Major Depressive Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

MAJOR DEPRESSIVE DISORDER A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FER...

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MAJOR

DEPRESSIVE DISORDER 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., 1960Major Depressive Disorder: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00696-0 1. Major Depressive Disorder-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.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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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 major depressive disorder. 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 MAJOR DEPRESSIVE DISORDER ................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Major Depressive Disorder ........................................................... 4 The National Library of Medicine: PubMed ................................................................................ 63 CHAPTER 2. NUTRITION AND MAJOR DEPRESSIVE DISORDER ..................................................... 109 Overview.................................................................................................................................... 109 Finding Nutrition Studies on Major Depressive Disorder........................................................ 109 Federal Resources on Nutrition ................................................................................................. 110 Additional Web Resources ......................................................................................................... 110 CHAPTER 3. ALTERNATIVE MEDICINE AND MAJOR DEPRESSIVE DISORDER .............................. 113 Overview.................................................................................................................................... 113 National Center for Complementary and Alternative Medicine................................................ 113 Additional Web Resources ......................................................................................................... 119 General References ..................................................................................................................... 120 CHAPTER 4. DISSERTATIONS ON MAJOR DEPRESSIVE DISORDER ................................................ 121 Overview.................................................................................................................................... 121 Dissertations on Major Depressive Disorder............................................................................. 121 Keeping Current ........................................................................................................................ 122 CHAPTER 5. PATENTS ON MAJOR DEPRESSIVE DISORDER ........................................................... 123 Overview.................................................................................................................................... 123 Patents on Major Depressive Disorder ...................................................................................... 123 Patent Applications on Major Depressive Disorder .................................................................. 124 Keeping Current ........................................................................................................................ 126 CHAPTER 6. PERIODICALS AND NEWS ON MAJOR DEPRESSIVE DISORDER ................................. 127 Overview.................................................................................................................................... 127 News Services and Press Releases.............................................................................................. 127 Academic Periodicals covering Major Depressive Disorder ...................................................... 129 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 133 Overview.................................................................................................................................... 133 NIH Guidelines.......................................................................................................................... 133 NIH Databases........................................................................................................................... 135 Other Commercial Databases..................................................................................................... 137 APPENDIX B. PATIENT RESOURCES ............................................................................................... 139 Overview.................................................................................................................................... 139 Patient Guideline Sources.......................................................................................................... 139 Finding Associations.................................................................................................................. 141 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 143 Overview.................................................................................................................................... 143 Preparation................................................................................................................................. 143 Finding a Local Medical Library................................................................................................ 143 Medical Libraries in the U.S. and Canada ................................................................................. 143 ONLINE GLOSSARIES................................................................................................................ 149 Online Dictionary Directories ................................................................................................... 149 MAJOR DEPRESSIVE DISORDER DICTIONARY ............................................................... 151 INDEX .............................................................................................................................................. 201

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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 major depressive disorder 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 major depressive disorder, 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 major depressive disorder, 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 major depressive disorder. 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 major depressive disorder, 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 major depressive disorder. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON MAJOR DEPRESSIVE DISORDER Overview In this chapter, we will show you how to locate peer-reviewed references and studies on major depressive disorder.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and major depressive disorder, 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 “major depressive disorder” (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: •

Major Depressive Disorder: Psychopathology, Medical Management and Dental Implications Source: JADA. Journal of the American Dental Association. 132(5): 629-638. May 2001. Contact: Available from American Dental Association. ADA Publishing Co, Inc., 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2867. Website: www.ada.org. Summary: This article familiarizes dental practitioners with major depressive disorder (MDD), a psychiatric illness in which mood, thoughts, and behavioral patterns are impaired for long periods. The illness distresses the person and impairs his or her social functioning and quality of life. MDD is characterized by marked sadness or a loss of interest or pleasure in daily activities, and is accompanied by weight change, sleep

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Major Depressive Disorder

disturbance, fatigue, difficulty concentrating, physical impairment, and a high suicide rate. In 2000, the World Health Organization (WHO) identified MDD as the fourth ranked cause of disability and premature death in the world. The disorder is common in the United States, with a life time prevalence rate of 17 percent and a recurrence rate of more than 50 percent. MDD may be associated with extensive dental disease, and people may seek dental treatment before becoming aware of their psychiatric illness. MDD frequently is associated with a disinterest in performing appropriate oral hygiene techniques, a cariogenic (cavity promoting) diet, diminished salivary flow (xerostomia), rampant dental caries, advanced periodontal disease, and oral dysesthesias (numbness, tingling, burning, or pain). Many medications used to treat MDD magnify the xerostomia (dry mouth) and increase the incidence of dental disease. Appropriate dental management requires a vigorous dental education program, the use of saliva substitutes and anticaries agents containing fluorides, and special precautions when prescribing or administering analgesics and local anesthetics. Dentists cognizant of these signs and symptoms have an opportunity to recognize patients with occult (hidden) MDD. After confirmation of the diagnosis and institution of treatment by a mental health practitioner, dentists usually can provide a full range of services that may enhance patients' self-esteem and contribute to the psychotherapeutic aspect of management. 1 figure. 4 tables. 74 references. •

Independent Factors Associated with Major Depressive Disorder in a National Sample of Individuals with Diabetes Source: Diabetes Care. 26(1): 104-111. January 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study undertaken to determine whether perceived poor physical health, duration of diabetes, and smoking are associated with major depressive disorder in a national sample of individuals with diabetes. Data on 1,810 individuals with diabetes from the 1999 National Health Interview Survey (NHIS) were analyzed. Independent factors associated with major depressive disorder were age greater than 64 years, female sex, at least high school education, income less than 124 percent of federal poverty level, perceived worsening of health status, and smoking. The authors conclude that in addition to other psychosocial factors such as younger age, female sex, lower income, and smoking, perceptions about the effect of diabetes on overall health seems to play an important role in the etiology of depression. 4 tables. 47 references.

Federally Funded Research on Major Depressive Disorder The U.S. Government supports a variety of research studies relating to major depressive disorder. 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.

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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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 major depressive disorder. 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 major depressive disorder. The following is typical of the type of information found when searching the CRISP database for major depressive disorder: •

Project Title: ADVANCED NEUROIMAGING: ETHICAL, LEGAL, AND SOCIAL ISSUES Principal Investigator & Institution: Illes, Judy; Center for Biomedical Ethics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2006 Summary: (provided by investigator) New capabilities of advanced neuroimaging technology have created the possibility of evaluating and predicting complex human behavior and disease in unprecedented ways. Our work to date has demonstrated a steady expansion of studies with evident social and policy implications, including studies of human cooperation and competition, moral reasoning, self-control, brain differences in violent people, genetic influences, and variability in patterns of brain development. Akin to genetic testing in the 1990s, such capabilities raise ethical issues about the conduct of research, clinical practice, and communication of information to the public. The overall goal of the present research, therefore, is to delineate the challenges introduced by these capabilities, focusing on functional magnetic resonance imaging (fMRI) as a model. Specifically, (Aim 1) in the research domain, we will identify emerging trends in human neuroimaging studies that have ethical, legal and social implications through focus groups, surveys and personal interviews with neuroimagers, stakeholders, and a multidisciplinary Advisory Board, and disseminate our findings and recommendations broadly. In conjunction, we will also publish a casebook of anomalous functional brain activation findings identified in research participants recruited to studies as healthy controls. (Aims 2 and 3) Building on Aim 1 and the methodological promise of fMRI in two major clinical areas, we will identify the benefits and risks of functional neuroimaging in providing quantitative diagnostic confirmation of mental illness, using Major Depressive Disorder as the model. We will examine how practitioners anticipate that functional activation images will change their practice patterns and how patients anticipate that images will change their perception about their own condition. We will further identify ethical challenges in predicting subclinical disease with fMRI, using Alzheimer's Disease (AD) as the model, and consider the medical and social consequences of prediction using functional neuroimaging, predictive imaging for different clinical AD subgroups, and informed consent, access and cost, issues of privacy, counseling and education. Results of our work will reach scholars, professional and patient-advocacy groups across the neurosciences, bioethics, law and policy communities, and the media, and promote responsible communication and use of complex new information about human behavior represented by visual images of brain function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AGE RELATED HIPPOCAMPAL ATROPHY IN RECURRENT MAJOR DEPRESSIVE DISORDER Principal Investigator & Institution: Sheline, Yvette I.; Associate Professor; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: The project "Age-related hippocampal atrophy in recurrent major depression" seeks to define the nature of changes in brain structures due to recurrent episodes of depression. It is hypothesized that recurrent depression may accelerate normal hippocampal aging, perhaps through neuronal glucocorticoid toxicity resulting from depression- induced hypercortisolemia. A cross-sectional study of 40medically healthy patients with recurrent early onset major depression and 40 case-matched normal controls will test for differences in regional brain structure volumes, cognitive function, HPA axis function, and clinical variables. In addition, recent studies have found bone density loss in depressed women relative to controls. It is unclear whether this was caused by differences in cortisol or in estrogen status. We will ezamine both cortisol and estrogen status as well as bone density in our sample. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANIMAL DEPRESSION

MODELS OF CHILDHOOD AND ADOLESCENT

Principal Investigator & Institution: Bylund, David B.; Professor and Chair; Pharmacology; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2003; Project Start 14-AUG-2003; Project End 31-MAY-2006 Summary: (provided by applicant): Major Depressive Disorder (clinical depression) is a severe and potentially incapacitating mental illness that is common in children and adolescents, with an estimated lifetime prevalence of 15 -20 % in this population. An important difference between clinical depression in children and adolescents, as compared to adults, is its response to antidepressant drugs. Tricyclic antidepressants have not been shown to be effective in treatment of child and adolescent clinical depression. Although antidepressant drugs have numerous neurochemical actions, the therapeutic mechanisms of action of antidepressant drugs in relieving depression remain unknown. In non-depressed persons antidepressant drugs are not euphoriant or stimulant. Therefore, investigations related to which of the many neurochemical effects of antidepressant drugs are functionally related to their therapeutic efficacy in relieving depression requires research using a behavioral animal model of clinical depression. To better understand the neurobiology underlying the differences between children and adolescents, and adults in the response to pharmacological treatment of clinical depression, animal models of childhood and adolescent depression are needed. Currently, there are no established juvenile animal models of clinical depression. Although the models developed in adult animals can serve as a starting point, they must be adapted and validated in juvenile animals due the many differences between juvenile and adult animals. The overall goal of this proposal is to assess the validity and usefulness of two well-established rat animal models of adult clinical depression as models of childhood and adolescent clinical depression. Specifically, we propose to assess the usefulness of the forced-swim test and of learned helplessness as animal models for clinical depression in juvenile rats. The key questions which are addressed by this proposal are: 1) Do juvenile rats respond to antidepressant drugs with decreased immobility in the forced swim? 2) Do juvenile rats develop learned helplessness after inescapable stress in both the acute and persistent paradigms, as demonstrated by

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shuttlebox testing? 3) Do juvenile rats respond to antidepressant drugs in the both acute and persistent learned helplessness paradigms with decreased escape latencies in shuttlebox testing? Ultimately, the models may facilitate a better understanding of the underlying neurobiology of clinical depression, and serve as predictive measures of antidepressant efficacy in children and adolescents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIDEPRESSANT & CBT FOR INSOMNIA TO DEPRESSION OUTCOME Principal Investigator & Institution: Manber, Rachel; Acting Associate Professor; Psychiatry and Behavioral Sci; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2006 Summary: (provided by applicant): Context: The purpose of the proposed Exploratory/Developmental R21 Grant is to pilot test a combined treatment of an antidepressant medication and cognitive-behavioral therapy for insomnia (CBTi) in patients with depressive disorders who have concomitant difficulty initiating and/or maintaining sleep. The proposed combined approach targets the patients' insomnia, because this common depression symptom is often associated with less favorable outcome of standard treatment and with increased risk of relapse. Specific aims: 1) To test whether the proposed intervention improves response to acute treatment (12 weeks) for depression, as measured the percent of patients who remit and the time course to remission, relative to the control treatment; 2) To test whether the proposed citalopram + CBTI intervention enhances longer-term outcome by reducing the proportion of participants who relapse during a 6-months follow-up phase, relative to the control treatment. Research Design and Method: In this prospective, randomized, controlled study, participants will be randomized to receive 12 weeks of acute treatment with the SSRI citalopram plus either CBTI or a validated, placebo psychotherapy for insomnia. Participants will be followed-up for 6 months after the end of acute treatment phase. Participants will be transitioned to community care during the first follow-up month. Participants: Participants will be 58 men and women ages 18 to 65 who 1) meet DSM-IV criteria for Major Depressive Disorder; 2) have a score greater than or equal to14 on the first 17 items of the 24-item Hamilton Depression Rating Scale (HRSD); 3) have difficulty initiating sleep (sleep onset latency > 30 minutes) and/or maintaining sleep (wake after sleep onset > 30 minutes per night at least 3 nights per week), to be confirmed by one week of sleep diary recording. Participants will also have to meet all study exclusion criteria. The ethnic distribution of the sample will be representative of the ethnic distribution in the San Francisco Bay Area. Women-to-men ratio is expected to be 2:1 as it is the case for depression. Main Outcome Measure(s): The primary outcome measures are the HRSD and the depression portion of the SCIDIV, to be administered at baseline, at the end of weeks 1, 2, 4, 8, and 12 of the acute phase, and at the end of 1, 2, 3, and 6 months of the follow-up phase. Other important measures include the Beck Depression Inventory (weekly), measures of sleep (diaries and wrist activity monitors, weekly) and measures of provider and patient expectations, adherence, and compliance. Expected Outcomes: We hypothesize that the group of patients who receive the combination of citalopram and CBTI will have higher remission and partial response rates following acute treatment and lower relapse rates during follow-up as compared to the group that receive citalopram and placebo psychotherapy for insomnia. The study will assess the feasibility and acceptability of the combination of the two treatments and will provide estimates of effect sizes, and attrition rate. The findings from the proposed pilot study will inform the design of a subsequent full-scale randomized controlled trial.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIDEPRESSANT USE DURING PREGNANCY Principal Investigator & Institution: Wisner, Katherine L.; Professor; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 15-AUG-1999; Project End 31-JUL-2005 Summary: Women of childbearing age are at high risk for major depressive disorder (MDD). The lifetime risk for MDD in community samples has varied from 10-25 percent for women, with peak prevalence between 25-44 years of age. Despite these facts, information to guide women and physicians through a consideration of antidepressant use during pregnancy is limited. The American Psychiatric Association Committee on Research on Psychiatric Treatments identified MDD during pregnancy as a priority area for generation of treatment recommendations. In addition to separation of the effects of exposure to drug from exposure to MDD less than the work group identified areas in which data are urgently needed: 1) whether minor physical anomalies occur with greater frequency in drug-exposed infants, 2) if maternal weight gain and infant birth weight are compromised by drug exposure, 3) replication of the sole study which addresses behavioral teratogenicity, and 4) management strategies to reduce neonatal toxicity. Obtaining this information is the impetus for this grant application. The antidepressants to be investigated are the serotonin specific reuptake inhibitors (SSRI), because these agents have become first-line treatments for MDD. The study is a 5-year prospective, naturalistic investigation of the effects of treatment of pregnant women with SSRI. Three groups of mothers will be recruited over the first three years of the study and they and their children will be followed for 24 months post-birth. The pregnant women: 1) treated with an SSRI who are nondepressed, 2) with MDD who do not take SSRI, and 3) without MDD or SSRI treatment. Data from this investigation will increase our sophistication in making risk-benefit decisions during pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AUTONOMIC DYSREGULATION IN PRIMARY INSOMNIA Principal Investigator & Institution: Richardson, Gary S.; Senior Research Scientist; Behavioral Services; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp-046 Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Chronic insomnia is a disorder afflicting as many as 10 percent of adults in the US, a substantial proportion of whom have no identifiable underlying cause for the sleep complaint, i.e. primary insomnia (PI). Several lines of evidence implicate central sympathetic nervous system (SNS) dysregulation in the pathogenesis of PI. First, patients with this disorder show evidence of SNS arousal, including increased basal metabolic rates, elevated circulating catecholamines, and increased daytime alertness relative to the degree of nocturnal sleep disruption. Along with the SNS, the hypothalamic pituitary adrenal (HPA) axis is also hyperactive in insomnia, implicating a central mechanism common to both axes. Second, epidemiological studies establish a strong link between patients with PI and patients with major depressive disorder (MDD), also characterized by central activation of the SNS and HPA axes. Third, corticotropic releasing factor (CRF), a link between the SNS and HPA axes implicated in the pathogenesis of MDD, causes sleep disruption and hyper-arousal when centrally administered in animal models. In this proposal, we present a model of primary insomnia in which the pathogenic mechanism of this

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disorder is hypothesized to be dysregulation of central CRF neurons, specifically the delayed restoration of normal CRF levels following stress. This model provides a conceptual foundation for 1) the temporal (intermittent) pattern of manifest sleep disruption in patients with underlying tendency to P1; 2) the link between insomnia and stress; 3) the epidemiological link between MDD and P1; and 4) the hyper-arousal in PI with activation of SNS and HPA axes. It also provides a focus for future therapeutic efforts for this important disorder, suggesting that antagonists of CRF may be useful in reversing insomnia, and in blocking the processes that eventuate in MDD. We propose three experiments to test the CRF model and some of its predictions. In the first experiment, we will examine the status of the SNS and HPA axes in patients with P1, and the clinical correlates of SNS-HPA activation in this population. Second, we will assess the role of the CRF-SNS response in perpetuating insomnia by comparing the effects of sleep disruption (audio tones) in patients with P1 and normal controls, using sleep continuity, urinary catecholamines, daytime function, and subsequent sleep as dependent measures. Finally, we will use a new measure of central CRF function, the DEX-sleep latency test, to test the hypothesis that central CRF tone is higher in patients with P1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BEHAVIORAL AND IMMUNOLOGICAL FACTORS IN CORONARY DISEASE Principal Investigator & Institution: Kop, Willem J.; Assistant Professor; Henry M. Jackson Fdn for the Adv Mil/Med Rockville, Md 20852 Timing: Fiscal Year 2002; Project Start 06-JUL-2001; Project End 31-MAY-2006 Summary: adapted from Investigator's abstract) Recent studies demonstrate that the immune system plays an important role in coronary artery disease (CAD). Research also shows that psychological factors such as major depressive disorder and acute mental stress are involved in the clinical progression of CAD. Depression is associated with higher levels of immune parameters that play a role in CAD (cytokines, markers of low grade inflammation, infectious pathogen burden, and adhesion molecules), and most of these measures also increase in response to acute physical and mental stress. The pathophysiological mechanisms linking depression and mental stress with adverse cardiovascular outcomes may therefore be mediated by immunological factors. The proposed research will examine clinical outcomes in patients who undergo percutaneous coronary revascularization, because a major problem remains the frequent (20 percent-40 percent) occurrence of coronary restenosis and new cardiac events in the 6 months after the intervention. These adverse outcomes have substantial impact on the costs of medical care and patients' quality of life. Since previous research has not examined the role of behaviorally-induced changes in immune parameters in the prediction of CAD progression, the following immunological measures will be examined: cytokines (IL-1B, IL-4, IL-6, IFNy, TNFa), acute phase proteins (CRP, fibrinogen), lymphocyte counts and differential, adhesion molecules (ICAM-1, LFA, Lselectin), and a composite measure of pathogen burden (CNV, H. pylori, C. pneumoniae). Using a longitudinal design, this project will determine the time course of changes in depression and changes in immune parameters. Moreover, the present study will determine the contribution of behavioral and immunological factors in the clinical progression of coronary disease following coronary angioplasty. These data may therefore improve the identification of patients at risk for recurrent cardiac events and restenosis after coronary angioplasty, and provide further understanding of the pathophysiological mechanisms involved in coronary disease progression.

