHRENIA Principal Investigator & Institution: Petrides, Georgios; Associate Professor; Long Island Jewish Medical Center 270-05 76Th Ave New Hyde Park, Ny 11040 Timing: Fiscal Year 2002; Project Start 01-DEC-2000; Project End 30-NOV-2003 Summary: (Applicant's abstract): As many as 30% of schizophrenic patients are resistant to standard antipsychotic medications. Clozapine represents a unique treatment in our armamentarium for schizophrenia as it is helpful in treating 30-50% of the treatmentrefractory patients. However, 50-70% of these unfortunate patients do not respond adequately to clozapine, and are left without any viable treatment options. They continue to suffer unrelentingly, and represent a considerable burden to their families and society. This study will investigate electroconvulsive therapy (ECT) as an augmentation strategy for patients who have failed to adequately respond to clozapine. The choice of ECT is based on three converging lines of evidence: in the preantipsychotic medication era, ECT was often an effective treatment for schizophrenia; the combination of ECT and antipsychotic medications provides enhanced clinical response; and several case series suggest a benefit when ECT is added to clozapine. Continued clozapine monotherapy and clozapine augmentation with ECT in clozapine refractory schizophrenic patients will be compared in a prospective, random assignment
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study. We will treat patients who have had at least 12 weeks of an adequate clozapine trial. Sixty-four subjects (32 randomized to clozapine and 32 randomized to clozapine plus ECT) will be treated for up to eight weeks; subjects in the ECT plus clozapine arm will receive up to 16 to 20 bilateral treatments. A naturalistic follow-up will compare subjects who receive continuation ECT with those who do not for an additional 6 months. The results of the study will guide clinicians faced with the problem of how to treat patients who have not been helped by standard antipsychotic medications and do not show an adequate response to clozapine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ATYPICALS
EFFECTIVENESS
OF
SWITCHING:
CONVENTIONALS
TO
Principal Investigator & Institution: Essock, Susan M.; Professor; Psychiatry; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2004 Summary: Effectiveness of Switching: Conventionals to Atypicals Over the past several years, new, so-called "atypical," antipsychotic medications have become available to treat schizophrenia. Olanzapine and risperidone are the two most widely prescribed antipsychotics; together they account for over 40 percent of all antipsychotic prescriptions. Given their wide usage, we know surprisingly little about the effectiveness of these newer medications in routine practice settings. Despite a decade of availability of atypical antipsychotics, about 40 percent of the antipsychotic prescriptions filled in the United States today are still for conventional agents. Given that the atypical antipsychotics may be more effective than the conventional ones and have less burdensome side effects, should people who are relatively stable on the older medications but who are still symptomatic or troubled by medication side effects be switched to an atypical medication? What are the benefits and risks associated with such medication switches? A total of 300 consenting patients with schizophrenia from a large, diverse public mental health system, who are living in the community and taking conventional antipsychotic medications but who are still troubled by symptoms or medication side effects, will be randomly assigned to stay on their current conventional antipsychotic medication (N =100) or to switch to olanzapine (N =100) or risperidone (N=100). This design specifically controls for process of changing medications because one group continues on current treatment. The proposed study, therefore, will assess what incremental risks and benefits can be expected from switching from a conventional to a first-line atypical antipsychotic agent. All medications will be open label, and treatment will be by the study participants' routine providers. Study participants will be asked to stay in their assigned treatment condition for 6 months, after which time medication decisions will be up to the patient and the prescribing psychiatrist. Study participants will be interviewed with quantitative instruments at baseline and at followup intervals for 1 year to determine clinical course and the types of services used. The study will determine the incremental risks and benefits of switching from a conventional to the most commonly prescribed atypical antipsychotics, and the relative risks and benefits of switching to olanzapine versus switching to risperidone. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECTS OF ANTIPSYCHOTIC DRUGS ON BRAIN AND BEHAVIOR Principal Investigator & Institution: Tarazi, Frank I.; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478
