LITHIUM 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., 1960Lithium: 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: 0-597-84009-1 1. Lithium-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 lithium. 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 LITHIUM .................................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Lithium ......................................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 58 The National Library of Medicine: PubMed ................................................................................ 61 CHAPTER 2. NUTRITION AND LITHIUM ........................................................................................ 107 Overview.................................................................................................................................... 107 Finding Nutrition Studies on Lithium ...................................................................................... 107 Federal Resources on Nutrition ................................................................................................. 112 Additional Web Resources ......................................................................................................... 112 CHAPTER 3. ALTERNATIVE MEDICINE AND LITHIUM .................................................................. 115 Overview.................................................................................................................................... 115 National Center for Complementary and Alternative Medicine................................................ 115 Additional Web Resources ......................................................................................................... 131 General References ..................................................................................................................... 134 CHAPTER 4. DISSERTATIONS ON LITHIUM .................................................................................... 135 Overview.................................................................................................................................... 135 Dissertations on Lithium ........................................................................................................... 135 Keeping Current ........................................................................................................................ 143 CHAPTER 5. CLINICAL TRIALS AND LITHIUM .............................................................................. 145 Overview.................................................................................................................................... 145 Recent Trials on Lithium ........................................................................................................... 145 Keeping Current on Clinical Trials ........................................................................................... 147 CHAPTER 6. PATENTS ON LITHIUM............................................................................................... 149 Overview.................................................................................................................................... 149 Patents on Lithium .................................................................................................................... 149 Patent Applications on Lithium................................................................................................. 184 Keeping Current ........................................................................................................................ 223 CHAPTER 7. BOOKS ON LITHIUM .................................................................................................. 225 Overview.................................................................................................................................... 225 Book Summaries: Federal Agencies............................................................................................ 225 Book Summaries: Online Booksellers......................................................................................... 226 The National Library of Medicine Book Index ........................................................................... 234 Chapters on Lithium .................................................................................................................. 236 CHAPTER 8. MULTIMEDIA ON LITHIUM ....................................................................................... 239 Overview.................................................................................................................................... 239 Bibliography: Multimedia on Lithium ....................................................................................... 239 CHAPTER 9. PERIODICALS AND NEWS ON LITHIUM .................................................................... 241 Overview.................................................................................................................................... 241 News Services and Press Releases.............................................................................................. 241 Newsletter Articles .................................................................................................................... 245 Academic Periodicals covering Lithium..................................................................................... 245 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 247 Overview.................................................................................................................................... 247 U.S. Pharmacopeia..................................................................................................................... 247 Commercial Databases ............................................................................................................... 248 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 251 Overview.................................................................................................................................... 251 NIH Guidelines.......................................................................................................................... 251
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NIH Databases........................................................................................................................... 253 Other Commercial Databases..................................................................................................... 255 The Genome Project and Lithium .............................................................................................. 255 APPENDIX B. PATIENT RESOURCES ............................................................................................... 259 Overview.................................................................................................................................... 259 Patient Guideline Sources.......................................................................................................... 259 Associations and Lithium .......................................................................................................... 262 Finding Associations.................................................................................................................. 262 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 265 Overview.................................................................................................................................... 265 Preparation................................................................................................................................. 265 Finding a Local Medical Library................................................................................................ 265 Medical Libraries in the U.S. and Canada ................................................................................. 265 ONLINE GLOSSARIES................................................................................................................ 271 Online Dictionary Directories ................................................................................................... 272 LITHIUM DICTIONARY............................................................................................................. 275 INDEX .............................................................................................................................................. 361
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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 lithium 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 lithium, 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 lithium, 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 lithium. 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 lithium, 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 lithium. The Editors
1
From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON LITHIUM Overview In this chapter, we will show you how to locate peer-reviewed references and studies on lithium.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and lithium, 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 “lithium” (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: •
Increase in Glomerular Filtration Rate in Patients with Insulin-Dependent Diabetes and Elevated Erythrocyte Sodium-Lithium Countertransport Source: New England Journal of Medicine. 322(8): 500-505. February 22, 1990. Summary: Increased sodium-lithium countertransport in erythrocytes is found in patients with insulin-dependent diabetes mellitus (IDDM) and nephropathy. To determine whether such an increase precedes the onset of nephropathy and, if so, whether it is associated with changes in renal function, erythrocyte sodium-lithium countertransport was measured in 52 patients with IDDM but not nephropathy or hypertension and in 32 control subjects. 17 of the 52 patients with IDDM (33 percent) had sodium-lithium countertransport activity that exceeded the maximal activity in the control subjects (0.39 mmol of lithium per hour per liter of cells). 18 of the 52 patients with IDDM were studied in more detail. The seven patients with raised sodium-lithium
4
Lithium
countertransport values had glomerular filtration rates (median, 159 ml per minute per 1.73 m(2) of body-surface area; range, 134 to 197) that were significantly higher (P less than 0.01) than those in the remaining 11 patients with IDDM and normal sodiumlithium countertransport (median, 126 ml per minute per 1.73 m(2); range, 110 to 176) or in the 10 control subjects (median, 128 ml per minute per 1.73 m(2); range, 93-151). In the seven patients with elevated sodium-lithium countertransport, the filtration fraction (median, 0.27; range, 0.22 to 0.37) was also greater (P less than 0.01) than that in control subjects (median, 0.22; range, 0.18 to 0.28). There were no differences in renal function between the patients with IDDM and normal sodium-lithium countertransport and the control subjects. The authors conclude that sodium-lithium countertransport is increased in patients with IDDM before the onset of nephropathy and is associated with hyperfiltration. Thus, elevated sodium-lithium countertransport activity may be an early marker of diabetic nephropathy. 28 references. (AA).
Federally Funded Research on Lithium The U.S. Government supports a variety of research studies relating to lithium. 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 lithium. 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 animals or simulated models to explore lithium. The following is typical of the type of information found when searching the CRISP database for lithium: •
Project Title: 500MHZ CONSOLE UPGRADE Principal Investigator & Institution: Ganem, Bruce; Franz and Elisabeth Roessler Professor; Chemistry and Chemical Biology; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2004 Summary: (provided by applicant): In this proposal we request a console upgrade for a Unity 500 MHz NMR Spectrometer manufactured by Varian Associates. The Unity 500 is three generations out of date and the performance no longer meets the needs of the majority of NIH users within the facility. The upgrade will improve the sensitivity, resolution, and reliability of the current instrument allowing for more sophisticated experiments and higher user throughput. The NMR Facility, which has been in existence for 30 years with a Ph.D. level professional NMR spectroscopist as Director, has a long track record of user training, instrument maintenance, and supervision. The Unity 500 MHz instrument user base consists mostly of faculty with a record of continuous NIH
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).
Studies
5
support. Beyond the major users, Cornell currently has three minor users whose groups are young and whose PIs will eventually rely on NIH support. These individuals and their students will use the requested instrumentation for a wide range of health-related projects. Professor B. Ganem (PI) is studying the design of new synthetic prodrugs based on the natural product COTC, which would be targeted specifically to prostate tissue, as well as on the synthesis of new inhibitors of glycosphingolipid metabolism; Professor T.P. Begley will use the instrumentation to study modified enzyme substrates, designed inhibitors, products and mechanistic probes; Professor J. Clardy is investigating fungal metabolites exhibiting anticancer, antiviral, and antibiotic activity; Professor B.R. Crane aims to understand how protein structure controls redox- and photochemistry in biological catalysis and signal transduction. Professor G.W. Coates will investigate new methods for the synthesis of architecturally well-defined biodegradable polymers for biomedical use; Prof. D.B. Collum is investigating organolithium solvation and aggregation states using NMR to obtain new insights into synthetically useful lithium reagents; Professor D.T. McQuade will use NMR in designing new synthetic approaches to highly functionalized polymers; Prof. J. Meinwald will investigate the structures of biologically significant molecules involved in chemical communication. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: A MOLECULAR MECHANISM FOR LITHIUM ACTION Principal Investigator & Institution: Klein, Peter S.; Assistant Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAY-2006 Summary: From applicant's abstract): Lithium is the first line of therapy in the treatment of bipolar disorder yet its mechanism of action remains unclear. The goal of this project is to apply basic research methods to the study of mental health in order to identify the molecular targets of lithium in the treatment of bipolar disorder. Previous work in this laboratory has shown that lithium inhibits the signaling molecule Glycogen Synthase Kinase-313 (GSK-3B) and activates the Wnt/l3-catenin signaling pathway, providing an explanation for the effects of lithium on the development of diverse organisms. Several laboratories have also shown that lithium inhibits GSK-3B in cultured neurons and in whole animals; however, GSK-3B still has not been demonstrated to be the relevant target of lithium in the treatment of neuropsychiatric disorders. Work supported by this ROl has led to the identification of a novel peptide inhibitor of GSK-3B derived from the GSK-3 jnteraction domain (GID) of axin. This peptide inhibits the enzymatic activity of GSK-313 in vivo and leads to strong activation of the Wnt signaling pathway, mimicking the activity of lithium. This peptide thus provides an alternative to lithium that can be used to test the hypothesis that inhibition of GSK-313 is important in the response to lithium in non-developmental settings, particularly in behavior. In the continuation of this project, the features of the GID peptide required for inhibition of GSK-3B will be further defined and the mechanism of inhibition will be characterized. Transgenic mice expressing the GID peptide, as well as downstream activators and inhibitors of Wnt signaling, will be generated using a neuron specific, postnatal promoter. These transgenic mice will be assessed in lithium-sensitive behavioral assays to test whether they either mimic (GID or Wnt activators) or block (antagonists of Wnt signaling) the behavioral effects of lithium. In addition, transgenic reporter mice will be generated to provide an in vivo read-out for activation of the wnt pathway in the brain. These reporter lines may allow localization of lithium sensitive regions in the mammalian brain. This approach may allow the development of new and safer therapeutic agents
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Lithium
for the treatment of bipolar disorder and should also help to elucidate the neuronal signaling pathways involved in the pathogenesis of this common and debilitating disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACUTE TREATMENT OF BIPOLAR II DEPRESSION Principal Investigator & Institution: Suppes, Patricia; Psychiatry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): This exploratory, stage 3 R21 proposal is designed to provide data on the acute treatment response of an understudied mental health population --bipolar II disorder (BDII). This disorder is characterized by major depression and periods of hypomania observable by others. There is now clear recognition of the stability of this diagnosis, and increased recognition of the severity and frequency of depressive symptoms. The overall severity, disability, and suicide risk is considered equal to bipolar I disorder. The available literature on treatment of BDII is reviewed. There are virtually no controlled acute treatment trials to direct treatment recommendations, nor is the treatment of BDII addressed in recent treatment guidelines. The most extensive data support lithium (Li) as one treatment group. Striking new findings with lamotrigine (LTG) support its efficacy in BDI acute depression and prophylaxis of rapid cycling BDII. Based on research done, including estimation of safety and tolerability, we chose to evaluate LTG and Li in this pilot study. We propose a randomized, open 16-week clinical trial comparing monotherapy Li versus LTG for sixty acutely depressed BDII patients. A physician and a blinded symptom rater will see patients every two weeks for a total of sixteen weeks. Safeguards are described to maintain patient safety. The primary aim will be to compare the relative treatment effectiveness of LTG versus Li. We hypothesize LTG will be more effective than Li at decreasing depressive symptoms. Secondary aims include assessment of tolerability, the potential of LTG to cause switching into hypomania, quality of life, and patient satisfaction. Measures will include the Hamilton Rating Scale for Depression, Montgomery-Asberg Rating Scale for Depression, Young Mania Rating Scale, Clinical Global Assessment for Bipolar Disorder, and other measures of quality of life, functioning, and physical symptoms and side effects. While full-scale intervention trials are clearly warranted in this population to establish databased recommendations for treatment, it is critical to collect pilot data to properly power and inform the design of a larger trial. This pilot study will provide data addressing the aims and sample size needed for a full-scale intervention trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ALKALOID SYNTHESIS VIA (3+2) CYCLOADDITIONS Principal Investigator & Institution: Pearson, William H.; Professor of Chemistry; Chemistry; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-APR-1995; Project End 28-FEB-2004 Summary: (Principal Investigator's Abstract) The principal objective of the proposed research is to continue to develop general and efficient methods for the synthesis of pyrrolidine-containing molecules of biological significance. A general synthetic method may be useful for the preparation of a wide variety of target molecules rather than a single class. The proposed research will attempt to use the anionic (3+2) cycloaddition of
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7
2-azaallyl anions with alkenes and the 1,3-dipolar cycloaddition of azomethine ylides with alkenes for the construction of a cross-section of biologically relevant target molecules. The 2-azaallyl anions are prepared by tin-lithium exchange on (2azaallyl)stannanes. The same (2-azaallyl)stannanes are also precursors of several novel types of non-stabilized azomethine ylides, which are also capable of (3+2) cycloadditions to produce pyrrolidines. These two types of reactive intermediates are proving to be complementary in their reactivity and diastereoselectivity. Applications of these methods to the synthesis of biologically interesting molecules is proposed in order to provide a context for methodology development. Each example is meant to test a different aspect of the (3+2) methodology. Targets include: (1) monomorine 1, the trail pheromone of the pharoah ant, (2) pictamine, a novel quinolizidine alkaloid isolated from tunicates with antimicrobial, antifungal, and antitumor activity, (3) lundurines B and C, isolated from Kopsia, the extracts of which find medicinal use for rheumatoid arthritis, dropsy, and tonsillitis in China, (4) 7-epiaustraline, a highly hydroxylated pyrrolizidine alkaloid with a unique hydroxymethyl group, a member of a class of such alkaloids that have activity as glucosidase I inhibitors, antiviral agents and antiretroviral agents, (5) scandine, a component of a Chinese folk medicine used for the treatment of rheumatic heart disease, and (6) erycibelline, a member of the tropane class of alkaloids. These targets will allow examination of the scope of the 2-azaallyl anion and azomethine ylide cycloaddition methods in several ways. For example, the types of anions or ylides required are diverse (e.g., simple aliphatic substituents, functionalized side chains, heterosubstituted versions, more conjugated versions, and cyclic versions), each with their unique chemistry and method of preparation. The issues of regiocontrol and stereocontrol, both absolute and relative, must be addressed. Tandem processes that involve the combination of (3+2) cycloaddition followed by additional reactions that lead to a second or third ring formation or a rearrangement are also being studied. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALKYLLITHIUM CYCLIZATIONS IN ORGANIC SNYTHESIS Principal Investigator & Institution: Rychnovsky, Scott D.; Professor; Chemistry; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): Synthetic chemistry is the technology underlying modern drug development. The successful mapping of the human genome was the first step towards identifying new receptors and pathways to treat chronic diseases. The path from bimolecular targets to realizing improvements in human health usually requires the synthesis of small molecule agonists, antagonists, or inhibitors. In this proposal we will develop a potentially powerful method to synthesize small nitrogen and oxygen spiro rings. New synthetic methods such as this one are an enabling technology for improving human health. The reductive cleavage of nitrile is a rarely used method for generating alkyllithium reagents. In many six-membered rings this reaction is completely stereoselective, and the resulting alkyllithium will couple with electrophiles with retention of configuration. We propose to use this reductive lithiation reaction, in combination with facile alkylations adjacent to nitrile groups, to develop a general and stereoselective synthesis of spiro rings. This method will be developed to prepare the spiro-tetrahydropyran rings. These reductive cyclization reactions will be used in a general synthesis of contrathermodynamic spiroacetals, structures commonly found in complex natural products. The third area of development is in the synthesis of spiropiperidines, where modification of the substrate will allow either configuration of the spiropiperidine to be prepared selectively. The synthetic targets for this proposal are
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Lithium
segments of natural products and natural products themselves. Segments of altohyrtin (spongistatin) and azaspiracid will be prepared using the approach to contrathermodynamic spiroacetals. Histrionicotoxin and pinnaic acid will be prepared using the spiropiperidine method. These compounds are of interest to synthetic and medicinal chemists, and have the types of rigid, polycyclic and polar structures found to show high bioactivity in many assays. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AN ULTRASONIC NEURAL STIMULATOR Principal Investigator & Institution: Towe, Bruce C.; Phoenix Biotech, Inc. 6051 E Cactus Wren Rd Paradise Valley, Az 85283 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2003 Summary: A remarkable and unexpected interaction effect between high frequency ultrasound energy and bioelectrically excitable tissue will be employed to the development of a line of advanced microstimulators for medical neurogenic applications An excised nerve preparation as well as hippocampal tissue slices of the rat brain will be used as physiologic models for further study of the ultrasound interactions with natural and applied bioelectric currents. The limits of ultrasound effectiveness in this application, some preliminary evaluations of its safety, and exploration of different methods of applying the ultrasound to neural tissue will be conducted. Micro-sized ultrasound transducers will be fabricated using photographic techniques and submillimeter diameter lithium niobate crystals in an effort to characterize the ultimate limits of its miniaturization and potential for implantation. This work will serve to underpin a new approach to neuro-electric stimulation that uses ultrasound energy to substantially reduce the current levels required to stimulate nerves in the body and possibly open up new applications of neural stimulation. PROPOSED COMMERCIAL APPLICATIONS: Ultrasonic neural stimulators would improve the effectiveness of therapeutic electrical stimulation which is currently a multibillion dollar market. The apparent advantages of ultrasound combined with lower levels of electrical stimulation suggest medical applications of the spinal cord, peripheral nerve and brain. This market is currently served with conventional electrostimulators by large medical device companies like Medtronic, Guidant, and others. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANALYSIS COTRANSPORTER
OF
ERYTHROCYTE
SODIUM-PHOSPHATE
Principal Investigator & Institution: Gunn, Robert B.; Professor; Physiology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 18-SEP-2000; Project End 31-AUG-2004 Summary: (Adapted from the Applicant's Abstract): The goal of this project is to understand the molecular mechanism of sodium-phosphate cotransport and sodiumlithium countertransport. Na-PO4 cotransport is an important physiological process vital to all mammalian cells through its active transport of inorganic phosphate, a central metabolite. Na-Li countertransport is a medically important cellular mechanism that pumps lithium out of cells. Its rate in erythrocytes inversely correlates with the effectiveness of Li therapy in bipolar disease and directly correlates with the development of essential hypertension. Despite their importance, these processes are not well understood because the responsible molecules have not been identified or have not been adequately characterized in model systems. Recently there has been progress in
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both of these areas. There is circumstantial kinetic and pharmacological evidence that the "brain specific" gene, BNP1 (or a related isoform), is the Na-PO4 cotransporter in K562 erythroleukemic cells and erythrocytes. The project will test three hypotheses. Hypothesis I: BNP1 is the erythrocyte Na-PO4 cotransporter. This hypothesis will be tested in Specific Aim 1 by demonstrating that BNP1 is the major isoform present in human erythropoietic cells and K562 cells and in Specific Aim 2 by demonstrating that BNP1 protein is present in those cells and mature erythrocytes. Hypothesis II: the erythrocyte Na-phosphate cotransporter is also the major Na-Na exchanger. This hypothesis will be tested in Specific Aim 3 by determining the stoichiometry of Na-PO4 cotransport and in Specific Aim 4 by characterizing the new Na transport caused by the heterologous expression of BNP1 in oocytes and in HEK293 cells using a new inducible promoter system. Hypothesis III: the Na-PO4 cotransporter is the long sought molecular basis for Na-Li countertransport. This hypothesis will be tested in Specific Aim 5 by determining the new Na-Li countertransport in BNP1 expressing oocytes and HEK293 cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANGIOTENSIN, HYPERTENSION
SODIUM
AND
GENES
IN
PRIMATE
Principal Investigator & Institution: Haywood, Joseph R.; Professor; Southwest Foundation for Biomedical Res San Antonio, Tx 782450549 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): Sodium-dependent hypertension has long been associated with a defect in renal function. Experimental models as well as human studies have also suggested that an alteration in genetic expression may contribute to the hypertensive process. Sodium-lithium countertransport (SLC) activity is one mechanism that helps maintain intracellular sodium concentrations, and in some hypertensive patients, SLC activity is increased. These individuals also experience an inappropriate response to sodium challenges that appears to result from a lack of suppression of the renin-angiotensin-aldosterone system (RAAS). The association between SLC activity and hypertension is genetically determined since it occurs in families. It is uncertain whether this reflects an alteration in the gene for SLC, one of the genes that may increase RAAS function, or an interaction between genes for the two systems. The goal of the proposed studies is to examine the relationship between SLC activity and the RAAS in a non-human primate model in which the SLC phenotype is high or low. The hypothesis to be tested is that a high SLC activity is associated with inappropriately high RAAS function and a greater arterial pressure sensitivity to dietary sodium. In three aims, the contributions of peripheral and central RAAS components to sodium-dependent hypertension will be studied in baboons with the high and low SLC phenotypes. In the first aim, regulation of the RAAS will be examined in high and low SLC animals during a step-wise increase in sodium intake. These experiments will determine whether animals with high SLC activity have a reduced ability to suppress the RAAS and develop salt-sensitive hypertension. The second aim will investigate the role of angiotensin and aldosterone in the stimulation of hypertension by sodium and their ability to cause blood pressure to rise in high and low SLC animals. This aim will determine whether by raising plasma angiotensin or aldosterone the high SLC animals are more likely to become hypertensive. The third aim will focus on central nervous system mechanisms associated with an inappropriately high RAAS in high and low SLC animals. These studies will determine whether the high SLC activity results in more sensitive central mechanisms driving the sympathetic nervous system to raise arterial
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Lithium
pressure. These studies will help provide data to determine whether an inappropriately high RAAS activity can cause hypertension. Importantly, this work will also reveal whether the genetically determined phenotype of high SLC is important in predisposing an animal to sodium-dependent hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEPRESSION
ANTIDEPRESSANT
PHARMACOGENETICS
OF
BIPOLAR
Principal Investigator & Institution: Goldberg, Joseph F.; Associate Professor; Psychiatry; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 20-APR-2002; Project End 31-MAR-2003 Summary: Previous efforts to identify biological correlates of anti-depressant response in bipolar disorder have yielded only modest success. The degree to which depression arises from serotonergic or other neurotransmitter abnormalities remains an unsolved question. Moreover, standard anti-depressants may be less effective for bipolar than unipolar depression and pose unique risks for inducing mania or cycle acceleration. Therefore, a compelling need exists to develop new methodologies to better anticipate treatment outcomes. The focus of this Career Development Award is to provide a translational research and training experience for the P.I. in applications of psychiatric genetics to clinically-based studies of psychopathology and treatment outcome in bipolar illness. As a model for this type of research, pharmacogenetic correlates of antidepressant response, focusing on serotonin system candidate gene polymorphisms, will be examined in a family-based cohort. While preliminary studies have identified candidate genes with polymorphisms of significance to psychopathology, or psychotropic drug action, pharmacogenetic applications ti bipolar disorder remain largely unexplored. The proposed core research project will be an ancillary study to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), an NIMH-sponsored multi-clinical trial. DNA samples will initially be obtained from a minimum of 100 depressed probands and family members; probands already optimized on valproate or lithium will undergo a 6-week trial of a serotonin reuptake inhibitor. In later years of the Award period, family-based genotype and SSRI antidepressant response data will be added from several hundred additional bipolar probands at collaborative research sites. Antidepressant responsivity will be analyzed relative to allele frequencies of 4 serotonin-related polymorphic candidate genes of known functional significance. Multivariate models will be developed to assess the relative statistical contribution of pharmacogenetic polymorphisms added to clinical factors potentially associated with treatment response. The primary aim of the career development plan is for the P.I. to acquire expertise in human genetics and candidate gene polymorphism analyses in order to inform future clinical studies of psychotropic drug response and other aspects of psychopathology that may represent phenotypes of bipolar disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AQUAPORIN-2 EXCRETION IN DISORDERS OF WATER BALANCE Principal Investigator & Institution: Cadnapaphornchai, Melissa A.; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-JUL-2005
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Summary: (adapted from the application) Normal water metabolism is essential to body fluid homeostasis. The major determinants of normal water balance include arginine vasopressin (AVP), renal function, and thirst. Recent investigations have described the cloning and characterization of the water channel aquaporin-2 (AQP-2), which is located in the principal cell of the kidney collecting duct. Under the influence of AVP, AQP-2 inserts into the apical membrane, allowing reabsorption of water to occur. Studies in animals and humans suggest that alterations in the regulation and expression of AQP-2 in certain physiologic and pathologic states may contribute to such complications as hyponatremia, hypoosmolality, and edema. During exocytic shuttling of AQP-2 to the apical collecting duct membrane, a small percentage of AQP-2 is lost in the urine. Measurement of this urinary AQP-2 protein can be reliably performed by radioimmunoassay; this test represents a novel tool for evaluation of AVP action in the collecting duct of the human kidney in health and disease. In these studies, we will examine urinary AQP-2 excretion in patients during pregnancy and the menstrual cycle, and in patients with congestive heart failure, cirrhosis, nephrotic syndrome, and acquired nephrogenic diabetes insipidus due to lithium therapy or autosomal dominant polycystic kidney disease. An interpretation of the relationship between urinary AQP-2, serum and urine osmolality, and plasma AVP will provide insight into the control of body fluid homeostasis. The role of the vasopressin V2 receptor antagonist, CIPC-41061, in the treatment of volume overload, edema, and hyponatremia will be explored. A comprehensive understanding of AQP-2 regulation in humans will lead to unique and more direct interventions in the therapy of disordered water metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIPOLAR DISORDER & ALCOHOL ABUSE COMORBIDITY Principal Investigator & Institution: Frye, Mark A.; Psychiatry & Biobehav Sciences; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 16-AUG-2001; Project End 31-JUL-2007 Summary: The applicant proposes to acquire new training in magnetic resonance spectroscopy and neuroendocrinology. These two areas of investigation will expand his clinical research expertise and further his research endeavors in attempting to better understand the neuroanatomic and neuroendocrinological underpinnings of bipolar disorder. The research training will then be used to translate these potential research gains into clinical applications to better understand and ultimately treat major psychiatric illnesses. This study will examine the impact of alcohol on the biochemistry, neuroendocrinology, and neuropsychological functioning of bipolar illness. The lifetime prevalence rate of alcohol abuse comorbidity in bipolar disorder is the highest of all Axis I diagnoses; furthermore, the presence of alcohol abuse in bipolar disorder is associated with a decreased response rate to the gold standard treatment lithium carbonate. Thus, by prevalence data and inadequate treatment response, this represents an enormous public health problem. In a cross-sectional analysis, patients with bipolar disorder and comorbid alcohol abuse or dependence, patients with bipolar illness without comorbid alcohol abuse or dependence, and age matched healthy controls will undergo 1 H-MR spectroscopy, Dexamethasone/CRH neuroendocrine challenge, and neuropsychological evaluation assessing executive function, verbal memory, and working memory. This study will evaluate whether there are differences amongst the three groups and if there is a relationship between N-acetylaspartate (NAA), hypothalamic-pituitary adrenal axis function, and neuropsychological functioning. These variables will also be evaluated as to their predictive potential for relapse under
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Lithium