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Project Title: BRAIN CHEMISTRY AND TREATMENT RESPONSE IN PEDIATRIC MDD Principal Investigator & Institution: Rosenberg, David R.; Professor; Psychiatry & Behav Neuroscis; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 16-AUG-2001; Project End 31-JUL-2006 Summary: (Provided by applicant): In recent years, there has been increased recognition of adolescent major depressive disorder (MDD) as a severe, highly prevalent and chronically disabling disorder. By most measures, adolescent MDD is continuous with adult MDD, including clinical course, secular trends, and psychobiologic correlates. Studies of the illness during adolescence can, therefore, clarify the contribution of neurodevelopmental abnormalities to the pathogenesis of the disorder. Neurobiological models for MDD have consistently implicated temporo-limbic, prefrontal cortical and basal ganglia circuits in the pathophysiology of the disorder. Strikingly, children and adolescents with MDD have been largely overlooked in brain imaging studies. In particular, there are no published studies using magnetic resonance spectroscopy (MRS) to investigate brain chemistry in depressed children and adolescents. Yet the inclusion of children and adolescents in these types of studies is critical in order to determine whether abnormalities in brain chemistry in depressed patients are the consequence of altered development over the life span, or if they are present even early in development thus representing a risk factor for subsequent development of depression. Preliminary studies by the applicants using MRS suggest increased caudate and anterior cingulate choline concentrations in psychotropic-naive pediatric MDD patients compared to age and sex matched controls. No differences in choline levels were observed between MDD patients and controls in occipital cortex choline levels. Pilot studies showed reductions in caudate but not occipital choline concentrations after 12 weeks of effective monotherapy with the selective serotonin reuptake inhibitor (SSRI) paroxetine. In this project, proton MRS will be used for the direct, in vivo and noninvasive evaluation and comparison of the impact of paroxetine vs. cognitive behavioral therapy (CBT) on brain chemistry as related to treatment efficacy in adolescents with MDD. Such an approach will help 1) determine whether psychotropic-naive adolescents with MDD differ from healthy controls in neurochemistry and 2) determine whether effective treatment with paroxetine and CBT results in localized and treatment-specific changes in brain chemistry. An understanding of the neurochemical disturbances in MDD may be important for the development of new treatment approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BRIEF ALCOHOL INTERVENTION WITH DEPRESSED PATIENTS Principal Investigator & Institution: Ramsey, Susan E.; Assistant Professor (Research); Rhode Island Hospital (Providence, Ri) Providence, Ri 029034923 Timing: Fiscal Year 2003; Project Start 05-SEP-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Heavy alcohol consumption is common among patients seeking treatment for depression. Heavy drinking is associated with a variety of medical and psychosocial problems. Heavy drinking is particularly problematic among depressed patients, increasing the likelihood of poor depression treatment outcomes. While methods for reducing alcohol use in this population have been unexplored to date, brief interventions to reduce heavy alcohol use have been well-validated in numerous patient populations and offer the promise to reduce heavy drinking among

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depressed patients and to improve depression treatment outcomes. We hypothesize that adding a brief alcohol intervention to standard psychiatric care, relative to standard psychiatric care alone, will reduce overall drinking volume and heavy drinking days among heavy-drinking depressed patients. Furthermore, we expect patients who receive the brief alcohol intervention to have better depression outcomes than patients receiving standard psychiatric care alone. We also expect that reduced alcohol consumption will mediate the effect of the brief alcohol intervention on depression outcomes. In addition, we will examine individual difference variables as predictors of change in alcohol use. The proposed study is a randomized, two-group design with repeated measures over time, comparing a brief, motivationally-focused alcohol intervention plus standard psychiatric care to standard psychiatric care alone. For this study, we will recruit a sample of 240 psychiatry clinic outpatients meeting structured diagnostic criteria for major depressive disorder who drink heavily but are not alcohol dependent. We expect that the results of this study will improve depression treatment outcomes for the significant sub-population of depressed patients who drink heavily and are likely to do poorly in depression treatment in the absence of a change in their drinking behavior. The intervention proposed in this study represents a novel approach to reducing heavy drinking among depressed patients that, if effective, can be readily integrated into depression treatment in a variety of treatment settings. In addition, this study will provide valuable information on the association between alcohol use and depression outcomes and on the mechanisms of change in alcohol use among heavy-drinking depressed patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BUPROPION IN ADOLESCENTS WITH COMORBID ADHD & DEPRESSION Principal Investigator & Institution: Daviss, William B.; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 06-DEC-2002; Project End 30-NOV-2007 Summary: (provided by applicant): Attention deficit hyperactivity disorders (ADHD) in youth occur comorbidly with other psychiatric conditions approximately two thirds of the time. Major depressive disorder and dysthymic depression are common, occurring in as many as 40% of youth with ADHD. The comorbid occurrence of ADHD and depression (ADHD + Dep) may cause substantial long-term morbidity. While psychopharmacology is widely used to treat juvenile ADHD and/or depression, no research has established an efficacious treatment for ADHD + Dep, or for most other comorbid ADHD disorders. This five year Mentored Patient-Oriented Research Career Development Award (RCDA) will provide the candidate, a board certified child and adolescent psychiatrist, training to undertake pharmacological trials of youth with ADHD and comorbid disorders. The candidate has had extensive previous clinical experience and some research experience in the pharmacological treatment of juvenile ADHD + Dep. The RCDA will provide the candidate formal training in pharmacology, clinical trial design, and statistical analyses as well as the empirical assessment of juvenile ADHD, depression, and other comorbid psychopathology. The candidate will also receive training in ethical issues germane to juvenile psychopharmacology studies. Training will occur through a combination of formal coursework, guided readings, and consultation with mentors having relevant expertise. This training will be applied in a pharmacologic study of adolescents with ADHD and depression (major depression, dysthymia). The protocol will consist of a 2-week washout/observational period, then an 8-week randomized, placebo-controlled trial (RCT) to determine the efficacy of

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bupropion SR. Then a 24-week open label continuation phase will be used to determine if treatment response and tolerability persist. Exploratory analyses will assess correlations of initial treatment response with both pharmacological variables (plasma levels of bupropion and its metabolites; noradrenergic and dopaminergic effects as estimated by reuptake blockade of rat synaptosomes) and psychosocial variables (baseline psychopathology and psychosocial impairment). The candidate' s training and research experiences during the RCDA will enable him to pursue larger, more scientifically rigorous pharmacologic trials of youth with ADHD and depressive or other comorbid psychopathology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CBT FOR HIV MEDICATION ADHERENCE AND DEPRESSION Principal Investigator & Institution: Safren, Steven A.; Assistant Professor, Harvard Medical Sch; Fenway Community Health Center 7 Haviland St Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2005 Summary: (provided by applicant): Introduction: This is an amended application to develop a cognitive-behavioral therapy for HIV medication adherence and major depression. Depression is prevalent in HIV and is associated with poor self-care behaviors including poor adherence to antiretroviral medications. Patients with HIV and depression are at risk for poor health outcomes and possibly increased morbidity. Cognitive-behavioral therapy is the most widely studied and efficacious psychosocial intervention for depression. Overview of project goals and conceptual model of intervention: The main goal of this project is to complete NIH-defined stage 1 activities in developing a cognitive behavioral intervention for depression and ART medication adherence. We propose to estimate the effect size of the intervention on improved depression, improved adherence to medications, and improved health status as defined by a clinically significant reduction in HIV viral load. Following the goals of the R21 mechanism, this will allow for the collection of the necessary pilot data to conduct a fullscale intervention study. We hypothesize that the psychosocial intervention will achieve improved health status in two ways: by directly increasing adherence to antiretroviral medications using the adherence skills training, and by treating the depression which otherwise makes it difficult for patients to acquire or use these adherence skills. Overview of research plan: Patients with a detectable viral load who have a diagnosis of major depressive disorder will be randomized into either: (1) "CBT," the combination of CBT for depression and HIV medication adherence or (2)"Enhanced Clinical Management," a single-session adherence intervention (Safren et al., 1999, 2001). Those who are assigned to Enhanced Clinical Management will be re-assigned to CBT after the acute phase of the study (4 months) if they have not improved on key outcome variables. Eligibility requirements at this stage of treatment development were selected to maximize the chances of finding an effect with a circumscribed sample (and minimizing the possibility of a type-II error). This will allow for an adequate power analysis for a full-scale intervention trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHILDHOOD DEPRESSION: REMISSION AND RELAPSE Principal Investigator & Institution: Emslie, Graham J.; Professor, Chair, and Director; Psychiatry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-APR-1986; Project End 30-JUN-2005

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Summary: (Adapted from Applicant's Abstract): Major depressive disorder (MDD) in children and adolescents is a serious psychiatric disorder causing substantial morbidity and mortality. Until recently the lack of clear empirical evidence of effective pharmacological treatment for acute treatment has made irrelevant research on the efficacy of continuation treatment. Having completed a double-blind placebo controlled trial of fluoxetine in MDD, this application aims to extend our work in the psychopharmacological treatment of MDD in children and adolescents, by studying a) the effectiveness of continuation of medical treatment; b) social school, family and cognitive outcomes following acute treatment and continuation treatment; and c) predictors of treatment non-response and relapse. The proposed study will consist of two phases; acute open treatment (12 weeks) and randomized placebo controlled discontinuation (6 months). Two hundred child and adolescent outpatients (ages 8-18 years) with MDD following a two week diagnostic evaluation, will be treated with fluoxetine (10-40mg) for 12 weeks. Responders of acute treatment (n=120) will be randomized to pill placebo or to continue same dose of fluoxetine, and will be followed for an additional 24 weeks. The primary outcome variable will be response to acute treatment and relapse during continuation phase treatment. There have been no studies of need for continuation treatment in depression in the pediatric age group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COGNITIVE THERAPY FOR HIGH RISK & REFRACTORY DEPRESSION Principal Investigator & Institution: Jarrett, Robin B.; Professor; Psychiatry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-DEC-1998; Project End 30-NOV-2003 Summary: This request for an Independent Scientist Award (KO2) fosters the candidate's research proficiency in personality disorders and treatment development within the context of three randomized clinical trials (RCTs) on the efficacy of cognitive therapy (CT) in reducing the likelihood of mood disorders in high risk or refractory outpatients. Project 1 (an ongoing R01) compares continuation phase CT (C-CT) to evaluation only (control) in reducing the risk of relapse during the first eight months following response to acute phase CT in outpatients with recurrent major depressive disorder (MDD). Approximately 156 male and female outpatients, aged 18-65, have entered 20 sessions of acute phase CT. Approximately 84 responders were randomized to either 8 months of: (a) 10 C-CT sessions, or (b) 10 evaluation only (control sessions); subjects are followed for an additional 16 months CT free. Relapse/recurrence (DSM IF MDD) is assessed by a blind evaluator using the LIFE at 4, 8, 12, and 24 months postacute phase CT and at suspected relapse/recurrence, or exit. Project 2 is a proposed, multi-site collaboration with University of Pittsburgh (Western Psychiatric Institute and Clinic; WPIC). This blinded, controlled RCT will evaluate the efficacy of and indications for eight months of C-CT, pharmacotherapy (the standard of care) (FLX: fluoxetine), and pill placebo (PBO: the control) in outpatients with recurrent MDD who are at higher risk for relapse/recurrence. "Higher risk" is a score >6 on the Hamilton Rating Scale for Depression (HRS-D) during the last six weeks of acute phase CT, while "lower risk" is defined as a score of 6 or less. The primary hypotheses is that higher risk patients who receive either C-CT or FLX have a longer time until relapse than higher risk patients who receive acute phase CT only plus PBO. The lower risk patients will be followed for 24 months without CT and are predicted to have a 20% relapse/recurrence rate in the first 8 months after acute phase CT. Project 3 is a proposed, multi-site collaboration with WPIC comparing the differential efficacy of a trial of: (a) FLX and (b) FLX plus CT in

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outpatients with recurrent MDD who were refractory to 20 sessions of acute phase CT. Blind evaluation of outcome will aid in testing the prediction that combination therapy is more efficacious for refractory depression than FLX alone. The KO2 focuses the candidate on (a) identifying the residual symptoms and social impairment remaining after CT and (b) designing treatment sequences to restore full functioning. These RCTs have great public health significance because they will help identify (a) when CT reduces the risk of relapse-recurrence for patients suffering from recurrent MDD, an illness with high morbidity and mortality, and (b) if refractory MDD is best treated with combination therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEPRESSION

COGNITIVE-BEHAVIORAL

APPROACHES

TO

SEASONAL

Principal Investigator & Institution: Rohan, Kelly J.; Assistant Professor; Henry M. Jackson Fdn for the Adv Mil/Med Rockville, Md 20852 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2004 Summary: (provided by applicant): Seasonal affective disorder (SAD), a recurrent fallwinter depression with periods of remission in spring and summer, is a highly prevalent mental health problem, especially at Northern latitudes. Although remission rates vary across studies, it is estimated that a significant minority (i.e., as many as 40-50% of SAD sufferers) is refractory to treatment with light therapy--the "gold standard" for SAD treatment. Alternative and/or supplementary treatments are needed. Cognitivebehavioral therapy (CBT) is effective for non-seasonal Major Depressive Disorder, but has not been adequately explored in the case of SAD. Our preliminary work suggests that individuals with SAD demonstrate a negative cognitive style, behavioral withdrawal, and rumination, and further research on cognitive-behavioral models for SAD is needed. Our pilot work further suggests that CBT, alone or combined with light, may be as effective as light alone in reducing acute SAD symptoms and may have more durable effects than light therapy into the subsequent winter season (Rohan et al., 2001; 2002). In an apparent synergistic effect, the combination of CBT and light therapy together produced superior remission rates to either treatment alone at post-treatment and at one-year follow-up. Two studies are proposed to explore cognitive-behavioral models and treatments for SAD. STUDY 1 expands our pilot study by increasing sample size, adding a control group, and employing a longer-term follow-up. It involves a comparison of light therapy, CBT, their combined "synergistic" effects, and a minimal contact/delayed treatment control in treating a current SAD episode over a six-week trial. Light therapy will be administered according to standard protocol. Manualized CBT will be conducted in groups, meeting twice a week. Indices of symptom severity and remission and relapse rates will be examined throughout the winter and during the summer. To examine the prophylactic value of these treatments, participants from our ongoing pilot study will be assessed for symptom severity and presence of a Major Depressive Episode during the winter (i.e., one year following treatment completion). STUDY 2 compares individuals with SAD, those with non-seasonal depression, and never-depressed controls on various cognitive-behavioral factors including automatic thoughts, dysfunctional attitudes, schemata, rumination, activity frequency and enjoyment, and reactivity to light-related stimuli. The proposed studies will contribute to the development of CBT approaches to SAD and to understanding interactions between biological and psychological factors in SAD symptomatology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COLLABORAIVE LONGITUDINAL STUDY OF PERSONALITY DISORDERS Principal Investigator & Institution: Gunderson, John G.; Professor; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2002; Project Start 01-MAR-1996; Project End 31-MAY-2005 Summary: APPLICANT'S ABSTRACT): This application is a revision of an application for 5 years continuation that was submitted in 1999. At that time a one year extension was awarded; this application is for four years. The overall aim of this study is to provide a comprehensive picture of the course and outcome of four specific personality disorders (PDs): schizotypal (STPD), borderline (BPD), avoidant (AVPD), and obsessivecompulsive (OCPD). The present application continues a multi-site collaborative effort to follow a carefully diagnosed sample of 668 subjects having either these representative PDs or major depressive disorder (MDD) (controls) for the period from 3 to a maximum of 6 years after recruitment. Sixty new minority subjects will be recruited and followed for at least 2 years. Using a prospective, longitudinal, repeated measures design, we will develop the same basic knowledge about course and outcome for the PDs that has previously resulted from similar investigations of affective and anxiety disorders, thus addressing an important gap in our knowledge. The extended period of follow-up is essential to discern clinically meaningful descriptions of course and outcome and their determinants. The sample is large enough and sufficiently diverse demographically to attain a unique array of results generalizable to most clinical settings. To accomplish our overall aim, we propose three approaches: I. descriptive, II. predictive, and III. validating. The descriptive approach will provide data on diagnostic stability of PDs, on presence and course of comorbid Axis I disorders, on persistence of functional impairment, and on utilization of health care resources that allow comparison between the PDs and to similar data on Axis I disorders. The predictive approach will identify clinically meaningful determinants of prognosis within and across PDs. The validating approach will examine the homogeneity of descriptive and longitudinal features for the PDs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COLLABORATIVE LONGITUDINAL STUDY OF PERSONALITY DISORDER Principal Investigator & Institution: Skodol, Andrew E.; Professor; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 100321098 Timing: Fiscal Year 2002; Project Start 01-MAR-1996; Project End 31-MAY-2005 Summary: APPLICANT'S ABSTRACT): This application is a revision of an application for 5 years continuation that was submitted in 1999. At that time a one year extension was awarded; this application is for four years. The overall aim of this study is to provide a comprehensive picture of the course and outcome of four specific personality disorders (PDs): schizotypal (STPD), borderline (BPD), avoidant (AVPD), and obsessivecompulsive (OCPD). The present application continues a multi-site collaborative effort to follow a carefully diagnosed sample of 668 subjects having either these representative PDs or major depressive disorder (MDD) (controls) for the period from 3 to a maximum of 6 years after recruitment. Sixty new minority subjects will be recruited and followed for at least 2 years. Using a prospective, longitudinal, repeated measures design, we will develop the same basic knowledge about course and outcome for the PDs that has previously resulted from similar investigations of affective and anxiety disorders, thus addressing an important gap in our knowledge. The extended period of follow-up is