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Clozapine
Timing: Fiscal Year 2004; Project Start 01-MAR-2004; Project End 28-FEB-2006 Summary: (provided by applicant): This revised R03 proposal, submitted in response to a RFA (PA-00-114) encouraging research on developmental psychopharmacology, will study behavioral and molecular effects of antipsychotic drugs on cerebral dopamine (DA) and serotonin (5-HT) systems in developing vs. adult rats. DA and 5-HT receptors are critical sites of action of most antipsychotics, probably mediating, at least in part, clinically useful psychiatric benefits as well as adverse neurological effects. DA and 5HT receptors are also implicated in the neurobiology of several neuropsychiatric disorders including schizophrenia, which affects children and adolescents as well as adults. Childhood-onset schizophrenia, an uncommon form of the disease, produces severe developmental and life-long morbidity and disability. Nevertheless, the neuropathology and pathophysiology of juvenile schizophrenia are far less well studied than in the adult disorder largely owing to the lack of access to postmortem brain tissue from young patients. There is also a striking paucity of systematic investigation of the pharmacology of antipsychotic agents in pediatric psychotic patients or of parallel studies in maturing laboratory animals. This project will examine effects of antipsychotic drug administration on brain and behavior in young and mature animals, and will compare rats at three selected ages: juveniles, adolescents, and adults. Behavioral effects of representative typical (fluphenazine), atypical (clozapine) and newer (olanzapine) antipsychotic agents will be assessed in behavioral paradigms that are predictive of antipsychotic activity or neurological side effects at the three ages to compare responses developmentally, and to establish age-specific half-maximal effective doses (ED50) for each tested agent. The calculated ED50 doses will be used to examine long-term effects of the same agents on expression of representative DA (D2 and D4) and 5-HT (5-HT1A and 5-HT2A) receptors, that we have found to be altered by repeated administration of antipsychotic drugs in adult rats. Expression of genes (mRNA) for these receptors will then be quantified to further clarify age related molecular mechanisms underlying hypothesized changes in receptor levels. Expected findings should clarify potency and mechanisms of action of antipsychotic drugs in juvenile and adolescent vs. adult rats, and should evolve new principles for improved treatments for childhood-onset schizophrenia and other major pediatric psychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC SCREEN FOR ANTIPSYCHOTIC DRUG RESPONSE Principal Investigator & Institution: Pickar, David; Chief Science Officer; Gabriel Pharma, Llc 6500 Seven Locks Rd, Ste 220 Cabin John, Md 20818 Timing: Fiscal Year 2002; Project Start 25-SEP-2002; Project End 24-MAR-2003 Summary: (provided by applicant): Screening for antipsychotic drug response is a research priority to identify new drugs with long-term efficacy and minimal side effects for drug resistant individuals. Schizophrenia, a major public health problem afflicting approximately 1% of Americans, costs over $40 billion annually. The discipline of pharmacogogenomics utilizes genetic information to predict therapeutic drug response. New atypical antipsychotic drugs enhance therapeutics and outcomes of schizophrenia, but differences in individual patient response exist. Other treatment barriers include undesirable side effects impeding medication compliance, an important public health priority. Pharmacogenetics' promises to identify a priori response predictors guiding informed pharmacotherapeutics, enabling patient screening for tolerance and medication compliance. Key NIMH clinical studies of schizophrenic patients yielded unique longitudinal clinical information. We propose to combine this clinical information with contemporaneous patient DNA samples (Cl-DNA database) to test