naturalistic follow-up where mood stability, alcohol craving and relapse, medication compliance, and functional capacity will be monitored. This naturalistic follow-up period may identify preliminary neurobiological factors associated with relapse and provide direction for further controlled interventional study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BLOOD PRESSURE CONTROL IN JUVENILES--LONGITUDINAL STUDY Principal Investigator & Institution: Pratt, J. Howard.; Professor of Medicine; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 30-SEP-1985; Project End 30-JUN-2003 Summary: (Adapted from Investigator's Abstract) The proposed studies are an extension of longitudinal investigations of mechanisms for the development of primary hypertension. They are performed on a biracial cohort of children, adolescents, and young adults who are mostly normotensive. These studies are based on the premise that the pathophysiology of hypertension begins early in life, and further that blood pressure (BP) studies carried out at this age avoid the confounding cardiovascular and renal changes that typically occur when subjects are hypertensive. In the previous period of funding, distinct racial differences relevant to BP regulation were observed; first, longitudinal BP increased over time faster in blacks than in whites; second, aldosterone excretion was lower in blacks than in whites due in part to suppression of the reninangiotensin system (RAS); and third, the level of serum angiotensinogen was higher and a variant of the angiotensinogen gene (AGT), T235, which has been associated with hypertension, was the predominant allele in the blacks. In the proposed studies, the focus will be principally on the role of sodium retention and how this is regulated by angiotensin II (AII), a product derived from angiotensinogen, and the amiloridesensitive sodium channel (ENaC), an important site for reabsorption of sodium in the distal nephron. The studies utilize the longitudinal BPs of the cohort - the mean of multiple values as well as the change in BP over time. The cohort will be supplemented through recruitment of additional members and increased participation by parents. In Specific Aim No. 1 three substudies will be performed: (1) Since the T235 allele may be in linkage disequilibrium with a locus that increases the angiotensinogen level, the applicants will now construct haplotypes with T235 to identify a subset(s) of T235 alleles that associate with a higher angiotensinogen level, and potentially a hypertensinogenic locus on AGT. (2) To examine whether a higher angiotensinogen level in black children is related to race alone or is related specifically to the higher prevalence of hypertension in the parents. (3) Finally, the relation of newly identified variants of genes for ENaC to longitudinal BP, the RAS, and the urinary excretion of aldosterone and potassium to look for molecular variations of this ion channel as contributors to a higher BP will be examined. Specific Aim No. 2 will be performed in the General Clinical Research Center where the effects of AII on renal hemodynamics and sodium resorption can be examined. Since increases in vascular resistance in the kidney that may be mediated by AII may increase resorption of sodium, the applicants will measure renal blood flow (RBF) to test the hypotheses that RBF is lower in blacks than in whites, and is inversely related to level of angiotensinogen and longitudinal BP. In response to a sodium challenge imposed by an infusion of normal saline, the clearance of endogenous lithium, a measure of AII-directed sodium reabsorption in proximal tubule, and the fractional excretion of sodium, a measure of overall natriuretic capacity, will be examined in relation to race, angiotensinogen level, and longitudinal BP. An ongoing
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longitudinal study of BP is extended with cross-sectional analyses of potential genetic and renal influences on BP, factors that could contribute to the etiology of primary hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BRAIN DEVELOPMENT IN EXPERIMENTAL EPILEPSY Principal Investigator & Institution: Wasterlain, Claude G.; Professor of Neurology; Neurology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-DEC-1978; Project End 30-NOV-2002 Summary: The long-term objective of this project is to understand the relationship between seizures and brain development. During the last period of this project, we established that some types of seizures, in the absence of systemic complications, can damage the immature brain. We also have preliminary evidence that this damage is, in turn, epileptogenic. This application has two goals: first, to determine whether seizureinduced neuronal injury in the immature brain leads to neuronal apoptosis, and to understand its mechanism. Second, to find out whether seizure-induced damage in the immature brain is epileptogenic. We will study the mechanism of neuronal death in the lithum-pilocarpine model of status epilepticus in the immature rat. We will carefully monitor physiological variables such as arterial blood pressure or blood gases, to ascertain that neuronal injury in the that model is the result of the seizures themselves. We will determine the time course of neuronal injury, describe its morphology by electron-microscopy and confocal fluorescesence microscopy in the CA1 pyramids, the inner dentate granule cells, and the large neurons of the dentate hilus; we will determine whether neuronal death is dependent upon protein synthesis; we will look for evidence of early DNA breakdown by restricted endonucleases by the TUNEL method for identify double- stranded DNA breaks in individual cells; and by laddering on agarose gel electrophoresis; we will look for evidence of caspase activation by immunocytochemistry and in Western blots using antibodies against proteolytic fragments cleaved from actin and from poly ADP-ribose polymerase, by using inhibitors of caspases, by using in situ hybridization and Northern blots to detect increased expression of individual caspases. The time course of this phenomena will reveal the biochemical cascade leading to apoptosis in specific cells. We will also use specific inhibitors to study the dependency of most necrotic and apoptotic death of neurons upon the activation of muscarinic cholinergic receptors, of NMDA receptors, and upon the activity of nitric oxide synthase. Second, we will determine whether seizure induced damage in the immature brain is epileptogenic by monitoring seizures in chronic animals subjected to status epilepticus at P15, P21, P28, or as adults. We will chronically administer anticonvulsants after the end of status epilepticus, and study their effects on the development of spontaneous seizures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CARDIAC TERATOGENICITY OF LITHIUM Principal Investigator & Institution: Linask, Kersti K.; Professor; Cell Biology; Univ of Med/Dent Nj-Sch Osteopathic Med Osteopathic Medicine Stratford, Nj 08084 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 30-APR-2005 Summary: (Adopted from the Applicant's Abstract): Lithium (Li++) is widely used in the prophylaxis and treatment of bipolar disorder (manic depression) which for women clusters during childbearing years. Controversy continues to exist on the use of lithium
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Lithium
during pregnancy and teratogenic effects of during cardiac embryogenesis. Data from lithium birth registries and clinical studies indicate an increased risk in congenital abnormalities with the heart predominantly affected. There have been no cellular and molecular studies addressing lithium's role specifically in cardiac teratogenicity in animal models. Good informative epidemiologic studies among children of women treated with Li++ during pregnancy are difficult to perform. Li++ has been shown to have dramatic effects on morphogenesis in the vertebrate embryo through the Wnt/Bcatenin signaling pathway by its inhibition of glycogen synthase kinase-3. How Li++ may exert its teratogenic effects during cardiogenesis is not known. Our research indicates that Li++ affects cytoplasmic 8-catenin in precardiac cells and that these effects are amplified during development. The broad goals are: 1) To determine how Li++ is responsible for the increased incidence of congenital cardiac defects in humans, by analyzing on the cell and molecular level Li++ effects on avian and mouse heart development. 2) Using echocardiography and microarray analyses to determine the effects and pathways by which Li++ acts on the embryonic mouse heart. The hypotheses to be tested are: Hypothesis: Li++ affects cell reorganization into an epithelium and results in wider hearts (2) Hypothesis: Li++ effects on the cardiac compartment are related to its mimicking Wnt signaling and the resulting increased cytoplasmic B-catenin pools. Hypothesis: Elevation of B-catenin by misexpression in the precardiac mesoderm leads to abnormal cardiac cell differentiation and compartmentalization. (2B): Hypothesis: Misexpression of LEF1 inhibits the activation of specific genes that are necessary for subsequent normal cardiac morphogenetic processes to take place. (3) Hypothesis: Li++ exposure in mouse embryos affects cardiac cell function and gene expression. Such studies will provide important insights on a molecular level into the use of Li++ on embryonic human cardiac development during pregnancy. Until the safety of lithium is conclusively proven, one must assume teratogenic potential and harm to the fetus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMISTRY OF LITHIUM AMIDES Principal Investigator & Institution: Collum, David B.; Professor; Chemistry and Chemical Biology; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2001; Project Start 01-APR-1989; Project End 31-MAR-2004 Summary: We will investigate structure-reactivity relationships in N-lithiated species by focussing upon three lithium amides: lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium hexamethyldisilazide (LiHMDS), and lithium diisopropylamide (LDA). 6Li15N double labelling spectroscopic methods have already provided aggregation and solvation states, relative free energies and enthalpies of solvation, and even mechanisms of ligand substitution. The spectroscopic investigations will support and augment the rate and mechanistic studies. We will emphasize the correlation of solvation energy, aggregate structure, and reactivity through detailed mechanistic and rate studies of four synthetically important reactions of lithium amides: (1) ketone enolization, (2) imine metallation, (3) epoxide and alkyl halide elimination, and (4) orthometallation. Additional recurring themes include: (1) develop hemi-labile ligands to control reaction rates and selectivities, (2) explore the scope and mechanism by which Lewis acids and related electrophilic additive influence reactivity, (3) establish the necessary mechanistic foundations to allow ligands (solvents) to be employed catalytically, and (4) determine how the intervention of lithium amide-LiX mixed aggregates influence reaction rates and mechanisms. Significant progress is assured by substantial preliminary results and
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the mechanistic transparency of these particular reactions. Overall, the lithium amides offer a promising opportunity to understand the complexities presented by organolithium chemistry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CNS GLP-1: MULTIPLE ROLES IN INGESTION AND ADIPOSITY Principal Investigator & Institution: Seeley, Randy J.; Professor; Psychiatry; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 30-JUN-2006 Summary: Disorders of food intake, either under consumption by patients with wasting illness or over-consumption in ever-growing rates of obesity, are major health burdens and cost the U.S. billions of dollars in additional health care and lost productivity. Failure to develop effective treatments for these conditions is in large part due to a lack of clear understanding as to how food intake is regulated. Thus, research to explain the processes by which ingestive behavior is controlled is likely to have a major impact on the health of the population. Glucagon-like-peptide-1-(7-36) amide (GLP-1) is an intestinal hormone that has important effects on insulin secretion and glucose metabolism. GLP-1 is also produced in the Central Nervous System (CNS), exclusively in a discrete group of neurons in the caudal brainstem. A single receptor, specific for GLP-1, is expressed in pancreatic beta-cells and by neurons in specific regions of the brain including the hypothalamus, amygdala and caudal brainstem. The neuroanatomical distribution of the central GLP-1 system suggests a role as a relay center for transmitting visceral information to higher centers and there is emerging data indicating that signaling through the central GLP-1 receptor is involved in several aspects of the regulation of food intake. The central hypothesis of this proposal is that signaling through the CNS GLP-1 system is common to the non- homeostatic, meal, and adiposity regulating influences on food intake. The first specific aim will evaluate the hypothesis that signaling through the CNS GLP-1 receptor is a common mechanism through which diverse noxious stimuli activate the response to visceral illness. The second specific aim will use mouse experiments and a conditional genetic targeting system to evaluate the hypothesis that mice with targeted disruption of the GLP-1 receptor develop alternative systems to mediate visceral illness. The third specific aim will evaluate the role of the CNS GLP-1 system in mediating GI-peptide induced satiety. The fourth specific aim will use tissue selective knockouts of the GLP-1 receptor to evaluate the hypothesis that the effects of peripherally administered GLP-1 agonists on body adiposity are mediated by GLP-1r on the pancreatic beta-cell rather than by GLP1r in the CNS. While overwhelming evidence indicates that GLP-1 can influence food intake, controversy continues to surround the circumstances under which GLP-1 exerts that influence. The execution of the current proposal will result in a more complete understanding of the GLP-1 system and so will add greatly to the overall picture about how food intake and body weight are regulated. This information could lend itself to the development of therapeutic strategies for both wasting conditions as well as obesity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEPRESSION
COGNITIVE
THERAPY
AND
PHARMACOTHERAPY
FOR
Principal Investigator & Institution: Hollon, Steven D.; Professor; Psychology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2001; Project Start 01-MAY-2000; Project End 30-APR-2005
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Lithium
Summary: (Adapted from the Applicant's Abstract): This is a request for five years of salary support via a NIH Independent Scientist Award (K02). I have long sought to integrate psychosocial and biological models of depression, and I hope to use the RCA to enhance my understanding of basic neurobiology and developmental issues relevant to its nature and treatment. I also want to enhance the relevance of my work to applied clinical settings (effectiveness). In particular, I am interested in whether cognitive therapy has a more enduring effect than drugs in the treatment of depression. Earlier studies suggested that this might be the case, but the recent NIH TDCRP found cognitive therapy to be less effective than drugs in the treatment of more severely depressed outpatients and reported little evidence of any enduring effect. Both sets of studies have been criticized for failing to provide optimal implementations of the respective modalities, drugs in the earlier studies and cognitive therapy in the TDCRP. We are currently conducting (with colleagues at Penn) a placebo-controlled comparison of cognitive therapy versus drugs in the treatment of more severely depressed outpatients that seek to address both sets of concerns. I am also collaborating with Neil Jacobson in Seattle in a similar placebo-controlled trial designed to determine whether behavioral activation (which is simpler to implement) carries the full weight of change in cognitive therapy. Further, we plan to examine (with colleagues at Penn and Rush) whether adding cognitive therapy to drugs can both enhance the breadth of response and obviate the need to keep patients on long-term maintenance medications. Finally, we are collaborating with colleagues at each of these sites to study the impact of treatment on the offspring of our depressed patients. We think that more can be done to study the full range of benefits associated with successful treatment. My goal has been to examine the role of both psychological and biological processes in the moderation and medication of treatment effects and to do so in a manner that has the greatest possible impact on actual clinical practice. I hope to use my growing expertise in neurobiology and development to better understand the processes that underlie the treatment and prevention of depression and to use that understanding to enhance the effectiveness of clinical practice in applied settings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COMBINATION THERAPY IN BIPOLAR RAPID CYCLING Principal Investigator & Institution: Calabrese, Joseph R.; Professor and Director; Psychiatry; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2005 Summary: (provided by applicant): Using double-blind enriched discontinuation designs, early lithium maintenance studies demonstrated that 60-80 percent of patients with bipolar disorder had a satisfactory clinical response. However, these older studies excluded lithium-refractory subgroups such as all bipolar II disorder. When the response rate of lithium is considered across the wide spectrum of bipolar disorders, it may approach 50 percent. A large subgroup of lithium-resistant patients is rapid-cyclers. Fourteen to 53 percent of patients with bipolar disorder cycle rapidly and the majority is bipolar II and female. Seventy-two to 82 percent of rapid-cyclers exhibit poor response to lithium. Thus, a substantial percentage of poor response to lithium is attributable to rapid cycling. Preliminary data from MH-50165 suggest that combination therapy with lithium and divalproex results in marked antimanic, but modest antidepressant efficacy in patients with rapid cycling; 75 percent of non-response is attributable to resistant depression. More broadly effective regimens are needed. To address this need, we propose to compare the safety and efficacy of the triple regimen lithium, divalproex, and lamotrigine to the double-regimen lithium and divalproex. Cancer chemotherapy
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trials have employed random assignment to parallel arms to compare the safety and efficacy of 2 partially effective, chemotherapeutic agents to 3 partially effective agents; the evidence from MH-50165 suggests that rapid-cycling is sufficiently treatmentrefractory to merit a study employing similar methodology. The primary objective of this pilot study is to conduct an exploration of the relative efficacy of the triple vs. double regimen as "first-line" therapy among unselected patients in the acute and continuation outpatient management of depression, hypomania, or mania. The proposed study will be used as pilot data for a future full-scale, STEP Prograin multicenter maintenance trial. In this revised competitive renewal, we propose a singlecenter, STEP-Program affiliated, 6-month, randomized, double-blind, balanced parallelgroup comparison of these two regimens of combination therapy in 90 patients with rapid-cycling bipolar disorder presenting depressed over a three-year period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTINUATION ECT VERSUS PHARMACOTHERAPY Principal Investigator & Institution: Husain, Mustafa M.; Associate Professor; Psychiatry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-FEB-1997; Project End 30-APR-2004 Summary: (Provided by Applicant): This is a competing renewal application seeking two years of additional funding to complete the ongoing multi-site study, "Continuation ECT: Efficacy and Safety." The goal of this research is to compare continuation ECT with an aggressive combination pharmacotherapy strategy (nortriptyline plus lithium) in the prevention of depressive relapse after successful ECT for major depression. As of May 30, 2001, we have successfully enrolled 470 patients into the acute ECT phase of the study (Phase I) and 159 patients into the two treatment arm randomized phase (Phase II). This represents 73 percent of the necessary recruitment target. An additional 56 randomized patients will be enrolled to meet the target randomized sample size of 216. Completion of patient recruitment, follow-up, and analysis of results can be accomplished with the additional 24 months requested in this application. Electroconvulsive therapy (ECT) is a highly effective treatment for major depressive disorder (MDD). Relapse after acute phase ECT or pharmacotherapy remains a major public health problem. Recent studies show an alarmingly high rate of relapse after ECT despite conventional pharmacotherapy (C-PHARM). Continuation ECT (C-ECT) is also in widespread clinical use, however, its efficacy and safety have never been rigorously tested. The role of C-ECT in relapse prevention of seriously ill patients with MDD urgently needs to be defined. The ongoing study is a prospective, six-month, randomized clinical trial in which patients with MDD who remit with an acute course of bilateral ECT are randomized to one of two treatment arms: C-PHARM (nortriptyline + lithium) or C-ECT. The major hypothesis is that C-ECT will more effectively prevent relapse than C-PHARM. The two continuation therapies also will be compared in their effects on cognitive performance, global functioning, side effects, and perceived health status. Study design features include rigorous remitter criteria, blinded neuropsychological assessments, rigorous quality control procedures including independent, blind rating of videotaped Hamilton Depression Rating Scale and SCID interviews, and independent oversight of data collection and analysis. When completed, this project will provide the first and definitive data on the role of C-ECT in the treatment of serious affective illness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CONTINUATION ECT VS PHARMACOTHERAPY: EFFICACY & SAFETY Principal Investigator & Institution: Rummans, Teresa A.; Associate Professor of Psychiatry; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-FEB-1997; Project End 30-APR-2004 Summary: (Provided by Applicant): This is a competing renewal application seeking two years of additional funding to complete the ongoing multi-site study, "Continuation ECT versus Pharmacotherapy." The goal of this research is to compare continuation ECT with an aggressive combination pharmacotherapy strategy (nortriptyline plus lithium) in the prevention of depressive relapse after successful ECT for major depression. As of May 30, 2001, we have successfully enrolled 470 patients into the acute ECT phase of the study (Phase I) and 159 patients into the two treatment arm randomized phase (Phase II). This represents 73 percent of the necessary recruitment target. An additional 56 randomized patients will be enrolled to meet the target randomized sample size of 216. Completion of patient recruitment, follow-up, and analysis of results can be accomplished with the additional 24 months requested in this application. Electroconvulsive therapy (ECT) is a highly effective treatment for major depressive disorder (MDD). Relapse after acute phase ECT or pharmacotherapy remains a major public health problem. Recent studies show an alarmingly high rate of relapse after ECT despite conventional pharmacotherapy (C-PHARM). Continuation ECT (C-ECT) is also in widespread clinical use, however, its efficacy and safety have never been rigorously tested. The role of C-ECT in relapse prevention of seriously ill patients with MDD urgently needs to be defined. The ongoing study is a prospective, six-month, randomized clinical trial in which patients with MDD who remit with an acute course of bilateral ECT are randomized to one of two treatment arms: C-PHARM (nortriptyline + lithium) or C-ECT. The major hypothesis is that C-ECT will more effectively prevent relapse than C-PHARM. The two continuation therapies also will be compared in their effects on cognitive performance, global functioning, side effects, and perceived health status. Study design features include rigorous remitter criteria, blinded neuropsychological assessments, rigorous quality control procedures including independent, blind rating of videotaped Hamilton Depression Rating Scale and SCID interviews, and independent oversight of data collection and analysis. When completed, this project will provide the first and definitive data on the role of C-ECT in the treatment of serious affective illness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CONTINUATION ECT VS PHARMACOTHERAPY: EFFICACY AND SAFETY Principal Investigator & Institution: Kellner, Charles H.; Professor and Chairman; Psychiatry; Univ of Med/Dent Nj Newark Newark, Nj 07103 Timing: Fiscal Year 2002; Project Start 01-FEB-1997; Project End 30-APR-2004 Summary: (Provided by Applicant): This is a competing renewal application seeking two years of additional funding to complete the ongoing multi-site study, "Continuation ECT versus Pharmacotherapy." The goal of this research is to compare continuation ECT with an aggressive combination pharmacotherapy strategy (nortriptyline plus lithium) in the prevention of depressive relapse after successful ECT for major depression. As of May 30, 2001, we have successfully enrolled 470 patients into the acute ECT phase of the study (Phase I) and 159 patients into the two treatment arm randomized phase (Phase II). This represents 73 percent of the necessary recruitment target. An additional 56
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randomized patients will be enrolled to meet the target randomized sample size of 216. Completion of patient recruitment, follow-up, and analysis of results can be accomplished with the additional 24 months requested in this application. Electroconvulsive therapy (ECT) is a highly effective treatment for major depressive disorder (MDD). Relapse after acute phase ECT or pharmacotherapy remains a major public health problem. Recent studies show an alarmingly high rate of relapse after ECT despite conventional pharmacotherapy (C-PHARM). Continuation ECT (C-ECT) is also in widespread clinical use, however, its efficacy and safety have never been rigorously tested. The role of C-ECT in relapse prevention of seriously ill patients with MDD urgently needs to be defined. The ongoing study is a prospective, six-month, randomized clinical trial in which patients with MDD who remit with an acute course of bilateral ECT are randomized to one of two treatment arms: C-PHARM (nortriptyline + lithium) or C-ECT. The major hypothesis is that C-ECT will more effectively prevent relapse than C-PHARM. The two continuation therapies also will be compared in their effects on cognitive performance, global functioning, side effects, and perceived health status. Study design features include rigorous remitter criteria, blinded neuropsychological assessments, rigorous quality control procedures including independent, blind rating of videotaped Hamilton Depression Rating Scale and SCID interviews, and independent oversight of data collection and analysis. When completed, this project will provide the first and definitive data on the role of C-ECT in the treatment of serious affective illness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTINUATION ECT VS PHARMACOTHERAPY--EFFICACY AND SAFETY Principal Investigator & Institution: Petrides, Georgios; Professor; Long Island Jewish Medical Center 270-05 76Th Ave New Hyde Park, Ny 11040 Timing: Fiscal Year 2002; Project Start 01-FEB-1997; Project End 30-APR-2004 Summary: (Provided by Applicant): This is a competing renewal application seeking two years of additional funding to complete the ongoing multi-site study, "Continuation ECT versus Pharmacotherapy." The goal of this research is to compare continuation ECT with an aggressive combination pharmacotherapy strategy (nortriptyline plus lithium) in the prevention of depressive relapse after successful ECT for major depression. As of May 30, 2001, we have successfully enrolled 470 patients into the acute ECT phase of the study (Phase I) and 159 patients into the two treatment arm randomized phase (Phase II). This represents 73 percent of the necessary recruitment target. An additional 56 randomized patients will be enrolled to meet the target randomized sample size of 216. Completion of patient recruitment, follow-up, and analysis of results can be accomplished with the additional 24 months requested in this application. Electroconvulsive therapy (ECT) is a highly effective treatment for major depressive disorder (MDD). Relapse after acute phase ECT or pharmacotherapy remains a major public health problem. Recent studies show an alarmingly high rate of relapse after ECT despite conventional pharmacotherapy (C-PHARM). Continuation ECT (C-ECT) is also in widespread clinical use, however, its efficacy and safety have never been rigorously tested. The role of C-ECT in relapse prevention of seriously ill patients with MDD urgently needs to be defined. The ongoing study is a prospective, six-month, randomized clinical trial in which patients with MDD who remit with an acute course of bilateral ECT are randomized to one of two treatment arms: C-PHARM (nortriptyline + lithium) or C-ECT. The major hypothesis is that C-ECT will more effectively prevent relapse than C-PHARM. The two continuation therapies also will be compared in their
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effects on cognitive performance, global functioning, side effects, and perceived health status. Study design features include rigorous remitter criteria, blinded neuropsychological assessments, rigorous quality control procedures including independent, blind rating of videotaped Hamilton Depression Rating Scale and SCID interviews, and independent oversight of data collection and analysis. When completed, this project will provide the first and definitive data on the role of C-ECT in the treatment of serious affective illness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--CLINICAL PSYCHOPHARMACOLOGY Principal Investigator & Institution: Young, Robert C.; President; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 30-APR-2002 Summary: The Psychopharmacology/Biochemistry Laboratory (PBL) Core directed by Dr. Young, will comprise a research biochemist and a technician. It will utilize existing facilities for high performance liquid chromatography (HPLC) and radioimmunoassay (RIA). The PBL Core will serve as a resource for other investigators, providing drug assays and catecholamine neurotransmitter measures, developing additional assay procedures, and serving a consultative role. The PBL will offer training in HPLC, RIA and other laboratory techniques for research fellows and other staff. The PBL will also conduct a research program focused on pharmacologic in geriatric major depression and mania. The PBL research program represents an extension of ongoing studies of nortriptyline (NT) in major depression and of geriatric mania. The goals are to improve guidelines for clinical and research use of NT and lithium (Li) salts by examining concentration-effect relationships and to examine changes in catecholamine neurotransmitter measures during treatment. Differences in patients with cognitive impairment or abnormal brain morphology are evaluated. The first of two pilot studies proposed will examine relationships between plasma NT and 10-hydroxynortriptyline (10-OH- NT) concentrations and therapeutic response and changes in noradrenergic function in geriatric major depressives, with and without cognitive impairment, treated with fixed dose. Differences in patients with large ventricle-brain ration are also tested. The second pilot study will examine therapeutic response to conventional vs. low plasma Li in geriatric manic patients with and without cognitive impairment. Efficacy and change in noradrenergic and dopaminergic measures will be compared in the two treatment groups; differences in patients with cognitive impairment will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CRYSTAL STRUCTURE OF COLICIN IA DETERMINATION BY CRYOCRYSTALLOGRAPHY Principal Investigator & Institution: Wiener, Michael C.; Associate Professor; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 28-FEB-2002 Summary: Using 1) flash-freezing and 2) large-format MAR imaging plate at beamline 71, resolution has been extended to 2.35 E from previous limit of 2.8 E. This 2.8 E data set was obtained from frozen crystals with resolution limited by the smaller MAR imaging plates. Freezing has eliminated the radiation damage plaguing earlier experiments. A wide range of cryosolvents and artificial mother liquors were examined. Replacement of ammonium sulfate/citrate buffer by lithium sulfate/acetate buffer was successful. This artificial mother liquor will be used for heavy atom soaks. After screening low-
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resolution data in the lab, the promising candidates will be brought to SSRL. The best candidate to date is CH3HgCl; single-site Cys mutants will also be utilized (native has no cysteines). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CYSTEINE STRING PROTEINS: CELLULAR & MOLECULAR FUNCTION Principal Investigator & Institution: Umbach, Joy A.; Associate Professor; Molecular & Med Pharmacology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 27-JUL-1993; Project End 31-JUL-2005 Summary: This application has two long-range goals. The first is to advance our understanding of cellular and molecular functions of cysteine string proteins (csps). Csps are a family of proteins associated with secretory organelles in nerve cells and elsewhere. The second is to pursue recent findings which indicate that lithium (Li) ions modulate csp gene expression in vitro and in vivo. While the first goal entails basic investigations of the role of csps in secretion, the latter goal is likely to have moreimmediate clinical relevance. This is because Li, which is used in the management of bipolar-affective disorders, remains a mechanistic enigma. Thus, further study of the LIcsp link may afford insights into the therapeutic role of Li, as well as into the cause and improved treatment of bipolar syndromes. To approach these long-term goals, the current proposal has three specific aims: First, we will study regulatory, and functional/anatomical correlates of Li's effect on csp gene expression. These investigations will illuminate the signaling pathways that mediate this effect of Li, and also suggest whether Li is likely to modify the secretory behavior of discrete populations of neurons in the brain. Second, we propose to characterize further the secretory functions of a unique relative of csp. It is our hypothesis that this protein substitutes for csp in csp null mutant fruit flies. Using genetic, biochemical and physiological strategies, we plan to evaluate the role of this "csp substitute" in wild type and csp mutant Drosophila, as well as in vertebrates. Finally, we plan to exhibit calciumion independent regulated secretion of cortical granules. Perturbation of csp function in this system will afford insight into molecular contributions of csps to regulated secretion. Taken together, these aims constitute substantial progress toward resolving the role of csps in normal and pathological circumstances. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CYTOTOXIC NITROGEN HETEROCYCLES Principal Investigator & Institution: Vedejs, Edwin; Moses Gomberg Professor of Chemistry; Chemistry; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-JUL-1978; Project End 30-JUN-2005 Summary: (provided by applicant) This program will investigate fundamental aspects of heterocycle activation and coupling in the context of a synthetic program designed to prepare potent cytotoxic agents. The targets include FK317 metabolites, Nmethylaziridinomitosene B, diazonamide A, and structures containing hindered peptide subunits such as hemiasterlin, an inhibitor of tubulin polymerization. Selected synthetic intermediates will be submitted to the NCI Drug Screening Program, and specific targets in the FK317 and N-methylaziridinomitosene B project will be evaluated for DNA alkylation and crosslinking ability in collaboration with Prof. P. Hopkins (Univ. of
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Washington). Synthetic efforts in the aziridinomitosene area will exploit recently developed methods for anionic cyclization to prepare FK317 metabolites and to test their role in the activation cascade. Advances in oxazole lithiation will be used to synthesize N-methylaziridinomitosene B and the corresponding hydroquinone. Solvolysis products of the hydroquinone will be identified under controlled pH conditions to resolve mechanistic issues. The Diazonamide A project will focus on synthetic methodology, including the introduction of quaternary carbon with control of absolute configuration in a benzofuranone, ring closure of a hindered peptide in a relatively rigid polycyclic environment, and assembly of an oxazole- and indole-containing biaryl macrocycle. The oxazole activation technology will also be used to assemble heterocyclic structures containing di-oxazoles, tri-oxazoles, and oxazolylindoles. Similar structures often appear in marine natural products. Methodology for high yield coupling of hindered peptides has been developed as part of the diazonamide A project and will be extended to the synthesis of the exceptionally hindered hemiasterlins and related structures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DRUGS OF ABUSE AND LEARNED AVERSIONS: SOLVING A PARADOX Principal Investigator & Institution: Grigson, Patricia Sue.; Associate Professor; Neural and Behavioral Sciences; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2001; Project Start 01-AUG-1996; Project End 30-JUN-2004 Summary: Rats will decrease intake of a saccharin conditioned stimulus (CS) following pairing with an illness-inducing agent such as LiCI, a preferred high concentration of sucrose, or a drug of abuse such as morphine or cocaine. The suppressive effects of the illness inducing agent are clear evidence for aversive conditioning and are referred to as conditioned taste aversions. The suppressive effects of the rewarding sucrose solution reflect appetitive conditioning and are referred to as anticipatory contrast effects because the saccharin CS is thought to be devalued as it comes to predict the future availability of the preferred sucrose reward. Finally, despite the well-known rewarding properties of drugs of abuse, the suppressive effects of these drugs have been viewed as conditioned taste aversions for over 25 years. We have, however, recently posed an alternative interpretation that eliminates this apparent paradox. Specifically, we have suggested that rats suppress intake of a saccharin CS following saccharin-morphine pairings, for example, because the saccharin CS is devalued as it comes to predict the future availability of the highly rewarding drug of abuse. Thus, we postulate that the same rewarding properties that increase self-administration of the drug also serve to devalue the gustatory cue that predicts its availability. The results from the Progress Report support this new hypothesis by showing that the suppressive effects of drugs of abuse and sucrose, but not LiCI, are influenced by the deprivation state of the animal, the nature of the gustatory CS, the caloric value of the CS, lesions of the gustatory thalamus, and the strain of the rat. The goals of this project are to (I) further identify the relevant parameters of the phenomenon, (II) establish the merits of the reward comparison hypothesis and (III), introduce self-administration to this paradigm. The addition of the self- administration procedure will not only more closely approximate the contrast protocol, but also will allow us to begin to study how reward comparison ma affect drug-seeking and drug-taking behavior. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EFFECTS OF LITHIUM ON CHOLINERGIC ACTIVITY Principal Investigator & Institution: Jope, Richard S.; Psychiatry; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-FEB-1984; Project End 30-JUN-2005 Summary: Adapted from applicant's abstract): Lithium is the mainstay treatment for bipolar affective disorder, with 0.1 percent of the population being treated. Understanding lithium's complex mechanisms of action will help reveal causes of mood disorders and development of targeted drugs. This project focuses on specific hypotheses concerning lithium's actions, in conjunction with studies of basic neuronal signaling mechanisms. Also, valproate and carbamazepine are therapeutic for bipolar disorder, so biochemical actions common to lithium and these two drugs would strengthen the link to their therapeutic effects. The prime actions of these drugs appear to alter signaling activities which impact on neural plasticity, encompassing regulation of signals leading to transcription factor activation and to regulation of the cytoskeleton. Specific Aim-1 will test the hypotheses that lithium, valproate, and carbamazopine modulate signaling activities associated with the receptor-coupled phosphoinositide signal transduction system, using muscarinic receptor-expressing human neuroblastoma SH-SY5Y cells as a model system. There are three components to this aim. Component I will test the hypotheses that (a) muscarinic stimulation increases protein tyrosine phosphorylation, including Gq/11, and protein complex formation, (b) tyrosine phosphorylation is necessary for phosphoinositide signaling and activation of AP-1 and Egr-l, (c) these processes are modulated by anti-bipolar drugs. comDonent 2 will test the hypotheses that (a) muscarinic stimulation increases Gq/11 pahnitoylation, (b) pahnitoylation is necessary for optimal signaling, (c) palmitoylation and tyrosine phosphorylation of Gq/11 regulate one another, (d) palmitoylation is modulated by the therapeutic drugs. Component 3 will test the hypotheses that (a) muscarinic stimulation of signaling is modulated by RGS2 (Regulators of G-protein Signaling), (b) association of RGS2 with Gq/11 is regulated by specific mechanisms, (c) RGS2's action is modulated by the therapeutic drugs. Specific Aim 2 will test the hypotheses that lithium causes alterations in neuronal cytoskeletal organization and function through inhibition of glycogen synthase kinase-3p (GSK3~) resulting in decreased tau and MAP-1B phosphorylation and increased ,B-catenin and Tcf/Lef DNA binding in SH-SY5Y cells. There are three components to this aim.Component I will test the hypotheses that (a) lithium site-specifically reduces phosphorylation of tau and MAP-1B, (b) this is evident at therapeutic lithium concentrations, (c) valproate and carbamazepine affect phosphorylation, (d) these drugs alter localization of tau and MAP-1B, (e) and microtubule stability. Component 2 will test the hypotheses that (a) lithium increases pcatenin levels, (b) this increases cadherin binding (mediates cell adhesion), (c) lithium increases p-catenin-dependent Tcf/Lef transcription factor activation, (d) valproate and carbamazepine have similar effects. Component 3 will test the hypotheses that (a) in postmortem human bipolar brain, tau and MAP-1B have increased site-specific phosphorylation and other alterations opposite those in lithium-treated cells, (b) overexpressed GSK3p in SH-SY5Y cells will model the bipolar condition and will demonstrate enhanced effects of lower concentrations of lithiurn. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GLUCOGEN SYNTHASE KINASE 3BETA AND BIPOLAR DISORDER Principal Investigator & Institution: Li, Xiaohua; Psychiatry & Behav Neurobiol; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008