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essential to discern clinically meaningful descriptions of course and outcome and their determinants. The sample is large enough and sufficiently diverse demographically to attain a unique array of results generalizable to most clinical settings. To accomplish our overall aim, we propose three approaches: I. descriptive, II. predictive, and III. validating. The descriptive approach will provide data on diagnostic stability of PDs, on presence and course of comorbid Axis I disorders, on persistence of functional impairment, and on utilization of health care resources that allow comparison between the PDs and to similar data on Axis I disorders. The predictive approach will identify clinically meaningful determinants of prognosis within and across PDs. The validating approach will examine the homogeneity of descriptive and longitudinal features for the PDs, as defined by the categorical DSM system, and how this compares with alternative dimensional schemes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COLLABORATIVE LONGITUDINAL STUDY OF PERSONALITY DISORDER Principal Investigator & Institution: Shea, M Tracie.; Associate Professor; Psychiatry and Human Behavior; Brown University Box 1929 Providence, Ri 02912 Timing: Fiscal Year 2002; Project Start 01-MAR-1996; Project End 31-MAY-2005 Summary: (APPLICANT'S ABSTRACT): The overall aim of this study is to provide a comprehensive picture of the course and outcome of four specific personality disorders (PDs): schizotypal (STPD), borderline (BPD), avoidant (AVPD), and obsessivecompulsive (OCPD). The present application continues a multi-site collaborative effort to follow a carefully diagnosed sample of 668 subjects having either these representative PDs or major depressive disorder (MDD) (controls) for the period from 3 to a maximum of 6 years after recruitment. Sixty new minority subjects will be recruited and followed for at least 2 years. Using a prospective, longitudinal, repeated measures design, we will develop the same basic knowledge about course and outcome for the PDs that has previously resulted from similar investigations of affective and anxiety disorders, thus addressing an important gap in our knowledge. The extended period of follow-up is essential to discern clinically meaningful descriptions of course and outcome and their determinants. The sample is large enough and sufficiently diverse demographically to attain a unique array of results generalizable to most clinical settings. To accomplish our overall aim, we propose three approaches: I. descriptive, II. predictive, and III. validating. The descriptive approach will provide data on diagnostic stability of PDs, on presence and course of comorbid Axis I disorders, on persistence of functional impairment, and on utilization of health care resources that allow comparison between the PDs and to similar data on Axis I disorders. The predictive approach will identify clinically meaningful determinants of prognosis within and across PDs. The validating approach will examine the homogeneity of descriptive and longitudinal features for the PDs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEPRESSION AND BRAIN METABOLISM Principal Investigator & Institution: Iosifescu, Dan V.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 03-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): In this application for an NIMH Mentored PatientOriented Research Career Development Award (K-23), the candidate proposes to

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develop expertise in the study of major depressive disorder (MDD), clinical evaluation of treatment response, and brain energy metabolism. The research component of this proposal involves an open, acute and prospective follow-up of subjects with MDD treated with citalopram. Several studies utilizing phosphorus-31 magnetic resonance spectroscopy (P31-MRS) have shown that subjects with MDD, compared with healthy volunteers, appear to have decreased brain levels of several compounds characteristic for the cellular high-energy phosphorus metabolism. However, no studies to date report measurements before and after treatment. We propose to study MDD subjects who respond to antidepressant treatment, MDD subjects refractory to antidepressant treatment, and healthy volunteers. We will use P-31 MRS to measure brain levels of phosphorus compounds at baseline, two weeks into treatment and at the end of treatment (in order to separate the brain metabolic effects of antidepressant medications from the effects of MDD). We aim to correlate brain levels of high-energy phosphorus compounds with the clinical symptoms of MDD and the clinical response to antidepressant treatment. The study outlined here has the potential to advance our knowledge on the pathophysiology of MDD. With the K-23 Award, the candidate seeks to gain expertise in: (1) designing and carrying out clinical trials for MDD, (2) biostatistical methods, and (3) magnetic resonance spectroscopy techniques as applied to clinical trials. The career development plan in this proposal includes a rich, multidisciplinary didactic component, with coursework in research design and biostatistics at the Harvard School of Public Health, magnetic resonance imaging at the Massachusetts Institute of Technology, and research ethics. The integrated research study and career development plan outlined here will lay the foundations for future independent investigation by the candidate in this area. The development of a larger scale R01 project investigating the role of brain energy metabolism in a population of treatment-resistant subjects with MDD will be started during the last two years of the award period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEPRESSION AND PRODUCTIVE WORK ACTIVITY Principal Investigator & Institution: Lerner, Debra J.; Associate Professor; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2002; Project Start 08-SEP-2000; Project End 31-AUG-2004 Summary: (Applicant's abstract): While depression is a leading cause of work disability in this nation, disability reduction efforts remain hampered by a lack of research. This study's long-term goal is to prevent work disability due to depression. A longitudinal study is proposed that addresses on-the-job work disability among employed primary care patients with depression. The sample will include 350 patients who have Major Depressive Disorder (MDD) and/or dysthymia and are employed at baseline, and two comparison groups: 1)) 200 workers with rheumatoid arthritis (PA), a physically limiting condition with one of the highest work disability rates; and 2) 100 "healthy" controls. The study has 3 specific aims: 1) to prospectively assess and compare the rates at which four types of work disabilities (job loss, work time loss, reduced work hours and on-the-job limitations) occur among the groups; 2) to identify variables that contribute to successful and unsuccessful work outcomes among patients with depression; 3) to determine whether the variables that contribute to work disability are the same for depression and RA. The project's health-relatedness is its focus on a major public health problem (work disability due to depression) within an increasingly important segment of the mental health care delivery system (primary care). Subjects will be recruited from primary care practices, 18-62 years of age, employed at baseline

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and not planning to stop working for at least 2 years. Data will be collected from patient surveys (baseline and months 3, 6, 12 and 18), patient charts and clinic pharmacy records. We will also administer a new validated survey instrument; The Work Limitations Questionnaire, which assesses on-the-job performance and productivity and, thus, captures aspects of work disability not reflected in job loss and absenteeism data. The statistical analysis will: 1) establish the magnitude of the four types of work disability and work productivity costs within the depression sample); 2) identify variables that predict work disability or a sustained ability to work; and 3) determine the differential impact of a mental and a physical illness on work disability rates, the predictors of work disability and productivity costs. Study results will contribute to the design of disability prevention and productivity improvement programs and policies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEPRESSION/METABOLIC SYNDROME IN MEXICAN-AMERICAN WOMEN. Principal Investigator & Institution: Licinio, Julio; Professor of Psychiatry and Medicine/En; Psychiatry & Biobehav Sciences; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): This grant application has been developed to test the hypothesis that insulin resistance and hyperglycemic trends parallel plasma cortisol levels in major depressive disorder (MDD). We will also test the more focused hypothesis that treatment of depressive symptoms ameliorates state of insulin resistance. We will approach these hypotheses by studying depressed MexicanAmerican women from a rigorously characterized cohort of patients who have been recruited into our NIGMS-funded project in pharmacogenomics of antidepressant treatment response (GM61394). This application builds on the enormous resource provided by that prospective study, which provides the opportunity to recruit and treat these individuals. That project is a carefully designed, prospective clinical phase IIA randomized longitudinal study, using two pharmacological agents (desipramine and fluoxetine) with demonstrated efficacy in the treatment of MDD in the MexicanAmerican population. Clinical status is assessed with clinical interview and ratings such as the Hamilton Ratings Scale for Depression, Beck Depression Inventory, and Hamilton Anxiety Rating Scale. These instruments have been extensively validated in Spanish. That project is a treatment study with single- and double-masking, with random assignment of treatment, and with outcomes assessed with clinical measures. All subjects will undergo comprehensive intake assessments, and will then have follow-up assessments. Treatment will be provided according to our approved protocol. We propose to conduct detailed endocrine, nutritional, and metabolic studies in normalweight Mexican-American women, who are otherwise medically healthy and who will be extensively characterized for our pharmacogenomic study. This proposal will permit the ascertainment of degree of insulin resistance in MDD through the assessment of endocrine (HPA axis and leptin measurements), nutritional, body composition, and metabolic function (insulin sensitivity will be assessed by oral glucose tolerance test, glucose clamp and arginine stimulation test) before and after treatment. Treatment outcome data will be correlated with endocrine and metabolic endpoints. Several lines of evidence suggest diabetes mellitus is often associated with depression and that depression increases the risk of developing diabetes. This work will address this important area by the study of an population group who is markedly under represented in patient-oriented investigation.

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Project Title: DEVELOPMENTAL DEPRESSED TWINS

NEUROMORPHOMETRY

IN

YOUNG

Principal Investigator & Institution: Botteron, Kelly N.; Assistant Professor of Psychiatry; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 02-FEB-2001; Project End 31-JAN-2006 Summary: Early onset major depressive disorder (MDD) is highly heritable and associated with structural changes in prefrontal-limbic-striatal circuit structures. In young adult females with early onset MDD, the investigators have demonstrated structural differences in the subgenual prefrontal cortex(SGPFC) and amygdala. Specifically we and others have demonstrated reduced volume in the left SGPFC and the right amygdala. Their pilot studies provide evidence that the contributions of genetic and environmental influences differ between the two regions. In recent studies of monozygotic twins discordant for MDD, the investigators have demonstrated that 1) left SGPFC volume reduction in MDD is consistently present in the twin with MDD in comparison to their unaffected co-twin and 2) right amygdala volume reduction and loss of usual amygdala asymmetry is demonstrated in both twins. Thus, they currently have evidence for at least two types of findings: structural changes which are present in ill twins (reduced left SGPFC) and changes which are present in at risk twins (amygdala). They hypothesize that these structural differences may be neurodevelopmental in origin and secondary to environmental or genetic factors, respectively. An alternative hypothesis is that these changes may be secondary to the illness process and represent a neurodegenerative or "scar " phenomenon. Relevant to the neurodevelopmental hypothesis, they have recently demonstrated significant age related increases in SGPFC volume in normal 8 to 21 year old girls in a cross-sectional design. The investigators propose a study examining an sample of epidemiologically ascertained young twins using high resolution MRI in order to examine four interrelated goals: 1) to quantify differences in prefrontal-limbic circuit neuromorphometry in young females with MDD; 2) to characterize neurodevelopmental or neurodegenerative patterns of change in these circuits using a prospective longitudinal design; 3) to estimate through twin genetic modeling the contribution of additive genetic or environmental influences to observed structural differences; and 4) to increase the power of neuromorphometric characterization through the use of automated cortex extraction methods and high-dimensional fluid warping in order to precisely delineate shape changes between subject populations and across developmental time periods. The twin subjects derive from a large established epidemiologically ascertained sample of female twins born in Missouri. The investigation of a twin population will allow for the direct estimation of genetic and environmental contributions to structural changes and developmental changes noted longitudinally. The combination of cutting edge genetic modeling and automated image analysis with newer sophisticated shape analysis offers a unique constellation of resources which will allow for a powerful exploration of the above hypotheses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DOPAMINE FUNCTION IN SOCIAL PHOBIA & RELATED CONDITIONS Principal Investigator & Institution: Schneier, Franklin R.; Associate Professor; Psychiatry; Columbia University Health Sciences Po Box 49 New York, Ny 10032

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Timing: Fiscal Year 2002; Project Start 06-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The overall goal of this proposal is to support the continuing development of the applicant as a scientist studying generalized social phobia (GSP) (also known as generalized social anxiety disorder), related traits, behaviors and disorders. The applicant will develop his capacity to utilize brain imaging methods in close collaboration with imaging experts, in order to assess brain function associated with these conditions. Training goalsfocus on increasing the applicant's understanding of single photon computerized tomography (SPECT) and positron emission tomography (PET) techniques and dopamine (DA) neurociruitry. A research goal is to integrate multiple imaging findings in GSP and related conditions, toward testing models of DA neurocircuitry. This program builds on recent findings of low DAD2 receptor and DA transporter binding in GSP and the related trait of detachment. The applicant will further characterize DA system dysfunction in collaboration with N.Y. State Psychiatric Institute's Functional Brain Mapping Division, directed by Dr. Marc Laruelle. The applicant will use PET and SPECT to study the relationship of D2 receptors, DA transporters, and DA release in patients with GSP (specific aim 1). Main hypotheses are that striatal D2 receptor and DA transporter binding will be low, and DA release will be blunted. Specific aim 2 will test whether DA system findings in GSP represent a trait or a state finding that changes with treatment. Hypotheses are that low D2 binding at baseline and change in D2 binding during treatment will be associated with symptomatic improvement during treatment Specficity offindings to GSP will be studied by assessing D2 receptor binding and amphetamine-induced DA release in patients with major depressive disorder with atypical features, which like GSP is characterized by interpersonal sensitivity, (specific aim 3). Specific aim 4 will study associations of biologically salient traits of detachment, submissive behavior, capacity for social reward, and social memory with GSP and DA function. Long-term goals include integration of phenomenology related to GSP with imaging measures, treatment outcome, animal findings, and genetics. Better understanding of the neurocircuitry associated with GSP holds promise for improving diagnosis and treatment strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DOUBLE-BLIND STUDY OF SAME VS ESCITALOPRAM IN MDD Principal Investigator & Institution: Price, Lawrence H.; Professor of Psychiatry; Butler Hospital (Providence, Ri) 345 Blackstone Blvd Providence, Ri 02906 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Major depressive disorder (MDD) is a common, typically recurrent and disabling disorder, costing the U.S. over $44 billion/year in direct and indirect costs, and with point prevalence rates estimated at 5%-9% for women, and 2%-3% for men. More than one third of patients suffering from MDD appear to use alternative therapies in the U.S. Routinely prescribed in Europe for nearly 30 years and released four years ago in the U.S. as an over-the-counter dietary supplement, s-adenosyl-l-methionine (SAMe) has gained significant popularity as an agent marketed for improving mood and emotional well being. A number of relatively small double-blind studies have shown that parenteral or oral preparations of SAMe, compared with a number of standard tricyclic antidepressants, were generally equally effective, and tended to produce fewer side effects A relatively smaller number of studies have also examined the efficacy of SAMe compared to placebo, with the majority of these studies showing a significant advantage of SAMe over placebo. The recent report of the Southern California Evidence-Based Practice Center for the U.S. Department of Health and Human Services [Agency for Healthcare Research and

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21

Quality (AHRQ Publication 2002; http://www.ahrq.gov) ] states that "The results of these studies justify additional randomized clinical trials to evaluate the efficacy and tolerability of SAMe for treatment of depression." No adequately powered placebocontrolled study of SAMe in depression has ever been conducted in the U.S. We therefore propose a five-year, placebo-controlled, two-site study to assess the efficacy and safety of SAMe and of a standard selective serotonin reuptake inhibitor (SSRI), escitalopram in outpatients with MDD. This proposal is a parallel comparison of the efficacy and safety of SAMe, escitalopram, and placebo, with a crossover phase during which non-responders to any of these three treatments receive open-label treatment with the combination of escitalopram and SAMe. It is important to assess the efficacy of this combination therapy because patients frequently self-medicate with SAMe during standard antidepressant treatment. The primary aim of the proposed study is to test the acute antidepressant efficacy and tolerability of both SAMe and escitalopram, each compared to placebo, for the treatment of MDD. Secondary aims are to assess the acute effects of SAMe or escitalopram vs. placebo on remission rates, quality of life, and psychosocial functioning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFICACY OF DYNAMIC THERAPY VS SSRI FOR DEPRESSION Principal Investigator & Institution: Barber, Jacques P.; Associate Professor; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 03-JUL-2001; Project End 30-JUN-2006 Summary: Major Depressive Disorder (MDD) is one of the most prevalent psychiatric disorders. A number of psychosocial and pharmacological treatments have been developed which have proven to be efficacious for major depression. In general, different forms of psychotherapy for depression have been found efficacious. One of the most widely used forms of psychotherapy, dynamic therapy, however, has received very little research attention. For example, no study has yet compared the efficacy of dynamic therapy to serotonin selective reuptake inhibitor (SSRI) or to a placebo control condition among depressed patients. The primary aim of this proposal is to conduct a randomized clinical trial to examine the efficacy of a widely used form of manualized dynamic psychotherapy (supportive expressive psychodynamic therapy or SE) relative to an antidepressant medication condition (SSRI-Sertraline) replaced if clinically indicated by a serotonin-norepinephrine reuptake inhibitor (SNRI-venlafaxine) + Clinical Management (CM) and pill placebo + CM for patients with MDD. The secondary aims are: (a) to test whether SSRI/SNRI + CM is more effective than SE therapy among the more severely depressed outpatients in the sample; (b) to gather preliminary data on the relapse/recurrence rate of depression for patients who received SE versus SSRI/SNRI + CM; and (c) to examine predictors of outcome and mediators of change in these treatments. Steps toward effectiveness research have been taken by minimizing exclusion criteria, including a flexible medication switching condition, examining a wide range of outcome and functioning variables and assessing health care usage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ELECTROACUPUNCTURE FOR MAJOR DEPRESSION: A PILOT STUDY Principal Investigator & Institution: Mulsant, Benoit H.; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260

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Timing: Fiscal Year 2003; Project Start 08-SEP-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Major depression is a common and serious mental illness. It is associated with a markedly lower quality of life, significant functional impairment, and premature death due to suicide or comorbid physical illness. Over the past 50 years, effective and safe treatments for major depression have been developed, including antidepressant pharmacotherapy, psychotherapy, and electroconvulsive therapy. However, many Americans who suffer from a depressive disorder either do not accept to receive one of these conventional treatments or do not complete an adequate course of treatment. A growing number of Americans with depression are choosing to be treated with complementary and alternative therapies. Acupuncture, in particular, is increasingly being used to treat depression even though only limited data support its safety and efficacy. The proposed pilot study builds upon the complementary expertise of a group of investigators of conventional antidepressant treatments and a group of practitioners of alternative medicine. It will use a randomized parallel-group design to compare the safety, efficacy, and tolerability of electroacupuncture (EA) and sham electroacupuncture (SA) for the treatment of major depression. Over a 15-month period, 60 adult outpatients with a major depressive disorder of mild or moderate severity (as defined by the DSM-IV) will be randomized to either 12 sessions of EA or SA to be provided over 6 weeks. Safety and symptomatic improvement (as measured with the Hamilton Rating Scale for Depression) will constitute the primary outcome measures. Tolerability and functional improvement will constitute secondary outcome measures. The data generated by this pilot project will be used to support the feasibility of conducting, and inform the design of, a large multicenter study comparing the efficacy of two forms of acupuncture with a conventional treatment for depression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COGNITION