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feasibility of a new genetic screen for pharmacogenetics of antipsychotic drug response. This Cl-DNA database has longitudinal behavioral ratings of antipsychotic treatment, placebo washout and treatment with the current gold standard stypical antipsychotic, clozapine (limited due to small but real risk of death). This study will provide preliminary validation for pharmacogenomic investigation by screening drug response to clozapine in relation to variants for the gene coding for catechol-O-methyl transferase, a known marker for dopamine. Phase II will modify, refine and expand the Cl-DNA database for full-scale validation with additional data from other antipsychotic treatments. This proposal will create a unique screen with broad and immediate research application including drug development and clinical practice and important preliminary information regarding gene variants in relation to clozapine treatment. The goal is a commercial individualized treatment screen to identify genetic of antipsychotic drug response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HIGH THROUGHPUT IN VIVO DRUG DISCOVERY-PHASE 1 Principal Investigator & Institution: Leahy, Emer; Psychogenics, Inc. 4 Skyline Dr Hawthorne, Ny 10532 Timing: Fiscal Year 2004; Project Start 06-FEB-2004; Project End 31-JAN-2006 Summary: (provided by applicant): The current trend in drug discovery is to develop drugs with a high level of selectivity for a single receptor. Although this is a real improvement for certain therapeutic areas, this may present a real issue for the development of novel treatments for neurological and psychiatric disorders. Indeed, neuropsychiatric disorders are complex, multigenic disorders that involve multiple neuronal circuits. Therefore, it is not surprising that many of the most efficacious drugs in psychiatry, such as clozapine, are considered "dirty drugs" (i.e. have multiple targets), that were discovered by screening in vivo, i.e. looking at their behavioral impact using various animal models, rather than making predictions of their function based on their receptor profile. Although attractive, this approach was neither efficient nor scalable until now. PsychoGenics is developing a proprietary, high throughput, in vivo platform known as Smart Cube TM, which is being used to screen and select drug candidates with potential to treat major psychiatric disorders including depression, psychosis, and anxiety disorders. This approach examines the behavioral response of a mouse to various challenges under normal and perturbed (e.g. drug treated) conditions. Using computer vision algorithms, behavior is captured and bioinformatic tools are applied to reveal the temporal behavioral profile or "signature" in response to treatment. PsychoGenics is building a database of signatures for known and approved compounds, which it can use to compare to the profiles of NCEs. PsychoGenics aims to demonstrate that this behavior-driven approach to drug discovery can yield clinical candidates selected from high quality libraries designed with compounds that have drug-like chemical and structural properties. The goal is to screen 120 compounds in Abstract compounds in Smart CubeTM in Phase I to find "hits" which, with the aid of novel computational chemistry algorithms, undergo behavior-driven (i.e. Smart Cube TM) lead optimization in Phase II. Using this behavior-driven approach, PsychoGenics has already identified two compounds for the treatment of ADD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Clozapine
Project Title: HIPPOCAMPAL RECURRENT INHIBITION AND N-ACETYL ASPARTYL GLUTAMATE Principal Investigator & Institution: Greene, Robert W.; Research Health Scientist; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: The behavioral abnormalities associated with schizophrenia are likely to involve pathological function of the limbic system. Functional and structural neuroimaging studies in the limbic region of schizophrenic brains have provided compelling evidence in support of this assertion. Ingestion of phencyclidine (PCP) or systemic injection of ketamine produces a syndrome that mimics the symptoms of acute schizophrenic psychosis. These pharmacological observations raise the possibility that a decrease of normal NMDA receptor (NMDAR) function can elicit psychotic symptoms similar to those suffered by schizophrenic patients. Recently, Mohn, et al (1999) describe a transgenic mouse model of schizophrenia, a partial knock out of the NR1 subunit of the NMDAR (5% expression), with behavioral deficits such as increased motor activity, stereotype and deficits in social and sexual interactions. This partial "knock down" of NR1 expression is rescued by haloperidol and clozapine. However, the mechanism(s) of action of decreased NMDA- receptor function that result in the observed deficits in information processing integral to the syndrome of psychosis have been little investigated. Our findings have lead to the following hypotheses: the psychotogenic action of NMDA antagonists may be attributed to selective blockade of the NMDAdependent drive of inhibitory circuits (Grunze). The decreased excitatory drive of interneurons disrupts network function so that abnormal information processing consistent with cognitive deficits associated with psychosis, ensues. In particular, [Specific Aim I] it is hypothesized that the EPSP of CAL interneurons has a significant NMDA-dependent component