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Summary: (provided by applicant): This project will study the regulation of glycogen synthase kinase 3beta, its modulation by mood stabilizers and its potential role in bipolar disorder. The five-year plans to enable the candidate to develop into an independent psychiatric investigator to conduct translational research in bipolar disorder. The project provides extensive training in new research skills, including studying transcription factors and gene expression, using gene microarray techniques, and conducting clinical research. The central hypothesis for the research is that abnormal functioning of GSK3beta plays a role in the development of bipolar disorder. The hypothesis is based on the recent evidence that bipolar disorder may involve impaired neural plasticity and neural degeneration, and GSK3beta, a protein kinase with multiple regulatory functions in neuronal tissues, is a major intracellular target of the mood stabilizer lithium. Our preliminary results also indicate that three mood stabilizers have modulatory effects on GSK3beta. Three Specific Aims will be pursued to test the central hypothesis and accomplish the overall objective of this application. Specific Aim 1 will determine the role of GSK3beta in the brain-derived neurotrophic factor (BDNF)-induced cyclic AMP responsive element binding protein (CREB) transcription factor activity and its modulation by mood stabilizers. BDNF-mediated signaling and CREB will be studied because they are components of a neural-specific signaling system that appears to be impaired in mood disorders. Specific Aim 2 will determine the role of GSK3beta in BDNF-induced gene expression and its modulation by mood stabilizers. Gene expression will be studied because it is thought to be impaired in bipolar disorder and is modified by treatment with mood stabilizers. This hypothesis will be tested by measuring gene expression using gene microarray. The Specific Aims 1 and 2 provide training in studies of regulation of transcription factors and gene expression to obtain new skills in molecular biology, which is an important training component of this application. Specific Aim 3 will measure GSK3beta activity in peripheral blood lymphocytes of patients with bipolar disorder before and after treatment with lithium. This Specific Aim has a clinical research component to bridge the clinical and basic studies, and to facilitate the candidate's development of skills in translational research. The proposed research is innovative, because it will identify the role of GSK3beta in the development of bipolar disorder. The proposed research is expected to have a significant impact on understanding the pathophysiology and improving the treatment of bipolar disorder. At the completion of these studies, the candidate will have established a solid background in molecular biology techniques and clinical research enabling her to be an independent psychiatric researcher who possesses the ability to use molecular biology techniques to answer clinical questions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IN VIVO STUDIES OF THE PI PATHWAY IN BIPOLAR DISORDER Principal Investigator & Institution: Soares, Jair C.; Associate Professor; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 10-MAY-2000; Project End 30-APR-2002 Summary: The candidate is an Assistant Professor of Clinical Psychiatry at the Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine. He is proposing a career development plan designed to acquire additional clinical skills, and research skills in platelet membrane neurochemistry and neurochemical brain imaging with in vivo magnetic resonance spectroscopy (MRS). These skills will be used to investigate in vivo the intracellular phosphatidylinositol (PI) pathway, and examine the hypothesis of a dysfunction in this pathway in bipolar disorder patients. The PI pathway may be dysfunctional in bipolar disorder, and this may be an important
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mechanism underlying its pathophysiology, and the mechanisms of action of lithium and other treatments for this condition. Thirty unmedicated patients meeting criteria for bipolar type I according to DSM-IV (10 manic, 10 depressed, and 10 euthymic), and 20 lithium-treated euthymic bipolar patients will be studied. As a comparison group, 20 age, sex, and educational-matched healthy controls will be recruited. Patients will provide blood samples for determination of platelet membrane phosphoinositides, which will be done with two-dimensional thin-layer chromotography followed by scanning laser densitometry. They will also undergo a 1.5 T proton MRS brain scan, which will allow the quantitation of myoinositol in a voxel placed in the anterior cingulate. The career development plan will prepare the candidate for a full-time clinical research career devoted to the investigation of possible neurobiological mechanisms implicated in causation of bipolar disorder, and the mechanisms of action for the treatment of this condition. It is designed to allow the candidate's transition into an independent career in patient-oriented research in this field. These activities may result in substantial contributions to a better understanding of the pathophysiology of bipolar disorder, and ultimately contribute to the development of new treatments for this condition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INSULIN REGULATED NA+ AND CA2+ TRANSPORT IN HYPERTENSION Principal Investigator & Institution: Romero, Jose R.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 30-JUN-2003 Summary: (adapted from the application) This application is to provide support for Jose R. Romero, Ph. D. to allow him protected time for further supervised patient‑oriented research and training to become an independent biomedical scientist. To this end, a formal career development plan and curriculum for his development have been designed. The scientific focus of this application is to study sodium and calcium transport abnormalities at the cellular level that are present in blood cells from insulin resistant hypertensive patients. Various groups have independently shown that insulin resistance and the compensatory hyperinsulinemia are associated with essential hypertension. Erythrocytes, lymphocytes and platelets have been widely used as surrogate cells to what happens in cells that are more closely involved in the hypertensive process. Elevated Na/H exchanger (NHE), hyperinsulinemia and altered cytosolic calcium (Cacyt) handling are frequent abnormalities associated with essential hypertension. Genetic and epidemiological studies have characterized elevated NHE activity in blood cells as an intermediate phenotype in the hypertensive process. Our preliminary findings suggest that NHE activity in red blood cells (RBC) from these patients is insulin resistant but can still modulate sodium transport at high insulin levels. However this response is blunted in comparison to the effect on normotensives. In addition, we have seen that insulin levels correlate with sodium/lithium countertransport, a mode of operation of the NHE. Furthermore, our preliminary data show that incubation of lymphocytes with insulin causes Cacyt to increase in hypertensive patients. These findings have led us to the hypothesis to be tested in this project: insulin resistance is associated with functional defects in sodium and/or calcium transport pathways in hypertensive patients and these pathways are similarly abnormal in target tissues (endothelial cells) of the hypertensive process. To address this problem we have identified the following specific objectives. We will study the effects of insulin and Cacyt on the kinetics of NHE
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activation in RBC and lymphocytes from hypertensive individuals that have been characterized by markers of insulin resistance. We propose that the phosphorylation state and/or the turnover rate of NHE are enhanced by either Cacyt and/or insulin. We will also study the effect of insulin on Cacyt in lymphocytes from hypertensives with varying degrees of insulin sensitivity. Finally, we will investigate whether the cation alterations observed in blood cells can be seen in primary cultures of vascular endothelial cells obtained from subjects that have been characterized by markers of insulin resistance. Through these mechanisms the insulin resistance and hyperinsulinemia in hypertensive individuals may be linked to NHE abnormalities and/or elevated Cacyt levels. The information obtained from this project will demonstrate the role of insulin resistance in sodium and calcium transport. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LITHIUM STEREOSELECTIVITY
MIXED
AGGREGATES
&
ENOLIZATION
Principal Investigator & Institution: Pratt, Lawrence M.; Fisk University Nashville, Tn 372083051 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2006 Summary: This proposed research will develop the use of lithium dialkylamide mixed aggregates as reagents for the stereoselective synthesis of enolates. Lithium enolates are important reagents in the synthesis of carbon-carbon bonds, and are used extensively in the pr3eparation of medicinal compounds. Synthesis of chiral drugs often depends on the availability of stereoselective aldol condensations and other reactions of enolates the stereoselectivity of these reactions is often limited by the availability of pure diastereomeric enolates. The stereoselectivity of these reactions is often limited by the availability of pure diastereomeric enolates. Enolates are generally prepared by deprotonation of aldehydes, ketones, and esters, and the stereoselectivity of enolates. Enolates are generally prepared by deprotonat8ion of aldehydes, ketones, and esters, and the stereoselectivity of enolate format8ion is dependent on the structure of the base that is used. Lithium dialkylamide mixed aggregates with alkyllithiums and lithium halides will be tested as inexpensive and easily prepared reagents for this purpose. The enolization reactions will be performed by addition of the carbonyl compound to a solution of the lithium dialkylamide or its mixed aggregates. The enolate will be trapped as the trimethylsilyl enol ether and the E/Z ratio determined by gas chromatography. The enolization reactions will be performed with several carbonyl substrates to determine the effects of stereoelectronic factors and to predict the stereoselectivity of enolization of carbonyl compounds that are actually used in drug synthesis. Ab initio calculations will be used to determine the activation energies leading to the E and Z 4enolates. Deprotonation activation energies will be calculated for lithium dialkylamides and their alkylithium and lithium halide mixed aggregates. The calculations will be performed on a variety of aldehyde, ketone, and ester substrate to capture the behavior of a range of stereoelectronic effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LITHIUM RESPONSIVE BIPOLAR DISORDER AND CNS MYO INOSITOL Principal Investigator & Institution: Glitz, Debra A.; Clinician-Educator; Psychiatry & Behav Neuroscis; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2001; Project Start 15-AUG-1999; Project End 30-JUN-2003
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Summary: Bipolar Affective Disorder (BD) is a common, severe, chronic and lifethreatening illness. The discovery of lithium's efficacy revolutionized the treatment of patients with BD, and after more than two decades, lithium continues to be the mainstay of treatment. The effect on the broader community has been highlighted by one estimation that the use of lithium saved the United States US4 billion dollars in a recent year period, by reducing associated medical costs and restoring productivity. However, despite its role as one of psychiatry's most important treatments, lithium's mechanisms of action remain to be fully elucidated. Furthermore, increasing evidence suggests that a significant number of patients respond poorly to lithium therapy, with an estimated 20 percent to 40 percent failing to show an adequate therapeutic response to lithium. Studies such as these indicate two important and highly clinically relevant directions for future research: firstly, the need to better identify patients likely to respond to lithium treatment, and secondly, the necessity to develop more effective treatment regimens. The most widely accepted hypothesis underlying lithium's therapeutic efficacy is the inositol depletion hypothesis. This hypothesis posits that lithium produces a relative depletion of myo-inositol (mI) in critical areas of brain and it is this depletion of a major precursor of the phosphoinositide second messenger system which ultimately results in its therapeutic effects. Despite the attractiveness of the inositol depletion hypothesis, it has never been investigated in BD patients. Thus, there is a clear need to determine if lithium reduces the levels of mI critical brain regions of individuals with BD, and if individual differences in susceptibility to lithium-induced CNS mI reductions represent major factors determining resistance or sensitivity to lithium's therapeutic effects. The proposed research will utilize non-invasive proton magnetic resonance spectroscopy (MRS) technology to determine if lithium treatment alters regional mI concentrations in the human brain. In addition, the research will determine if alterations in brain mI levels are associated with responsiveness to lithium's antidepressants effects. This research offers the potential not only to facilitate in the identification of patients most likely to respond to lithium treatment, but may also facilitate the development of novel therapeutic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LITHIUM-ION BATTERIES FOR IMPLANTED MEDICAL DEVICES Principal Investigator & Institution: Koch, Victor R.; Covalent Associates, Inc. 10 State St Woburn, Ma 01801 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 30-SEP-2002 Summary: State-of-the-art rechargeable batteries are incapable of providing the high energy densities required in order to free the device-implanted patient from a tethered external power source. The ability to provide a left ventricular assisted device patient or implanted artificial heart patient with significant more time "off-tether" would greatly improve his or her quality of life. Therefore, the aim of our proposed research is to develop advanced electrolyte materials and formulations thereof that would safely enable the extraction of more energy from an implanted lithium- ion (Li-ion) rechargeable battery. Specifically, we proposed to prepare and evaluate a group of gel polymer electrolytes comprising ionic liquids that are non-flammable, electrochemically stable, and thermally robust. Li-ion cells incorporating the new electrolytes will be built and tested with a focus on establishing the intrinsic stability of the gel polymer electrolyte in direct contact with highly delithiated cathode materials. To this end we will employ differential scanning calorimetry to determine the onset of thermochemical reactions between cathode material and electrolyte as a function of the cathode's state of charge. If successful, we will embark on a program to build and quality prototype Li-ion
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batteries that will allow implanted devices to safely operate on internal power for longer period of time. PROPOSED COMMERCIAL APPLICATIONS: Not Available Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LONG TERM LITHIUM FOR AGGRESSIVE CONDUCT DISORDER Principal Investigator & Institution: Malone, Richard P.; Associate Professor of Psychiatry; Psychiatry; Mcp Hahnemann University Broad & Vine Sts Philadelphia, Pa 19102 Timing: Fiscal Year 2001; Project Start 20-SEP-1997; Project End 30-APR-2003 Summary: In 1992, two major journals (Archives of General Psychiatry, Journal of the American medical Association) dedicated entire issues to aggression and violence, including in children and adolescents, underlining it as a major public health concern. Poorly-tested psychotherapeutic agents are administered to children and adolescents, often on a long-term basis, to reduce aggression. Many pressures, including managed care, will increase the utilization of pharmacotherapy in the outpatient setting to treat serious problems. Lithium is the most promising agent for the pharmacotherapy of aggression in children and adolescents, as evidenced by short-term trials. However, it has not been demonstrated that lithium is an effective treatment for aggression in children and adolescents in the outpatient setting, or on a long-term basis. The proposed study is a 2-phased clinical trial of lithium for the treatment of aggression in conduct disorder. Both phases will be double-blind and placebo-controlled, with randomization and employ a parallel groups design. Subjects will be 75 children and adolescents, aged 9 to 17 years, diagnosed with conduct disorder and displaying a profile of severe aggression. Phase 1 will contain a short-term 8-week controlled trial, with twice as many subjects randomized to lithium as placebo, increasing the pool of potential lithium responders to continue to Phase 2. In Phase 2, lithium responders from phase 1 will enter a 6-month long-term controlled trial. Every attempt will be made to define responders to lithium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MAGNETIC RESONANCE SPECTROSCOPY IN AFFECTIVE ILLNESS Principal Investigator & Institution: Moore, Constance M.; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-JUL-2006 Summary: The specific aim of this application is to afford the applicant, a physicist, the opportunity to become an independent researcher applying magnetic resonance spectroscopy (MRS) in affective disorders. Two components are proposed to accomplish this: formal academic training in psychology and neuroscience; and two research projects. There is an established literature that suggests the pathophysiology of affective illness may lie in irregularities in second messenger and signal transduction pathways; in particular the phosphatidylcholine (PtdCho) and phosphatidylinositol (PtdIno) cycles. Elements of the PthCho and PtdIno cycles are detectable using proton (1 H) and phosphorous (31 P) MRS, in particular choline containing compounds (Cho), myoInositol containing compounds (Ino), phosphomonoesters (PME), phosphodiesters (PDE) and the nucleotide triphosphates (NTPs). Over the five year course of the study 35 subjects with Major Depressive Disorder (MD), 35 subjects with Bipolar I Disorder (BD) and 20 comparison subjects (NC) will be recruited. A priori regions of interest are the anterior cingulate gyrus and the caudate nuclei since functional neuroimaging studies have noted mood state dependent alterations in metabolic activity in these
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regions and preliminary MRS data from these brain regions have demonstrated moodstate, medication, and diagnosis- dependent alterations in Cho, Ino, beta-NTP and PME. In the first two years of funding subjects will be examined using proton echo planar spectroscopic imaging (PEPSI) at 1.5 T. For the final three years of funding subjects will be examined using 1H decoupled 31P MRSI at 4.0 T. The use of PEPSI at 1.5 T and 1H decoupled 31P MRSI at 4.0 T will allow for the acquisition of spectra from smaller regions of interest, such as the anterior cingulate and the caudate, than is possible with older techniques. In addition, PEPSI affords a time advantage which allows for the absolute quantification of the metabolites detected. All subjects will be examined on two occasions six weeks apart and the following hypotheses will be tested: Increased right cingulate cortex Cho will be associated with depression. A decrease in the left cingulate cortex Cho will occur as a result of antidepressant treatment. Decreased right cingulate cortex Ino will be associated with depression. Decreased caudate nucleus beta-NTP will be associated with depression. An increase in caudate nucleus PME will occur as a result of lithium treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MAINTENANCE THERAPIES IN BIPOLAR DISORDERS Principal Investigator & Institution: Frank, Ellen; Professor; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 01-JUN-1977; Project End 30-NOV-2002 Summary: The primary goal of this investigation is to examine the additive prophylactic potential of an individual psychotherapy based on interpersonal and social rhythm principles in bipolar I patients maintained on lithium carbonate. An adaptation of maintenance interpersonal psychotherapy, this intervention takes into account the specific vulnerabilities, symptoms, and interpersonal problem areas associated with bipolar disorder. Acutely ill patients in a manic or depressed episode are randomly assigned to either individual psychotherapy or medication clinic visits in addition to appropriate pharmacotherapy. Patients who stabilize (HRSD and Bech- Rafaelsen < 7 for four weeks) are then randomly assigned to preventative treatment with either individual psychotherapy or medication clinic visits in addition to pharmacotherapy. Thus, patients in this study will receive one of four possible treatment strategies: 1) preliminary phase psychotherapy followed by preventative phase psychotherapy; 2) preliminary phase medication clinic visits followed by preventative phase medication clinic visits; 3) preliminary phase psychotherapy followed by preventative phase medication clinic visit; or 4) preliminary phase medication clinic visits followed by preventative phase psychotherapy. Those patients who experience a relapse (during the initial twelve weeks of the preventative phase) or a recurrence (after week 12 of the preventative phase) will be treated with appropriate pharmacotherapy and continued in psychotherapy or medication clinic visits as dictated by their original randomization assignment. These patients will then be followed for the remainder of what would have been their time in the protocol had they remained well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MBRS/SCORE PROGRAM AT FISK UNIVERSITY Principal Investigator & Institution: Collins, Warren E.; Biology; Fisk University Nashville, Tn 372083051 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 29-SEP-2005
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Summary: The long term objective of the MBRS SCORE Program at Fisk University is to enhance the research environment at the university and encourage more minority faculty participation in biomedical research. Participating faculty propose to contribute to the solution of health related issues by performing research in six different areas. The projects will address the following: (1) Effect of lead on cognitive defects with specific emphasis on serotonin receptors; (2) Effects on lead on cognitive defects with specific emphasis on serotonin receptors; (2) Efforts to develop a mathematical model for tracheal gas insufflation; (3) Evaluate the performance of a series of porous glass ceramics on enzyme carriers, and to study the utilization of those materials to immobilize enzyme; (4) Development of an analytical procedure, Atomic force Microscopy, for high-resolution atomic imaging of biological samples; (5) the use of Lithium dialkylamides and their mixed aggregates to serve as intermediates in the generation of aldehydes, ketones, and esters, a major organic problem in drug synthesis, and (6) to determine if the difference in Raman spectra between epithelial cells and mesothelial derived blood cells are sufficiently great to allow reliable differentiation between them using Raman spectra. We specifically aim to increase the number of faculty who are performing health related research funded by external sources, stimulate/create a research infrastructure and environment in the university campus with the aim in mind to stimulate more students and other faculty persons to enter biomedical sciences research, and to contribute to the biomedical sciences literature sciences literature in the research areas stated above. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF RENAL TUBULAR CELL INJURY Principal Investigator & Institution: Schwartz, John H.; Professor; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 01-JUL-1998; Project End 31-MAY-2006 Summary: (provided by applicant): Goals: The overall goals of this application are to examine the role of a the 13-catenin-Lef signaling pathway in contributing to the alterations in gene expression associated with acute renal injury and to elucidate the role of this pathway in modulating events associated with recovery of renal function. Specific aims Each specific aims will test one of three interrelated hypotheses: Specific aim 1: To test the hypothesis that ATP depletion-repletion activates the Beta-catenin Lef pathway in cultured proximal tubular cells. Specific aim 2: To examine our hypothesis that ATP depletion-repletion results in beta-catenin-Lef mediated activation of gene expression. Specific aim 3: To test our hypothesis that the Beta-catenin-lef-1 pathway alone or in association with NF-kappB inhibits apoptosis induced by ATP depletionrepletion. Long-term goals: To elucidate the mechanisms involved in the process of recovery and repair from acute renal failure (ARF). Significance: Elucidation of the mechanisms involved in recovery and repair may lead to insight that facilitate the development of therapeutic interventions that promote recovery from ARF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MEDICATIONS IN PREGNANCY: DEFINING EXPOSURE Principal Investigator & Institution: Stowe, Zachary N.; Associate Professor and Director; Psychiatry and Behavioral Scis; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 21-SEP-2002; Project End 31-JUL-2007
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Summary: (provided by applicant): This is an application for RFA-OD-02-002 to fund a Specialized Center of Research on Sex and Gender Factors Affecting Women's Health representing the collaborative efforts of five departments and two academic institutions. The central theme of the application is "pharmacokinetic, pharmacodynamic, and pharmacogenetic (PK/PD/PG) modeling of anti-epileptic drugs (AED) and psychotropic medications during pregnancy and lactation using both human and rodent paradigms: defining fetal/neonatal exposure and influence on obstetrical outcome" ' The primary objectives of the center include: 1) PK/PD/PG modeling of anti-epileptic drugs (AED) and psychotropic medications antidepressants, lithium) during pregnancy and lactation. These novel data will provide information about the metabolism, distribution, and extent of fetal/neonatal exposure to these medications. The data for this modeling will be obtained from women with neurological disorders (Epilepsy, Tourette's Syndrome) and mental illness (Bipolar Disorder, Major Depression, Obsessive Compulsive Disorder, Panic Disorder). These patient populations were selected based on the typical chronic course of illness and utilization of similar medications between the groups. The PK/PD modeling from subjects with different illnesses and ethnic groups enhances the pharmacogenetic (PG) comparison of metabolic capacity and protein binding. 2) These clinical data will be complemented by a series of laboratory animal studies in two strains of rodent (one deficient in 2D6 activity) to provide fetal and neonatal central nervous system (CNS) tissue concentrations, neonatal CNS clearance, and neurotransmitter receptor effects of antenatal and postnatal exposure to AEDs and psychotropic medications. 3) Prospective assessment of these women will provide documentation of all additional exposures (prescription medications, over the counter preparations, herbal remedies, maternal illness events, environmental toxins) and delineation of the course of illness during pregnancy and postpartum. The ultimate clinical import of these data will be clarification of the factors influencing medication metabolism and distribution, thereby providing an estimate fetal/neonatal exposure, factors influencing such exposure, and novel data regarding the potential "dose versus outcome" comparison. The multidisciplinary team of this center application represent two academic medical centers and five departments organized into 2 clinical projects, 1 laboratory investigation, supported by 3 core components and an executive committee with extensive research/clinical experience. The achievement of the objectives address several research priority areas noted in ORWH Agenda for Research on Women's Health for the 21st century. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AVERSION
MOLECULAR
MECHANISMS
OF
CONDITIONED
TASTE
Principal Investigator & Institution: Houpt, Thomas A.; Assistant Professor; Biological Science; Florida State University 97 South Woodward Avenue Tallahassee, Fl 323064166 Timing: Fiscal Year 2001; Project Start 01-AUG-1996; Project End 30-NOV-2004 Summary: Conditioned taste aversion (CTA) is a form of associative learning in which an animal avoids and reacts aversively to the taste of a food that has previously been paired with illness. CTA has been described in many species, from invertebrates to humans, and has important implications in drug and radiation therapies. It is also a model for altered responsiveness in ingestive behaviors, as in eating disorders. We have discovered that the induction of the immediate-early gene c-Fos by intraoral infusion of sucrose in the medial intermediate region of the nucleus of the solitary tract (iNTS) and the central nucleus of the amygdala (CeA) in the rat appears to be a specific and quantifiable neuronal correlate of the expression of a CTA previously acquired by
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pairing intraoral infusions of sucrose with lithium chloride. We hypothesize that cFos expression reveals functionally important brain sites mediating CTA, and that the time course of CTA consolidation and c-Fos expression in some of these sites reveals the time and place of gene expression that mediates CTA learning. We will make fiber-sparing, excitotoxic lesions of brain sites that express c-Fos after CTA acquisition and expression. Alterations in CTA induced by lesions will be measured by quantifying intake, taste reactivity, and c-Fos expression. We will quantify the time course of consolidation of long-term CTA memory, and determine the critical period of gene expression required for consolidation with site-specific injections of protein synthesis inhibitors. We will then use single-cell antisense RNA amplification to identify the neurochemical phenotype and gene expression profile of c- Fos-positive cells in critical brain sites at critical times of consolidation. This proposal presents a novel approach to CTA by correlating the effects of fiber-sparing lesions on behavior with effects on the pattern of c-Fos expression, and by examining molecular correlates of the transition from shortterm to long-term memory in CTA learning. These experiments will contribute to an understanding of the neural pathways and molecular mechanisms underlying changes in food preferences that occur in eating disorders such as obesity and anorexia nervosa. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR TARGETS OF LITHIUM AND VALPROATE Principal Investigator & Institution: Greenberg, Miriam L.; Professor; Biological Sciences; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2001; Project Start 01-MAY-1997; Project End 28-FEB-2005 Summary: Adapted from applicant's abstract): Bipolar affective disorder is a severe, chronic and disabling illness that affects 1-2 percent of the population and is a leading cause of hospitalization. Recurring bouts of mania and depression devastate family relationships and impair career progress. Approximately 15 percent of affected people commit suicide. Only two drugs are currently approved by the FDA for treatment of this disorder, lithium and valproate. While lithium has revolutionized the treatment of bipolar disorder and remains one of psychiatry's most important therapies, 20-40 percent of all patients fail to show an adequate antimanic response to lithium. Similarly, valproate has limited efficacy. There is evidence that lithium and/or valproate affect the phosphoinositide second messenger signal transduction system, protein kinase C, glycogen synthase kinase, transcription activation by AP-1, and B-cell Iymphoma protein 2 (bc1-2). However, the therapeutic mechanisms of action of these drugs have not been elucidated. Although lithium and valproate are structurally dissimilar and may not exert their effects in exactly the same manner, identification of genes regulated by both drugs may provide insight into common mechanisms of action. We are utilizing the yeast model system to elucidate molecular mechanisms of action common to lithium and valproate. Yeast is currently the only eukaryote in which we can combine genetic, molecular, and functional genomic approaches to identify lithium and VPA targets. We have identified genes that are affected by both lithium and valproate in pathways for phosphoinositide metabolism (INOI and IN02), secretion and exocytosis (SEC14 and SCS2), fatty acid metabolism (PDC5), and transcription activation (DOT6). The goal of the proposed experiments is to determine how lithium and valproate affect activity and expression of these genes. The specific aims are: 1) Targets in inositol metabolic pathway: Determine how lithium and valproate affect expression of INOI and other genes regulated by the transcriptional activator IN02. 2) Targets in other pathways that are affected by inositol: Characterize lithium and valproate targets in secretion, the unfolded protein response, fatty acid synthesis and transcription activation. 3) Targets
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not affected by inositol: Genome-wide expression analysis to identify all yeast genes regulated by lithium and valproate. Ultimately, an understanding of target gene function may provide insight into the molecular basis of the disease process, and may assist in the identification of biochemical and/or genetic predictors of drug responsiveness. The yeast model system may also be utilized in future testing of safer and more effective treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MUTATION STUDY OF NA+ BINDING SITE OF THROMBIN Principal Investigator & Institution: Di Cera, Enrico; Professor; Biochem & Molecular Biophysics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 01-APR-1997; Project End 31-MAR-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEURAL MECHANISMS OF EXTINCTION Principal Investigator & Institution: Mickley, G A.; Professor and Chair; Psychology; Baldwin-Wallace College 275 Eastland Rd Berea, Oh 44017 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2003 Summary: (provided by the applicant): Broad, long-term objective: To determine the neural substrate of the learning and extinction of a conditioned aversion. Evidence suggests that the expression of c-Fos produced by the immediate-early gene (lEG) c-fos may not only mediate sensory experience but may also be instrumental in the formation of conditioned taste aversions (CTAs). The proposed work combines behavioral and immunohistochemical techniques in order to explore the role of this LEG in learning and extinction. Background: While a great deal of effort has gone into discovering the means by which the brain remembers new information, relatively little work has addressed the processes by which the brain discards or discounts less useful data. It is uncertain whether the process of extinction represents an "unlearning" of material or if it is an acquisition of new information suggesting that the old material, while retained, is no longer useful and should therefore be ignored. There is empirical evidence on both sides of this issue. Methods and Objectives: We will create CTAs in rats by pairing the taste of saccharin (SAC; CS) with an i.p. injection of Lithium Chloride (L1C1; US). Later, some animals will receive extinction trials (i.e., given access to the SAC solution without the LiC1). Additional conditioned, yoked controls and explicitly unpaired CS-US yoked controls will not receive extinction trials. When subjects in the CTA/extinction group have reach pre-specified criterion of saccharin consumption, these subjects and their yoked controls will be perfused and their brains prepared for c-Fos immunohistochemistry. The objectives of the proposed work include: (1) Identifying brain areas important in the acquisition and extinction of a CTA as well as in the sensation of the CS and US; (2) Documenting the relationship between CTA acquisition/extinction and c-Fos protein expression in the brain; (3) Discovering the dynamic changes in neural activity that accompany the stages of extinction; and (4) Gaining insights into whether CTA extinction is a "forgetting" of information (i.e., fading of memory CS = illness), a "reversal" of conditioning (i.e., unlearning of CS = illness) or the acquisition of additional information (i.e., CS = safety in certain contexts). Will extinction of the CTA reverse the pattern of c-fos expression seen in conditioned animals? Alternatively, will the brain nuclei originally expressing c-fos continue to do so? What additional brain areas become active during different stages of extinction?