ELECTROPHYSIOLOGICAL

ASSESSMENT

OF

DEPRESSIVE

Principal Investigator & Institution: Ilardi, Stephen S.; Psychology; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2004; Project Start 01-SEP-2004; Project End 31-AUG-2007 Summary: (provided by applicant): Major depressive disorder is characterized by a well-documented array of maladaptive cognitive phenomena, but the clinical assessment of depressive cognition has remained largely uninformed by recent methodological and theoretical advances in the domain of cognitive neuroscience. This study examines the application of two prominent cognitive neuroscience techniques that appear to be of great translational promise in the assessment of depressive cognition. Specifically, we will apply (a) divided visual field (DVF) stimulus presentation, which isolates the function of left and right cerebral hemispheres, and (b) analysis of quantitative electroencephalograph (QEEG) event-related potentials (ERP), which provide sensitive detection of cognitive processes reflected in real-time brain events. The study will include depressed outpatients (n = 60), assessed both in-episode and at a 3month follow-up, as well as social phobic patient controls (n = 30) and never-depressed controls (n = 30). Depressed and social phobic participants will be recruited from a large community mental health center at a rate of approximately 2 per month and 1 per month, respectively, over 2.5 years. All participants will complete, at both assessment time points, the following: 8 brief tasks utilizing the ERP P300 component and DVF to evaluate hemispheric lateralization of selective attention to verbal and nonverbal depression-relevant stimuli, 2 tasks utilizing the ERP P400 component to evaluate the

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degree to which depressive self statements are perceived as self-congruent, a DVF verbal semantic priming task, and 3 self-report cognitive measures. It is hypothesized, on the basis of pilot data and theoretical considerations, that there will be observed a stable, trait-like negativistic right-hemispheric (RH) processing bias for verbal information among in-episode and fully remitted depressed patients (with positivistic RH bias among controls), and that the DVF/ERP paradigms will prove superior to selfreport measures in detecting trait-like depressive cognition. Secondary analysis will explore the ability of study measures to predict acute outcome in outpatient treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •


ELUCIDATING

THE

NEUROBIOLOGY

OF

POSTPARTUM

Principal Investigator & Institution: Moses-Kolko, Eydie L.; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 05-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): This revised Mentored Patient-Oriented Research Career Development Award Application (K23 describes a program of training and research using positron emission tomography (PET) to identify neurobiological processes mediating women's depressive syndromes that occur at reproductive transitions. Career development activities will focus on PET advanced analysis and modeling techniques reproductive endocrinology, cellular and molecular neuroscience, Psychiatric assessment, and clinical research design and statistical methods. These skills will be applied to the study of serotonin-IA (5HT1A receptor binding potential (BP) and resting cerebral blood flow (CBF) in DSM-lV-defined major depressive disorder (MDD) with postpartum onset. The association of female gonadal steroids (FGS with MDD and its treatment suggests FGS are important mediators of depressive disorders in women Because postpartum major depression (PPD) occurs in the setting of massive endocrine shifts, this provides a unique opportunity to explore the neurobiology of depressive syndromes that occur a reproductive transitions. Based upon existing characterization in the literature and in our PET Facility of depressive populations using probes for 5HT1A receptor BP ([11C] WAY-100635) and CBF ([15O] water) methods for measuring these targets will be applied in women with PPD, non-postpartum MDD postpartum healthy controls, and non-postpartum healthy controls. Hypothalamic-pituitary-ovarian (HPO and hypothalamic-pituitary-adrenal (HPA) axis function will be assessed in relation to PET measures Multidisciplinary didactic training, research experience, and preliminary data garnered from the proposed application will enable the candidate to become an independent investigator of the neurobiology of depressive syndromes associated with reproductive transitions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXERCISE TRAINING AND DEPRESSION IN OLDER ADULTS Principal Investigator & Institution: Blumenthal, James A.; Professor; Psychiatry; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-APR-1994; Project End 30-JUN-2005 Summary: Aging of the population and the increased prevalence of chronic diseases among the elderly are major challenges facing our society and medical community. More than 20% of Americans will experience an episode of depression serious enough to warrant diagnosis and treatment. Treatment of major depressive disorder (MDD) has focused on reduction of symptoms and restoration of functioning. Although

24


antidepressant medication has been particularly effective in this regard, many patients either fail to respond to medication or suffer from significant side effects. Thus, there continues to be a need to identify alternative approaches for treating depression, particularly in the elderly. There is now good reason to believe that exercise may be one such approach. The study proposed in the application will build upon the applicant's previous work in which they demonstrated the feasibility and efficacy of exercise as a treatment for MDD in older men and women. The major aim of this project will be to test the hypothesis that a program of home exercise is as effective as supervised exercise and medication in reducing depression relative to placebo controls. As a further extension of past work, the Principal Investigator proposes to examine the differential effectiveness of exercise for a significant subgroup of patients identified by Magnetic Resonance Imaging of the brain as having "vascular depression." Two hundred sixteen men and women, aged > 55 years, with MDD will be randomly assigned to supervised exercise, home exercise, drug (sertraline), or placebo. Before and after treatment patients will undergo evaluation of depression and exercise testing, assessment of vascular functioning including endothelial dysfunction and baroreceptor control, and psychometric testing to assess cognitive function and other measures of quality of life. Six month follow-up will assess relapse rates. The data generated from this study will have important practical implications by determining the extent to which exercise may benefit older men and women with MDD. The study also will provide information regarding the relationship between vascular depression and various indices of vascular and neurocognitive function, and the extent to which these indices may be modifiable by treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FAMILY STUDY OF COCAINE DEPENDENCE Principal Investigator & Institution: Bierut, Laura J.; Director; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 30-JUN-2005 Summary: (Applicant's abstract): This 5-year case control family study of cocaine dependence will examine familial and non-familial antecedents and consequences associated with cocaine dependence. The specific aims of this study are: (i) to examine familial transmission of cocaine dependence and related psychopathology; (ii) to study interrelationships between individual 'and familial factors that are associated with cocaine use, abuse, and dependence; (iii) to specify predisposing factors and outcomes of cocaine use, abuse, and dependence, and their relationship to family factors; and (iv) to compare results of this study with data from a large multi- site family study of alcoholism, the Collaborative Study on the Genetics of Alcoholism (COGA). To accomplish these goals, 500 cocaine dependent subjects in treatment, 500 communitybased subjects, and their nearest aged full siblings will be recruited (total of 2000 subjects). Personal interviews will be performed to determine the rates of cocaine use, abuse, and dependence along with alcohol, nicotine, and other substance dependence. In addition, lifetime psychiatric histories will be obtained for major depressive disorder, anxiety disorders, post-traumatic stress disorder, conduct disorder, attention deficit, and hyperactivity. Adverse circumstances including school difficulties, high-risk sexual behaviors, IV drug use violence, and legal difficulties will be assessed. Histories of all first-degree relatives will be obtained from all the subjects. This information will permit analyses of individual and familial factors that are involved in the development of cocaine use, abuse, and dependence, and familial patterns of psychopathology related to cocaine dependence. By surveying groups of high and low risk individuals for the

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25

development of cocaine use, abuse, and dependence, the proposed study will generate a unique understanding of the natural history, etiology, and consequences of cocaine dependence in our communities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FETAL REACTIVITY AND MATERNAL PSYCHOPATHOLOGY Principal Investigator & Institution: Emory, Eugene K.; Professor; Psychology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): This research will study the effects of maternal depression, psychosocial stress, and psychotropic medication on fetal/infant neurobehavioral development. Participants will include pregnant women diagnosed with: major depressive disorder who are prescribed antidepressant medications (i.e., SSRIs) (n = 40); major depressive disorder who are not prescribed SSRIs (n = 40), and a control group of pregnant women without a psychiatric diagnosis (n = 80) who are matched to the depressed groups on race, age, and SES. Actocardiographic technology will assess fetal behavioral and heart rate response to mild vibratory stimulation at 26-28 weeks gestation and again, between 32-34 weeks gestation. At each visit maternal psychiatric/stress symptoms will be measured with the Beck Depression and Anxiety Inventories, the Schedule of Recent Life Events and the Perceived Stress Scale. Maternal coping skills will be measured with the Coping Responses Inventory. Maternal urine samples will be assayed for prescribed medication and/or illicit drugs. Maternal saliva will be assayed for cortisol. Medical ultrasound records will be examined for physical length, head circumference and presence of abnormalities. During labour, fetal heart rate will be monitored and umbilical cord blood will be assayed for cortisol. On the first postnatal day, a behavioral observation will be obtained from neonates, they will be administered the BNBAS, salivary cortisol samples will be gathered and obstetrical/postnatal complications documented. In addition, another psychometric assessment will be made of each mother and saliva and urine samples obtained. A onemonth follow-up will consist of another behavioral observation of the infant, readministration of the BNBAS, obtaining mother/infant salivary cortisol samples, as well as a final maternal psychometric assessment and urine sample. Parametric statistical analyses and regression modeling will examine the relationships between maternal psychiatric symptoms, antidepressant medication, psychosocial stress and maternal coping, fetal and postpartum behavior and maternal/fetal/infant cortisol. It is predicted that fetal/infant physiological, behavioral, and hormonal patterns will vary with maternal diagnosis, degree of psychosocial stress and maternal coping strategy, and medication status and that with the amelioration of depressive symptoms via SSRIs, fetal/infant developmental profiles among the depressed women will more closely approximate those of the non-depressed control group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE-EXPRESSION CHANGE AND ANTI-DEPRESSANT RESPONSE Principal Investigator & Institution: Sathyanesan, Samuel N.; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): The goal of this project is to develop molecular tools that can be used to aid in the diagnosis and treatment of depression. Medications currently used to treat depression are only effective approximately 50% of the time and

26


few, if any, objective measures exist, which predict response to a given treatment. Thus, the availability of molecular probes to guide the initial choice of treatment and/or to monitor response to treatment at the molecular level (which may occur weeks in advance of clinical response) would offer an enormous advance in the treatment of depression. We will interview, and draw blood from, individuals with Major Depressive Disorder as well as non-depressed control subjects. We will extract RNA from the blood and perform microarray analysis to measure changes in the expression of a large number of genes in response to anti-depressant treatment, as well as differences in the level of expression of these genes, which may be present in affected individuals prior to treatment. This project builds on our previous work looking at geneexpression changes in transgenic mice and animals treated with anti-depressants and will allow us to expand those studies to a clinical setting. It involves a collaboration between basic science researchers in the Division of Molecular Psychiatry, headed by Dr. Ronald Duman, and clinical researchers at three Yaleaffiliated clinics: the Yale Depression Research Clinic, Yale Behavioral Gynecology Clinic, and the VA-CT Neuropsychiatry Clinic. These clinics serve over five hundred patients each year, and include both men and women from a wide variety of ethnic and socio-economic groups. This project will complement ongoing work in the Division of Molecular Psychiatry funded by our NIH Program Project Grant "The Neurobiology of Major Psychiatric Disorders". Ongoing studies using microarray analysis to detect gene-expression changes in the brains of animals treated with anti-depressants and in post-mortem tissue from human subjects with major depressive disorder will enable us to correlate any changes observed in the present study with those occurring in both animal and human brains. Results from these studies should lead to an RO1 proposal aimed at extending these findings. Briefly, further studies would involve examening differences among different types of depressive disorders and the correlation between geneexpression changes and treatment-response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC ALCOHOLISM

EPIDEMIOLOGY

OF

SOCIAL

PHOBIA

AND

Principal Investigator & Institution: Nelson, Elliot C.; Assistant Professor; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: This proposal is for a NIAAA Mentored Clinical Scientist Development Award (KO8) to foster the development of Dr. Elliot Nelson's career by supporting his work with Dr. Andrew Heath and Dr. Richard Todd. The award will enable the candidate to explore the relationship of alcohol dependence and social phobia, controlling for comorbid major depressive disorder (MDD). The candidate's career development will include a program of formal coursework and independent tutorials focusing on biostatistics, genetic epidemiology, research methodology (including the mediation of alcohol dependence and dangerous behavior risks), and behavioral and quantitative genetics. The skills acquired will be applied to both the analysis of existing data and to an independent research project designed to provide a better understanding of the mediation of shared risk. The preliminary data from adolescent female twins suggests that comorbid alcohol dependence is likely to be seen at increased rates in individuals with social phobia and that these subjects are also at increased risk for dangerous behaviors such as having unprotected sex, suicidal ideation, suicide plans, and suicide attempts. The goals of the proposal are to collect two waves of data on l00 control pairs and l00 pairs where at least one twin has a history of social phobia. We will

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27

use these data, plus existing data-sets, to address the following Specific Aims: l) To characterize prospectively the profile of comorbid illness observed in individuals with social phobia; 2) To determine prospectively the risk for alcohol dependence and harmful alcohol use given a primary diagnosis of social phobia; 3) To use multivariate twin analysis to characterize the relative contributions of disorder-specific and shared genetic and environmental risk factors for social phobia, alcohol dependence, and MDD; 4) To examine whether a variety of dangerous behaviors are seen more frequently in individuals with social phobia, and determine their association with the development of alcohol problems; 5) To examine the routes by which the shared risks appear to be mediated (including both risks of comorbid illness and dangerous behaviors). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS OF EARLY ONSET DEPRESSION Principal Investigator & Institution: Depaulo, J Raymond.; Associate Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: (Adapted from investigator's abstract) Major depressive disorder (MDD) has at least a 5-10% lifetime population prevalence and causes severe morbidity and mortality including suicide. Heritability in twins is 0.4-0.70. Mapping of susceptibility genes may be feasible with the recurrent, early-onset subtype (MDD-RE) which demonstrates a three- to eight-fold increase in risk to first-degree relatives of probands, vs. twofold for all MDD. The complex pattern of transmission suggests multigenic transmission and/or locus heterogeneity, so that large samples may be required. We propose a four-year, six-site project to collect an estimated 770 pedigrees which contain 1,000 independent affected sibling pairs (ASPs), extended by first-degree relationships to include additional affected relatives, plus unaffected relatives (parents and sibs) for genetic phase information. All sites will have identical inclusion criteria, clinical assessment DIGS and FIGS interviews and the NEO personality inventory), interviewer training and reliability monitoring, consensus diagnostic procedures, data management system, and administrative oversight including a quality assurance program. Permanent cell line specimens will be created and DNA extracted at the NIMH-sponsored cell repository. A 10 cM genome scan will be completed on all affected subjects at the Center for Inherited Disease Research (CIDR), which has approved this project for CIDR access. A three-stage design is proposed: regions with maximum lod scores (MLS) exceeding a liberal simulation-based threshold will be identified in a genome scan of the affected individuals from the first half of the sample, and candidate regions selected which continue to meet this threshold after unaffected individuals are typed in these regions and added to the analysis. Evidence for linkage in these regions will then be tested in the entire sample with parametric and non-parametric analyses using stringent simulation-based thresholds for 5% genome-wide significance. In the four-year project period, genetic analyses can be completed on 80% of the sample (over 600 pedigrees, 800 ASPs), with the remaining families to be available by the end of the project period for immediate completion of the genome scan on these pedigrees at CIDR. A timetable is proposed for rapid sharing of all biological materials, blinded clinical data, genotypes and linkage analyses with the scientific community through the NIMH-sponsored Center for Genetic Studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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•


Project Title: GENETICS OF RECURRENT EARLY ONSET DEPRESSION Principal Investigator & Institution: Scheftner, William A.; Rush University Medical Center Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: (Adapted from investigator's abstract) Major depressive disorder (MDD) has at least a 5-10% lifetime population prevalence and causes severe morbidity and mortality including suicide. Heritability in twins is 0.4-0.70. Mapping of susceptibility genes may be feasible with the recurrent, early-onset subtype (MDD-RE) which demonstrates a three- to eight-fold increase in risk to first-degree relatives of probands, vs. twofold for all MDD. The complex pattern of transmission suggests multigenic transmission and/or locus heterogeneity, so that large samples may be required. We propose a four-year, six-site project to collect an estimated 770 pedigrees which contain 1,000 independent affected sibling pairs (ASPs), extended by first-degree relationships to include additional affected relatives, plus unaffected relatives (parents and sibs) for genetic phase information. All sites will have identical inclusion criteria, clinical assessment DIGS and FIGS interviews and the NEO personality inventory), interviewer training and reliability monitoring, consensus diagnostic procedures, data management system, and administrative oversight including a quality assurance program. Permanent cell line specimens will be created and DNA extracted at the NIMH-sponsored cell repository. A 10 cM genome scan will be completed on all affected subjects at the Center for Inherited Disease Research (CIDR), which has approved this project for CIDR access. A three-stage design is proposed: regions with maximum lod scores (MLS) exceeding a liberal simulation-based threshold will be identified in a genome scan of the affected individuals from the first half of the sample, and candidate regions selected which continue to meet this threshold after unaffected individuals are typed in these regions and added to the analysis. Evidence for linkage in these regions will then be tested in the entire sample with parametric and non-parametric analyses using stringent simulation-based thresholds for 5% genome-wide significance. In the four-year project period, genetic analyses can be completed on 80% of the sample (over 600 pedigrees, 800 ASPs), with the remaining families to be available by the end of the project period for immediate completion of the genome scan on these pedigrees at CIDR. A timetable is proposed for rapid sharing of all biological materials, blinded clinical data, genotypes and linkage analyses with the scientific community through the NIMH-sponsored Center for Genetic Studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETICS OF RECURRENT EARLY-ONSET DEPRESSION Principal Investigator & Institution: Levinson, Douglas F.; Associate Professor; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: (Adapted from investigator's abstract) Major depressive disorder (MDD) has at least a 5-10% lifetime population prevalence and causes severe morbidity and mortality including suicide. Heritability in twins is 0.4-0.70. Mapping of susceptibility genes may be feasible with the recurrent, early-onset subtype (MDD-RE) which demonstrates a three- to eight-fold increase in risk to first-degree relatives of probands, vs. twofold for all MDD. The complex pattern of transmission suggests multigenic transmission and/or locus heterogeneity, so that large samples may be required. We propose a four-year, six-site project to collect an estimated 770 pedigrees which contain 1,000 independent affected sibling pairs (ASPs), extended by first-degree relationships