that is larger than the NMDA component of the feedforward Schaffer collateral input to CA1 pyramidal neurons, and/or EPSC is more sensitive to NMDA antagonists. Accordingly, NMDAR antagonists have a selectively greater effect on the EPSP's of interneurons (in the CA1 region of the hippocampus the EPSP's and EPSC's that we will test, original from either feed-forward-CA3-or feedbackward-CA1-input or from both) compared EPSC's of projection cells. Pathological NMDAR hypofunction could result from multiple mechanisms, including but not limited to 1) factors affecting NMDAR- binding to glutamate; 2) factors affecting NMDAR-associated channel activity; 3) factors affecting downstream mechanisms associated with NMDAR activation (for example those linked to the NMDA-associated PSD-complex). We plan to examine the first of these mechanisms. We [Specific Aim 4a] hypothesize that an endogenous compound, N-acetyl- aspartylglutamate (NAAG), has NMDAR antagonist activity and can selectively block the NMDAR-component of EPSC's on interneurons in the CA1 region of the hippocampus. We further [Specific Aim 4b] hypothesize that the turnover of NAAG is sufficiently high that inhibition of NAAG's catabolic enzyme will block the NMDAR-component of EPSC's and exposure to a soluble form of these catabolic enzyme [Specific Aim 4c] will enhance the NMDARcomponent by decreasing endogenous NAAG. Our preliminary data demonstrates that inhibition of GCP II increases endogenous NAAG sufficient to significantly reduces NMDAR synaptic activation in CA1 pyramidal cells and interneurons in the hippocampal slice, probably as a result of the high rate of turnover of NAAG in vitro. The effects on NMDAR activity of a knockout of the GCP III gene are hard to predict in part because: 1) the mechanisms responsible for the rate of production of the NAAG mediating this response are unknown; 2) NMDAR activity in response to a chronic increase in NAAG is unknown. Nevertheless, a state of chronic NMDAR hypofunction is a distinct possibility that, in consideration of its association with psychosis ought to be
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examined as a first step towards the phenotypic characterization of these animals. We [Specific Aim 5] hypothesize that NMDAR function will be reduced in the CA1 region of the hippocampi of GCP II knockout mice compared to wild type mice. If true, thee ko mice may serve in behavioral studies of NMDAR hypofunction in the development and maintenance of place (or other specific associations) hippocampal cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INSULIN SCHIZOPHRENIA
SENSITIVITY/SECRETION/
GLUCOSE
IN
Principal Investigator & Institution: Henderson, David C.; Executive Secretary (Dfo); Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LABEL D4 DOPAMINE RECEPTOR IN PREFRONTAL CORTEX & HIPPOCAMPUS OF MONKEY BRAIN Principal Investigator & Institution: La Garza, Richard De.; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: At least five subtypes of DA receptors, D1-D5, have been identified While the receptor distribution and some functional sequelae of D1, D2, and D3 receptors are known, information regarding the physiological or pathological role of D4 receptors is scant Mounting evidence indicates potential involvement of these receptors in "noveltyseeking" behaviors, psychostimulant effects, attention deficit hyperactivity disorder, Parkinson's disease and depression To clarify the role of this receptor subtype in primates, we developed a map of D4 receptor distribution in rhesus monkey brain and compared it with reported D4 mRNA sites Because of its reported selectivity for the D4 receptor, the D4 receptor probe [3H]U-101,958 (1-benzyl-4-[N-(3-isopropoxy-2pyridinyl)-N-methyl]-aminopiperidine) was custom-synthesized for the current study Autoradiography was conducted in triplicate in three separate animals (N=3) with adjacent coronal sections (20 um) to measure total ([3 H]U-101, 958, 1 nM) and nonspecific binding Specific binding was measured in the presence of clozapine or L745,870 Data was generated from eight anterior-to-posterior coronal planes and 75 distinct subnuclei and cortical areas A region-specific distribution of [3H]U-101,958 binding was detected The highest densities (>20 pmol/g tissue equivalents) of [3H]U101,958 binding sites (clozapine baseline) were found in areas 12, 14 and 9 of the prefrontal cortex High levels of [3H]U-101,958 binding sites (>17 pmol/g) were also observed in other prefrontal cortex regions, inferior temporal gyrus, subiculum, fusiform gyrus, uncus, paraventricular nucleus of thalamus, median eminence of the hypothalamus, medial longitudinal fasciculus, and hippocampus [3H]U-101,958 binding sites in caudate/putamen were clearly below levels observed in the prefrontal cortex and other cortical areas Lower levels (