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What is the correlation between behavioral indicators of learning/extinction and c-fos expression in various brain nuclei known to be involved in CTA memory? Health relatedness: This project will reveal some of the neural mechanisms of learning and memory and therefore will advance the development of treatments for various neurological disorders, deficits in extinction (e.g., posttraumatic stress disorder) and conditioned aversions associated with cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEURAL DEVALUATION
SUBSTRATES
OF
DRUG-INDUCED
REWARD
Principal Investigator & Institution: Baldwin, Anne E.; Neural and Behavioral Sciences; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006 Summary: (provided by applicant): Rats will suppress intake of a saccharin solution that predicts either passively administered or self-administered drugs of abuse. For many years it was believed that drugs of abuse were actually producing a conditioned taste aversion, similar to that induced by lithium chloride. However there is substantial evidence to suggest that the suppressive effects of drugs of abuse are actually caused by a devaluation of the natural reinforcer in anticipation of the more potent drug reward--a reward comparison (Grigson, 1997). Little is known about the neural substrates involved this phenomenon, however recent studies have shown that lesions of the gustatory thalamus disrupt the suppressive effects of passively administered cocaine or morphine. Additionally, the classical conditioning involved in reward comparison suggests the involvement of the amygdala, a region thought to be important for both appetitive and aversive associative learning. The involvement of this region is also supported by anatomical findings of a strong projection from the gustatory pathway to the central nucleus of the amygdala. Using lesion techniques, the proposed experiments will examine the contribution of the gustatory thalamus and central nucleus of the amygdala to the suppressive effects of drugs of abuse (Specific Aim 1). The neurochemical basis of these contributions will then be examined via microinfusion techniques (Specific Aim 2). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEURONAL MEDIATION OF ETHANOL INDUCED TASTE AVERSIONS Principal Investigator & Institution: Thiele, Todd E.; Alcoholism and Drug Abuse Inst; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 30-JUN-2001 Summary: The applicant of this award is an experience animal behavior research scientist who has studied the properties or alcohol using several behavioral paradigms. His immediate career goal is to go beyond the behavioral analysis of alcohol-related behaviors and begin a career investigating the biological mechanisms involved in determinants of risk for alcohol abuse. The training program outlined in this grant would be critically important for allowing the applicant to reach his goals by providing him with a unique set of skills for examining the anatomy and molecular physiology of neuronal pathways involved in alcohol's aversive effects and how these interact with earning to influence alcohol-seeking behavior. As a result, he will develop a scientific identity which will make him a truly competitive behavioral neuroscientist as he seeks his long-term career goal of obtaining an academic faculty position. The training environment at the University of Washington includes laboratories and faculty in the
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Departments of Psychology and Psychiatry. In addition to courses and technical training, a steering committee will provide the applicant with regular input and feedback throughout the project. The hypotheses outlined in the present proposal are designed to examine the neurochemical pathways that mediate the aversive properties to alcohol and alcohol-induced conditioned taste aversions (CTA). Previous research, using cFos-like immunoreactivity (cFLI) as an indication of cellular activation, has shown that the brainstem regions thought to be involved in taste aversion learning (particularly, the nucleus of the solitary tract (NTS)) are activated by alcohol and by tastes that have been paired with this drug. Proposed experiments are designed to assess the following questions about the cellular activity in the brainstem associated with alcohol administration and CTA expression: A) What are the sources of neuronal input to the brainstem which cause this cellular activation and which may mediate taste aversion learning? To examine this question, electrolytic lesions will be made in specific brain regions and subsequent effects on cFLI in the NTS and CTA acquisition/expression will be assessed. B) What is the neurochemical phenotype of cells in the brainstem that are activated by alcohol and by tastes paired with alcohol? Double-labeling-procedures with in situ hybridization histochemistry and immunohistochemistry will be used to examine this question. And C), What neurotransmitters and receptors are responsible for mediating this cellular activity in the NTS, and are these neurotransmitter systems involved with taste aversion learning? This question will be addressed by using specific receptor antagonists and receptor autoradiography. A better understanding of the neuronal mechanisms that underlie the aversive effects associated with ethanol may allow one to more accurately predict the predisposition towards alcoholism, and may be useful for the development of pharmacological treatments targeted at preventing alcohol abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NMR AND FLUORESCENCE STUDY OF LI+ INTERACTIONS IN CELLS Principal Investigator & Institution: Mota De Freitas, Duarte E.; Professor; Chemistry; Loyola University of Chicago Chicago, Il 60611 Timing: Fiscal Year 2001; Project Start 01-SEP-1990; Project End 31-JUL-2004 Summary: Lithium salts continue to be the most promising drugs in the treatment of acute episodes and the prevention of relapses in patient suffering from manic depression or bipolar illness. Even though lithium salts have been used clinically in the treatment of bipolar patients for fifty years, their pharmacologic mode of action is unclear. The main goals of the research proposed in this applications are: (i) to advance the understanding at the molecular and cellular levels of the pharmacologic action of the Li+ ion in the treatment of bipolar disorder by analyzing the binding and transport properties of Li+, Mg2+ ions in human neuroblastoma and lymphoblatoma cells, and in purified wild-type and mutated guanine nucleotide-binding (G) proteins by using nuclear magnetic resonance (NMR) spectroscopy, and fluorescence spectroscopy and imaging; and (ii) to test the application of these spectroscopic and imaging methods to the identification of bipolar patients who are likely to respond to lithium treatment or are most susceptible to experiencing lithium toxicity. The proposed spectroscopic and imaging methods will test two interrelated mechanisms of actions Li+: a cell membrane abnormality, and a competition mechanism between Li+ and Mg2+ ions for membrane binding sites (in particular, anionic phospholipids and the metal-binding domain of G proteins). Our preliminary studies with cultured cells and G proteins indicate that the spectroscopic and imaging methods proposed in this study provide new information on
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Li+ interactions with cell components; this new information could not have been obtained with other techniques routinely used for Li+ analysis. In addition to contributing to an advancement of the understanding at the molecular and cellular levels of the pharmacologic action of the Li+ ion in the treatment of bipolar illness, the results of this study may also be useful in the diagnosis and prognosis of bipolar patients. More precisely defined molecular parameters, such as Li+ binding constants to the lymphoblastoma membranes from bipolar patients and their phospholipid composition, may by useful for predicting the success of Li+ therapy and the likelihood of Li+ toxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL SILICON DETECTORS FOR EXAFT STUDIES Principal Investigator & Institution: Squillante, Michael R.; Vice President of Research; Radiation Monitoring Devices, Inc. 44 Hunt St Watertown, Ma 02472 Timing: Fiscal Year 2001; Project Start 01-SEP-1998; Project End 30-APR-2003 Summary: (Provided by Applicant): The availability of intense sources of synchrotron Xrays has made possible advanced studies of biological materials using the method of Xray absorption spectroscopy (XAS). The advances, both in intensity as well as optics of these sources enables exploition of ultra-dilute spectroscopy and fluorescence QuEXAFS techniques [Farrow]. Current biophysical research utilizing these techniques includes studies of enzyme reactions, hemoglobin, and general study of metabolic processes. In these biological XAS studies, the experiments are now mostly limited by the X-ray detectors because they are not able to take full advantage of the available X-ray flux. Central to the design of modern XAS instrumentation is a very low noise X-ray detector, which must detect the fluorescence X-rays from the samples. It is important for the detector to operate with very high energy resolution and maintain that resolution at very high count-rates. Currently, germanium and lithium drifted silicon are the most popular detectors for XAS and EXAFS studies. Both these detector systems, while capable of excellent energy resolution, have some limitations. Si(Li) detectors have relatively high capacitance for larger sizes which increases their noise when operated at fast integration times. For High purity germanium (HPGe) detectors, the presence of Ge Ka fluorescence (9.876 keV) and the associated escape peaks in energy range of interest compromises the EXAFS data collection for hard X-ray experiments. In order to overcome these limitations, we propose to investigate a novel low capacitance detector design with high purity silicon as the detector material. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OLFACTORY NEURONS FROM BIPOLAR PATIENTS Principal Investigator & Institution: Hahn, Chang-Gyu G.; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 23-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant) This proposal seeks a structured research training program, which will enable Chang-Gyu Hahn. M.D. Ph.D. to become an independent investigator as he demonstrates the utility of olfactory receptor neurons (ORNs) to examine the neurobiology underlying bipolar disorder. Career Goals and Objectives: With the career goat of being able to apply the most advanced molecular techniques to clinically relevant research paradigms through the ORN system, he proposes a career development plan focusing on following areas. 1) ionic imaging and the neurobiology of the human ORN system and 2) Single cell antisense RNA amplification technique.
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Career Development Activities: The candidate will receive specialized training in ionic imaging in human olfactory neurons (guided by Nancy Rawson, PILD, co-mentor) and in single cell molecular technique (supervised by James Eberwine, Ph.D., co-mentor). Dr. Karl Rickels will provide individual supervision for the treatment outcome study component of the specific aim 2. Dr. Robert H. Lenox will oversee the career development program through integrating formal courses, lab meetings and supervisions. Background: ORNs, the only CNS neurons that are obtainable through olfactory epithelial biopsy, provide a unique opportunity to investigate molecular events in neurons from living subjects. By obtaining ORNs during specific stages of the illness, in conjunction with a longitudinal follow-up of patients, pathophysiologic significance of molecular events in neurons can be linked to bipolar disorder. Hypothesis: Our preliminary data suggest that intracellular calcium responses to odbrants are altered in bipolar disorder. I) Intracellular calcium responses of ORNs to odorants are predominantly a decrease as a trait of bipolar disorder. 2) The decreased ICa responses in ORNs from bipolar patients are due to altered expression of the genes that are involved in calcium flux. 3) The percentage of ORNs that respond to odorant stimulation is overall decreased following lithium treatment. 4) ORNs in explant cultures from bipolar patients will show similar ICa responses as in vivo ORNs of patients. Specific Aims: 1) To characterize trait- and mood state- dependent alterations in ICa homeostasis and gene regulation in ORNs from bipolar patients. 2) To identify therapeutically relevant changes in ICa homeostasis following lithium treatment. 3) To characterize ORN cultures from bipolar patients using odorant induced ICa responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OMEGA-3 FATTY ACIDS IN BIPOLAR DISORDER PROPHYLAXIS Principal Investigator & Institution: Stoll, Andrew L.; Assistant Professor; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-JUL-2003 Summary: The purpose of the proposed clinical trial is to assess the efficacy of omega-3 fatty acids (03FA) in preventing recurrence in patients with bipolar disorder, type 1. Omega-3 fatty acids from fish oil (a mixture of docosahexanoic (DHA) and eicosapentanoic (EPA) acids), are polyunsaturated lipids which inhibit intracellular signal transduction in a manner comparable to lithium and divalproex, 2 drugs with efficacy in bipolar disorder. An initial 4 month, double-blind, placebo-controlled, addon study of 03FA treatment in 30 recently ill bipolar patients revealed that the omega-3 treated group had a significantly greater duration of remission compared to the placebo group (p = 0.002 Mantel-Cox). 03FA are non-toxic, essential dietary lipids, and there were few side-effects to the 03FA treatment. This initial indication of efficacy, combined with the need for safe and effective prophylactic treatments for bipolar disorder, warrant undertaking a larger and more rigorously designed 1-year prophylactic study, to be completed over a 3-4 year funding period. In the proposed 2-site primary study, 120 outpatients with bipolar disorder, type I, will be randomly assigned to receive addon treatment with 03FA or placebo, for one year. The primary goal of this study is to assess the prophylactic effects of 03FA in a cohort of bipolar patients with a relatively high risk of recurrence. In contrast to the pilot study, the proposed trial will tightly control the baseline clinical state and concurrent pharmacotherapy of the subjects to provide a more homogeneous bipolar population. This will be accomplished through a lead-in and stabilization phase where patients will be gradually shifted to receive a standardized regimen (lithium or divalproex). Only subjects who are euthymic or subsyndromal at the end of the lead-in period will be eligible for the 1-year prophylactic
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study. The following biological markers will be examined as measures of compliance with the study protocol and/or as possible predictors of response to 03FA: 1. Plasma and erythrocyte fatty acid content. 2. The niacin skin patch test (a possible marker of in vivo omega-3 fatty acid activity). 3. Preliminary development of methods to noninvasively measure the 03FA content in brain using C13 magnetic resonance spectroscopy. If 03FA are indeed effective mood stabilizers for bipolar disorder, this project would provide additional evidence of aberrant signal transduction mechanisms in the pathophysiology of bipolar disorder, and may herald the advent of a new class of rationally designed mood stabilizing drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OPTIMIZATION OF ELECTROCONVULSIVE THERAPY Principal Investigator & Institution: Isenberg, Keith E.; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 05-FEB-2001; Project End 31-JAN-2006 Summary: (Adapted from Applicant's Abstract): Patients treated with electroconvulsive therapy typically present with the most severe forms of major depression. Likely due to the increasing representation of medication-resistant patients, ECT response rates have diminished relative to earlier decades. This diminished response rate and early relapse following response are critical clinical problems in the use of ECT. Using the CSMD mechanism, this project addresses two key issues in the optimization of ECT in patients with major depression: whether patients treated with ECT should receive concurrent treatment with antidepressant medications (to enhance ECT outcome and/or prevent early relapse) and the role of electrode placement (high dosage right unilateral (RUL) ECT versus low dosage bilateral (BL) ECT) in maximizing short-term response and minimizing side effects. Patient enrollment, treatment, and evaluation will be conducted at Wake Forest University, Washington University, and the Western Psychiatric Institute and Clinic, with staff at the New York State Psychiatric Institute responsible for study coordination and monitoring. The study uses a random assignment, double-masked, parallel group design with two phases. In Phase 1, stratified by the classification of medication resistance, patients are randomized to concurrent treatment with nortriptyline (NT, n=210], venlafaxine (VEN, n=210) or placebo (PL, n=210), and simultaneously to high dosage (6 times threshold) RUL ECT (n=315) or low dosage (1.5 times threshold) BL ECT (n=315). Based on substantial preliminary data, the hypotheses will be tested that (1) compared to PL, concurrent NT or VEN results in superior symptomatic response, without a meaningful difference in side effects, and (2) RUL and BL ECT are equal in efficacy, but with significant advantages to high dosage RUL ECT in the magnitude of short- and long-term cognitive side effects. Support for these hypotheses in a large and diverse sample should have widespread ramifications for clinical practice. In the Phase 2 double-masked, 6-month continuation trial, remitters who received PL during ECT are randomized to NT and lithium (LI) or to VEN-LI. Patients who had been randomized to concurrent NT or VEN during ECT receive continuation treatment with NT-LI or VEN-LI, respectively. Standard practice involves the discontinuation of antidepressant medications prior to ECT, the abrupt discontinuation of ECT upon response, and then a switch to continuation pharmacotherapy. This practice likely diminishes response to ECT and heightens relapse in the first several weeks following ECT. Phase 2 of this study, centering on the comparison of patients treated with an antidepressant medication (NT or VEN) or placebo during ECT, will provide the very first data on whether starting an
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antidepressant medication from the beginning of the ECT course reduces the rate of early relapse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC BIPOLAR COLLABORATIVE MOOD STABILIZER TRIAL Principal Investigator & Institution: Scheffer, Russell E.; Psychiatry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: (Adapted from Applicant's Abstract): Bipolar disorder (BPD) in children and adolescents is increasingly recognized as a common and virulent disorder, but evidencebased treatment approaches are lacking. This revised, proposed study develops evidence to address this significant knowledge gap, and helps to develop more empirically based treatments of child and adolescent BPD. This three-site, collaborative treatment study proposes to evaluate the acute phase, comparative efficacy of two mood stabilizers, lithium (LI) and divalproex sodium (DVP) versus placebo (PBO) in outpatient children and adolescents with symptomatic, nonpsychotic BPD I in the mixed or manic phase. Investigators at 3 sites (UTSW, Case Western Reserve & Univ. of Cinn.) will randomize 150 patients over 3 years. To our knowledge, this represents the first randomized, controlled the comparing the efficacy of each mood stabilizer versus placebo in this population. This will be accomplished by randomly assigning subjects in a double-blinded fashion to 8 weeks of treatment with either LI, DVP, or PBO. The primary aim of this project is to compare the efficacy of LI, DVP, and PBO in the acute phase treatment of symptomatic bipolar I disorder, in children and adolescents ages 8-17 yr. Our hypothesis is that differential efficacy will be observed with the following predicted order of response: DVP equals LI > PBO. The secondary aims are: 1)To provide descriptive data and effect size estimates of combined treatment with LI and DVP in patients who do not respond acutely to either one alone; 2) To collect systematic safety data on the incidence of weight gain, polycystic ovaries, and hyperandrogenism, in bipolar adolescent females treated with LI, DVP, or LI + DVP; 3) To collect data on possible predictors of acute treatment response to the two active treatments; 4) To provide descriptive information on the stability of acute phase response to monotherapy with either LI or DVP over 16 weeks of continuation phase treatment. We will systematically collect data concerning the short- and long-term safety and tolerability of mood stabilizers in children and adolescents. No studies have looked at the question of weight gain, polycystic ovaries, and endocrine abnormalities in female bipolar adolescents treated with mood stabilizers. Because of the frequent use of mood stabilizers in bipolar adolescents, this is an important area to systematically collect prospective data on. We will also be able to provide descriptive data and effect size estimates of combined treatment with LI and DVP in patients who do not respond acutely to either one and collect data on possible predictors of acute treatment response to the two active treatments. Lastly, this trial will provide descriptive information on the stability of acute phase response to monotherapy over a 16 week continuation phase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC BIPOLAR COLLABORATIVE MOOD STABILIZER TRIALS Principal Investigator & Institution: Kowatch, Robert A.; Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229
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Timing: Fiscal Year 2001; Project Start 07-SEP-2000; Project End 31-AUG-2004 Summary: (Adapted from Applicant's Abstract): Bipolar disorder (BPD) in children and adolescents is increasingly recognized as a common and virulent disorder, but evidencebased treatment approaches are lacking. This revised, proposed study develops evidence to address this significant knowledge gap, and helps to develop more empirically based treatments of child and adolescent BPD. This three-site, collaborative treatment study proposes to evaluate the acute phase, comparative efficacy of two mood stabilizers, lithium (LI) and divalproex sodium (DVP) versus placebo (PBO) in outpatient children and adolescents with symptomatic, nonpsychotic BPD I in the mixed or manic phase. Investigators at 3 sites (UTSW, Case Western Reserve & Univ. of Cinn.) will randomize 150 patients over 3 years. To our knowledge, this represents the first randomized, controlled the comparing the efficacy of each mood stabilizer versus placebo in this population. This will be accomplished by randomly assigning subjects in a double-blinded fashion to 8 weeks of treatment with either LI, DVP, or PBO. The primary aim of this project is to compare the efficacy of LI, DVP, and PBO in the acute phase treatment of symptomatic bipolar I disorder, in children and adolescents ages 8-17 yr. Our hypothesis is that differential efficacy will be observed with the following predicted order of response: DVP equals LI > PBO. The secondary aims are: 1)To provide descriptive data and effect size estimates of combined treatment with LI and DVP in patients who do not respond acutely to either one alone; 2) To collect systematic safety data on the incidence of weight gain, polycystic ovaries, and hyperandrogenism, in bipolar adolescent females treated with LI, DVP, or LI + DVP; 3) To collect data on possible predictors of acute treatment response to the two active treatments; 4) To provide descriptive information on the stability of acute phase response to monotherapy with either LI or DVP over 16 weeks of continuation phase treatment. We will systematically collect data concerning the short- and long-term safety and tolerability of mood stabilizers in children and adolescents. No studies have looked at the question of weight gain, polycystic ovaries, and endocrine abnormalities in female bipolar adolescents treated with mood stabilizers. Because of the frequent use of mood stabilizers in bipolar adolescents, this is an important area to systematically collect prospective data on. We will also be able to provide descriptive data and effect size estimates of combined treatment with LI and DVP in patients who do not respond acutely to either one and collect data on possible predictors of acute treatment response to the two active treatments. Lastly, this trial will provide descriptive information on the stability of acute phase response to monotherapy over a 16 week continuation phase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC BIPOLAR COLLABORATIVE MOOD STABILZER TRAIL Principal Investigator & Institution: Findling, Robert L.; Director; Psychiatry; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: (Adapted from Applicant's Abstract): Bipolar disorder (BPD) in children and adolescents is increasingly recognized as a common and virulent disorder, but evidencebased treatment approaches are lacking. This revised, proposed study develops evidence to address this significant knowledge gap, and helps to develop more empirically based treatments of child and adolescent BPD. This three-site, collaborative treatment study proposes to evaluate the acute phase, comparative efficacy of two mood stabilizers, lithium (LI) and divalproex sodium (DVP) versus placebo (PBO) in outpatient children and adolescents with symptomatic, nonpsychotic BPD I in the mixed or manic phase. Investigators at 3 sites (UTSW, Case Western Reserve & Univ. of Cinn.)