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29

to include additional affected relatives, plus unaffected relatives (parents and sibs) for genetic phase information. All sites will have identical inclusion criteria, clinical assessment DIGS and FIGS interviews and the NEO personality inventory), interviewer training and reliability monitoring, consensus diagnostic procedures, data management system, and administrative oversight including a quality assurance program. Permanent cell line specimens will be created and DNA extracted at the NIMH-sponsored cell repository. A 10 cM genome scan will be completed on all affected subjects at the Center for Inherited Disease Research (CIDR), which has approved this project for CIDR access. A three-stage design is proposed: regions with maximum lod scores (MLS) exceeding a liberal simulation-based threshold will be identified in a genome scan of the affected individuals from the first half of the sample, and candidate regions selected which continue to meet this threshold after unaffected individuals are typed in these regions and added to the analysis. Evidence for linkage in these regions will then be tested in the entire sample with parametric and non-parametric analyses using stringent simulation-based thresholds for 5% genome-wide significance. In the four-year project period, genetic analyses can be completed on 80% of the sample (over 600 pedigrees, 800 ASPs), with the remaining families to be available by the end of the project period for immediate completion of the genome scan on these pedigrees at CIDR. A timetable is proposed for rapid sharing of all biological materials, blinded clinical data, genotypes and linkage analyses with the scientific community through the NIMH-sponsored Center for Genetic Studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: (GENRED)

GENETICS

OF

RECURRENT

EARLY-ONSET

DEPRESSION

Principal Investigator & Institution: Zubenko, George S.; Professor; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: (Adapted from investigator's abstract) Major depressive disorder (MDD) has at least a 5-10% lifetime population prevalence and causes severe morbidity and mortality including suicide. Heritability in twins is 0.4-0.70. Mapping of susceptibility genes may be feasible with the recurrent, early-onset subtype (MDD-RE) which demonstrates a three- to eight-fold increase in risk to first-degree relatives of probands, vs. twofold for all MDD. The complex pattern of transmission suggests multigenic transmission and/or locus heterogeneity, so that large samples may be required. We propose a four-year, six-site project to collect an estimated 770 pedigrees which contain 1,000 independent affected sibling pairs (ASPs), extended by first-degree relationships to include additional affected relatives, plus unaffected relatives (parents and sibs) for genetic phase information. All sites will have identical inclusion criteria, clinical assessment DIGS and FIGS interviews and the NEO personality inventory), interviewer training and reliability monitoring, consensus diagnostic procedures, data management system, and administrative oversight including a quality assurance program. Permanent cell line specimens will be created and DNA extracted at the NIMH-sponsored cell repository. A 10 cM genome scan will be completed on all affected subjects at the Center for Inherited Disease Research (CIDR), which has approved this project for CIDR access. A three-stage design is proposed: regions with maximum lod scores (MLS) exceeding a liberal simulation-based threshold will be identified in a genome scan of the affected individuals from the first half of the sample, and candidate regions selected which continue to meet this threshold after unaffected individuals are typed in these regions and added to the analysis. Evidence for linkage in these regions will then be tested in

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the entire sample with parametric and non-parametric analyses using stringent simulation-based thresholds for 5% genome-wide significance. In the four-year project period, genetic analyses can be completed on 80% of the sample (over 600 pedigrees, 800 ASPs), with the remaining families to be available by the end of the project period for immediate completion of the genome scan on these pedigrees at CIDR. A timetable is proposed for rapid sharing of all biological materials, blinded clinical data, genotypes and linkage analyses with the scientific community through the NIMH-sponsored Center for Genetic Studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENOMIC STUDIES IN BIPOLAR AND MAJOR DEPRESSION Principal Investigator & Institution: Bunney, William E.; Della Martin Chair of Psychiatry; Psychiatry and Human Behavior; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2004; Project Start 30-SEP-1999; Project End 31-AUG-2009 Summary: (provided by applicant): Neural Phenotypes in Bipolar & Depressive Disorders: The Center application proposes to test two, related hypotheses. The primary hypothesis is that two of the most serious mood disorders, bipolar disorder (BPD) land major depressive disorder (MDD) have distinct neural phenotypes or biological signatures in the brain as identified by a set of non-overlapping alterations in the pattern of expression of individual genes or functionally related ensembles of genes. The secondary hypothesis is that a smaller set of genes will show alterations in common in these diseases and may represent mechanisms related to common vulnerability to mood disorders or a common impact to those disorders on the brain. Project 1 contributes to the investigation of these hypotheses with three Aims. Aim I: Confirm, characterize and investigate selected genes and pathways which are strongly implicated in BPD and MDD contrasted with controls and schizophrenics. Methods to be employed to achieve the goals of Aim 1 include qRT -PCR, in situ hybridization studies, Western blot protein function studies and SAGE (serial analyses of gene expression). Two findings have been selected for in-depth characterization and study (The FGF system which was significantly dysregulated in MDD and mitochondrial dysfunction which is strongly implicated in both MDD and BPD). Aim l will extend the microarray studies to additional limbic and non-limbic structures in BPD and MDD contrasted with controls. There is scientific consensus that the limbic system is a key circuit in the pathophysiology of BPD and MDD. This will represent the first study evaluating gene expression in 3 limbic structures in controls and mood disorder patients. Aim 3 will test the ability to blindly predict and discriminate BPD from MDD and SZ. Based on the neural phenotypes defined by the initial cohorts, predict and discriminate BPD, MDD from SZ in a new cohort of 15 BPD, 15 MDD and 15 controls. Information derived from the following sets of data will be utilized in the predictive analyses: Unique nonoverlapping genes for BPD and MDD; the same genes significantly different in opposite directions in BPD and MDD; genes shared in common between BPD and MDD; GO and KEGG pathway and function analyses of BPD and MDD. The identification of validated and replicated genes and pathways that can predict MDD as distinct from BPD will constitute a major contribution to investigating the etiology of these disorders and toward! identifying novel targets for their treatment or prevention. These investigations have many conceptual and technical links with other Center projects and depend on the support provided by all of the proposed Cores. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIPPOCAMPAL ATROPHY IN MAJOR DEPRESSION Principal Investigator & Institution: Stockmeier, Craig A.; Associate Professor; Psychiatry and Human Behavior; University of Mississippi Medical Center 2500 N State St Jackson, Ms 39216 Timing: Fiscal Year 2004; Project Start 01-DEC-2003; Project End 30-NOV-2007 Summary: (provided by applicant): Plasticity in the hippocampus plays a role in learning and memory, and in neurobiological responses to stress and antidepressant drug action. A significant increase in neuron and glial cell density and a decrease in neuronal soma size has been detected in hippocampus of 19 subjects with major depressive disorder (MDD). The changes in density in MDD were independent of suicide or gender. It is hypothesized that a decrease in hippocampal neuropil, in response to diminished markers of neural growth and synaptic connection, resulting in an increase in neuronal and glial density, is the microscopic basis for the histopathology of the hippocampus in MDD. Aims 1-3 examine the hypothesis that in MDD there is a decrease in hippocampal neuropil, as compared to normal controls. Aims 4-5 examine the hypothesis that there will be diminished markers of neural growth and synaptic connection in the hippocampus in MDD. In Aim 1, stereological experiments in MDD will estimate the total cell number and density of neurons and gila and the corresponding volume throughout the entire hippocampus. In Aim 2, the Golgi silver method will be used to measure spine density, number of dendritic branch points and total length of apical and basal dendritic trees of pyramidal neurons in hippocampal CA1 & CA3 subfields in MDD. In Aim 3, the density and size of glial fibrillary acidic protein (GFAP) -immunoreactive cell bodies, and the areal fraction occupied by GFAPimmunoreactivity in astrocytes will be measured in the hippocampus in MDD. In Aim 4, experiments are designed to stereologically estimate the total immunoreactive cell number and packing density of markers of synaptic plasticity [brain derived neurotrophic factor (BDNF), growth associated protein-43 (GAP-43) and polysialylatednerve cell adhesion molecule (PSA-NCAM)] throughout the hippocampus in MDD. In Aim 5, experiments will be carried out to quantify mRNA for BDNF and GAP-43 in CA3 and CA4 of the rostral hippocampus in MDD. It is predicted that the hypothesized decrease in expression of BDNF and GAP-43 protein in Aim 4 will be secondary to related decreases in gene expression in the hippocampus. Cellular changes detected in MDD postmortem may underlie hippocampal atrophy detected by some in living subjects with MDD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HOSTILITY, PTSD & PHYSICAL HEALTH RISK FACTORS IN WOMEN Principal Investigator & Institution: Beckham, Jean C.; Associate Professor; Psychiatry; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 25-JUL-2001; Project End 30-JUN-2005 Summary: Posttraumatic stress disorder (PTSD) is a prevalent mental disorder in both men and women, and lifetime prevalence rates are higher in women. While there is growing evidence supporting an association between PTSD, hostility and health in males, few controlled studies have examined anger, hostility and health in women with posttraumatic stress disorder (PTSD). Anger and hostility are symptomatic of PTSD and there is ample data from epidemiological and laboratory data demonstrating that males with PTSD have greater levels of hostility than males without PTSD. However, comprehensive empirical assessment of hostility in women with PTSD is lacking.

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Similarly, although there are growing literatures examining the deleterious effects of hostility and physical health, and PTSD and physical health, the majority of this research has focused on males with PTSD. Our pilot data indicated that women with PTSD have higher self- reported hostility and decreased functional health status compared to women with other psychiatric diagnoses. The proposed project has three major aims: (1) to conduct a multi-modal (behavioral, interview based, self-report, and informant report) assessment of hostility in women with PTSD as compared to women with major depressive disorder and psychiatrically healthy women; (2) to examine the relationship between hostility and health parameters in women with PTSD using multi-method health assessment including self-reported health, health habits, functional health status, cardiovascular function measures during ambulatory monitoring and an anger task, and physician medical chart review; and (3) an examination of a recent model of the mechanisms between PTSD and disease including PTSD severity, hostility, cardiovascular function, health risk behaviors, symptom perception, and illness behavior. Seventy-five women with PTSD, 50 women with major depressive disorder (but without lifetime or current PTSD), and 50 women without PTSD or major depressive disorder will be recruited. Major depression was chosen as a comparison group as a number of studies have documented both increased hostility among depressed patients and a strong association between depression and health outcomes. The proposed study will important information regarding the relationship between hostility, other risk factors (e.g., poor health habits) and health in a relatively understudied sample. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPACT OF RESPONSE-FOCUSED AFFECT MODULATION STRATEGIES Principal Investigator & Institution: Demaree, Heath A.; Psychology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2004 Summary: (provided by applicant): Over the past several decades, researchers have made tremendous progress in understanding human emotion regulation. Some of the most notable advances have emanated from the collection of cognitive, affective, and physiological data from individuals while using a "response-focused" emotion modulation technique, namely "suppression" (trying to decrease emotional expression after the onset of the affective experience). From these data it has been suggested that response-focused strategies are associated with increased sympathetic arousal and, in the case of suppression, decreased behavioral output and self-reported positive affect (when trying to suppress a positive feeling-state). The true effects of response-focused strategies are unknown, however, because other such techniques (like emotional exaggeration) have been very rarely studied. The proposed research is designed to replicate and extend the research on "response-focused" affect modulation by assessing the impact of both suppression and exaggeration (relative to natural-viewing conditions) across positive, negative, and neutral emotional states. In the autonomic domain, significant research advances will be made by using very discrete measures of sympathetic and parasympathetic arousal at the myocardium (pre-ejection period and respiratory sinus arrhythmia, respectively). Previous researchers have used such measures as finger pulse amplitude and skin temperature to measure sympathetic arousal (and no parasympathetic indices have ever been collected!). By assessing autonomic arousal at the heart, the present research may have tremendous value in understanding why persons with affect dysregulation problems (e.g., Major Depressive

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Disorder, Bipolar Disorder) are significantly more likely to experience cardiovascular disease. Moreover, the proposed research will assess the impact of response-focused strategies on behavioral output, cognitive functioning (left- and right-frontal neuropsychological tasks), and self-reported mood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPROVING HISPANIC RETENTION IN ANTIDEPRESSANT THERAPY Principal Investigator & Institution: Lewis-Fernandez, Roberto; Director and Associate Professor; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 100321098 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): The overall goal is to develop a culturally congruent intervention for use in outpatient pharmacological practice by a psychiatrist that will increase retention of Hispanics with major depressive disorder (MDD) in antidepressant therapy. Despite major advances in the treatment of psychiatric disorders, Hispanics continue to underutilize mental health services relative to nonHispanic Whites and to their own mental health need, as evidenced by lower rates of treatment entry and retention. Hispanic dropout from medication therapy for MDD attains rates two to three times those of non-Hispanic Whites. Mental health utilization in general is lowest among less acculturated, migrant Hispanics, even after controlling for socioeconomic factors and psychiatric diagnosis, suggesting that cultural factors are important causes of underutilization. Our pilot work with depressed, culturally traditional Hispanics entering antidepressant therapy suggests that cultural incongruence between patients' and psychiatrists' expectations and concerns about treatment produces ambivalence about taking medication or following physician instructions, which in turn interferes with retention. This association between ambivalence about treatment and dropout is predicted by the "transtheoretical model of change", a schematization of the stages individuals experience in the process of behavior change. However, the validity of this model for Hispanics has not been empirically tested. Motivational Interviewing (MI) is an effective brief psychotherapy that has improved retention among patients with dually diagnosed depression and substance abuse by targeting ambivalence about entering and remaining in treatment. However, MI has not been adapted for Hispanic patients in antidepressant therapy. The specific aims of this study are to: a) culturally adapt and manualize MI for depressed Hispanics in antidepressant therapy; b) explore the efficacy of 4 sessions of this manualized intervention for improving retention during a 12-week open- label trial with a 2nd generation antidepressant and at 6-month follow-up among 65 Hispanics seeking outpatient medication therapy for non-psychotic MDD; c) explore the predictive validity of the "transtheoretical model of change" for treatment retention by examining the relationship between the retention measures and baseline stage of change and stage progression during treatment; d) examine the efficacy of MI for helping patients progress through the stages of change. This study will yield pilot data on the efficacy of a manualized cultural adaptation of MI for enhancing retention of Hispanics in antidepressant therapy and on the predictive validity of the "transtheoretical model of change" in this population. This pilot data will allow us to apply for an R01 to further study this intervention and model in a controlled clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INFORMATION-PROCESSING BIASES IN DEPRESSION Principal Investigator & Institution: Gotlib, Ian H.; Professor; Psychology; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 01-JAN-1999; Project End 31-DEC-2006 Summary: (provided by applicant): Depression is among the most prevalent of all psychiatric disorders, accounting for over 20% of economic costs for all mental illness. An important public health priority is the development of methods for identifying factors that both increase individuals' vulnerability to depression and hinder recovery from this disorder. Pursuing this objective, we have been conducting research that broadens the focus of cognitive models of depression by examining patterns of biological reactivity to emotional stimuli. Extrapolating from our earlier studies and from existing models, we predicted that individuals diagnosed with Major Depressive Disorder (MDD) would exhibit increased autonomic arousal and neural activation in response to negative stimuli. But our findings indicated otherwise; in both fMRI and psychophysiological studies, MDD individuals demonstrated less activation and arousal in response to both positive and negative stimuli than did nondepressed controls. Moreover, greater activation and reactivity predicted improved functioning over the following year, independent of MDD severity. In reconciling and integrating these results with our earlier findings, we are broadening and refining cognitive theories of depression to include a consideration of affective chronometry, sensitivity to reward stimuli, and biological functioning, not only to describe the functioning of depressed individuals, but also to predict recovery from this disorder. The studies proposed in this application are designed to test a more comprehensive formulation of depression and to systematically rule out important alternative explanations for our obtained results. Based on our initial findings, we posit that when confronted with an emotionallyvalenced stimulus, depressed persons immediately attend to it; if the stimulus persists, they shut down their processing and disengage from it. Moreover, those depressed individuals who are able to stay engaged with emotional stimuli are likely to recover from depression most quickly. The overall objective of this proposed project is to advance our understanding of the cognitive and neurobiological responses in MDD to emotional stimuli. We are particularly interested in the effects of stimulus type (i.e., affective valence), stimulus duration (i.e., affective chronometry), and the potential effects of specific patient characteristics (e.g., anhedonia, comorbid Axis-II personality disorder) on emotional functioning in depression. We propose to examine informationprocessing biases and reward responsivity, as well as concomitant neural activation and psychophysiological arousal, in response to emotional stimuli in depressed and nondepressed participants. Findings from the proposed studies testing these formulations will contribute importantly to the development of an integrative psychobiological theory of depression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IV COCAINE ABUSE TREATMENT: A LABORATORY MODEL Principal Investigator & Institution: Foltin, Richard W.; Professor of Neuroscience; Anatomy and Cell Biology; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-JAN-1990; Project End 31-MAY-2007 Summary: (provided by applicant): This protocol continues implementation of a laboratory model to evaluate medications potentially useful in the treatment of cocaine abuse, investigating problems relevant to understanding and reducing uncontrolled

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cocaine use. Psychiatric comorbidities are pervasive in the cocaine-dependent population, and are significant in the population seen in community treatment centers. However, these comorbidities are rarely addressed in either clinical trials or laboratory settings. While it has been hypothesized that treatment for cocaine dependence could be improved by targeting cocaine users with specific psychiatric comorbidities, this has not been systematically evaluated. We will examine the relationship between psychiatric comorbidity and potential medications for cocaine dependence using two approaches. First, we will compare the subjective and reinforcing effects of cocaine under controlled laboratory conditions, in groups of abstinent cocaine abusers with Major Depressive Disorders (MDD), Attention Deficit/Hyperactivity Disorder (ADHD) or no psychiatric comorbidity. If cocaine use in individuals with comorbid disorders is related to their comorbid. disorder, then the behavioral effects of cocaine should vary across the groups being studied. Second, we will compare responses to cocaine under three separate conditions: maintenance on 1) gabapentin, 2) venlafaxine, and 3) the combination of the two medications. The laboratory, setting of the current proposal offers a unique opportunity to test the hypothesis that individuals with comorbid MDD or ADHD respond differently to cocaine than those without a comorbid psychiatric disorder, and that treating the MDD or ADHD alone will not sufficiently reduce the response to cocaine. Treating the comorbid disorder or decreasing the behavioral effects of cocaine will be necessary but not sufficient pharmacotherapy for individuals with comorbid disorders. A combination of the gabapentin for cocaine and venlafaxine for depressive symptoms will have a synergistic effect in these individuals. The laboratory is an ideal setting in which to carry out this research, allowing us to carefully monitor participants and collect maximal data with the fewest number of participants. The proposed research offers a unique opportunity to evaluate medications in cocaine-dependent individuals with MDD, ADHD or no comorbid disorder, and will provide important information about differential responses of these groups to cocaine and to gabapentin and venlafaxine, alone and in combination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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 2002; 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 regions and preliminary MRS data from these brain regions have demonstrated mood-