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will randomize 150 patients over 3 years. To our knowledge, this represents the first randomized, controlled the comparing the efficacy of each mood stabilizer versus placebo in this population. This will be accomplished by randomly assigning subjects in a double-blinded fashion to 8 weeks of treatment with either LI, DVP, or PBO. The primary aim of this project is to compare the efficacy of LI, DVP, and PBO in the acute phase treatment of symptomatic bipolar I disorder, in children and adolescents ages 8-17 yr. Our hypothesis is that differential efficacy will be observed with the following predicted order of response: DVP equals LI > PBO. The secondary aims are: 1)To provide descriptive data and effect size estimates of combined treatment with LI and DVP in patients who do not respond acutely to either one alone; 2) To collect systematic safety data on the incidence of weight gain, polycystic ovaries, and hyperandrogenism, in bipolar adolescent females treated with LI, DVP, or LI + DVP; 3) To collect data on possible predictors of acute treatment response to the two active treatments; 4) To provide descriptive information on the stability of acute phase response to monotherapy with either LI or DVP over 16 weeks of continuation phase treatment. We will systematically collect data concerning the short- and long-term safety and tolerability of mood stabilizers in children and adolescents. No studies have looked at the question of weight gain, polycystic ovaries, and endocrine abnormalities in female bipolar adolescents treated with mood stabilizers. Because of the frequent use of mood stabilizers in bipolar adolescents, this is an important area to systematically collect prospective data on. We will also be able to provide descriptive data and effect size estimates of combined treatment with LI and DVP in patients who do not respond acutely to either one and collect data on possible predictors of acute treatment response to the two active treatments. Lastly, this trial will provide descriptive information on the stability of acute phase response to monotherapy over a 16 week continuation phase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHARMACOTHERAPY OF HIGH-RISK BIPOLAR DISORDER Principal Investigator & Institution: Oquendo, Maria A.; Associate Clinical Professor; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 30-JUN-2005 Summary: (Adapted from the Applicant's Abstract): This R01 application, based at New York State Psychiatric Institute (NYPSI) requests five years of support for a prospective, parallel group, double blind, random assignment treatment study of high-risk (previous suicide attempters) patients with Bipolar Disorder, who are in a mixed or depressed phase. This study will compare the effects of acute and maintenance treatment with lithium and valproate in the prevention of suicidal behavior in these subjects. Subjects (N=280) will be well characterized in terms of Axis I and II diagnosis, psychopathology (measures of suicidal behavior including ideation and acts) and aggression and impulsivity. This study will have three distinct phases: an acute stabilization phase, a treatment continuation phase and a treatment maintenance phase. Upon study entry, subjects will be randomized to lithium or valproate. Depressed patients will be stabilized using paroxetine (or two other alternative antidepressants) and patients with psychosis or in a mixed state will receive olanzapine (or two other antipsychotics). Up to six months will be devoted to an acute stabilization phase. In the continuation phase subjects will be maintained on lithium or valproate and an antidepressant or antipsychotic for up to 6 months. The acute phase ends when patients have achieved at least two weeks of euthymia. During the 18 months maintenance phase, most subjects will be maintained on mood stabilizer alone. They have operationalized rescue procedures that will be available for patients with a recurrence of an episode. Over the
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course of the study, patients will be assessed for changes in psychopathology, mood symptoms, suicidal behavior, aggressive behavior and substance abuse. They predict that subjects on lithium will have less suicidal behavior, including completion, attempt or hospitalization for suicidal ideation than subjects on valproate and that this effect will be independent of mood stabilization. The project will test the following hypotheses: (1) Lithium treatment will be superior to valproate in the prevention of suicidal behavior (suicidal acts or episodes of suicidal ideation with a plan that would require a change in treatment such as addition of a rescue medication or hospitalization). (2) The two treatment groups will not differ in terms of the total number of episodes of, or total duration in, a major depression or mixed mood states requiring commencement of a rescue medication over 18 months of the maintenance phase. (3) Lithium treatment will be superior to valproate in decreasing aggression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LEARNING.
PHOSPHATASES
IN
CONDITIONED
TASTE
AVERSION
Principal Investigator & Institution: Lockwood, Denesa R.; Biological Science; Florida State University 97 South Woodward Avenue Tallahassee, Fl 323064166 Timing: Fiscal Year 2003; Project Start 23-JAN-2003; Project End 22-JAN-2006 Summary: (provided by applicant): Conditioned taste aversion (CTA), a form of associative learning, is characterized by behavioral changes after the pairing of a novel palatable taste with a toxin (such as lithium chloride, LiCI), resulting in aversive responses to the taste during subsequent presentations. Although much is known about its behavioral characteristics, the molecular mechanisms that underlie CTA learning are not well understood. Much of the work done at the cellular level has concentrated on immediate early genes or transcription factors; less is known about the upstream second messenger cascades that may be involved. There is evidence for critical roles for protein kinase activity in CTA; however, the study of termination of this activity by dephosphorylation has not been examined. Therefore, I will focus on protein phosphatase 1 (PP-I), which dephosphorylates substrates and terminates kinaseinitiated second messenger activation. Of the serine/threonine phosphatases, PP-1 is the most widely expressed and best characterized, with many substrates including glutamate receptors, protein kinases, transcription factors and structural molecules. By controlling the phosphorylation state of its substrates, PP-1 is involved in the regulation of many cellular functions including neurotransmission, dendritic spine physiology and gene transcription. This proposal will examine the role of PP-1 in CTA learning by using pharmacological antagonists to inhibit PP-1 activity and by determining a time course for the phosphorylation of two PP-1 substrates, the NR1 subunit of the NMDA receptor and cAMP response element binding protein (CREB). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHYSIOLOGY OF MALE REPRODUCTIVE HORMONES IN AGING Principal Investigator & Institution: Fox, Christopher R.; Center for Res in Reproduction; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2003 Summary: Testosterone concentrations decline by 1-2% annually as men age, and free testosterone concentrations decline even more rapidly (3-4% per year). Lower serum testosterone concentrations have been associated with important health consequences, including reduced bone mineral density, increased risk of hip fracture, loss of muscle
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mass, decreased libido and fertility, and increased cardiovascular disease. HYPOTHESIS I will test whether glucocorticoids mediate down- regulation of urea transporter proteins by altering transcription. Specific Aim 1 will test whether glucocorticoids down-regulate UT-A and/or UT-B protein or mRNA expression. Specific Aim 2 will determine the element mediating glucocorticoid-induced suppression of urea transporter promoter activity. HYPOTHESIS II will test whether chronic lithium administration down-regulates urea transporter protein(s) by increasing glucocorticoids. Specific Aim 3 will test whether adrenalectomy prevents long-term down-regulation of urea transporter protein(s) in lithium-treated rats. Specific Aim 4 will test whether elevated lithium levels perturb urea transporter phosphorylation or function in rat inner medulla or in EcR-293 cells that have been stably transfected with a specific urea transporter isoform. HYPOTHESIS III will test whether urea transporter proteins are down- regulated during aldosterone-escape. Specific Aim 5 will test whether mineralocorticoids down-regulate UT-A and/or UT-B protein or mRNA expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PKC SIGNALING AND THE TREATMENT OF BIPOLAR DISORDER Principal Investigator & Institution: Kuhn, Donald M.; Professor; Psychiatry & Behav Neuroscis; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 30-JUN-2003 Summary: (Adapted from applicant's abstract): BD, manic-depressive illness is a severe, chronic and disabling disorder with a life-time prevalence of 1.2 percent. The discovery of lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with BD, but, despite its role as one of psychiatry's most important treatments the biochemical basis for lithium's antimanic and mood-stabilizing actions remains to be fully elucidated. Elucidation of the mechanism(s) by which lithium stabilizes an underlying dysregulation of limbic and limbic-associated function also offers the potential to delineate the underlying etiology/pathophysiology of BD. A major problem inherent in neuropharmacologic research, however, is the difficulty in attributing therapeutic relevance to any observed biochemical finding. One potential approach to ascribe therapeutic relevance to any biochemical findings is to identify common biochemical targets which are modified by drugs belonging to the same therapeutic class but possessing distinct chemical structures (e.g., lithium and valproic acid (VPA)). A large body of data has shown that lithium exerts major effects on the PKC signaling pathway. Most of the data, however, has been derived from preclinical rodent studies, thereby precluding an adequate understanding of the therapeutic relevance of these biochemical findings. These studies indicate two important and highly clinically relevant directions for future research: first, it is important to determine if similar modulation of the PKC signaling pathway is also brought about by other pharmacological agents with proven efficacy in the treatment of BD such as VPA; and second, it is critical to ultimately elucidate the relationship between these biochemical changes and clinical response, which may lead to the identification of biochemical and/or genetic predictors of outcome. Thus, in this proposal, the investigator's specific aims are to: 1) Characterize the effects of VPA on the PKC signaling pathway in the brain. In order to ascribe potential therapeutic relevance to the biochemical findings, they will be investigated in parallel with lithium: a) in specific brain regions, and b) in a clinically meaningful temporal profile, namely acutely, chronically, following medication withdrawal, and medication re-administration. 2) Determine the relationship between the lithium or VPA-induced changes in the PKC signaling system in rat brain and in rat peripheral cells; ultimately the investigator wishes to determine
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the relationship between treatment-induced changes in the PKC signaling system and treatment response in BD patients. The demonstration of a relationship between the changes in the CNS and the periphery in rodents will allow for a subsequent investigation in BD patients. This is imperative because, in order to establish therapeutic relevance for any biochemical findings, it is necessary to demonstrate: a) that these biochemical effects do, in fact, occur in patients administered the pharmacological agents in a clinically relevant paradigm; and b) that there is a relationship between the biochemical changes and treatment response. Ultimately, elucidating the mechanisms by which lithium and VPA stabilize mood should improve the prospects for the development of more effective long-term treatments, and for the identification of biochemical predictors of treatment response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PORTABLE DEFIBRILLATOR FUZZY-LOGIC-BASED BATTERY METER Principal Investigator & Institution: Singh, Pritpal; Us Nanocorp, Inc. 74 Batterson Park Rd Farmington, Ct 06032 Timing: Fiscal Year 2002; Project Start 05-JUN-2000; Project End 31-AUG-2004 Summary: (provided by applicant):Reliable operation of a portable defibrillator depends critically on the "condition" of its battery. This condition is determined by available energy and at what power level this energy can be delivered to a load. With the initiative towards widespread deployment of portable defibrillators, a low-cost device capable of accurately measuring both state-of-charge (SOC) and state-of-health (SOH) of batteries used in these devices is necessary to ensure that missed defibrillation attempts due to battery failure are eliminated. US Nanocorp and Villanova University are collaborating in the pioneering development of an innovative, powerful approach, based on fuzzy logic, to battery SOC and SOH determination that is reliable, accurate, and economical. Traditional measures used to determine battery SOC and SOH such as battery voltage, temperature and impedance form a highly complex, nonlinear relationship with SOC/SOH. The fuzzy logic approach offers a relatively simple yet powerful method to easily model such a relationship. The Phase I project proved feasibility of this approach for estimating SOH of lead acid battery packs used in portable defibrillators. In the Phase II project, the fuzzy logic approach will be used to develop a low-cost device that can be incorporated into Li-ion battery packs for next generation portable defibrillators. PROPOSED COMMERCIAL APPLICATION: Production of battery management equipment is an emerging opportunity in a worldwide battery market of $25B, where growth in portable power devices has been increasing at a 20% annual rate. Traditional methods are cumbersome and nongeneric. The proposed fuzzy logic method is very powerful in its efficiency and adaptability to a wide variety of battery chemistries and types. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PRECONCENTRATORS BASED ON SELF-ASSEMBLED REAGENTS Principal Investigator & Institution: Cox, James A.; Professor; Chemistry and Biochemistry; Miami University Oxford 500 E High St Oxford, Oh 45056 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2005 Summary: (provided by applicant): The long-term objective of our program is to develop analytical methods on micromachined platforms for biomedical analytes. The present proposal deals with the separation and preconcentration of selected analytes
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onto reagents that are tethered to gold electrodes or nanoclusters. The tethering is via molecular self-assembly. Fluorogenic crown ethers will be modified with alkanethiol tags and attached to gold by spontaneous formation of the thiolate. Selective uptake of lithium or potassium ion by the crown will provide the separation step. Release of the entire assembly into a flowing carrier solution by oxidation of the thiolate will be one strategy that will allow quantifying the results at a downstream detector. Prior to the next measurement, the assembly will be re-made or a new electrode will be placed in the system. Alternatives of the basic experiment include other combinations of capture reagent and analyte, e.g. a cyclophane and phenylalanine or adrenaline; tethering reagents to gold nanoclusters embedded in a flow-through silica sol-gel electrode; and chemical release that retains the integrity of the self-assembled monolayer on gold. These systems are designed specifically to be integrated with microchip and micromachined platforms to yield Total Analytical Systems. Applications as disposal devices for selective determinations of analytes in blood are envisioned. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROGRAM FOR DEVELOPMENT OF BNCT AGENTS Principal Investigator & Institution: Kahl, Stephen B.; Professor; Pharmaceutical Chemistry; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 28-FEB-2005 Summary: (adapted from applicant's abstract): The long-term goal of this program is the development of tumor seeking boron compounds for use as radiochemotherapeutic agents for boron capture therapy (BNCT) of cancer. BNCT relies on the selective tumor uptake and retention of a non-toxic boron-containing drug followed by irradiation of the rumor region with a beam of very low energy neutrons. Capture of a neutron by a (10)B nucleus causes a prompt fission reaction in which the boron nucleus splits to form an alpha particle, a lithium nucleus and a gamma ray. These fission products deposit most of their substantial energies within one cell diameter and are considered high linear energy (LET) fragments. Binary therapies such as BNCT have the potential to increase local control of cancer by increasing the radiation dose to cancer cells and simultaneously reducing radiation-induced morbidity to surrounding normal tissue and vasculature. The objective of this proposal is to provide over its five year length one or more boronated porphyrins suitable for clinical BNCT application. This highly translational objective is to be accomplished through an integrated program of directed synthesis and a tier protocol of biological and radiobiological pre-clinical testing. In order to meet this goal, three specific aims, relating to structure-activity/toxicity relationships in these compounds are to be addressed. The Principal Investigator and his team will 1) examine several linkage chemistries for attaching closo carboranes in order to reduce toxicity; 2) attach closo polyhedral borane anions to optimize sensitizer pharmacokinetics; and 3) evaluate methods of attaching more than 40 boron atoms per molecule to maximize tumor boron concentration. Synthetic efforts during the first 2-3 years will focus on the synthesis and characterization of boronated porphyrins from each of five basic structural motifs. Initial biological testing of potential candidates in normal rats will establish maximum tolerated dose and histological profiles and will be followed by biodistribution in athymic nude rats bearing an intracerebral glioma. Successful candidates will be further studied in vitro and in BNCT protocols using an accelerator-produced epithermal beam at the Lawrence Berkeley National Laboratory. The proposed syntheses during the last two years will concentrate on compounds having the most promising structural motif.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTON MRSI STUDIES OF BIPOLAR DISORDER Principal Investigator & Institution: Renshaw, Perry F.; Director; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-MAY-2003 Summary: (Verbatim from the Applicant's Abstract) This revised application requests three years of funding to support a research program which employs proton magnetic resonance spectroscopic imaging (MRSI) to evaluate subjects with Bipolar I Disorder and healthy comparison subjects. In pilot studies of individuals with bipolar disorder, we have used 1H MRSI to evaluate brain cytosolic choline levels and, more recently, myo-inositol levels. Both choline and myo-inositol play critical roles in second messenger signaling cascades and recent reviews have suggested that mood stabilizes may demonstrate their clinical effects by altering signal transduction pathways within the brain. Studies will be conducted at two sites, the McLean Hospital Brain Imaging Center in Belmont, MA, and the University of Washington in Seattle, WA. Over the course of this project, a total of 72 subjects with bipolar disorder and 42 comparison subjects will be enrolled and complete repeated MRSI studies. Identical clinical assessments and MRSI protocols will be employed at both sites. Bipolar subjects will be placed on standardized formulations of lithium or valproic acid and will be followed clinically at two week intervals for the ten week duration of the study. By evaluating subjects who are receiving two alternative treatments, we will be able to assess both the shared and unique effects of these pharmacologically effective medications on brain chemistry and the relationship of these effects on mood. Patients with bipolar disorder will be scanned on three occasions at weeks 2,6, and 10 of this study. Mood at time of each scan will be assessed using the Young Mania Rating Scale and the Hamilton Depression Rating Scale. A priori regions of interest for this study will include the bilateral caudate nuclei and the anterior cingulate cortex, as pilot studies suggest that these brain regions demonstrate mood state, medication, and diagnosis dependent alteration in choline and myo-inositol resonance intensities. MRSI data from bipolar subjects will be compared to similar data from 42 healthy comparison subjects. We believe that abnormalities in brain choline and myo-inositol metabolism may, in part, mediate the pathophysiology of abnormal mood in bipolar disorder and that the therapeutic efficacy of lithium may derive from an inhibition of choline transport and/or from changes in myo-inoitol and choline metabolism within the brain. The results of these studies may provide important new insights into the neurochemical alterations which mediate the symptoms of bipolar disorder as well as information relevant to the development of novel therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PSYCHOPHARMACOLOGY OF PEDIATRIC BIPOLAR DISORDER Principal Investigator & Institution: Axelson, David A.; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 01-MAY-2000; Project End 30-APR-2005 Summary: The career development activities and research plan outlined in this Research Career Development Award (RCA) are designed to provide the means for the candidate to translate relevant aspects of neurobiology and independently formulate and implement psychopharmacologic treatment trials in pediatric bipolar disorder (BP). Pediatric BP is a devastating illness that can result in permanent disruption of a child's
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normal development, emotional suffering, aggression and suicide. Pharmacotherapy has been the cornerstone of the management and treatment of pediatric BP. However, there is very little controlled research addressing medication treatment of children and adolescents with BP. In addition, treatment research in child psychiatry has generally not addressed developmental differences in neurobiology or pharmacology, nor attempted to identify biological factors that may be predictors or mediators of treatment response. The proposed study will be the first dose-ranging study of a medication for depression in pediatric BP. It will explore the relationship between platelet 5-HT reuptake blockade and treatment response, as well as examine potential predictors of treatment response. The candidate is certified in child and adolescent psychiatry, and is completing the second year of an NIMH-sponsored post-doctoral research fellowship. Dr. James Perel, Professor of Psychiatry and Pharmacology and Director of the Clinical Pharmacology Program at the University of Pittsburgh's Western Psychiatric Institute and Clinic (WPIC) will serve as Sponsor. The coursework and directed readings in advanced topics of psychopharmacology, clinical trial design, developmental neurobiology and pharmacology, emotional regulation and circadian rhythm, will prepare the candidate to perform biologically-informed treatment research in pediatric BP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REACTIVITY AND SELECTIVITY OF REACTIONS IN POLAR MEDIA Principal Investigator & Institution: Grieco, Paul A.; Professor; Chemistry and Biochemistry; Montana State University (Bozeman) Bozeman, Mt 59717 Timing: Fiscal Year 2001; Project Start 01-JUL-1980; Project End 31-MAR-2003 Summary: The major focus of this grant renewal application is to further examine the reactivity and selectivity of a number of organic reactions in highly polar media such as 3.0-5.0 M lithium perchlorate-diethyl ether with applications to molecules of biological interest. During the course of this investigation we will continue to search for substitutes for lithium perchlorate in ether. In addition we remain focused on anions that are more weakly coordinating than perchlorate. This proposal is divided into three parts. The first section concentrates on studying the reaction of nucleophiles with oxabicyclo[2.2.1]heptanes and oxabicyclo [3.2.1]octanes i highly polar media. All the proposed studies will be of a fundamental nature in order to define the scope, limitations, and mechanism of this potentially very useful new reaction. Applications to the total synthesis of epothilone B, ulapualide A, aplyronine A, morphine, and the C(19)-C(27) aliphatic building block of rifamycin S are proposed. The second part of this grant application focuses on extending the ionic intramolecular Diels-Alder reaction in polar media for the construction of carbocyclic ring systems. Substrates will be examined wherein conformationally restricted tethered dienes are attached to the alpha, beta, and delta carbon atoms of the dienophiles. Application to syntheses of quadrone, magellaninone and pentalenene are proposed. In the third part of this grant application we will examine unique solvent systems (e.g. Li2B12H12-acetone, MgB12H12-acetone) in hopes of finding new opportunities for altering transition states while accelerating organic reactions. In addition we plan to examine lithium borates and lithium phosphates wherein the anions are chiral in hopes of catalyzing substitution reactions of allylic and benzylic acetates via single diastereomeric ion pairs which undergo facial discrimination in the attack by a nucleophile. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF UREA TRANSPORT BY ADRENAL STEROIDS Principal Investigator & Institution: Sands, Jeff M.; Professor of Medicine; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2006 Summary: Terrestrial life would be miserable without the ability to concentrate the urine. Glucocorticoids are the primary catabolic hormone that causes protein breakdown and ureagenesis. Urea excretion into the urine is the primary mechanism for eliminating this excess nitrogen from the body. A urea transporter is critically important to the theories proposed to explain the physiologic processes occurring when urine is concentrated. Only 14 years ago, evidence for such a transporter was largely speculative, but we provided experimental evidence that there is facilitated urea transport in the kidney inner medullary collecting duct. Subsequently, cDNA isoforms for facilitated urea transporters were cloned from kidney medulla (UT-A1, UT-A2, UT-A3, UT-A4), testis (UT-A5), and erythrocytes (UT-B). Recently, we cloned the rat and human genes for the UT-A family of urea transporters and showed that there are 2 promoters: promoter I, located 5' to exon 1, that controls transcription of UT-A1, UT-A3, and UTA4; and promoter II, located in intron 12, that controls transcription of UT-A2. Our group has also made major progress in understanding the long-term regulation of urea transport by studying 5 animal models associated with an impaired urine concentrating ability. Our studies led to the surprising result that facilitated urea permeability and UTA1 protein abundance are increased during in vivo conditions associated with a reduced urine concentrating ability and plasma vasopressin level. We also found that UT-A1 protein abundance is decreased during in vivo conditions associated with increased glucocorticoids. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RELAPSE PREVENTION OF BIPOLAR TYPE-II DISORDER Principal Investigator & Institution: Amsterdam, Jay D.; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2006 Summary: (Adapted from applicant's abstract) Bipolar Type U (BP U) disorder affects 1.5-2.5 percent of the U.S. adult population and results in annual healthcare costs of about $20 billion. BP II disorder is characterized by a high recurrence of major depressive episodes (MDE) and is associated with substantial morbidity and mortality. The recognition of effective treatments for recurrent MDE is of critical importance. Unfortunately, relatively little attention has been given to its treatment. Concern over a "manic switch" during treatments of BP U MDE have impeded the development of effective antidepressive treatments and relapse prevention therapies for this illness. We have recently published pilot data demonstrating that fluoxetine may be a safe and effective monotherapy for the treatment of BP U MDE and for relapse-prevention treatment of BP II MDE. We propose to determine whether fluoxetine monotherapy is an effective treatment for both the initial and relapse-prevention treatment of BP II MDE. We will also determine whether fluoxetine monotherapy is associated with a low incidence of manic and hypomanic switch episodes in these patients. To answer these questions, 184 BP II patients will be recruited over 4 years from the Depression Research Unit (DRU)-which screens 400-500 new patients per year (of which about 25 percent meet DSM-IV criteria for BP II or NOS disorder). Patients will be treated initially with fluoxetine for 10 weeks and patients who remit from their MDE will be randomized, in a double-blind fashion, to receive one of the following relapse-prevention treatments for
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one year: i) fluoxetine monotherapy (20mg/daily) ii) lithium monotherapy (6001200mg/daily) iii) the combination of lithium (600-1200mg/daily) and fluoxetine (20mg/daily), or iv) placebo. We believe that our study has the potential to have a significant impact upon current clinical practice in the appropriate management of bipolar depressed patients; an extremely important public-health matter. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROBOTIZED EXPRESSION PROFILING OF MOUSE AMYGDALA Principal Investigator & Institution: Eberwine, James H.; Professor; Pharmacology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 19-SEP-2000; Project End 31-AUG-2003 Summary: (Applicant's abstract): The amygdaloid complex is involved in the "processing" of multiple behaviors including fear, anxiety and learning and memory. There is also evidence that biochemical changes occur in the amygdala as a result of disease including schizophrenia, bipolar disease and cocaine and opiate abuse. The neuronal circuitry connecting various nuclei of the amygdala allowing internuclei communication has also been elucidated for aspects of fear conditioning. Given the central role of the amygdala in processing various types of CNS information an elucidation of the relative levels of mRNA abundance for the mRNAs that are present in the amygdala might provide insight into what neurochemical signals the amygdala responds to. Further since neuronal pathways have been dissected characterization of the expression profile in individual interconnected nuclei may provide information about how one region of the amygdala transfers information to another. We propose to generate molecular fingerprints of neurons within different regions of the amygdala using single cell and single nuclei aRNA amplification and microarray analysis in normal mice. Additionally we will determine how the profiles of these nuclei change in a mouse pharmacological model of bipolar disease involving amygdala response to withdrawal from lithium after chronic lithium treatment. As part of this proposal we propose to robotize the aRNA amplification procedure so that we can generate l000 individual sample templates each partitioned into an individual well in 96 well plates. While we are not proposing to perform 1000 microarray experiments (samples will be pooled as described in the text) having individual cells will permit each to be analyzed separately as required. In an effort to create a National resource of expression profiling data and amplified cells from the amygdala for use by other investigators the normal sample plates will be made available to anyone who requests them on a cost basis. The normal sample expression profiling data will be made available on a public website as soon as the data is confirmed by two array analyses. These data should be useful to investigators studying the amygdala as well as to "bioinformaticists" who are in need of large data sets from multiple samples. Such large data sets should prove useful in the development of pattern search algorithms that are sorely needed to property analyze such complex gene expression data sets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SIGNAL TRANSDUCTION IN BIPOLAR ILLNESS Principal Investigator & Institution: Friedman, Eitan; Professor and Director; Pharmacology and Physiology; Mcp Hahnemann University Broad & Vine Sts Philadelphia, Pa 19102 Timing: Fiscal Year 2001; Project Start 15-APR-1999; Project End 31-JUL-2001