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state, 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: MAJOR MENTAL DISORDERS AND HIV--HEALTH SERVICES USE Principal Investigator & Institution: Crystal, Stephen; Research Professor; None; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2002; Project Start 20-AUG-2000; Project End 31-JUL-2005 Summary: This study will investigate the provision of health care services to a statewide population of HIV-positive Medicaid participants whose service needs are complicated by major psychiatric comorbidities, particularly schizophrenia and schizoaffective disorder. The overall objective is to generate much-needed knowledge about care of these persons so that policies and programs, which have largely been developed on the basis of findings from inpatient samples, can better address their complex needs. The research will use a unique database created by merging multiple New Jersey Medicaid administrative and claims records with HIV/AIDS Registry data, covering the years 1988-1999 for 8,996 individuals, including (according to preliminary classifications) 577 who received at least one inpatient or two outpatient diagnoses with schizophrenia or schizoaffective disorder, with a mean of 55 encounters with schizophrenia diagnoses. We will also examine, as a secondary focus, individuals diagnosed with mood disorders including bipolar disorder and recurrent major depressive disorder, and will explore the association between combinations of psychiatric and substance abuse comorbidities and use of health care services. The study will examine the types and combinations of psychiatric diagnoses reported by health care providers during health care encounters with HIV+ persons on Medicaid; refine claims-based diagnostic classifications; explore the impact of psychiatric conditions on the types and amounts of health care services used over the course of HIV; analyze receipt of mental health services and the type and consistency over time of psychotropic use; and examine the relationship between comorbid major mental disorders, with and without comorbid substance abuse, and patterns of antiretroviral therapy including type of regimen, incidence of use, consistency of use over time, and dropout from treatment. Results of these analyses will provide an important information base for the development of policies and programs to improve the care of this under-studied group within the population living with HIV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MATERNAL NEUROBEHAVIOR

ANTIDEPRESSANT

USE

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FETAL

Principal Investigator & Institution: Salisbury, Amy L.; Women and Infants HospitalRhode Island 101 Dudley St Providence, Ri 029052499 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The overall goal of the proposed research career development program is to prepare the investigator, Dr. Amy Salisbury, for a career as an independent investigator in the areas of fetal behavioral development and maternal mental health. The investigator's focus in these areas represents a strong aspiration to understand the mechanisms and mediators in the development of childhood mental illness. As a first step in achieving the long-term goals, Dr. Salisbury will study fetal and newborn neurobehavior in women with Major Depressive Disorder (MDD), diagnosed by structured interview, with and without antidepressant (S SRI) exposure. This study will be executed with intensive training in methodologies with at-risk fetuses and newborns (Dr. Barry Lester), fetal monitoring techniques (Dr. Janet DiPietro), structured interview techniques (SCID, SADS) and ongoing didactic training and clinical supervision with top experts in the field of mood disorders and medication management in women (Dr. Katherine Wisner and Dr. Teri Pearistein), and maternalfetal medicine (Dr. Stephen Carr). Dr. Lester will serve as the primary mentor of this program and resource provider throughout the award period. Additional skills will be attained through coursework on research design and regression analyses at Brown University as well as advanced obstetric ultrasound training. The proposed program of career development will build on Dr. Salisbury's established research and clinical skills in fetal and newborn behavior. The investigator has the full support of the Brown Medical School, Women & Infants' Hospital, and her sponsors to achieve the goals outlined in this career development program. The broad, long-term objective of the research plan is to determine if there are differential effects of SSRI exposure and MDD on fetal and newborn neurobehavioral development. The data will provide information about how the fetal CNS responds to the two maternal biological environments as well as contribute to the urgently needed information for treatment guidelines of mood disorders during pregnancy. The specific aims of the proposed research plan are 1. To determine the effect of maternal S SRI-treated MDD (euthymic) versus nonSSRI exposed active MDD on fetal neurobehavior and controls, 2. To determine the effect of maternal S SRI-treated MDD versus non-SSRI exposed active MDD on newborn neurobehavior and controls. A secondary aim of this study is to examine the stability of the individual differences of neurobehavioral measures from the fetal to newborn period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MDD IN ADOLESCENTS & YOUNG ADULTS: PATHWAYS & PROCESSES Principal Investigator & Institution: Klein, Daniel N.; Professor; Oregon Research Institute Eugene, or 97403 Timing: Fiscal Year 2002; Project Start 09-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): We seek support to analyze existing data from the Oregon Adolescent Depression Project (OADP) to better understand the pathways into and out of major depressive disorder (MDD) and the processes that mediate and moderate risk during the peak incidence period of adolescence-young adulthood. The OADP is a multi-generational project that includes a study of the prevalence and risk factors for adolescent psychopathology in a large community sample; a longitudinal

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follow-up of participants into young adulthood; a family study of first-degree relatives; and a longitudinal study of their children. We seek to extend previous OADP grants by addressing four broad issues that integrate these components using state-of-the-art data analytic procedures: 1) Onset of MDD in adolescents and young adults. Having a depressed parent is a critical risk factor for MDD. We will examine the specificity of the parental MDD-offspring MDD association and factors that moderate risk for MDD in offspring of depressed parents; explore environmental and person characteristics that mediate the relation between parent and offspring MDD; and compare risk factors for first-onset of MDD in adolescence versus young adulthood. 2) Course of MDD in adolescents and young adults. Adolescent MDD has a variable course. We will explore whether parental MDD is a useful marker for divergent pathways out of MDD; determine whether risk factors for first onset versus recurrent MDD differ; identify predictors of cumulative depression over time; and explore whether adolescents and young adults are changed or "scarred" by the experience of MDD. 3) Stress and depression. MDD is associated with elevated stress both before and after episodes. Using seven annual assessments of life events and depressive symptoms between adolescence and young adulthood, and latent growth curve and growth mixture modeling, we will examine reciprocal relationships between stress and depression; whether parental MDD and personal history of MDD moderate stress-depression relationships; and individual differences in stress trajectories. 4) Behavior problems in young children of depressed parents. The multigenerational structure of the OADP provides an opportunity to examine some of these issues in the children of the original OADP cohort. We will use latent growth curve modeling to identify distinct groups of developmental trajectories of psychopathology in offspring, and examine grandparental, parental, and familial predictors of these trajectories. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTIFACETED HOME CARE DEPRESSION PROGRAM Principal Investigator & Institution: Ell, Kathleen R.; Professor; None; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-JUL-2004 Summary: (Applicant's abstract): High rates of depression among the elderly with physical illness and impaired functioning are well documented. Efficacious treatments for depression among the elderly are available, but all too often depressed elderly are either not diagnosed or not treated properly. Elderly patients have been consistently found to underutilize formal mental health services. On the other hand, the elderly are heavy utilizers of general health or primary care services. The Multi-faceted Home Care Depression Program (MHCDP) is a fully integrated, stepped care, collaborative, multimodal home care model designed to influence the process of home care, the home care provided by physicians and nurses, and patient self-management. It aims to improve the detection and treatment of major depressive disorder (MD} and dysthymia. A controlled, block-randomized clinical trial is proposed to test the effectiveness, acceptability, feasibility, and cost of the MHCDP among 600 enrolled subjects aged 65 years and older who are receiving services in a large urban/rural home care program (SunPlus). The direct cost of detection and treatment under MHCDP is covered through existing reimbursement mechanisms and MHCDP is fully integrated within standard home care practices. Key components of the MHCDP are: 1) a phased baseline detection strategy which includes a depression symptom inventory (SCL-90 Depression) and a structured diagnostic assessment procedure (PRIME-MD PHQ-9) that is brief and will be implemented during the existing standard admitting RN evaluation conducted

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(during a 2-hour home visit) on all patients referred for home care services; 2) a stepped care treatment algorithm that includes patient choice of medication or psychosocial treatment; and 3) specific quality of care enhancements that are fully integrated within existing standard home care practice. These include training existing psychiatric team nurses and social workers in structured Problem-Solving Treatment, informational materials for referring primary care physicians, nurse and social worker training, home care management services to monitor and facilitate depression treatment and to address barriers to care, patient and family/caregiver education, and follow up provided by psychiatric nurses and social workers. Major Hypotheses and Research Questions: (1) MHCDP intervention will result in greater reduction of depressive symptoms vs. usual care; (2) MHCDP will result in greater frequency of primary care physician prescription for drug or psychosocial treatment vs. usual care; and (3) MHCDP will increase patient acceptance of and adherence to treatment and satisfaction with care vs. usual care. In addition, we will conduct: (1) comparisons of functional status, quality of life, suicidal ideation, and service utilization between intervention vs. usual care patients; and (2) cost-benefit comparisons of estimates of direct costs of the intervention and usual care arms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROANATOMY AND PHARMACOTHERAPY OF OCD AND MAJOR DEPRES Principal Investigator & Institution: Saxena, Sanjaya; Psychiatry & Biobehav Sciences; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 10-JUN-1999; Project End 31-MAY-2004 Summary: This application proposes Sanjaya Saxena, M.D. for a Mentored PatientOriented Research Career Development Award. The overall goals are to provide him with the conceptual background and research skills necessary for him to conduct patient-oriented research on obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Under the guidance of his Primary Mentor and Expert Consultants, he will be trained in neuroanatomy, neuropsychopharmacology, functional neuroimaging, quantitative image analysis, biostatistics, research design, and research ethics. Building upon his prior work in functional brain imaging in OCD and MDD, as well as in pharmacotherapy for refractory OCD, his research during the Award period will include two main studies, proposed herein, on the functional neuroanatomy, pharmacotherapy, and differential time course of response to treatment of OCD and MDD, studying a total of 42 subjects: 1) Cerebral Metabolic Changes with Treatment of Concurrent OCD and MDD: This study will use [18F]-fluoro-deoxyglucose positron emission tomography (FDG-PET), to delineate the specific brain system mediation of OCD symptoms and MDD symptoms occurring simultaneously, in patients treated with paroxetine, a medication shown to be effective for both disorders. Differential metabolic changes occurring along parallel, frontal-subcortical circuits within the same brain will be measured after four weeks and again, after twelve weeks of treatment, and will be correlated with changes in specific symptoms. Understanding the mediation of OCD and MDD by frontal-subcortical circuits, as well as the differential time course of pharmacological effects on these circuits, may lead to improved treatments for both of these common disorders in the future. 2) Cerebral Metabolic Predictors of Response to Paroxetine and Risperidone in Refractory OCD: This study has the following specific aims: a) to identify cerebral metabolic patterns with FDG-PET that might predict response to paroxetine alone vs. paroxetine plus risperidone, b) to identify symptoms or

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other clinical variables, such as level of insight or delusionality, which might predict response to adjunctive risperidone, and c) to examine the efficacy of adjunctive risperidone for OCD patients who are refractory to paroxetine. With the additional skills and experience acquired during the Award period, Dr. Saxena will be well-prepared to compete for independent research support, and to conduct patient-oriented, neuroimaging and pharmacological research on OCD and MDD, with the long-term goal of improving treatment for these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •


NEUROIMAGING

MARKERS

OF

VULNERABILITY

TO

Principal Investigator & Institution: Dahl, Ronald E.; Professor; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: (provided by applicant) Neuroimaging studies of mid-life major depressive disorder (MDD), have revealed abnormalities of cerebral function and structure that persist beyond depressive episodes. To test hypotheses about the neurobiological basis of MDD, the systems implicated by these studies will be examined in a unique and informative sample of young adults: Subjects now age 18 to 24 previously identified in childhood as having MDD or as being at 'high risk' (HR) for developing MDD by virtue of having multiple affected relatives. These samples will be compared against healthy, low-risk' (LR) controls (who have no evidence of having first or second degree relatives with mood disorders) with respect to PET and MRI imaging measures of neurophysiology, serotoninlA receptor binding potential (BP), and neuromorphometry that proved abnormal in both the symptomatic and asymptomatic phases of mid-life MDD). Since these abnormalities involve brain structures implicated in emotional behavior by lesion analysis, electrophysiological orPET/fMRI-brain mapping studies, they appear likely to be relevant to the pathogenesis of mood disorders. It remains unclear, however, whether such abnormalities reflect developmental or acquired processes that predate the onset of depressive episodes, or whether they instead comprise sequelae of recurrent illness or treatment in MDD. The proposed project addresses this question by bringing these measures closer to the developmental period in young adults with childhood-onset MDD and by assessing their existence in subjects at high risk for MDD. Three samples will be selected: childhood-onset MDD subjects who are unmedicated and in remission, HR subjects who are psychiatrically healthy, and LR healthy controls. PET measures of serotoninlA (5-HTIA) receptor binding and glucose metabolism will be acquired using serial injection of the 5-HTJA receptor ligand, jcarbonyl-11C] WAY-100635, and 18F-fluorodeoxyglucose. MRI-based neuromorphometric assessments of the subgenual prefrontal cortex (PFC; where reduced grey matter was found in both in vivo MRI and post mortem neuropathological studies of MDD) will also be performed. We will test the hypotheses that, relative to the LR control group, both the MDD and the HR groups will have reduced 5-HT1A receptor BP in the mesiotemporal cortex and the raphe, decreased left subgenual PFC volume, increased left amygdala metabolism, and decreased dorsomedial/dorsal anterolateral PFC metabolism. In post hoc comparisons, the relationship between the PET data and plasma and salivary cortisol levels will be assessed to test the hypotheses that 5-HT1A receptor binding down-regulation in MDD is related to elevated cortisol exposure, and to explore whether HR subjects with past evidence of HPA-axis dysregulation have reduced 5-HT1A receptor BP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OFFSPRING OF OUTPATIENTS WITH DYSTHYMIC DISORDER: OUTCOMES AND MEDIATORS OF RISK Principal Investigator & Institution: Lizardi, Humberto; Herbert H. Lehman College 250 Bedford Park Blvd. West Bronx, Ny 10468 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: The NICHD has as one of its missions the support of projects that examine the effects of parental care on the social and emotional adjustment of children. This project is designed to address several aims that specifically fit this mission. There are several decades worth of literature examining major depressive disorder in parents as a risk factor for offspring maladjustment. However, the literature on outcomes in the children of parents with dysthymic disorder is limited. The proposed research is designed to address this gap in the literature. More specifically, the aims of this project are to compare outpatients with DSM-IV early-onset dysthymic disorder with concurrent major depressive disorder (double depression), DSM-IV early-onset dysthymic disorder without a concurrent major depressive disorder (pure dysthymic disorder), DSM-IV episodic major depressive disorder, and normal controls with no history of Axis I disorder on the following: 1) functioning in major role areas; 2) their parenting; 3) their cognitive processes; 4) rates of psychiatric disorders in their offspring; 5) functioning by their offspring in major role areas; 6) cognitive processes in their offspring; and 7) mediators of the risk for adverse outcomes in offspring. Participants will include 45 subjects in each group. The parent groups will be compared on both interview and self-report measures of social functioning. In addition, the offspring of the four groups will be compared on rates of psychopathology, as determined by a teamconsensus method, and on social and cognitive functioning. Offspring adjustment will be assessed blind to the diagnostic status of the parents. Mood disorders represent a significant public health problem in the United States. Research contributing to our understanding of the correlates of double depression and pure dysthymic disorder in parents and the mediators of risk for offspring maladjustment will enable us to identify vulnerable children and to develop effective intervention programs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PET IMAGING--COMORBID COCAINE DEPENDENCE AND DEPRESSION Principal Investigator & Institution: Rubin, Eric; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 100321098 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-AUG-2005 Summary: (Applicant's Abstract) Comorbidity of cocaine dependence and major depressive disorder (MDD) poses an important clinical challenge. The relatively high incidence of such comorbidity and a variety of previous investigations raise intriguing questions about neurobiological connections between these disorders. We will use positron emission tomography (PET) of human brain metabolism, before and after treatment of the comorbid disorders, as a window into such neurobiological relationships. Our team combines expertise in advanced functional brain imaging with experience in the diagnosis and treatment of comorbid MDD and cocaine dependence. Subjects for this study will be carefully screened volunteers in four samples: cocainedependent (CD) only, MDD alone, CD comorbid with MDD, and normal controls. Equal numbers of males and females will be recruited to assess gender differences. The MDD and CD+MDD groups will be treated for 12 weeks with venlafaxine, an antidepressant which our pilot data indicates is effective in the comorbid population. Specific

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hypotheses about the profile of cerebral metabolism in these groups will be examined as follows: 1) at baseline in all groups, 2) following treatment, when baseline and posttreatment scans will be compared to identify brain sites potentially involved in treatment effects, and 3) following treatment, when baseline scans for responders and non-responders in each treatment group will be correlated with treatment outcome to identify pre-treatment metabolic features which predict responsiveness. We will apply advanced quantitative procedures for examining global, regional, and "network" brain metabolism, and will correlate these measures with standardized measures of treatment success. This methodologic rigor will contribute to understanding the pathophysiology and treatment of patients with comorbid depression and cocaine dependence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHARMACOLOGICAL INTERVENTION PROJECT Principal Investigator & Institution: Cornelius, Jack R.; Professor of Psychiatry and Pharmaceutic; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: Recently, the first large-scale double-blind, placebo-controlled study of a selective serotonin reuptake inhibitor (SSRI) antidepressant in depressed adolescents was completed (Emslie et al., 1997) That study demonstrated efficacy for fluoxetine in non-AUD adolescents with major depressive disorder (MDD). Our own research group recently completed a first double-blind, placebo-controlled study of fluoxetine in adults with comorbid MDD and alcohol dependence (Cornelius et al., 1997). That study demonstrated efficacy for fluoxetine in decreasing both the depressive symptoms and the alcohol use of adult depressed alcoholics. Our own research group also recently completed a pilot study involving open label fluoxetine in adolescents with comorbid AUD and MDD. That pilot study demonstrated within-group efficacy for fluoxetine for decreasing both the drinking and the depressive symptoms of that population, and suggested that fluoxetine is a safe medication in this population (Cornelius, et al., In Press). However, to date, no double-blind, placebo-controlled study of any SSRI medication has been conducted in adolescents with a comorbid AUD and MDD. In this proposed study, a first large scale prospective double-blind, placebo-controlled study will be undertaken involving the SSRI medication fluoxetine versus placebo in the treatment of adolescents with an alcohol use disorder and major depression (AUD/MDD). The goals of the study include the following: 1) to compare the efficacy of the SSRI medication fluoxetine plus Treatment As Usual (TAU) to placebo plus TAU for the alcohol use and the depressive symptoms of an adolescent sample (ages 15 to 18) of subjects with comorbid diagnoses of an AUD and MDD; 2) to assess specific predictors of medication response in that study; and to perform a preliminary evaluation of the longer-term efficacy of fluoxetine in these patients, in a 9-month naturalistic follow-up period beyond the 3 month acute phase study. We hypothesize that fluoxetine plus TAU will demonstrate efficacy for decreasing both the drinking and the depressive symptoms of this population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHYSIOLOGIC STUDIES OF ANGER IN DEPRESSED PATIENTS Principal Investigator & Institution: Dougherty, Darin D.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-AUG-2004