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Summary: (adapted from applicant's abstract): The pathophysiology of bipolar affective disorder (BAD) is not well understood, although its symptoms can be effectively treated with lithium ion and other mood stabilizing agents. In both animal and human studies, we have observed that lithium impairs the activation of protein kinase C (PKC), an enzyme that is stimulated by receptor-mediated formation of diacylglycerol and catalyzes the phosphorylation of many important neuronal proteins. In studies utilizing both platelets and postmortem brains from BAD subjects, we have noted increases in both membrane- associated PKC and in translocation of the enzyme in response to stimulation of cell surface receptors. As part of an attempt to understand the underlying mechanism for these changes, we examined receptor-mediated activation of membrane G proteins in BAD subjects. Enhanced coupling between serotonin receptors and G proteins was found in brains of BAD. These results suggest that the altered affect that characterizes BAD may be associated with an exaggerated transinembrane signaling in one or more neurotransmitter pathways and that lithium exerts its therapeutic action by suppressing receptor initiated transmembrane signal flow. The aim of the proposed investigation is to continue to test the hypothesis that BAD is related to enhanced G protein-mediated transmembrane signaling and that the mood stabilizing drugs elicit. t their therapeutic efficacy by reducing the transduction of signals initiated by G proteincoupled neurotransmitter receptors. Specifically, in the proposed experiments we plan to (1) directly assess in postmortem brain regions of BAD subjects, the coupling of serotonin and a, adrenergic receptors to G proteins both under basal and receptor stimulated conditions and explore the potential mechanisms which may contribute to the altered coupling in BAD brains and (2) define the specific mechanisms which contribute to the elevation in membrane associated PKC activity BAD. To this end we plan to investigate RACK I protein expression as well as calpain and activated calpain levels in BAD brains. We will also (3) assess platelet G protein functions and PKC activity in BAD subjects before and during treatment with mood stabilizing drugs in an_attempt to further test these parameters as markers of therapeutic response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SIGNALING PATHWAYS REGULATING NEURONAL SURVIVAL Principal Investigator & Institution: D'mello, Santosh R.; Molecular and Cell Biology; University of Texas Dallas 2601 N Floyd Rd Richardson, Tx 75080 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2005 Summary: (provided by the applicant): Apoptosis is a specific mode by which cells of all types including neurons, die. While a normal feature of the developing nervous system, apoptotic death of neurons also occurs in neurodegenerative diseases, following stroke and traumatic injury, and upon exposure to neurotoxins. In these cases, apoptosis is undesirable and often leads to serious neurological deficits. The mechanisms by which these different physiological and pathophysiological stimuli abrogate the signaling pathways that normally maintain neuronal survival are far from clear. The signal transduction pathways mediating cell survival and the molecular components that comprise them can be conveniently studied in culture. Such studies have identified many molecules that are likely to be important in regulating survival of neurons in vitro as well as in vivo and which might be affected by neurotoxic stimuli or in neuropathologic conditions. The goal of this application is to examine the role of two known survival-regulatory molecules-the Akt kinase and the nuclear factor-KB (NFkappaB) transcription factor-in a well established paradigm of neuronal apoptosis that uses cultures of rat cerebellar granule neurons. Survival of these neurons in culture can be maintained by at least four factors-elevated extracellular potassium (high K+ or HK),
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IGF- 1, cyclic AMP, and lithium. Although activating distinct molecules at the cellsurface, our hypothesis is that the signaling pathways utilized by these different survival factors converge on Akt and/or NF- kappaB. The specific aims of the application are as follows: 1. Knowing that Akt is necessary for IGF-l- mediated survival, to determine whether it is also involved in survival promotion by HK, cyclic AMP, and lithium. 2. To determine the mechanism by which NF- kappaB mediates survival by HK and to examine whether it is also required for survival by IGF- 1, cyclic AMP, and lithium. Special emphasis will be placed on the roles of the transcriptional coactivator, CBP, and the NF-kappaB inhibitor, IkappaB-B. 3. To determine the relationship between Akappat and NF-kappaB activation in the inhibition of apoptosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SKIN MONITORING
BIOENGINEERING:
NONINVASIVE
TRANSDERMAL
Principal Investigator & Institution: Guy, Richard H.; Adjunct Professor; University of Geneva 3 Place De L'universite Geneva, Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): The long-term objective is to develop and optimize a novel, noninvasive, iontophoretic approach for clinical monitoring via the skin. The lowlevel current density drives both charged and highly polar (yet neutral) compounds across the skin at rates much greater than passive diffusion. As the skin offers a uniquely accessible body surface across which information can be extracted, we hypothesize that truly noninvasive and highly sensitive devices, which exploit uniquely paired flows of at least two substances, can be developed for iontophoretic monitoring applications. The research strategy will optimize iontophoretic and sensing technology to satisfy three key criteria for success: (a) fundamental understanding of electrotransport across the skin; (b) reproducible enhancement of transdermal permeability to identify clinical monitoring opportunities via the skin; and (c) characterization and validation of simple, user-friendly devices for sample collection coupled with sensitive and specific analytical tools. The specific aims of the project are:[1] To refine understanding of electrotransport across the skin; to exploit the interactions (and independence) of solute and ion flows in the presence of an applied electric field. [2] To demonstrate that the simultaneous, 'reverse iontophoretic' extraction of a target analyte, together with an endogenous substance of essentially constant concentration within the body, can offer truly noninvasive, clinical monitoring. [3] To engineer simple, elegant, prototypical devices, of small volume (100 mu-L or less), into which reverse iontophoretically extracted samples may be efficiently collected. [4] To couple these systems to highly sensitive and specific chromatographic and electrochemical analytical tools both off-line and, eventually, on-line, in situ. Proof-of-principle targets three analytes of significant interest: glucose, phenylalanine and lithium. Furthermore, the bioengineering and analytical chemistry advances envisaged will allow broad, 'massscreening' of the substances extracted (and extractable) by reverse iontophoresis revealing additional opportunities for the approach. In summary, this project aims to evaluate iontophoretic bioengineering technology in vivo in man; specifically, applications with respect to clinical chemistry and therapeutic drug monitoring are foreseen. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURAL STUDY OF ENZYMES OF INOSITOL BIOSYNTHESIS Principal Investigator & Institution: Stec, Boguslaw; Chemistry; University of Texas El Paso El Paso, Tx 79968 Timing: Fiscal Year 2002; Project Start 10-SEP-2002; Project End 31-AUG-2006 Summary: The long-term objective of this project is to understand how new functionality is acquired by the enzymes and how new biochemical pathways evolve from the need to create more specialized functions. We plan to realize this goal by creating the 'library' of structures pertinent to a selected enzymatic function. A collection of enzymes from primitive to more advanced organisms (Archaea to Eukarya) will be created that will allow us to extract conserved or noel structures and to correlate them with new emerging function. More specifically, we are interested in enzymes involved in the synthesis of myo-inositol. Myo-inositol is generated by the conversion of Dglucose-6- in enzymes involved in the synthesis of myo-inositol is generated by the conversion of D-glucose-6- phosphate to L-myo-inositol-1-phosphate (via inositol-1phosphate synthase, IPS) followed by specific dephosphorylation via inositol monophosphate (IMPase). This group of enzymes in archaea is particularly interesting because it provides a simplified model of inositol processing. The immediate goal of this study will be to obtain critical insights into the structure and function of both groups of enzymes. Specifically, we plan (1) to characterize crystallographically the previously cloned and purified IPS from A. fulgidus that is typical of the smaller IPS enzymes from bacteria and archaea, has no known homologs among PDB deposits, and which, in particular, requires divalent metal ion for the aldolase step. A series of crystallographic experiments: Apo- IPS (in particular, requires divalent metal ion for the aldolase step. A series of crystallographic experiments: Apo-IPS (in the presence of EDTA), the complexes with Mn2+ and/or Zn2+, G-6-P (no NAD+) (no G-6-P), is expected to provide the details of the enzymatic reaction. (2) We will also determine structures of dual activity enzymes from hyperthermophiles that very specifically catalyze the hydrolysis of inositol-1-phosphate (inositol monophosphatase, IMPase activity)) and fructose-1,6-bisphosphatase, FBPase, activity) from A. fulgidus and Thermatoga maratima. Our structural analysis of M. jannaschii, IMPase (MJ0109) in the presence of various substrates/products in combination with inhibitory/activating metal ions has provided unique insights into this bifunctional enzyme as well as a framework for the proposed studies. These IMPase/FBPase proteins, which are weakly inhibited by Li+, will be compared and contrasted with the (3) structure of E. coli IMPase (also known as SuhB), whose structure will also be solved, that is strongly inhibited by Li+ and cannot hydrolyze FBP similarly to mammalian IMPase. (4) Once the crystal structures of all the enzymes are determined, we plan to conduct a series of crystallographic as well as biochemical studies to determine the details of the proposed catalytic mechanism for IMPS and IMPases. Additionally we will try to resolve the controversy concerning metal ion roles in IMPase activity and the mode of Li+ inhibition. The structural comparison of highly Li+- sensitive eukaryotic and E. coli IMPases to Li+-insensitive hyperthermophilic IMPases is expected to provide a testable hypothesis about the mode of Li+ inhibition and the structural features for the dual specificity of the archaeal homologues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SYNTHETIC STUDIES OF CHIRAL ORGANOMETALLICS Principal Investigator & Institution: Gawley, Robert E.; Professor; Chemistry; University of Miami Coral Gables University Sta Coral Gables, Fl 33124 Timing: Fiscal Year 2001; Project Start 01-MAY-1998; Project End 31-AUG-2005
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Summary: Many of today's drugs contain saturated nitrogen heterocyclic rings, thus, it is important to develop new ways to synthesize and modify nitrogen heterocycles. Likewise, it has become important to produce chiral drugs in enantiomerically pure form. For decades, the only stereoselective reactions known to organic chemists were additions of a fourth ligand to heterotopic faces of a trigonal atom. This category includes almost all stereoselective reactions in organic synthesis, and we have accumulated significant insight into the electonic, steric, and dynamic factors that influence these processes. In the past 10 years, significant advances in applying electrophilic substitutions of chiral organometallics (especially organolithiums) as new methods for asymmetric synthesis have been made. This reactivity mode is different from most other asymmetric syntheses in that it involves substitution of a metal attached to a stereogenic carbon atom. Substitution of the metal for an electrophile completes the enantioselective synthesis. Mechanistic understanding of developing methodology is necessary to advancing the field. When contemplating electrophilic substitutions of stereogenic carbanions, one must consider configurational stability, steric course, and aggregation state. If the electrophile is prochiral, two new stereocenters are formed and the question of diastereoselectivity arises. Answering these questions is not always possible; but without answers, mechanistic interpretation is speculative, at best. The specific aims of this project are: 1. To continue our investigation into the scope and limitations of alpha-aminoorganolithium electrophilic substitutions and sigmatropic rearrangements, with emphasis on stereoselectivity in compounds with multiple stereocenters. Explore further extensions of the methodology such as ringclosing metathesis. 2. To develop improved methods of preparation of chiral organometallics. 3. To further explore the solution and solid state structure of chiral organometallics. Evaluate the effects of ligating atoms and metal effects on configurational and structural dynamics of chiral carbanions. 4. To pursue our recent findings relating to possible stereoelectronic effects on transmetalation and the nature of heteroatom participation in tin-lithium exchanges using rapid injection NMR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TARGETING DISABILITIES FOR REHAB IN BIPOLAR DISORDER Principal Investigator & Institution: Jaeger, Judith; Director & Associate Professor; Long Island Jewish Medical Center 270-05 76Th Ave New Hyde Park, Ny 11040 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 28-FEB-2006 Summary: (Applicant's abstract): Bipolar disorder (BPD), a lifelong condition affecting almost 2 million Americans, is the sixth leading cause of disability among all medical conditions in established market economies. The illness is characterized by a chronic course of recurring cycles of affective disorder (e.g., mania or depression) and remission. Despite the magnitude of its affliction and its disability toll, there has been little or no systematic research on the causes of the disability in life functioning (LF) in BPD. Disability in LF is found to persist even during periods of system remission and should not be considered simply the result of clinical psychopathology. Neuropsychological (NP) deficits have been observed in BPD. The NP deficits, like disability in BPD, have also been shown to persist during remission. While the relation between NP deficits and disability in schizophrenia receives considerable research attention, such studies for BPD have not been reported to the best of our knowledge. We propose a longitudinal investigation of the relationship between NP deficits and LF in BPD. We hypothesize that NP deficits are associated with persistent disability. Our goal is to study the nature of these relationships thereby informing the development of more effective interventions targeted to disability in BPD. A sample of 210 patients will be followed
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monthly, starting with an acute illness exacerbation, for a period of 2 years. Subjects will undergo repeated assessments for NP and LF measures and clinical state. Comprehensive assessments including an NP battery are administered at 3 "fixed" time points (baseline, 1 month and 1 year) and at up to 2 additional time points "triggered" by a remission following the index episode and a remission following a second illness episode should a second episode occur during the follow-up period. Monthly assessments will monitor clinical state, LF and services used throughout the follow-up period. The principal aim is to determine whether and to what degree measures of NP deficit and clinical symptom ratings are associated with disability in LF over the course of a 24 month period. Secondary aims are 1) to compare these relationships in BPD with those observed in a cohort of individuals with schizophrenia and schizoaffective disorder presently being studied in another R01 funded project and 2) to acquire descriptive information of actual service use patterns in BPD patients recovering from a severe relapse of affective symptoms. More effective rehabilitation and support services are needed to reduce disability in BPD. But first we need a better understanding of the causes of disability and the services currently being provided. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF INOSITOL SIGNALING IN HUMAN DISEASE Principal Investigator & Institution: York, John D.; Pharmacology and Cancer Biology; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 30-APR-2006 Summary: adapted from applicant's abstract): The long-range goal of this project is to elucidate how diverse extracellular stimuli elicit selective cellular responses through the activation of inositol polyphosphate (IP) signaling pathways. Defects in IP signaling pathways result in disease states such as human oculocerebrorenal syndrome or Lowe syndrome. There are over 30 IP molecules the majority of which have not been studied as messengers. It is our hypothesis that such IPs, designated a "orphans," may have important signaling roles. In support of this, we have recently defined novel signaling roles for orphan IPs in regulating membrane trafficking, cytoskeletal organization, gene expression and mRNA export. Additionally, we have uncovered a family of lithium targets with relevance to manic depressive disease. A new theme emerging from our work is that certain inositol signaling pathways are compartmentalized to the nucleus and directly effect nuclear function. This project focuses on the roles of orphan IF messengers in regulating, membrane trafficking, gene expression and messenger RNA export. We also seek to characterize a new family of I phosphatases that are potential targets of lithium relevance to bipolar disease. IP5 and IP6 are ubiquitous inositol phosphates that until our recent work had no clearly defined roles as signaling molecules. We have shown that PLC produces IP3, which is then sequentially phosphorylated to IP6 by two IP kinases, a nuclear dual-specificity IP3/IP4 kinase (Ipk2), and nuclear envelope/pore complex localized IP5 2-kinase (Ipkl). Ipk2p reveal is identical to a known transcription factor providing a crucial direct link of IP signaling and gene expression. Understanding the target genes regulated by Ipk2p-mediated transcription complexes, the IP receptors and the mechanism by which localized production of IP4/IP5 mediate changes in transcription will help define how nuclear IP signals regulate cell growth and development. Studies of Ipklp have uncovered a role for IP6 production in messenger RNA export Identification of the receptors, components involved and mechanisms of regulation will be instrumental in elucidating how IP signaling regulates messenger RNA export. We also plan to evaluate the function of IP5 and IP6 in mammalian systems. Do they serve a similar function to that in yeast? We
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plan to isolate and clone cDNA's encoding the enzymes that interconvert IP5 and IP6 in mammalian tissues namely IP5 2-kinase and IP6 2-phosphatase in order to determine how production of these metabolites is controlled. In addition, we plan to study the first dual-functional inositol lipid phosphatase with two autonomous active sites, one a polyphosphoinositide phosphatase and the other a 5-phosphatase similar to the OCRL-l protein that is mutated in Lowe syndrome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF SHAGGY/GSK-3 IN THE CIRCADIAN CLOCK Principal Investigator & Institution: Harms, Emily B.; Lab/Genetics; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): The Drosophila gene shaggy (sgg) has recently been shown to play a role in the fly circadian oscillator. SGG is the Drosophila ortholog of glycogen synthase kinase-3 (GSK-3), and appears to affect nuclear entry of protein complexes made up of the PERIOD (PER) and TIMELESS (TIM) proteins by promoting the phosphorylation of TIM. Since sgg loss-of-function mutations result in lethality, however, it has been difficult to determine what effect the loss of sgg function would have on the circadian clock. The work proposed here is aimed at further elucidating the role of SGG in the Drosophila circadian clock, as well as investigating whether GSK-3 plays a comparable role in mammals. In the fly, the focus of this proposal is to determine what effect the loss of SGG/GSK-3 phosphorylation of TIM would have on the circadian clock. Putative GSK-3 phosphorylation sites within TIM will be identified, mutated to residues that cannot be phosphorylated, and then placed into tim genomic transgenes to create transgenic flies. The mutant transgenic flies will be used to determine whether the phosphorylation site mutations indeed affect the phosphorylation and light responsiveness of TIM in vivo, and also whether the mutations impede the nuclear translocation of PER/TIM complexes. In the mammalian system, gsk-3 expression levels will be manipulated in mammalian fibroblast cells. The cells will be monitored for defects in circadian rhythmicity to assess a possible role for GSK-3 in the mammalian clock. In vitro kinase assays will be used to identify potential substrates of GSK-3 in the mammalian clock, and regulation of GSK-3 activity will be examined. Additionally, an involvement of GSK-3 in the mammalian clock may have important implications for the understanding and treatment of bipolar disorder in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE WINGLESS TRANSDUCTION PATHWAY IN SYNAPSE DEVELOPMENT Principal Investigator & Institution: Budnik, Vivian G.; Associate Professor; Neurobiology; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2004; Project Start 01-DEC-2003; Project End 30-NOV-2008 Summary: (provided by applicant): The long-term goal of this project is to elucidate the signaling mechanisms underlying new synapse formation in the fruit fly Drosophila. We have recently discovered that the secreted glycoprotein Wingless (Wg), best known for its crucial role in early morphogenesis and pattern formation, is also a fundamental organizer of glutamatergic synapses in the fruit fly. In this project we will use genetic, molecular, and electrophysiological strategies to investigate the ways in which the Wg
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pathway promotes synapse formation. In Aim 1 we will focus on the Wg receptor Dfrizzled2 - to discern how Wg transduction affects maturing terminals, and if the structural disruptions found on both sides of the synapse in mutants are independent or require antero/retrograde signaling. In Aim 2, Electrophysiological recordings and dye uptake experiments will probe fundamental questions in synaptic transmission such as the role of the active zone in exocytosis, the relationship between endo/exocytosis, and mechanisms for compensation of synaptic strength. Finally, in Aim 3 we will use genetic and yeast two-hybrid approaches to determine the specific signal transduction pathway activated by Wg during synapse development. In particular, we will test the hypothesis that at synapses Wg activated a non-canonical pathway. We will also uncover new proteins that bind directly to Dfrizzled2 and that may function to target and cluster it to synaptic sites. The proposed experiments will fundamentally advance the field of synapse development by characterizing a secreted protein, which is essential for setting up active zones and postsynaptic specializations. Our findings may also bring insights into mammalian synapse development, as these fly synapses show a tantalizing degree of molecular conservation with mammalian central synapses. Therefore our results with manipulating components of the Wg pathway could be important for deciphering the mechanisms underlying a number of neuropathologies, as well as to design strategies to repair nervous system damage after stroke, trauma, or disease. A notable example is the case of bipolar disorder, which has long been treated with lithium. Recent studies show that one of the targets for lithium is GSK3-8, a crucial enzyme in the Wg pathway. Our finding that the Wg pathway is essential for synapse development might provide new insights into this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TREATMENT AND OUTCOME OF EARLY ONSET BIPOLAR DISORDER Principal Investigator & Institution: Kafantaris, Vivian; Assistant Professor; Long Island Jewish Medical Center 270-05 76Th Ave New Hyde Park, Ny 11040 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 28-FEB-2006 Summary: (Adapted from the Applicant's Abstract): Onset of bipolar disorder during adolescence increases the risk of school failure, out-of-home placement, drug abuse and addiction, and suicide. In adolescents, bipolar disorder is often accompanied by delusions, hallucinations, or severe assaultive or destructive behaviors that require acute treatment with adjunctive antipsychotic medication in addition to a mood stabilizer. There are no data on when to withdraw antipsychotic medication or whether to withdraw it at all. Although it is important to identify patients who could be maintained on lithium alone to decrease the risk of developing long-term adverse effects such as tardive dyskinesia (TD), it is also important to prevent disruptive recurrences of episodes of illness. There is a high rate of failure on lithium maintenance treatment in general. For adolescents who have had psychotic features or assaultive, destructive behavior as part of their mania, continued adjunctive antipsychotic medication may offer additional prophylactic efficacy. In addition, a lower risk of TD with the novel antipsychotics may alter the risk: benefit ratio in favor of longer-term antipsychotic treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TREATMENT OF EARLY AGE MANIA (TEAM) Principal Investigator & Institution: Emslie, Graham J.; Professor, Chair, and Director; Psychiatry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105
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Timing: Fiscal Year 2002; Project Start 09-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): This proposal was developed in collaboration with NIMH Program staff and approved for submission by Council at its 1/18/01 meeting. The two aims are:(1) To investigate the effectiveness of medications for children and adolescents who have BP-1 (manic or mixed phase) or mania. (2) To pilot a complex, multistrata, adaptive strategy design. Based on the novelty of the design and on the need for a large (and therefore costly) sample size, the applicants were asked to submit a protocol for only the first two years of the five year plan. If the first two years are successfully implemented, funding for the additional three years will be sought. For the sake of clarity, the proposal is written for the entire five years, even though the budget is limited to the first two years. Thus, the research plan provides for examining 540 subjects ages 6.0-14.11 who have DSM BP-1 (manic or mixed phase) or mania. The structure of this collaborative U01 is one coordinating site and six data collection sites. The coordinating site, for data management and analyses and for training is Washington University, St. Louis, PI: Barbara Geller, M.D. The six sites for data collection are: (1) George Washington University, Washington, D.C., PI: Paramjit Joshi, M.D. (2) Johns Hopkins Medical Instituitions, Baltimore, PI: John walkup, M.D. (3) University of Pittsburgh, Western Psychiatric Institute and Clinic, PI: David Axelson, M.D. (4) University of Texas, Dallas, PI: Graham Emslie, M.D. (5) University of Texas, Galveston, PI: Karen Dineen Wagner, M.D. and (6) Washington University, St. Louis, PI; Joan Luby, M.D. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: WIRELESS ECG SYSTEM-ON-A-CHIP Principal Investigator & Institution: Kramer, Kevin M.; Advanced Medical Electronics Corporation Suite #190 Maple Grove, Mn 55369 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-OCT-2003 Summary: Proposed is the development of a wireless ECG chip that communicates using the new Bluetooth networking standard. Bluetooth is a wireless data communication system intended for low cost and low power networking. It is quickly becoming the standard wireless interconnect in portable computing. Industry adoption of the Bluetooth standard coincides with recent advances in system-on-a-chip (SOC) design tools and foundry processes that make custom integrated circuit (IC) design more economically feasible in specialized applications. Bluetooth 2.5 GHz frequency hopping radio and baseband functions are recently available for low-cost CMOS integrated circuit processes. AME proposes to integrate these core designs with proven analog blocks that implement ECG signal amplification, filtering, and digital conversion to create a single chip that allows direct acquisition of ECG signals, to a wireless Bluetooth computer network. An example application of this chip is to combine it with ECG electrode patches to make a system that attaches as a wireless ECG patch to the skin. The phase I project will establish the feasibility of a low-cost, miniature system by completing a simulation of the integrated functional blocks. Phase II will complete the chip design, layout, manufacturing, and testing of a fully integrated Bluetooth ECG chip. PROPOSED COMMERCIAL APPLICATIONS: The proposed wireless Bluetooth ECG chip can be applied to a variety of medical applications. For example, the wireless Bluetooth ECG chip can be combined with a flexible lithium polymer battery to create and ECG signal to network connection that can be integrated within an adhesive electrode. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: WNT13 & WNT13-SIGNALING IN ENDOTHELIAL CELL SURVIVAL Principal Investigator & Institution: Mao, Catherine S.; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 03-DEC-2001; Project End 30-APR-2002 Summary: Endothelial cells (EC) play a key role in the development and progression of vascular diseases involving vascular injury and chronic inflammation such as atherosclerosis. The identification of all the factors controlling EC behavior is crucial to design appropriate therapy. Recent evidence suggest that Wnt proteins and Wntsignaling components may represent a novel class of factors controlling EC behavior. We and others have shown that the expression of antagonists of the Wnt- signaling pathway, members of the FRP family, is increased during vascular injury, in association with vascular cell apoptosis. We have shown that lithium, an agonist of Wnt signaling pathway, induces a cell cycle arrest and a senescent-like phenotype in EC and activates the tumor suppressor p53-dependent pathway. These findings implicate lithium in the activation of a survival pathway in EC. Moreover, we recently showed that the Wnt13 gene is expressed in EC and up-regulated by inhibitors of EC proliferation (TNFalpha, lithium). Our goal is to investigate the role of an autocrine Wnt13 pathway in the control of EC survival and its underlying mechanisms of action. In aim 1, we will investigate the functional role of Wnt13 protein in the control of EC survival. This will be addressed by manipulating Wnt13 expression levels in EC, by over- and under-expression, and by following the resulting i) changes in EC survival in the absence or presence of apoptotic stimuli and ii) changes in EC gene expression profile by cDNA array, and by iii) testing whether Wnt13 mediates the effects of lithium on EC survival. In aim 2, we will identify downstream effectors of the Wnt13 signaling pathway in EC. The activation of a novel Ca2+- dependent Wnt-signaling pathway will be tested by measuring changes i) in intracellular Ca2+ concentration, ii) in the activity of the Ca2+-dependent kinase PYK2 and iii) in Wnt13- target gene expression in response to Wnt13 in the presence of known inhibitors or dominant-negative isoform of effectors of Ca2+-dependent pathways. This will be followed by the identification and characterization iv) of novel transcription factors involved in the Wnt13-signaling pathway. In aim 3, we will investigate the regulation of Wnt13 gene expression by survival signals. This will be achieved i) by quantification of Wnt13 mRNA levels in EC in response to lithium and other EC survival or apoptosis inducers, ii) by characterizing Wnt13 gene promoter/enhancer sequences and iii) by identifying the responsive sequence(s) and transcription factor(s) mediating lithium-dependent regulation of Wnt13 gene expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and
3 4
Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age.
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unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “lithium” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for lithium in the PubMed Central database: •
A Lithium Chloride-Extracted, Broad-Spectrum-Adhesive 42-Kilodalton Protein of Staphylococcus epidermidis Is Ornithine Carbamoyltransferase. by Hussain M, Peters G, Chhatwal GS, Herrmann M.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97084
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A Molecular Mechanism for the Effect of Lithium on Development. by Klein PS, Melton DA.; 1996 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38692
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Accuracy of the Pepin method to determine appropriate lithium dosages in healthy volunteers. by Stip E, Dufresne J, Boulerice B, Elie R.; 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=167187
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Changing prescription patterns for lithium and valproic acid in old age: shifting practice without evidence. by Shulman KI, Rochon P, Sykora K, Anderson G, Mamdani M, Bronskill S, Tran CT.; 2003 May 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153852
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Chronic Lithium Regulates the Expression of Adenylate Cyclase and Gi- Protein [alpha] Subunit in Rat Cerebral Cortex. by Colin SF, Chang H, Mollner S, Pfeuffer T, Reed RR, Duman RS, Nestler EJ.; 1991 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52984
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Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-d-aspartate receptor-mediated calcium influx. by Nonaka S, Hough CJ, Chuang DM.; 1998 Mar 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19446
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Crystallographic Evidence for the Action of Potassium, Thallium, and Lithium Ions on Fructose-1,6-Bisphosphatase. by Villeret V, Huang S, Fromm HJ, Lipscomb WN.; 1995 Sep 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41078
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Effectiveness and outcome predictors of long-term lithium prophylaxis in unipolar major depressive disorder. by Baethge C, Gruschka P, Smolka MN, Berghofer A, Bschor T, Muller-Oerlinghausen B, Bauer M.; 2003 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=193982
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Effects of dextroamphetamine, lithium chloride, sodium valproate and carbamazepine on intraplatelet Ca2+ levels. by Ulrich ML, Rotzinger S, Asghar SJ, Jurasz P, Tanay VA, Dunn SM, Radomski M, Greenshaw A, Silverstone PH.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161732
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The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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How should lithium-induced thyroid dysfunction be managed in patients with bipolar disorder? by Joffe RT.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=161685
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Hypothalamic-pituitary-thyroid system activity during lithium augmentation therapy in patients with unipolar major depression. by Bschor T, Baethge C, Adli M, Lewitzka U, Eichmann U, Bauer M.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=161745
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Is there a Population II analogy to the F star lithium dip? by Dearborn DS, Schramm DN.; 1997 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24592
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Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamateinduced inhibition of Akt-1 activity in neurons. by Chalecka-Franaszek E, Chuang DM.; 1999 Jul 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17587
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Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex. by Dixon JF, Hokin LE.; 1998 Jul 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20981
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Lithium Phthalocyanine: A Probe for Electron Paramagnetic Resonance Oximetry in Viable Biological Systems. by Liu KJ, Gast P, Moussavi M, Norby SW, Vahidi N, Walczak T, Wu M, Swartz HM.; 1993 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46735
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Lithium side-effects and predictors of hypothyroidism in patients with bipolar disorder: sex differences. by Henry C.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161639
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Lithium Stimulates Glutamate "Release" and Inositol 1,4,5-Trisphosphate Accumulation via Activation of the N-Methyl-D-Aspartate Receptor in Monkey and Mouse Cerebral Cortex Slices. by Dixon JF, Los GV, Hokin LE.; 1994 Aug 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44605
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Lithium toxicity after urinary diversion with ileal conduit. by Alhasso A, Bryden AA, Neilson D.; 2000 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27345
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Mechanism of Inositol Monophosphatase, the Putative Target of Lithium Therapy. by Pollack SJ, Atack JR, Knowles MR, McAllister G, Ragan CI, Baker R, Fletcher SR, Iversen LL, Broughton HB.; 1994 Jun 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44077
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Plant inositol monophosphatase is a lithium-sensitive enzyme encoded by a multigene family. by Gillaspy GE, Keddie JS, Oda K, Gruissem W.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=161071
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Redistribution of [beta]-catenin in response to EGF and lithium signalling in human oesophageal squamous carcinoma cell lines. by Jones LJ, Veale RB.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=194614
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Risk factors of thyroid abnormalities in bipolar patients receiving lithium: a case control study. by Ahmadi-Abhari SA, Ghaeli P, Fahimi F, Esfahanian F, Farsam H, Dehpour AR, Jahanzad I, Hatmi ZN, Dashti S.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161797
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Ritanserin as an adjunct to lithium and haloperidol for the treatment of medicationnaive patients with acute mania: a double blind and placebo controlled trial. by Akhondzadeh S, Mohajari H, Reza Mohammadi M, Amini H.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=194858
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Sinus Node Dysfunction Associated with Lithium Therapy in a Child. by Moltedo JM, Porter GA, State MW, Snyder CS.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124759
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Structure of Inositol Monophosphatase, the Putative Target of Lithium Therapy. by Bone R, Springer JP, Atack JR.; 1992 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50271
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The antibipolar drug valproate mimics lithium in stimulating glutamate release and inositol 1,4,5-trisphosphate accumulation in brain cortex slices but not accumulation of inositol monophosphates and bisphosphates. by Dixon JF, Hokin LE.; 1997 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20797
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Thyroid hormone treatment for lithium-induced thyroid dysfunction in mood disorder. by Ramasubbu R.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=161734
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Tol1, a Fission Yeast Phosphomonoesterase, Is an In Vivo Target of Lithium, and Its Deletion Leads to Sulfite Auxotrophy. by Miyamoto R, Sugiura R, Kamitani S, Yada T, Lu Y, Sio SO, Asakura M, Matsuhisa A, Shuntoh H, Kuno T.; 2000 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94529
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Toward a Crystal-Clear View of Lithium's Site of Action. by Baraban JM.; 1994 Jun 21; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=44072
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What do patients in a lithium outpatient clinic know about lithium therapy? by Schaub RT, Berghoefer A, Muller-Oerlinghausen B.; 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=167185
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 6
PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with lithium, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “lithium” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for lithium (hyperlinks lead to article summaries): •
A case of Parkinsonism due to lithium intoxication: treatment with Pramipexole. Author(s): Dallocchio C, Mazzarello P. Source: Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. 2002 May; 9(3): 310-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12093142&dopt=Abstract
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A comparison of lithium dilution cardiac output measurements made using central and antecubital venous injection of lithium chloride. Author(s): Jonas MM, Kelly FE, Linton RA, Band DM, O'Brien TK, Linton NW. Source: Journal of Clinical Monitoring and Computing. 1999 December; 15(7-8): 525-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12578051&dopt=Abstract
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A historical cohort study of kidney damage in long-term lithium patients: continued surveillance needed. Author(s): Bendz H, Aurell M, Lanke J. Source: European Psychiatry : the Journal of the Association of European Psychiatrists. 2001 June; 16(4): 199-206. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11418269&dopt=Abstract
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A life-threatening interaction between lithium and celecoxib. Author(s): Slordal L, Samstad S, Bathen J, Spigset O. Source: British Journal of Clinical Pharmacology. 2003 April; 55(4): 413-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12680891&dopt=Abstract
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A lithium clinic for bipolar patients: 2-year outcome of the first 148 patients. Author(s): Licht RW, Vestergaard P, Rasmussen NA, Jepsen K, Brodersen A, Hansen PE. Source: Acta Psychiatrica Scandinavica. 2001 November; 104(5): 387-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11722321&dopt=Abstract
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A lithium-induced conformational change in serotonin transporter alters cocaine binding, ion conductance, and reactivity of Cys-109. Author(s): Ni YG, Chen JG, Androutsellis-Theotokis A, Huang CJ, Moczydlowski E, Rudnick G. Source: The Journal of Biological Chemistry. 2001 August 17; 276(33): 30942-7. Epub 2001 June 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11408487&dopt=Abstract
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A novel slow-release formulation of lithium carbonate (Carbolithium Once-A-Day) vs. standard Carbolithium: a comparative pharmacokinetic study. Author(s): Castrogiovanni P. Source: Clin Ter. 2002 March-April; 153(2): 107-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12078335&dopt=Abstract
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A patient with lithium intoxication developing at therapeutic serum lithium levels and persistent delirium after discontinuation of its administration. Author(s): Omata N, Murata T, Omori M, Wada Y. Source: General Hospital Psychiatry. 2003 January-February; 25(1): 53-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12583932&dopt=Abstract
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A pilot study of concordance therapy for individuals with bipolar disorders who are non-adherent with lithium prophylaxis. Author(s): Scott J, Tacchi MJ. Source: Bipolar Disorders. 2002 December; 4(6): 386-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519098&dopt=Abstract
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A pilot study of rapid lithium administration in the treatment of acute mania. Author(s): Keck PE Jr, Strakowski SM, Hawkins JM, Dunayevich E, Tugrul KC, Bennett JA, McElroy SL. Source: Bipolar Disorders. 2001 April; 3(2): 68-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11333065&dopt=Abstract
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A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Author(s): Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J; Lamictal 606 Study Group. Source: Archives of General Psychiatry. 2003 April; 60(4): 392-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12695317&dopt=Abstract
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A possible interaction between lithium and rofecoxib. Author(s): Lundmark J, Gunnarsson T, Bengtsson F. Source: British Journal of Clinical Pharmacology. 2002 April; 53(4): 403-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11966674&dopt=Abstract
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A prospective study of the offspring of bipolar parents responsive and nonresponsive to lithium treatment. Author(s): Duffy A, Alda M, Kutcher S, Cavazzoni P, Robertson C, Grof E, Grof P. Source: The Journal of Clinical Psychiatry. 2002 December; 63(12): 1171-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12523878&dopt=Abstract
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A randomized controlled trial to evaluate the adjuvant effect of lithium on radioiodine treatment of hyperthyroidism. Author(s): Bal CS, Kumar A, Pandey RM. Source: Thyroid : Official Journal of the American Thyroid Association. 2002 May; 12(5): 399-405. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12097201&dopt=Abstract
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A randomized, double-blind, crossover study of methylphenidate and lithium in adults with attention-deficit/hyperactivity disorder: preliminary findings. Author(s): Dorrego MF, Canevaro L, Kuzis G, Sabe L, Starkstein SE. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2002 Summer; 14(3): 289-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12154153&dopt=Abstract
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Abnormal thiol reactivity of tropomyosin in essential hypertension and its association with abnormal sodium-lithium countertransport kinetics. Author(s): Watkins SL, West IC, Wilkinson R, Thomas TH. Source: Journal of Hypertension. 2001 March; 19(3): 485-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11288819&dopt=Abstract
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Accuracy of the Pepin method to determine appropriate lithium dosages in healthy volunteers. Author(s): Stip E, Dufresne J, Boulerice B, Elie R. Source: Journal of Psychiatry & Neuroscience : Jpn. 2001 September; 26(4): 330-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11590973&dopt=Abstract
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Acute lithium intoxication and neuroleptic malignant syndrome. Author(s): Gill J, Singh H, Nugent K. Source: Pharmacotherapy. 2003 June; 23(6): 811-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820823&dopt=Abstract
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Acute lithium intoxication. Author(s): Nagappan R, Parkin WG, Holdsworth SR. Source: Anaesthesia and Intensive Care. 2002 February; 30(1): 90-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11939450&dopt=Abstract
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Adjunctive quetiapine in bipolar patients partially responsive to lithium or valproate. Author(s): Sokolski KN, Denson TF. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2003 August; 27(5): 863-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921920&dopt=Abstract
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Adjuvant effect of lithium on radioiodine treatment of hyperthyroidism. Author(s): Bogazzi F, Bartalena L, Pinchera A, Martino E. Source: Thyroid : Official Journal of the American Thyroid Association. 2002 December; 12(12): 1153-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12593732&dopt=Abstract
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Alternatives to lithium and divalproex in the maintenance treatment of bipolar disorder. Author(s): Gnanadesikan M, Freeman MP, Gelenberg AJ. Source: Bipolar Disorders. 2003 June; 5(3): 203-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12780874&dopt=Abstract
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An implantable power supply with an optically rechargeable lithium battery. Author(s): Goto K, Nakagawa T, Nakamura O, Kawata S. Source: Ieee Transactions on Bio-Medical Engineering. 2001 July; 48(7): 830-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11442295&dopt=Abstract
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An open longitudinal study of patients with bipolar rapid cycling treated with lithium or lamotrigine for mood stabilization. Author(s): Walden J, Schaerer L, Schloesser S, Grunze H. Source: Bipolar Disorders. 2000 December; 2(4): 336-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11252647&dopt=Abstract
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Apolipoprotein E gene polymorphism is related to metabolic abnormalities, but does not influence erythrocyte membrane lipid composition or sodium-lithium countertransport activity in essential hypertension. Author(s): Stiefel P, Montilla C, Muniz-Grijalvo O, Garcia-Lozano R, Alonso A, Miranda ML, Pamies E, Villar J. Source: Metabolism: Clinical and Experimental. 2001 February; 50(2): 157-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11229422&dopt=Abstract
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Arguments for the specificity of the antisuicidal effect of lithium. Author(s): Muller-Oerlinghausen B. Source: European Archives of Psychiatry and Clinical Neuroscience. 2001; 251 Suppl 2: Ii72-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11824842&dopt=Abstract
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Association between lithium use and thyrotoxicosis caused by silent thyroiditis. Author(s): Miller KK, Daniels GH. Source: Clinical Endocrinology. 2001 October; 55(4): 501-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11678833&dopt=Abstract
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Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder. Author(s): Bschor T, Baethge C, Adli M, Eichmann U, Ising M, Uhr M, Modell S, Kunzel H, Muller-Oerlinghausen B, Bauer M. Source: Journal of Psychiatric Research. 2003 March-April; 37(2): 135-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842167&dopt=Abstract
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Association of personal and familial suicide risk with low serum cholesterol concentration in male lithium patients. Author(s): Bocchetta A, Chillotti C, Carboni G, Oi A, Ponti M, Del Zompo M. Source: Acta Psychiatrica Scandinavica. 2001 July; 104(1): 37-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11437748&dopt=Abstract
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Ataxia from lithium toxicity successfully treated with high-dose buspirone: a singlecase experimental design. Author(s): Megna J, O'dell M. Source: Archives of Physical Medicine and Rehabilitation. 2001 August; 82(8): 1145-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11494197&dopt=Abstract
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Bayesian pharmacokinetics of lithium after an acute self-intoxication and subsequent haemodialysis: a case report. Author(s): Kerbusch T, Mathot RA, Otten HM, Meesters EW, van Kan HJ, Schellens JH, Beijnen JH. Source: Pharmacology & Toxicology. 2002 May; 90(5): 243-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12076304&dopt=Abstract
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Biological predictors of lithium response in bipolar disorder. Author(s): Ikeda A, Kato T. Source: Psychiatry and Clinical Neurosciences. 2003 June; 57(3): 243-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12753562&dopt=Abstract
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Blepharospasm and apraxia of eyelid opening in lithium intoxication. Author(s): Micheli F, Cersosimo G, Scorticati MC, Ledesma D, Molinos J. Source: Clinical Neuropharmacology. 1999 May-June; 22(3): 176-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10367183&dopt=Abstract
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Brain lithium concentrations in bipolar disorder patients: preliminary (7)Li magnetic resonance studies at 3 T. Author(s): Soares JC, Boada F, Spencer S, Mallinger AG, Dippold CS, Wells KF, Frank E, Keshavan MS, Gershon S, Kupfer DJ. Source: Biological Psychiatry. 2001 March 1; 49(5): 437-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11274655&dopt=Abstract
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Brain lithium measurements with (7)Li magnetic resonance spectroscopy (MRS): a literature review. Author(s): Soares JC, Boada F, Keshavan MS. Source: European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 2000 May; 10(3): 151-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10793316&dopt=Abstract
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Brain-to-serum lithium ratio and age: an in vivo magnetic resonance spectroscopy study. Author(s): Moore CM, Demopulos CM, Henry ME, Steingard RJ, Zamvil L, Katic A, Breeze JL, Moore JC, Cohen BM, Renshaw PF. Source: The American Journal of Psychiatry. 2002 July; 159(7): 1240-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12091209&dopt=Abstract
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Calcium homeostasis in long-term lithium-treated women with bipolar affective disorder. Author(s): El Khoury A, Petterson U, Kallner G, Aberg-Wistedt A, Stain-Malmgren R. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2002 October; 26(6): 1063-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12452527&dopt=Abstract
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Calcium-dependent prevention of neuronal apoptosis by lithium ion: essential role of phosphoinositide 3-kinase and phospholipase Cgamma. Author(s): Kang HJ, Noh JS, Bae YS, Gwag BJ. Source: Molecular Pharmacology. 2003 August; 64(2): 228-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869627&dopt=Abstract
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Can lithium help to prevent suicide? Author(s): Gelenberg AJ. Source: Acta Psychiatrica Scandinavica. 2001 September; 104(3): 161-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11531652&dopt=Abstract
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Can the expression of histocompatibility antigen be changed by lithium? Author(s): Kang BJ, Park SW, Chung TH. Source: Bipolar Disorders. 2000 June; 2(2): 140-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11252654&dopt=Abstract
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Cardiac output measured by lithium dilution and transpulmonary thermodilution in patients in a paediatric intensive care unit. Author(s): Linton RA, Jonas MM, Tibby SM, Murdoch IA, O'Brien TK, Linton NW, Band DM. Source: Intensive Care Medicine. 2000 October; 26(10): 1507-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11126264&dopt=Abstract
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Case report and review of the perinatal implications of maternal lithium use. Author(s): Pinelli JM, Symington AJ, Cunningham KA, Paes BA. Source: American Journal of Obstetrics and Gynecology. 2002 July; 187(1): 245-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12114921&dopt=Abstract
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Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium. Author(s): King TD, Bijur GN, Jope RS. Source: Brain Research. 2001 November 16; 919(1): 106-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11689167&dopt=Abstract
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Central pontine myelinolysis manifested by temporary blindness: a possible complication of lithium toxicity. Author(s): Fabisiak DB, Murray GB, Stern TA. Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 2002 December; 14(4): 247-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630660&dopt=Abstract
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Changes in body weight and body mass index among psychiatric patients receiving lithium, valproate, or topiramate: an open-label, nonrandomized chart review. Author(s): Chengappa KN, Chalasani L, Brar JS, Parepally H, Houck P, Levine J. Source: Clinical Therapeutics. 2002 October; 24(10): 1576-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12462287&dopt=Abstract
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Changes in quantitatively assessed tremor during treatment of major depression with lithium augmented by paroxetine or amitriptyline. Author(s): Zaninelli R, Bauer M, Jobert M, Muller-Oerlinghausen B. Source: Journal of Clinical Psychopharmacology. 2001 April; 21(2): 190-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11270916&dopt=Abstract
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Changing prescription patterns for lithium and valproic acid in old age: shifting practice without evidence. Author(s): Shulman KI, Rochon P, Sykora K, Anderson G, Mamdani M, Bronskill S, Tran CT. Source: Bmj (Clinical Research Ed.). 2003 May 3; 326(7396): 960-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727769&dopt=Abstract
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Chronic treatment with both lithium and sodium valproate may normalize phosphoinositol cycle activity in bipolar patients. Author(s): Silverstone PH, Wu RH, O'Donnell T, Ulrich M, Asghar SJ, Hanstock CC. Source: Human Psychopharmacology. 2002 October; 17(7): 321-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12415549&dopt=Abstract
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Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetylaspartate concentrations in euthymic bipolar patients. Author(s): Silverstone PH, Wu RH, O'Donnell T, Ulrich M, Asghar SJ, Hanstock CC. Source: International Clinical Psychopharmacology. 2003 March; 18(2): 73-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598817&dopt=Abstract
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Clinical performance characteristics of a new photometric lithium assay: a multicenter study. Author(s): Christenson RH, Mandichak JJ, Duh SH, Augustyn JM, Thompson JC. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003 January; 327(1-2): 157-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12482631&dopt=Abstract
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Cognitive-behavioral management of patients with bipolar disorder who relapsed while on lithium prophylaxis. Author(s): Fava GA, Bartolucci G, Rafanelli C, Mangelli L. Source: The Journal of Clinical Psychiatry. 2001 July; 62(7): 556-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11488368&dopt=Abstract
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Combination lithium and divalproex sodium in pediatric bipolarity. Author(s): Findling RL, McNamara NK, Gracious BL, Youngstrom EA, Stansbrey RJ, Reed MD, Demeter CA, Branicky LA, Fisher KE, Calabrese JR. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2003 August; 42(8): 895-901. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12874490&dopt=Abstract
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Combining lithium and anticonvulsants in bipolar disorder: a review. Author(s): Pies R. Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 2002 December; 14(4): 223-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630658&dopt=Abstract
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Comments on lithium toxicity. Author(s): Johnson G. Source: The Australian and New Zealand Journal of Psychiatry. 2002 October; 36(5): 703; Author Reply 703. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12225461&dopt=Abstract
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Comparison of patients hemodialyzed for lithium poisoning and those for whom dialysis was recommended by PCC but not done: what lesson can we learn? Author(s): Bailey B, McGuigan M. Source: Clinical Nephrology. 2000 November; 54(5): 388-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11105800&dopt=Abstract
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Comparison of three a priori methods and one empirical method in predicting lithium dosage requirements. Author(s): Wright R, Crismon ML. Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 2000 September 15; 57(18): 1698-702. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11006797&dopt=Abstract
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Concomitant neuroleptic malignant syndrome and lithium intoxication in a patient with bipolar I disorder: case report. Author(s): Lin PY, Wu CK, Sun TF. Source: Changgeng Yi Xue Za Zhi. 2000 October; 23(10): 624-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11126155&dopt=Abstract
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Connection between lithium and muscular incoordination. Author(s): Grounds D. Source: The Australian and New Zealand Journal of Psychiatry. 2002 February; 36(1): 142-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11929455&dopt=Abstract
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Control of occupational exposure to hexavalent chromium and ozone in tubular wire arc-welding processes by replacement of potassium by lithium or by addition of zinc. Author(s): Dennis JH, French MJ, Hewitt PJ, Mortazavi SB, Redding CA. Source: The Annals of Occupational Hygiene. 2002 January; 46(1): 33-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12005130&dopt=Abstract
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Correction for the adverse influence of sodium-potassium cotransport on apparent sodium-lithium countertransport activity in human erythrocytes. Author(s): Hardman TC, Morrish Z, Patel M, Chalkley S, Noble MI. Source: Journal of Pharmacological and Toxicological Methods. 2002 January-February; 47(1): 19-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12387935&dopt=Abstract
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Cortical myoclonus during lithium exposure. Author(s): Caviness JN, Evidente VG. Source: Archives of Neurology. 2003 March; 60(3): 401-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12633152&dopt=Abstract
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Coupled, but not uncoupled, fluxes in a neuronal glutamate transporter can be activated by lithium ions. Author(s): Borre L, Kanner BI. Source: The Journal of Biological Chemistry. 2001 November 2; 276(44): 40396-401. Epub 2001 July 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11479303&dopt=Abstract
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CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium. Author(s): Grimes CA, Jope RS. Source: Journal of Neurochemistry. 2001 September; 78(6): 1219-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11579131&dopt=Abstract
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Crystal structure of an enzyme displaying both inositol-polyphosphate-1phosphatase and 3'-phosphoadenosine-5'-phosphate phosphatase activities: a novel target of lithium therapy. Author(s): Patel S, Yenush L, Rodriguez PL, Serrano R, Blundell TL. Source: Journal of Molecular Biology. 2002 January 25; 315(4): 677-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11812139&dopt=Abstract
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Cyclic AMP responsive element binding protein phosphorylation and DNA binding is decreased by chronic lithium but not valproate treatment of SH-SY5Y neuroblastoma cells. Author(s): Wang JF, Asghari V, Rockel C, Young LT. Source: Neuroscience. 1999; 91(2): 771-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10366032&dopt=Abstract
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Cytotoxic effects of two gamma linoleic salts (lithium gammalinolenate or meglumine gammalinolenate) alone or associated with a nitrosourea: an experimental study on human glioblastoma cell lines. Author(s): Ilc K, Ferrero JM, Fischel JL, Formento P, Bryce R, Etienne MC, Milano G. Source: Anti-Cancer Drugs. 1999 April; 10(4): 413-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10378677&dopt=Abstract
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Daily headache as a manifestation of lithium intoxication. Author(s): Bigal ME, Bordini CA, Speciali JG. Source: Neurology. 2001 November 13; 57(9): 1733-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11706129&dopt=Abstract
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Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder. Author(s): Davanzo P, Thomas MA, Yue K, Oshiro T, Belin T, Strober M, McCracken J. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2001 April; 24(4): 359-69. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11182531&dopt=Abstract
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Decreased plasma prolactin release in euthymic lithium-treated women with bipolar disorder. Author(s): El Khoury A, Tham A, Mathe AA, Aberg-Wistedt A, Stain-Malmgren R. Source: Neuropsychobiology. 2003; 48(1): 14-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12886035&dopt=Abstract
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Dental conditions in patients with bipolar disorder on long-term lithium maintenance therapy. Author(s): Friedlander AH, Birch NJ. Source: Spec Care Dentist. 1990 September-October; 10(5): 148-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11100224&dopt=Abstract
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Detection of endogenous lithium in neuropsychiatric disorders--a model for biological transmutation. Author(s): Kurup RK, Kurup PA. Source: Human Psychopharmacology. 2002 January; 17(1): 29-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12404704&dopt=Abstract
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Determination of lithium in human serum by electrothermal atomic absorption spectrometry. Author(s): Gonzalez S, Navarro M, Lopez H, Lopez MC, Perez V. Source: J Aoac Int. 2000 March-April; 83(2): 377-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10772175&dopt=Abstract
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Development of an automated photometric assay for serum lithium and use of binding equilibrium expressions to optimize results. Author(s): Thompson JC. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003 January; 327(1-2): 149-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12482630&dopt=Abstract
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Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. Author(s): Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Source: The American Journal of Psychiatry. 1999 August; 156(8): 1264-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10450271&dopt=Abstract
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Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study. Author(s): Kleindienst N, Greil W. Source: Neuropsychobiology. 2000; 42 Suppl 1: 2-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11093063&dopt=Abstract
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Differential pharmacokinetics of lithium in elderly patients. Author(s): Sproule BA, Hardy BG, Shulman KI. Source: Drugs & Aging. 2000 March; 16(3): 165-77. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10803857&dopt=Abstract
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Discontinuation of lithium augmentation in an elderly cohort. Author(s): Fahy S, Lawlor BA. Source: International Journal of Geriatric Psychiatry. 2001 October; 16(10): 1004-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11607947&dopt=Abstract
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Discontinuing lithium maintenance treatment in bipolar disorders: risks and implications. Author(s): Baldessarini RJ, Tondo L, Viguera AC. Source: Bipolar Disorders. 1999 September; 1(1): 17-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11256650&dopt=Abstract
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Discrepancies in the efficacy of lithium. Author(s): Grof P, Alda M. Source: Archives of General Psychiatry. 2000 February; 57(2): 191. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10665623&dopt=Abstract
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Do clinicians understand why individuals stop taking lithium? Author(s): Pope M, Scott J. Source: Journal of Affective Disorders. 2003 May; 74(3): 287-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738048&dopt=Abstract
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Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder? Author(s): Rapoport SI, Bosetti F. Source: Archives of General Psychiatry. 2002 July; 59(7): 592-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12090811&dopt=Abstract
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Do vitamins or minerals (apart from lithium) have mood-stabilizing effects? Author(s): Popper CW. Source: The Journal of Clinical Psychiatry. 2001 December; 62(12): 933-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11780872&dopt=Abstract
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Does EEG predict response to valproate versus lithium in patients with mania? Author(s): Reeves RR, Struve FA, Patrick G. Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 2001 June; 13(2): 69-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11534927&dopt=Abstract
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Does effective lithium prophylaxis result in a symptom-free state of manic-depressive illness? Some thoughts on the fine-tuning of mood stabilization. Author(s): Muller-Oerlinghausen B. Source: Comprehensive Psychiatry. 2000 March-April; 41(2 Suppl 1): 26-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10746901&dopt=Abstract
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Does lithium exert an independent antisuicidal effect? Author(s): Ahrens B, Muller-Oerlinghausen B. Source: Pharmacopsychiatry. 2001 July; 34(4): 132-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11518473&dopt=Abstract
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Does lithium treatment still work? Evidence of stable responses over three decades. Author(s): Baldessarini RJ, Tondo L. Source: Archives of General Psychiatry. 2000 February; 57(2): 187-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10665622&dopt=Abstract
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Does topiramate elevate serum lithium levels? Author(s): Pinninti NR, Zelinski G. Source: Journal of Clinical Psychopharmacology. 2002 June; 22(3): 340. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12006910&dopt=Abstract
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Dopamine receptor D2 and D4 genes, GABA(A) alpha-1 subunit genes and response to lithium prophylaxis in mood disorders. Author(s): Serretti A, Lilli R, Lorenzi C, Franchini L, Di Bella D, Catalano M, Smeraldi E. Source: Psychiatry Research. 1999 July 30; 87(1): 7-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10512150&dopt=Abstract