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Summary: This is an application for an NIMH Mentored Patient-Oriented Research Career Development Award (K23) titled "Physiologic Studies of Anger in Depressed Patients". It allows the candidate, who has experience with clinical psychopharmacology and positron emission tomography (PET) activation studies, to gain expertise in psychophysiology and in vivo neuroreceptor imaging techniques in the study of affective dysregulation in major depressive disorder (MDD). Numerous PET studies have demonstrated abnormal metabolic patterns in anterior paralimbic structures in patients with MDD. Numerous PET studies following negative emotion induction paradigms in healthy controls have demonstrated that anterior paralimbic structures are involved in the processing of negative emotions such as sadness and disgust. Few studies have utilized these paradigms to study emotional processing in subjects with MDD, a disorder characterized by profound disturbances of affect regulation. Patients with a well-characterized subtype of MDD, MDD with anger attacks, present with sudden uncharacteristic spells of anger accompanied by autonomic activation. This subtype of MDD provides an opportunity to characterize affect dysregulation of a specific type (anger) in a well-defined clinical population, ultimately helping to elucidate the pathophysiology of MDD. We propose to study three populations: MDD with anger attacks, MDD without anger attacks, and healthy control subjects. We will utilize narrative scripts to induce emotional states (angry, sad, and neutral states) and assess physiologic responses in the study populations utilizing psychophysiologic measures, PET activation studies, and PET in vivo neuroreceptor imaging techniques. By this proposal, the candidate seeks training in (1) clinical studies of MDD, (2) affective neuroscience, (3) statistics relevant to functional neuroimaging, and (4) neuroreceptor imaging with PET. This rigorous training plan, integrating strong didactics and multidisciplinary expertise, will teach the candidate how to synthesize information from diverse fields in studying affect dysregulation in MDD. This integrated program of training and research will advance our knowledge of the pathophysiology of MDD, yield new tools for studying emotional processing, and give the candidate the skills needed to achieve independence in a highly complex field. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PLACEBO-CONTROLLED STUDY OF SAME VS.ESCITALOPRAM IN MDD Principal Investigator & Institution: Fava, Maurizio; Professor of Psychiatry Harvard Medical; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Major depressive disorder (MDD) is a common, typically recurrent and disabling disorder, costing the U.S. over $44 billion/year in direct and indirect costs, and with point prevalence rates estimated at 5%-9% for women, and 2%-3% for men. More than one third of patients suffering from MDD appear to use alternative therapies in the U.S. Routinely prescribed in Europe for nearly 30 years and released four years ago in the U.S. as an over-the-counter dietary supplement, s-adenosyl-l-methionine (SAMe) has gained significant popularity as an agent marketed for improving mood and emotional well being. A number of relatively small double-blind studies have shown that parenteral or oral preparations of SAMe, compared with a number of standard tricyclic antidepressants, were generally equally effective, and tended to produce fewer side effects A relatively smaller number of studies have also examined the efficacy of SAMe compared to placebo, with the majority of these studies showing a significant advantage of SAMe over placebo. The recent report of the Southern California Evidence-Based Practice Center for the U.S.

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Department of Health and Human Services [Agency for Healthcare Research and Quality (AHRQ Publication 2002; http://www.ahrq.gov) ] states that "The results of these studies justify additional randomized clinical trials to evaluate the efficacy and tolerability of SAMe for treatment of depression." No adequately powered placebocontrolled study of SAMe in depression has ever been conducted in the U.S. We therefore propose a five-year, placebo-controlled, two-site study to assess the efficacy and safety of SAMe and of a standard selective serotonin reuptake inhibitor (SSRI), escitalopram in outpatients with MDD. This proposal is a parallel comparison of the efficacy and safety of SAMe, escitalopram, and placebo, with a crossover phase during which non-responders to any of these three treatments receive open-label treatment with the combination of escitalopram and SAMe. It is important to assess the efficacy of this combination therapy because patients frequently self-medicate with SAMe during standard antidepressant treatment. The primary aim of the proposed study is to test the acute antidepressant efficacy and tolerability of both SAMe and escitalopram, each compared to placebo, for the treatment of MDD. Secondary aims are to assess the acute effects of SAMe or escitalopram vs. placebo on remission rates, quality of life, and psychosocial functioning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POSTPARTUM DEPRESSION: OMEGA-3 FA VS PLACEBO Principal Investigator & Institution: Freeman, Marlene P.; Psychiatry; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Dr. Freeman is an Assistant Professor of Psychiatry at the University of Arizona and Director of the Women's Mental Health Program of the Department of Psychiatry. After receiving her M.D. from Northwestern University Medical School, she completed a psychiatry residency at the Harvard Longwood Psychiatry Residency Training Program and a Fellowship in Biological Psychiatry at the University of Cincinnati. Her immediate goals are: I) to obtain proficiency in clinical research methodology, with specific emphasis on gender-specific psychopharmacologic research, statistics, and ethical issues, and 2) to gain expertise in the research on mood disorders during pregnancy and the postpartum period. Long term goals are: 1) to become an independent investigator of mood disorders during pregnancy and postpartum, 2) to obtain an ROI award to support further study as an independent investigator, and 3) to serve as a mentor for junior investigators. The career development plan includes a structured didactic program designed to facilitate development to an independent investigator. Mentorship includes work with a primary mentor, Alan Gelenberg, M.D., and strong mentorship in the areas of women's psychiatry and omega-3 fatty acids. A multidisciplinary Advisory Committee will oversee the career development activities at the University of Arizona. The proposed research study is a double-blind, placebo-controlled 3-arm trial of omega-3 fatty acids (FA) in postpartum depression. Data suggest omega-3 fatty acids are efficacious in the treatment and prophylaxis of major depressive disorders. Omega-3 fatty acids may be especially relevant in the treatment of postpartum depression, due to the depletion of maternal omega-3 fatty acids that occurs during pregnancy. The purpose of this study is to determine the efficacy, as well as most effective dose, of omega-3 fatty acids for postpartum depression. Two omega-3 fatty acids in fish oil are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Two different active arms are included in this protocol, one in which patients receive 2.8 g of EPA plus DHA (1.7 g EPA and 1.1 g DHA) and another in which patients receive I g EPA. The active arms were carefully

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chosen on the basis of pilot treatment data and epidemiological data; they should produce optimal tissue levels. These doses should provide an adequate test of the efficacy of omega-3 fatty acids while being safe for the mother and breastfeeding baby. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREDICTING DEPRESSION OUTCOMES IN MEDICALLY ILL ELDERS Principal Investigator & Institution: Koenig, Harold G.; Associate Professor; Psychiatry; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 15-AUG-1999; Project End 31-JUL-2004 Summary: Older adults with congestive heart failure (CHF) and chronic pulmonary disease (CPD) are increasing in number. Their lives and ability to function are greatly affected by these illnesses, which frequently lead to recurrent hospital admissions to manage exacerbations. We have found that 26 percent of older persons with CHF or CPD fulfill criteria for major depressive disorder when hospitalized. Depression is often prolonged, affects recovery, and increases use of health services. About one-third of these depressed patients, however, will go into full remission within three months of hospital discharge, often without specific treatment for depression. Many of these patients improve because their physical illness improves. The other two-thirds of depressed patients will have persistent depression, whether or not their health improves. Minor depression is even more common than major depression, being present in 32 percent of such patients, and while it may have a better prognosis than major depression, it is nevertheless associated with considerable disability and poorer quality of life. Research Questions: We are interested in studying four conjoint trajectories of depression-physical health outcome in the first six months after hospital discharge: depression and health both improve, depression improves but health does not, health improves but depression does not, and neither depression nor health improves. What proportion of patients follow each trajectory? What psychosocial and health characteristics predict which trajectory they will follow? What are the barriers to effective treatment, how is depression currently treated in these patients, and what are predictors of treatment intensity? Methods: 1000 older patients with CHF or CPD and major (n=500) or minor depression (n=500) will be recruited from the inpatient services of Duke Hospital and two community hospitals and followed for six months after discharge. Detailed assessments of depression and severity of medical illness will be conducted by a research nurse during telephone and in-person evaluations. Significance: Such information is necessary to determine which of the many patients with major or minor depression need specific treatment, and which patients will improve on their own after discharge as their medical illness improves or fails to improve. It will also provide important information to both guide future clinical trials and identify barriers to effective treatment of depression in these patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PREFRONTAL CELL PATHOLOGY DISTINGUISHES MENTAL DISORDERS Principal Investigator & Institution: Rajkowska, Grazyna; Professor of Psychiatry; Psychiatry and Human Behavior; University of Mississippi Medical Center 2500 N State St Jackson, Ms 39216 Timing: Fiscal Year 2002; Project Start 23-SEP-2001; Project End 31-AUG-2004

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Summary: (provided by applicant) There are established differences and similarities in phenomenology and treatment between schizophrenia (SCHZ) and major depressive disorder (MDD). It is well known that depressed symptoms occur in SCHZ and psychotic symptoms are no uncommon for MDD. It is therefore justified to postulate that different brain regions and/or different cell types using specith neurotransmitters are crucial to distinguish the neuropathology of both disorders. Neuroimaging evidence implicates the dorsolateral prefrontal (dIPFC) and orbitofrontal (ORB) cortical areas in the neuropathology of SCHZ and MDD. Our recent quantitative histopathological studies in postmortem tissue reveal the differential involvement of the dIPFC and ORB region in the neurobiology of MDD and SCHZ. However, the specific types of neurons and glia, which underlie the prefrontal pathology of these mental disorders have not been identified yet. The overall objective of this proposal is to distinguish MDD and SCFIZ by using quantitative immunohistochemistry to identify the region-and layerspecific biochemical types o vulnerableneurons and glia constituting dysfunctional prefrontal Circuits. The specific hypotheses are: 1) Subjects with MDD will be characterized by lower numbers of immunoreactive neurons and glia and lower levels of trophic factors, BDNF an GDNF in both dIPFC and ORB. In contrast, subjects with SCHZ will exhibit reductions similar to MDD only in the ORI region, whereas in the dIPFC, SCHZ will be distinguished from MDD by higher neuronal and possibly, glial cell number. 2 Cellular changes observed in prefrontal regions from MDD and SCHZ patients are due to the disease process and therefore they will not be found in analogous regions from rat brains treated chronically with antidepressant or antipsychotic medications If these hypotheses are proven, a provocative interpretation would be that anatomic-functional changes in the dIPFC may b related to cognitive dysfunction. Where as changes in the ORB may be related to depressive symptoms. To test these hypotheses vulnerable cell types will be identified and quantified by the combination of immunohistochemistry and 3-D non-biase stereology. We will identify prefrontal cells with specific antibodies (Nonpyramidal neurons with antibodies to Ca2 binding proteins; Pyramidal neurons with antibodies against neurofilament protein NF-200; Astroglia with an antibody to GFAP; ani-Microglia with antibodies against the bchemokine receptor in subjects with MDD, subjects with SCHZ and in match psychiatrically-normal controls. The proposed study will illuminate disrupted cortical circuits involved in psychotic and depressed symptomatology and possibly cortical Sites of action for antidepressant and antipsychotic medications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION FOR INFANTS OF LOW-INCOME DEPRESSED MOTHERS Principal Investigator & Institution: Cicchetti, Dante; Clinical/Social Psychology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): This longitudinal investigation will evaluate the relative efficacy of two theoretically-informed approaches to preventing maladaptation, a depressotypic developmental organization, and emergent psychopathology in young offspring of low-income depressed mothers. Research participants will include 260 mothers and their infants; 195 mothers will have a current major depressive disorder and 65 demographically comparable mothers will have no lifetime history of mental disorder. All families will be at or below the federal poverty level. Depressed mothers and their infants will be randomly assigned to 1 of 3 treatment conditions: 1) Interpersonal Psychotherapy (IPT) for 4 months followed by an attention control for 8

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months; 2)IPT for 4 months followed by Infant-Parent Psychotherapy (IPP) for 8 months; and 3) Enhanced Community Standard (ECS) treatment for depression, involving facilitated referrals for standard interventions in the community. Baseline assessments will be conducted when infants are 12 months old, with subsequent re-assessments when infants are 14, 16, 24, 36, and 48 months of age. Assessments will measure three major areas: 1) Maternal depressive symptomatology and Major Depressive Disorder (MDD) diagnosis, social role functioning, support, and home contextual features; 2) the quality of the mother-child relationship and affective features of parenting; and 3) child functioning, stage-salient issues, and stress-reactivity. Longitudinal comparisons of the two active preventive intervention groups (IPT and IPT/IPP) with the ECS and nondisordered groups will be used to determine: 1) whether IPT and IPT/IPP are efficacious in reducing maternal depressive symptomatology and MDD relapse through the child's age of four; 2) whether treatment targeted on maternal depression is sufficient to alter the developmental course in offspring; and 3) whether intervention directly focused on the mother-child relationship also is necessary to promote positive outcomes and reduce risk for maladaptation and psychopathology in young offspring of depressed mothers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION OF RECURRENCE OF MAJOR DEPRESSIVE BEHAVIOR Principal Investigator & Institution: Craighead, W. Edward.; Professor; Psychology; University of Colorado at Boulder Boulder, Co 80309 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: Nearly one-quarter of young adults will experience a Major Depressive Disorder (MDD) by the age of 18, and about one-half of these individuals will suffer from a recurrence during the two years following the first episode. Because of the debilitating effects of MDD on the individual and society, including the overuse of medical services by these citizens, this is a major national health problem. We will begin by writing an intervention manual for an integrated interpersonal, cognitive, and behavioral program designed to prevent the recurrence of MDD among entering college freshmen. The program consists of 12 weekly group sessions conducted over both semesters of the freshmen year. We will also develop reliable adherence and competence measures to evaluate the fidelity and quality of the implementation of the preventive program. In the proposed pilot study we will randomly assign 96 college freshmen who have had a previous MDD but are not currently depressed to either the recurrence prevention program or to treatment as usual; all these students will participate in standard assessment, including diagnostic interviews, at baseline, 6-, 12-, and 18-months. During the first year we will write the manual, develop the adherence and competence measures, randomly assign 24 participants each to one of the two conditions, and re-assess them at 6 months. During the second year, we will randomly assign 24 more participants to each condition, re-assess them at 6 months, and follow-up the first year participants at 12- and 18-months. During the third year we will follow-up the second year participants at 12- and 18-months, analyze and report the data, and revise the prevention manual. Results from the proposed study should allow us to: develop a revised prevention manual which will be employed in a subsequent large randomized controlled trial studying the prevention of recurrence of MDD in college settings; estimate the effect and sample sizes for the subsequent prevention study; and, begin to develop a manual for prevention of recurrence of MDD among young adults in community mental health centers and HMOs.