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Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine. Author(s): Fava M, Alpert J, Nierenberg A, Lagomasino I, Sonawalla S, Tedlow J, Worthington J, Baer L, Rosenbaum JF. Source: Journal of Clinical Psychopharmacology. 2002 August; 22(4): 379-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12172337&dopt=Abstract
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Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Author(s): Bauer M, Bschor T, Kunz D, Berghofer A, Strohle A, Muller-Oerlinghausen B. Source: The American Journal of Psychiatry. 2000 September; 157(9): 1429-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10964859&dopt=Abstract
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Drug interactions of lithium and other antimanic/mood-stabilizing medications. Author(s): Dunner DL. Source: The Journal of Clinical Psychiatry. 2003; 64 Suppl 5: 38-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12720483&dopt=Abstract
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Drug research: the ups and downs of lithium. Author(s): Pilcher HR. Source: Nature. 2003 September 11; 425(6954): 118-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12968146&dopt=Abstract
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Dural sinus thrombosis with severe hypernatremia developing in a patient on longterm lithium therapy. Author(s): Kamijo Y, Soma K, Hamanaka S, Nagai T, Kurihara K. Source: Journal of Toxicology. Clinical Toxicology. 2003; 41(4): 359-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870877&dopt=Abstract
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Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data. Author(s): Perlis RH, Sachs GS, Lafer B, Otto MW, Faraone SV, Kane JM, Rosenbaum JF. Source: The American Journal of Psychiatry. 2002 July; 159(7): 1155-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12091193&dopt=Abstract
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Effect of lithium and sodium valproate ions on resting membrane potentials in neurons: an hypothesis. Author(s): Thiruvengadam A. Source: Journal of Affective Disorders. 2001 June; 65(1): 95-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11426517&dopt=Abstract
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Effect of lithium maintenance therapy on thyroid and parathyroid function. Author(s): Kusalic M, Engelsmann F. Source: Journal of Psychiatry & Neuroscience : Jpn. 1999 May; 24(3): 227-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10354657&dopt=Abstract
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Effect of lithium on growth of bone marrow stromal cells. Author(s): Huang W, Jiang D, Wang B, Wang Q. Source: Chinese Medical Journal. 1999 June; 112(6): 558-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11601339&dopt=Abstract
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Effect of lithium on phosphoinositide metabolism in human brain: a proton decoupled (31)P magnetic resonance spectroscopy study. Author(s): Yildiz A, Demopulos CM, Moore CM, Renshaw PF, Sachs GS. Source: Biological Psychiatry. 2001 July 1; 50(1): 3-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11457417&dopt=Abstract
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Effectiveness of haemodialysis with high-flux membranes in the extracorporeal therapy of life-threatening acute lithium intoxication. Author(s): Peces R, Pobes A. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2001 June; 16(6): 1301-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11390745&dopt=Abstract
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Effects of acute tryptophan depletion on mood and suicidal ideation in bipolar patients symptomatically stable on lithium. Author(s): Hughes JH, Dunne F, Young AH. Source: The British Journal of Psychiatry; the Journal of Mental Science. 2000 November; 177: 447-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11059999&dopt=Abstract
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Effects of chronic lithium treatment on the peripheral nervous system. Author(s): Faravelli C, Di Bernardo M, Ricca V, Benvenuti P, Bartelli M, Ronchi O. Source: The Journal of Clinical Psychiatry. 1999 May; 60(5): 306-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10362438&dopt=Abstract
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Effects of dextroamphetamine, lithium chloride, sodium valproate and carbamazepine on intraplatelet Ca2+ levels. Author(s): Ulrich ML, Rotzinger S, Asghar SJ, Jurasz P, Tanay VA, Dunn SM, Radomski M, Greenshaw A, Silverstone PH. Source: Journal of Psychiatry & Neuroscience : Jpn. 2003 March; 28(2): 115-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12670128&dopt=Abstract
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Effects of lithium addition on daily activity and psychiatric symptoms in schizophrenic inpatients. Author(s): Soya A, Terao T, Nakamura J. Source: J Uoeh. 2002 December 1; 24(4): 391-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12506855&dopt=Abstract
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Effects of lithium carbonate on hematopoietic cells in patients with persistent neutropenia following chemotherapy or radiotherapy. Author(s): Hager ED, Dziambor H, Winkler P, Hohmann D, Macholdt K. Source: Journal of Trace Elements in Medicine and Biology : Organ of the Society for Minerals and Trace Elements (Gms). 2002; 16(2): 91-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12195731&dopt=Abstract
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Effects of lithium on thrombopoiesis in patients with low platelet cell counts following chemotherapy or radiotherapy. Author(s): Hager ED, Dziambor H, Hohmann D, Winkler P, Strama H. Source: Biological Trace Element Research. 2001 November; 83(2): 139-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11762531&dopt=Abstract
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Effects of long-term lithium treatment on monoaminergic functions in major depression. Author(s): El Khoury A, Johnson L, Aberg-Wistedt A, Stain-Malmgren R. Source: Psychiatry Research. 2001 December 15; 105(1-2): 33-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11740973&dopt=Abstract
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Effects of rapid cycling on response to lithium maintenance treatment in 360 bipolar I and II disorder patients. Author(s): Baldessarini RJ, Tondo L, Floris G, Hennen J. Source: Journal of Affective Disorders. 2000 December; 61(1-2): 13-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11099736&dopt=Abstract
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Effects of short- and long-term lithium treatment on kidney functioning in patients with bipolar mood disorder. Author(s): Turan T, Esel E, Tokgoz B, Aslan S, Sofuoglu S, Utas C, Kelestimur F. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2002 April; 26(3): 561-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11999908&dopt=Abstract
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Effects of short and long-term lithium treatment on serum prolactin levels in patients with bipolar affective disorder. Author(s): Basturk M, Karaaslan F, Esel E, Sofuoglu S, Tutus A, Yabanoglu I. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2001 February; 25(2): 315-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11294478&dopt=Abstract
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Efficacy of continuous venovenous hemodialysis in the treatment of severe lithium toxicity. Author(s): Beckmann U, Oakley PW, Dawson AH, Byth PL. Source: Journal of Toxicology. Clinical Toxicology. 2001; 39(4): 393-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11527234&dopt=Abstract
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Efficacy of lithium treatment in Kleine-Levin syndrome. Author(s): Muratori F, Bertini N, Masi G. Source: European Psychiatry : the Journal of the Association of European Psychiatrists. 2002 July; 17(4): 232-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12231271&dopt=Abstract
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Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Author(s): Tohen M, Chengappa KN, Suppes T, Zarate CA Jr, Calabrese JR, Bowden CL, Sachs GS, Kupfer DJ, Baker RW, Risser RC, Keeter EL, Feldman PD, Tollefson GD, Breier A. Source: Archives of General Psychiatry. 2002 January; 59(1): 62-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11779284&dopt=Abstract
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Erythrocyte sodium lithium countertransport in heart transplantation. Author(s): Vareesangthip K, Thongtang V, Hanlakorn P, Pidetcha P, Suwannaton L, Ong-Aj-Yooth L. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3561-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11750515&dopt=Abstract
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Erythrocyte sodium-lithium countertransport and blood pressure: a genome-wide linkage study. Author(s): Weder AB, Delgado MC, Zhu X, Gleiberman L, Kan D, Chakravarti A. Source: Hypertension. 2003 March; 41(3 Pt 2): 842-6. Epub 2002 December 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624006&dopt=Abstract
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Erythrocyte sodium-lithium countertransport in African American women. Author(s): Hardman TC, Wierzbicki AS. Source: Journal of Human Hypertension. 2001 July; 15(7): 505-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11464263&dopt=Abstract
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Estimation of lithium dose requirement by body weight. Author(s): Lu ML, Shen WW, Chen KP. Source: Bipolar Disorders. 2002 August; 4(4): 274. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12190718&dopt=Abstract
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Evaluation of neuroprotection by lithium and valproic acid against ouabain-induced cell damage. Author(s): Hennion JP, el-Masri MA, Huff MO, el-Mailakh RS. Source: Bipolar Disorders. 2002 June; 4(3): 201-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12180275&dopt=Abstract
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Factors associated with patients' knowledge of and attitudes towards treatment with lithium. Author(s): Dharmendra MS, Eagles JM. Source: Journal of Affective Disorders. 2003 June; 75(1): 29-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781347&dopt=Abstract
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Family history of affective disorders and the significance for prophylactic effect of lithium treatment. Author(s): Nylander PO, Engstrom C, Nordqvist-Karlsson B, Astrom M. Source: Biological Psychiatry. 1999 April 15; 45(8): 1079-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10386198&dopt=Abstract
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Final report on the safety assessment of aluminum silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate, magnesium trisilicate, sodium magnesium silicate, zirconium silicate, attapulgite, bentonite, Fuller's earth, hectorite, kaolin, lithium magnesium silicate, lithium magnesium sodium silicate, montmorillonite, pyrophyllite, and zeolite. Author(s): Elmore AR; Cosmetic Ingredient Review Expert Panel. Source: International Journal of Toxicology. 2003; 22 Suppl 1: 37-102. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851164&dopt=Abstract
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Focal segmental glomerulosclerosis and lithium treatment. Author(s): Schreiner A, Waldherr R, Rohmeiss P, Hewer W. Source: The American Journal of Psychiatry. 2000 May; 157(5): 834. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10784485&dopt=Abstract
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Follicular mycosis fungoides associated with lithium. Author(s): Francis GJ, Silverman AR, Saleh O, Lee GJ. Source: Journal of the American Academy of Dermatology. 2001 February; 44(2): 308-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11174395&dopt=Abstract
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Fracture resistance of lithium disilicate-, alumina-, and zirconia-based three-unit fixed partial dentures: a laboratory study. Author(s): Tinschert J, Natt G, Mautsch W, Augthun M, Spiekermann H. Source: Int J Prosthodont. 2001 May-June; 14(3): 231-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11484570&dopt=Abstract
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Fracture strength of all-ceramic lithium disilicate and porcelain-fused-to-metal bridges for molar replacement after dynamic loading. Author(s): Chitmongkolsuk S, Heydecke G, Stappert C, Strub JR. Source: Eur J Prosthodont Restor Dent. 2002 March; 10(1): 15-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12051127&dopt=Abstract
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Genetic analysis of lithium-associated parathyroid tumors. Author(s): Dwight T, Kytola S, Teh BT, Theodosopoulos G, Richardson AL, Philips J, Twigg S, Delbridge L, Marsh DJ, Nelson AE, Larsson C, Robinson BG. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2002 May; 146(5): 619-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11980616&dopt=Abstract
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Genomic association/linkage of sodium lithium countertransport in CEPH pedigrees. Author(s): Schork NJ, Gardner JP, Zhang L, Fallin D, Thiel B, Jakubowski H, Aviv A. Source: Hypertension. 2002 November; 40(5): 619-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12411453&dopt=Abstract
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Glycogen synthase kinase-3 inhibition by lithium and beryllium suggests the presence of two magnesium binding sites. Author(s): Ryves WJ, Dajani R, Pearl L, Harwood AJ. Source: Biochemical and Biophysical Research Communications. 2002 January 25; 290(3): 967-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11798168&dopt=Abstract
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Goiter in a newborn exposed to lithium in utero. Author(s): Frassetto F, Tourneur Martel F, Barjhoux CE, Villier C, Bot BL, Vincent F. Source: The Annals of Pharmacotherapy. 2002 November; 36(11): 1745-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12398572&dopt=Abstract
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G-protein beta3-subunit gene variant, blood pressure and erythrocyte sodium/lithium countertransport in essential hypertension. Author(s): Poch E, Gonzalez-Nunez D, Compte M, De la Sierra A. Source: British Journal of Biomedical Science. 2002; 59(2): 101-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12113397&dopt=Abstract
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Guidelines for lithium monitoring: are they ideal? Author(s): Gupta N. Source: Acta Psychiatrica Scandinavica. 2001 July; 104(1): 76-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11437756&dopt=Abstract
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Have we undersold lithium for bipolar disorder? Author(s): Pies R. Source: Journal of Clinical Psychopharmacology. 2002 October; 22(5): 445-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12352265&dopt=Abstract
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Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children. Author(s): Meyer RJ, Flynn JT, Brophy PD, Smoyer WE, Kershaw DB, Custer JR, Bunchman TE. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2001 May; 37(5): 1044-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11325688&dopt=Abstract
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Hemodialysis reversal of lithium overdose cardiotoxicity. Author(s): Newland KD, Mycyk MB. Source: The American Journal of Emergency Medicine. 2002 January; 20(1): 67-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11781927&dopt=Abstract
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Herbal diuretics and lithium toxicity. Author(s): Pyevich D, Bogenschutz MP. Source: The American Journal of Psychiatry. 2001 August; 158(8): 1329. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11481175&dopt=Abstract
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High concentrations of lithium heparin decrease measured serum sodium in some analyzers. Author(s): Vuillaume I, Penet S, Rakza T, Storme L, Kacet N, Lequien P, Rousseaux J. Source: Clinical Chemistry. 1999 October; 45(10): 1880-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10508144&dopt=Abstract
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High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure. Author(s): Kupka RW, Nolen WA, Post RM, McElroy SL, Altshuler LL, Denicoff KD, Frye MA, Keck PE Jr, Leverich GS, Rush AJ, Suppes T, Pollio C, Drexhage HA. Source: Biological Psychiatry. 2002 February 15; 51(4): 305-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11958781&dopt=Abstract
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How effective is long-term lithium prophylaxis? Author(s): Vestergaard P. Source: Acta Psychiatrica Scandinavica. 2000 May; 101(5): 341-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10823291&dopt=Abstract
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How long should the lithium augmentation strategy be maintained? A 1-year followup of a placebo-controlled study in unipolar refractory major depression. Author(s): Bschor T, Berghofer A, Strohle A, Kunz D, Adli M, Muller-Oerlinghausen B, Bauer M. Source: Journal of Clinical Psychopharmacology. 2002 August; 22(4): 427-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12172345&dopt=Abstract
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How should findings on antisuicidal effects of lithium be integrated into practical treatment decisions? Author(s): Muller-Oerlinghausen B. Source: European Archives of Psychiatry and Clinical Neuroscience. 2003 June; 253(3): 126-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904976&dopt=Abstract
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Human red blood cells from prenatal hemopoiesis. Lithium flux (sodium dependent) asymmetry. Author(s): Corchs JL, Taborda D, Serrani RE. Source: Biocell. 2000 December; 24(3): 233-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11201659&dopt=Abstract
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Human sodium-coupled citrate transporter, the orthologue of Drosophila Indy, as a novel target for lithium action. Author(s): Inoue K, Zhuang L, Maddox DM, Smith SB, Ganapathy V. Source: The Biochemical Journal. 2003 August 15; 374(Pt 1): 21-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826022&dopt=Abstract
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Hypothalamic-pituitary-thyroid system activity during lithium augmentation therapy in patients with unipolar major depression. Author(s): Bschor T, Baethge C, Adli M, Lewitzka U, Eichmann U, Bauer M. Source: Journal of Psychiatry & Neuroscience : Jpn. 2003 May; 28(3): 210-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790161&dopt=Abstract
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Identification of three polymorphisms in the translated region of PLC-gamma1 and their investigation in lithium responsive bipolar disorder. Author(s): Ftouhi-Paquin N, Alda M, Grof P, Chretien N, Rouleau G, Turecki G. Source: American Journal of Medical Genetics. 2001 April 8; 105(3): 301-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11353454&dopt=Abstract
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In vitro immunoregulatory effects of lithium in healthy volunteers. Author(s): Maes M, Song C, Lin AH, Pioli R, Kenis G, Kubera M, Bosmans E. Source: Psychopharmacology. 1999 April; 143(4): 401-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10367558&dopt=Abstract
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Increased gray matter volume in lithium-treated bipolar disorder patients. Author(s): Sassi RB, Nicoletti M, Brambilla P, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC. Source: Neuroscience Letters. 2002 August 30; 329(2): 243-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12165422&dopt=Abstract
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Increased lithium dose requirement in a hyperglycemic patient. Author(s): Cyr M, Guia MA, Laizure SC. Source: The Annals of Pharmacotherapy. 2002 March; 36(3): 427-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11898805&dopt=Abstract
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Increased red cell sodium-lithium countertransport and lymphocyte cytosolic calcium are separate phenotypes in patients with essential hypertension. Author(s): Romero JR, Rivera A, Monari A, Ceolotto G, Semplicini A, Conlin PR. Source: Journal of Human Hypertension. 2002 May; 16(5): 353-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12082497&dopt=Abstract
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Inhibition of 20 S and 26 S proteasome activity by lithium chloride: impact on the differentiation of leukemia cells by all-trans retinoic acid. Author(s): Rice AM, Sartorelli AC. Source: The Journal of Biological Chemistry. 2001 November 16; 276(46): 42722-7. Epub 2001 September 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11555654&dopt=Abstract
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Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. Author(s): Zhang F, Phiel CJ, Spece L, Gurvich N, Klein PS. Source: The Journal of Biological Chemistry. 2003 August 29; 278(35): 33067-77. Epub 2003 June 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796505&dopt=Abstract
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Initial lithium and valproate combination therapy in acute mania. Author(s): Reischies FM, Hartikainen J, Berghofer A. Source: Neuropsychobiology. 2002; 46 Suppl 1: 22-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571429&dopt=Abstract
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Initial triple therapy of acute mania, adding lithium and valproate to neuroleptics. Author(s): Reischies FM, Hartikainen J, Berghofer AM. Source: Pharmacopsychiatry. 2002 November; 35(6): 244-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12518274&dopt=Abstract
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Inositol, lithium, and the brain. Author(s): Agranoff BW, Fisher SK. Source: Psychopharmacology Bulletin. 2001 Summer; 35(3): 5-18. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397875&dopt=Abstract
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Intensive treatment with lithium carbonate “once a day” in bipolar patients. Author(s): Tondo L, Tagliamonte A, Ghiani C, Mercenaro S. Source: Clin Ter. 2001 September-October; 152(5): 277-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11794846&dopt=Abstract
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Interaction of lithium with 5-HT(1B) receptors in depressed unipolar patients treated with clomipramine and lithium versus clomipramine and placebo: preliminary results. Author(s): Januel D, Massot O, Poirier MF, Olie JP, Fillion G. Source: Psychiatry Research. 2002 August 30; 111(2-3): 117-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12374629&dopt=Abstract
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Interaction of serotonin and melatonin with sodium, potassium, calcium, lithium and aluminium. Author(s): Lack B, Daya S, Nyokong T. Source: Journal of Pineal Research. 2001 September; 31(2): 102-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11555164&dopt=Abstract
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Interactions between lithium and non-steroidal antiinflammatory drugs. Author(s): Monji A, Maekawa T, Miura T, Nishi D, Horikawa H, Nakagawa Y, Tashiro N. Source: Clinical Neuropharmacology. 2002 September-October; 25(5): 241-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410052&dopt=Abstract
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Inter-episodic morbidity and drop-out under carbamazepine and lithium in the maintenance treatment of bipolar disorder. Author(s): Kleindienst N, Greil W. Source: Psychological Medicine. 2002 April; 32(3): 493-501. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11989994&dopt=Abstract
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Is lithium response related to G(s)alpha levels in transformed lymphoblasts from subjects with bipolar disorder? Author(s): Alda M, Keller D, Grof E, Turecki G, Cavazzoni P, Duffy A, Rouleau GA, Grof P, Young LT. Source: Journal of Affective Disorders. 2001 July; 65(2): 117-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11356234&dopt=Abstract
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Is lithium sill the gold standard in the treatment of bipolar disorders? Author(s): Moller HJ. Source: European Archives of Psychiatry and Clinical Neuroscience. 2003 June; 253(3): 113-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12938683&dopt=Abstract
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Is lithium still worth using? An update of selected recent research. Author(s): Baldessarini RJ, Tondo L, Hennen J, Viguera AC. Source: Harvard Review of Psychiatry. 2002 March-April; 10(2): 59-75. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11897747&dopt=Abstract
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Is response to prophylactic lithium a familial trait? Author(s): Grof P, Duffy A, Cavazzoni P, Grof E, Garnham J, MacDougall M, O'Donovan C, Alda M. Source: The Journal of Clinical Psychiatry. 2002 October; 63(10): 942-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416605&dopt=Abstract
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Is there a loss of efficacy of lithium in patients treated for over 20 years? Author(s): Berghofer A, Muller-Oerlinghausen B. Source: Neuropsychobiology. 2000; 42 Suppl 1: 46-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11093072&dopt=Abstract
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John Cade and lithium. Author(s): Walter G. Source: Psychiatric Services (Washington, D.C.). 1999 July; 50(7): 969. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10402625&dopt=Abstract
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John Cade and the discovery of lithium treatment for manic depressive illness. Author(s): Mitchell PB, Hadzi-Pavlovic D. Source: The Medical Journal of Australia. 1999 September 6; 171(5): 262-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10495760&dopt=Abstract
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John Cade's seminal lithium paper turns fifty. Author(s): Schioldann J. Source: Acta Psychiatrica Scandinavica. 1999 December; 100(6): 403-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10626917&dopt=Abstract
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John Frederick Joseph Cade: family memories on the occasion of the 50th anniversary of his discovery of the use of lithium in mania. 1949. Author(s): Cade JF. Source: The Australian and New Zealand Journal of Psychiatry. 1999 October; 33(5): 6158 and 4 Pages Following. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10544983&dopt=Abstract
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Latency and episodes before treatment: response to lithium maintenance in bipolar I and II disorders. Author(s): Baldessarini RJ, Tondo L, Hennen J, Floris G. Source: Bipolar Disorders. 1999 December; 1(2): 91-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11252665&dopt=Abstract
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Latest maintenance data on lithium in bipolar disorder. Author(s): Goodwin GM, Geddes JR. Source: European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 2003 August; 13 Suppl 2: S51-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957720&dopt=Abstract
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Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Author(s): Jope RS. Source: Trends in Pharmacological Sciences. 2003 September; 24(9): 441-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12967765&dopt=Abstract
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Lithium and synaptic plasticity. Author(s): Salinas PC, Hall AC. Source: Bipolar Disorders. 1999 December; 1(2): 87-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11252664&dopt=Abstract
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Lithium augmentation in treatment-refractory unipolar depression. Author(s): Lee W, Cleare A. Source: The British Journal of Psychiatry; the Journal of Mental Science. 2003 May; 182: 456; Author Reply 456-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724254&dopt=Abstract
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Lithium augmentation in venlafaxine-refractory depression. Author(s): Zullino D, Preisig M, Baumann P. Source: Journal of Clinical Psychopharmacology. 2001 April; 21(2): 242-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11270926&dopt=Abstract
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Lithium augmentation therapy in refractory depression-update 2002. Author(s): Bauer M, Forsthoff A, Baethge C, Adli M, Berghofer A, Dopfmer S, Bschor T. Source: European Archives of Psychiatry and Clinical Neuroscience. 2003 June; 253(3): 132-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904977&dopt=Abstract
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Lithium combinations in acute and maintenance treatment of unipolar and bipolar depression. Author(s): Fawcett JA. Source: The Journal of Clinical Psychiatry. 2003; 64 Suppl 5: 32-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12720482&dopt=Abstract
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Lithium effects on neutrophil motility in Shwachman-Diamond syndrome: evaluation by computer-assisted image analysis. Author(s): Azzara A, Carulli G, Petrini M. Source: British Journal of Haematology. 2003 October; 123(2): 369-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14531925&dopt=Abstract
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Lithium for schizophrenia. Author(s): Leucht S, McGrath J, Kissling W. Source: Cochrane Database Syst Rev. 2003; (3): Cd003834. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917990&dopt=Abstract
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Lithium gluconate 8% vs ketoconazole 2% in the treatment of seborrhoeic dermatitis: a multicentre, randomized study. Author(s): Dreno B, Chosidow O, Revuz J, Moyse D; THE STUDY INVESTIGATOR GROUP. Source: The British Journal of Dermatology. 2003 June; 148(6): 1230-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828753&dopt=Abstract
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Lithium in the acute treatment of bipolar disorders-a stocktaking. Author(s): Grunze H. Source: European Archives of Psychiatry and Clinical Neuroscience. 2003 June; 253(3): 115-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904974&dopt=Abstract
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Lithium in the long-term treatment of bipolar disorders. Author(s): Kleindienst N, Greil W. Source: European Archives of Psychiatry and Clinical Neuroscience. 2003 June; 253(3): 120-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904975&dopt=Abstract
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Lithium intoxication after administration of AT1 blockers. Author(s): Zwanzger P, Marcuse A, Boerner RJ, Walther A, Rupprecht R. Source: The Journal of Clinical Psychiatry. 2001 March; 62(3): 208-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11305712&dopt=Abstract
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Lithium intoxication due to carbamazepine-induced renal failure. Author(s): Mayan H, Golubev N, Dinour D, Farfel Z. Source: The Annals of Pharmacotherapy. 2001 May; 35(5): 560-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11346062&dopt=Abstract
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Lithium sensitizes tumor cells in an NF-kappa B-independent way to caspase activation and apoptosis induced by tumor necrosis factor (TNF). Evidence for a role of the TNF receptor-associated death domain protein. Author(s): Schotte P, Van Loo G, Carpentier I, Vandenabeele P, Beyaert R. Source: The Journal of Biological Chemistry. 2001 July 13; 276(28): 25939-45. Epub 2001 May 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11342564&dopt=Abstract
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Lithium therapy at the millennium: a revolutionary drug used for 50 years faces competing options and possible demise. Author(s): Fieve RR. Source: Bipolar Disorders. 1999 December; 1(2): 67-70. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11252660&dopt=Abstract
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Lithium treatment and suicide risk in major affective disorders: update and new findings. Author(s): Baldessarini RJ, Tondo L, Hennen J. Source: The Journal of Clinical Psychiatry. 2003; 64 Suppl 5: 44-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12720484&dopt=Abstract
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Lithium treatment of acute mania in adolescents: a large open trial. Author(s): Kafantaris V, Coletti DJ, Dicker R, Padula G, Kane JM. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2003 September; 42(9): 1038-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12960703&dopt=Abstract
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Lithium-associated psoriasis and omega-3 fatty acids. Author(s): Akkerhuis GW, Nolen WA. Source: The American Journal of Psychiatry. 2003 July; 160(7): 1355. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12832259&dopt=Abstract
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Maintenance of retinoic acid receptor alpha pools by granulocyte colony-stimulating factor and lithium chloride in all-trans retinoic acid-treated WEHI-3B leukemia cells: relevance to the synergistic induction of terminal differentiation. Author(s): Finch RA, Li J, Chou TC, Sartorelli AC. Source: Blood. 2000 September 15; 96(6): 2262-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10979975&dopt=Abstract
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Mania pre-lithium. Author(s): Cawte J. Source: The Australian and New Zealand Journal of Psychiatry. 1999 December; 33 Suppl: S7-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10622174&dopt=Abstract
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Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium. Author(s): Turecki G, Grof P, Grof E, D'Souza V, Lebuis L, Marineau C, Cavazzoni P, Duffy A, Betard C, Zvolsky P, Robertson C, Brewer C, Hudson TJ, Rouleau GA, Alda M. Source: Molecular Psychiatry. 2001 September; 6(5): 570-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11526471&dopt=Abstract
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Maternal lithium therapy and neonatal morbidity. Author(s): Zegers B, Andriessen P. Source: European Journal of Pediatrics. 2003 May; 162(5): 348-9. Epub 2003 February 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692718&dopt=Abstract
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Melancholic features and response to lithium prophylaxis in mood disorders. Author(s): Serretti A, Lattuada E, Franchini L, Smeraldi E. Source: Depression and Anxiety. 2000; 11(2): 73-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10812532&dopt=Abstract
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Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks. Author(s): Lenox RH, Wang L. Source: Molecular Psychiatry. 2003 February; 8(2): 135-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12610644&dopt=Abstract
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Molecular targets of lithium action. Author(s): Phiel CJ, Klein PS. Source: Annual Review of Pharmacology and Toxicology. 2001; 41: 789-813. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11264477&dopt=Abstract
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Mortality in 497 patients with affective disorders attending a lithium clinic or after having left it. Author(s): Kallner G, Lindelius R, Petterson U, Stockman O, Tham A. Source: Pharmacopsychiatry. 2000 January; 33(1): 8-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10721878&dopt=Abstract
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Nephrogenic diabetes insipidus persisting 57 months after cessation of lithium carbonate therapy: report of a case and review of the literature. Author(s): Guirguis AF, Taylor HC. Source: Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2000 July-August; 6(4): 3248. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11242610&dopt=Abstract
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Neurobiological findings before and during successful lithium therapy of a patient with 48-hour rapid-cycling bipolar disorder. Author(s): Voderholzer U, Weske G, Ecker S, Riemann D, Gann H, Berger M. Source: Neuropsychobiology. 2002; 45 Suppl 1: 13-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11893872&dopt=Abstract
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Neuroleptic malignant syndrome associated with amoxapine and lithium in an older adult. Author(s): Cochrane Database Syst Rev. 2002;(2):CD001867 Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 2000 June; 12(2): 107-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12076425
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Neuroleptic malignant syndrome following administration of risperidone and lithium. Author(s): Bourgeois JA, Kahn DR. Source: Journal of Clinical Psychopharmacology. 2003 June; 23(3): 315-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826996&dopt=Abstract
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Neuroleptic malignant syndrome in an adolescent receiving olanzapine-lithium combination therapy. Author(s): Berry N, Pradhan S, Sagar R, Gupta SK. Source: Pharmacotherapy. 2003 February; 23(2): 255-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587815&dopt=Abstract
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Neutrophil peripheral count and human leukocyte elastase during chronic lithium carbonate therapy. Author(s): Capodicasa E, Russano AM, Ciurnella E, De Bellis F, Rossi R, Scuteri A, Biondi R. Source: Immunopharmacology and Immunotoxicology. 2000 November; 22(4): 671-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11105780&dopt=Abstract
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New trial should clarify lithium use in bipolar disorder. Author(s): Geddes J, Goodwin G, Rendell J, Hainsworth J, Van der Gucht E, Young H. Source: Bmj (Clinical Research Ed.). 2002 August 24; 325(7361): 441. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12193365&dopt=Abstract
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Nonconvulsive status epilepticus from accidental lithium ingestion. Author(s): Roccatagliata L, Audenino D, Primavera A, Cocito L. Source: The American Journal of Emergency Medicine. 2002 October; 20(6): 570-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12369038&dopt=Abstract
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Nonketotic hyperosmolar syndrome from olanzapine, lithium, and valproic acid cotreatment. Author(s): Chen PS, Yang YK, Yeh TL, Lo Y