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Project Title: PROPHYLACTIC COGNITIVE THERAPY FOR DEPRESSION Principal Investigator & Institution: Thase, Michael E.; Professor; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 03-DEC-1999; Project End 30-NOV-2004 Summary: This is a blinded, controlled, randomized clinical trial to evaluate the efficacy of and indications for eight months of continuation phase cognitive therapy (C-CT), pharmacotherapy (fluoxetine; FLX), and pill placebo (PBO) in outpatients with recurrent major depressive disorder (MDD) who are at higher risk for relapse. The study will be conducted jointly by investigators at the University of Texas Southwestern Medical Center and the University of Pittsburgh School of Medicine. "Higher risk" is defined by incomplete remission during the final six weeks of acute phase CT, while "lower" risk is defined as a complete and stable remission (i.e., seven consecutive Hamilton Rating Scale for Depression scores of less than seven). This trial has great public health significance because it will help identify when CT reduces the risk of relapse for patients suffering from recurrent MDD, an illness with high morbidity and mortality. Patients with the highest risk for relapse can be targeted for the most vigorous preventative treatment. This study is also the first to evaluate continuation phase pharmacotherapy (FLX) after incomplete remission with acute phase CT. This contrast is important because many patients do not have adequate insurance coverage to support the full course of acute plus continuation phase CT. Further, the pharmacotherapy group will permit tests of mode-specific versus nonspecific therapeutic activity. Approximately 340 male and female outpatients, age 18 - 70, with DSM-IV unipolar, nonpsychotic, recurrent MDD will enter 16 sessions of acute phase CT. Approximately 114 responders at higher risk for relapse will be randomized to eight months of: (a) C-CT, (b) FLX, or (c) PBO. The lower risk patients (n = 56) will be followed for eight months after acute phase CT. Dependent variables measure response, relapse, recurrence, remission, and recovery. Blind evaluations occur at the end of the acute phase and at four and eight months postacute phase CT, as well as at suspected relapse or exit. Survival analyses are planned. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PSYCHOPATHOLOGY, ADOLESCENTS

COGNITION,

AND

SUICIDE

IN

Principal Investigator & Institution: Esposito-Smythers, Christianne L.; Ctr for Alcohol & Addict Studs; Brown University Box 1929 Providence, Ri 02912 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2006 Summary: (provided by investigator): Major depressive disorder, disruptive behavior disorders, and anxiety disorders are all significantly associated with suicidal ideation and attempts in adolescents. Yet, the nature of the relation between psychopathology and suicidality has been greatly understudied. The purpose of this 3-year application is to test a cognitive mediational model to explain this relationship. Specifically, it is hypothesized that psychopathology is related to suicidality through unique dysfunctional cognitive processes and products linked with various clinical disorders in adolescents. The proposed study will also explore the manner in which comorbid forms of psychopathology affect dysfunctional cognitive processes and products, and suicidality in adolescents. It is hypothesized that depressed adolescents with comorbid psychopathology will exhibit more severe dysfunctional cognitive processes and products, and thus further increase their suicide risk. Secondarily, gender differences

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across mediational and comorbidity related findings would be explored. More complex competing models will also be tested. The proposed study will employ a cross-sectional design to test hypotheses. Two hundred and fifty psychiatrically hospitalized adolescents will be asked to complete a diagnostic interview and symptom inventories to assess psychopathology, as well as performance based measures and questionnaires to assess dysfunctional cognitive processes, cognitive products, and suicidality. Analyses will include the use of structural equation modeling (SEM) techniques, hierarchical regression analyses, and analyses of variance (ANOVA). Information obtained from this study will help explicate cognitive patterns in suicidal adolescents with varying forms of psychopathology and could ultimately be used to tailor cognitivebehavioral and multimode interventions for these high risk youth. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RISK AND PREDICTORS OF POSTPARTUM DEPRESSION Principal Investigator & Institution: Cohen, Lee S.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 11-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The postpartum period is a time of heightened risk for the emergence of psychiatric illness, particularly in women who already have a history of mood disorder. Given the prevalence of depressive disorders during the childbearing years, it is crucial to identify women who are at highest risk for new onset or recurrence of depression during the postpartum period. Identification of those women at greatest risk for postpartum depression may allow for interventions that would limit maternal morbidity associated with untreated postpartum depression. This proposal outlines a multi-institutional collaborative research project (R01) in response to PA-00-074, in which risk for postpartum depression will be evaluated in women with histories of major depressive disorder. Subjects who have had at least one episode of DSM-IV major depression will be followed prospectively from late pregnancy (32-36 weeks gestation) up to six months after delivery using a series of standardized instruments. The primary aims of this investigation are (1) to identify clinical and psychosocial predictors of postpartum depression and functional impairment and (2) to determine the extent to which treatment (pharmacologic, nonpharmacologic or a combination) proximate to delivery modulates risk for postpartum relapse. How clinical and psychosocial variables including history of postpartum depression, severity of past depression, number of previous episodes, age at illness onset, depression during pregnancy, and social support affect risk for postpartum depression, as well as psychosocial functioning, will be investigated. The current submission is a natural extension of an ongoing academically productive collaboration in which risk for depressive relapse is evaluated in pregnant women with histories of major depression who either discontinue or maintain antidepressant treatment. This proposal provides an opportunity to study a rigorously followed population into a period of risk -- the postpartum period -- and to investigate the factors that confer or modulate risk for depression at this time. The three participating sites for this investigation include the Perinatal and Reproductive Psychiatry Clinical Research Program at the Massachusetts General Hospital, Harvard Medical School (Drs. Cohen, Nonacs and Otto), the Women's Life Center and Mood Disorders Research Program at UCLA (Dr. AItshuler, Dr. Hendrick), and the Emory Women's Mental Health Program at Emory University School of Medicine (Dr. Stowe). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RUPP-PI Principal Investigator & Institution: Walkup, John T.; Associate Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): This application responds to a Request for Applications from the NIMH to establish Research Units of Psychopharmacology and Psychosocial Interventions (RUPP-PI). The application builds on the expertise of our investigative group and our experience with multisite studies, especially NIH funded multisite psychopharmacological and psychosocial intervention studies. We have a track record of providing leadership and the capacity to function amiably and collegially in our collaborative efforts. The Scientific Aims of our research group are highly compatible with the spirit of the RFA for the RUPP-PI. Our goals are to develop and implement multisite: 1) efficacy studies that establish new evidence-based psychopharmacological and psychosocial treatments; 2) innovative efficacy studies that determine the optimal "dose" of treatments, optimal sequence of treatments, rational timing of discontinuation of treatments, and comparative treatment trials; 3) effectiveness studies that apply the results of efficacy studies in "real world" settings, such as schools, pediatric practices, and community mental health centers; 4) methods to effectively monitor long-term safety of psychotropic medications. The exemplar protocol contained in this proposal has unique public health significance, is feasible, inclusive, and designed to be implemented according to the highest ethical standards. It describes a 5-year multisite 3-arm, double blind, placebo substitution intervention to establish the optimal length of antidepressant treatment in children and adolescents with Major Depressive Disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: S-ADENOSYL METHIONINE(SAME)AUGMENTATION OF SSRIS IN MDD Principal Investigator & Institution: Papakostas, George I.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 27-JAN-2004; Project End 30-NOV-2008 Summary: (provided by candidate): This is a submission of an application for a mentored patient-oriented K-23 award, designed to enhance clinical training and research expertise in the area of major depressive disorder on (MDD) and the role of natural remedies in the development and treatment of depressive disorders. Natural remedies, although used for centuries throughout the world, have become increasingly popular in the US over the past few years. S-adenosyl methionine (SAMe) is one such compound. Although results obtained from double-blind preliminary studies support the hypothesis that this compound may have antidepressant effects, oral SAMe has not yet been studied as a potential augmenting agent for contemporary, first-line antidepressants, such as the Selective Serotonin Reuptake Inhibitors (SSRIs). As many as 29% to 46% of depressed patients show only partial or non-response to an adequate course of an antidepressant, with most patients taking an SSRI as an initial treatment. The goal of this project will be to assess the efficacy of oral SAMe compared to placebo as an augmentor of SSRIs in the treatment of major depression refractory to treatment with SSRIs. This application involves enrolling outpatients with MDD, with partial or no response to an SSRI trial of adequate dose and duration. Patients will be treated for 6 weeks in a double-blind fashion with either oral SAMe tosylate, up to 1600mg/day, or placebo for 6 weeks. We hypothesize that there will be a statistically significant

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difference in the response rates between the two treatment groups at endpoint, with a greater response rate in the group that received SAMe augmentation. The proposed study will be based at the Massachusetts General Hospital in the Depression Clinical and Research Program, under the mentorship of Maurizio Fava, MD, and will include consultation from experts in the area of MDD, alternative medicine, and biostatistics. There will also be a didactic component to the application project, including coursework research design, neuronal biology, biostatistics, and ethics. It is hoped that this project award will provide the critical fund of basic knowledge and practical experience necessary to aid the candidate in becoming an independent investigator in this area. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SELF SYSTEM THERAPY AND CHRONIC LOW BACK PAIN Principal Investigator & Institution: Keefe, Francis J.; Professor and Associate Director; Psychiatry; Duke University Durham, Nc 27710 Timing: Fiscal Year 2003; Project Start 15-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Patients with chronic low back pain (CLBP) cope with numerous major life challenges associated with their disorder, including changes in their ability to work, as well as decrements in physical and emotional well being. These changes alter CLBP patients' ability to pursue and achieve important personal goals and live up to personal standards. As a result, CLBP patients are highly likely to experience substantial difficulties with self-regulation, i.e., the ongoing process of evaluating and regulating one's behaviors so as to meet important personal goals and standards. In turn, the inability to attain important goals and standards increases risk for depression. The long-range goal of this research is to reduce the depression, pain, psychological disability, and physical disability experienced by CLBP patients suffering from depression. The proposed study seeks to evaluate the efficacy of Self-System Therapy (SST), a new therapy for depression specifically targeting problems in selfregulation. A total of 174 CLBP patients who meet DSM-IV criteria for major depressive disorder will be randomly assigned to one of three conditions: 1) Self-System Therapy (SST) - a twelve-session version of SST adapted to the concerns of CLBP patients; 2) Back Pain Education - a comparison condition that provides patients with information on the nature and treatment of chronic low back pain; or, 3) Standard Care Condition - a control condition in which patients will receive care requested by them and made available to them by their health care provider. Assessment measures to be gathered before and after treatment and at 6- and 12-month follow-up will include depression, physical and psychosocial disability, pain and coping self-efficacy, self-regulatory focus, and self-discrepancies. Daily measures of pain, mood, goal activation/attainment, and stress will also be gathered. Converting basic knowledge about the causes and consequences of unsuccessful self-regulation to the diagnosis and treatment of depression in CLBP patients represents a promising avenue for identifying treatment options appropriate for these individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SEROTONIN 1A RECEPTOR & METABOLIC IMAGING IN DEPRESSION Principal Investigator & Institution: Kupfer, David J.; Thomas Detre Professor and Chair; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 15-MAY-1999; Project End 31-JAN-2005

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Summary: (Applicant's abstract) Multiple lines of evidence suggest that serotonin1A (5HT1A) receptor function is abnormal in major depressive disorder (MDD) and that somatic antidepressant therapies effect changes in 5HT1A receptor function that are relevant to treatment efficacy. The data supporting these hypotheses have been obtained by assessing neuroendocrine and temperature responses to 5HT1A agonists in MDD subjects, measuring 5HT1A receptor binding in brain tissue acquired post mortem from small samples of MDD subjects, and examining changes in 5HT1A receptor binding in rats following antidepressant drug (AD) administration. However, there has been no direct demonstration of a central 5HT1A receptor abnormality or an effect of antidepressant treatment on 5HT1A receptor pharmacology in living depressed subjects. The development of a highly selective 5-HT1A receptor radioligand for positron emission tomography (PET) imaging, [carbonyl-11C]- WAY-100635, has recently made direct, noninvasive exploration of the central 5HT1A receptor binding potential (BP) possible in MDD. To advance knowledge regarding the neurobiology of MDD and the mechanisms of AD treatment, PET and [carbonyl-11C]WAY-100635 will be used to compare the 5HT1A receptor BP between MDD and healthy control subjects and between the pre-and post-treatment conditions in the MDD subjects. Images of 18Ffluorodeoxyglucose (FDG) uptake will be acquired in the same scan session to evaluate the relationship between regional 5HT1A receptor BP and the glucose metabolic abnormalities previously identified in MDD. Endocrine assessments of cortisol secretion are also examined prior to imaging to determine whether down-regulation of hippocampal 5HT1A receptors occurs in response to the hypercortisolism associated with MDD as it does in experimental animals during stress and glucocorticoid administration. The imaging and endocrine measures are repeated following an 8 week interval during which the depressives are treated with the antidepressant drug sertraline. Pilot imaging data suggest that the differences in the 5HT1A receptor BP between unmedicated depressives and controls are robust in the mesiotemporal cortex and the ventrolateral and ventromedial prefrontal cortex (PFC). If a link between reduced 5HT1A receptor BP in the mesiotemporal cortex (which includes the hippocampus) and abnormal cortisol secretion is established in MDD, then normalization of this abnormality during treatment may have prognostic implications. In the ventrolateral and ventromedial PFC, the magnitude of the abnormal reductions of 5HT1A receptor BP were proportionately larger than the abnormalities of metabolism and grey matter volume previously shown in these areas in MDD, suggesting the 5HT1A receptor imaging measures may provide sensitive markers of pathology that can guide future post mortem histological and histochemical studies of MDD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SERTRALINE FOR ALCOHOL DEPENDENCE AND DEPRESSION Principal Investigator & Institution: Pettinati, Helen M.; Director; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 31-MAR-2004 Summary: This is a competing continuation proposal to extend results from a 5- year NIAAA-funded project on sertraline for depressed alcoholics. Comorbidity in substance abusers traditionally has been associated with a more severe clinical picture and a poorer prognosis for drinking outcome, compared to cases of uncomplicated alcoholism. In clinical populations, one-third to one-half of patients seeking alcohol treatment have a lifetime major depressive disorder. Persistent depression in abstinent alcoholics is both disabling and a risk factor for relapse to drinking, and further clinical deterioration that may result in suicide. Because we have effective, FDA-approved pharmacotherapy for

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alleviating depressive symptoms, it is important that we are fully informed about the advantages (or disadvantages) of treating primary or secondary depression in alcoholics with antidepressant medications. Results from our initial, project suggested that comorbidly depressed alcoholics appeared to have reduced antidepressant effects from sertraline and sertraline did not reduce their drinking (more than placebo). To address these results, we propose a study that will examine if we can achieve a more optimal outcome in comorbidly depressed alcoholics by directly treating the alcoholism with naltrexone, and combining this pharmacotherapy with the use of sertraline for treating depression. Thus, the primary aim of this proposal is to examine in depressed alcoholic outpatients whether combining naltrexone (an FDA-approved pharmacological intervention to reduce drinking) with sertraline (an FDA-approved pharmacological intervention to treat depression) will result in greater reductions in both drinking and depression over either medication alone or placebo. A secondary aim is to examine whether certain patient features, e.g., extent of pre-treatment drinking or severity of depression, will predict response to sertraline, naltrexone, or the combination. Patients who present to the University of Pennsylvania Treatment Research Center will be recruited for participation in this study over a 5-year period. There will be 160 males and females with a current DSM-IV diagnosis of alcohol dependence and also of major depression (via PRISM) who will be randomized to one of four treatment groups (40 per group): 1) the combination of 100mg/day naltrexone and 200mg/day sertraline, 2) 100mg/day naltrexone, 3) 200mg/day sertraline, or 4) placebo. Subjects will also receive once- weekly sessions of Cognitive Behavioral Therapy that has been adapted to include a medication compliance enhancement component. The treatment phase will last 16 weeks (includes a week of baseline, and a week of single-blind, placebo lead-in, and 14 weeks of double-blind pharmacotherapy). The follow-up phase includes two visits at 6 and 9 months post-treatment entry. Overall, this project will determine if combining pharmacotherapies results in a better response in comorbidly depressed alcoholics than either medication alone or placebo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SLEEP AND AROUSAL DISTURBANCES IN PTSD Principal Investigator & Institution: Neylan, Thomas C.; Assistant Professor; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2004 Summary: (Adapted from applicant's abstract): This proposal is the first of several phases in a line of research on the biology of sleep disturbances in Post Traumatic Stress Disorder (PTSD). This proposal aims to examine the relationship between sleep architecture, particularly slow wave sleep, and hypothalamic-pituitary-adrenal axis activity in chronic PTSD. The investigators will study medication-free, non-substance abusing male and female Vietnam theater veterans with chronic PTSD with and without concurrent Major Depressive Disorder (MDD). They will examine the effects of metyrapone, an antiglucocorticoid agent that enhances slow wave sleep, on sleep architecture in PTSD subjects with and without MDD. The major aims of this study will be met with a two group design whose main comparisons will be between PTSD with current MDD (N=50) and PTSD without lifetime MDD (N=50). The investigators will test if differences in HPA activity contribute to the variability in sleep physiology in PTSD. The study will involve 5 nights of ambulatory polysomnography: 2 at home, and 3 in a hospital observation unit where 23 hour urinary free cortisol and a metyrapone challenge will be performed. The home sleep and hospital sleep are separated by 3

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nights. The order of home vs. hospital sleep studies will be counterbalanced to study order effects in adaptation to recording equipment and hospitalization. A third group of combat veteran controls without lifetime PTSD or MDD (N=20) will be recruited to allow an examination of the effect of PTSD on ambulatory sleep measures and adaptation to recording equipment and hospital setting. The control group will be studied with ambulatory polysomnography for 4 nights: 2 at home, and 2 in the hospital with no metyrapone challenge. Finally, the study will validate wrist actigraphy against ambulatory polysomnography and provide data on 24 hour sleep-wake activity levels in PTSD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIFECOURSE

SOCIAL

INEQUALITIES

IN

DEPRESSION

ACROSS

THE

Principal Investigator & Institution: Buka, Stephen L.; Associate Professor; Maternal and Child Health; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: This application addresses two major current themes in the epidemiology and prevention of adult mental disorders: a) social and economic disparities in health status: and b) early origins of adult health status. Where most of the current work in these areas has focused on physical health conditions (e.g., cardiovascular illness. diabetes) there is mounting evidence of the relevance of these lines of inquiry to psychiatric disorders. Furthermore, while socioeconomic disparities in depression in adulthood have been documented consistently, the mechanisms generating these disparities have yet to be fully elucidated. Accordingly, we seek to conduct new data analyses examining socioeconomic disparities in major depressive disorder in relation to adult and childhood socioeconomic status, and to examine the role of other childhood environmental factors in the development of depression. These investigations will be based on the Providence follow-up National Collaborative Perinatal Project, a thirtyyear, longitudinal study of 1,263 individuals who were enrolled at birth and systematically followed for an average of 27.8 years. Comprehensive prospective assessment of childhood environmental conditions have been obtained at multiple points in time and adult psychiatric diagnoses obtained using structured diagnostic interviews. We will employ a range of analytic strategies including discrete-time survival analyses. The specific aims of this study are to examine the effects of childhood socioeconomic status on the occurrence and severity of major depressive disorder in adulthood. Furthermore, we will assess the direct role of childhood environmental factors in the occurrence of depression as well as their potential to mediate the association between early-life socioeconomic conditions and subsequent depression. Finally, we will study the risk that substance abuse disorders pose on the incidence of depression and examine whether this risk is modified by childhood conditions. The prospective nature of this study, the comprehensive assessment of parental and childhood variables, and the rigorous measurement of psychiatric disorders in adulthood make this sample uniquely suited to addressing these aims. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOFTAD SUBSTANCE USE OUTCOMES FOLLOWING TAD Principal Investigator & Institution: Curry, John F.; Associate Professor; Psychiatry; Duke University Durham, Nc 27710

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Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Substance abuse is a major public health problem among adolescents in the United States, associated with serious negative outcomes including high-risk sexual behavior and the leading causes of adolescent death: accidents, homicide and suicide. Substance use disorders (SUD's) are one of the three most common forms of adolescent psychiatric disturbance. Prevention of such disorders is a public health priority. The National Institute on Drug Abuse (NIDA) and the National Institute of Mental Health (NIMH) recently released RFA: DA-03-007, calling for investigations into the impact of child psychopathology and childhood interventions on subsequent drug abuse. This project, Substance use Outcomes Following Treatment for Adolescent Depression (SOFTAD) is an extended follow-up of adolescents who have completed the NIMH Treatment for Adolescents with Depression Study (TADS). We developed and are coordinating TADS, a 12-site study comparing cognitive behavior therapy (CBT), fluoxetine (FLX), combined CBT and FLX acutely to one another and to placebo, and longitudinally to one another in 432 adolescents with Major Depressive Disorder (MDD). TADS is the first adolescent MDD treatment study to include measures of substance use and abuse. We propose to enhance the measurement of substance use outcomes and related family factors and to extend the follow-up period from TADS treatment to five years in order to address critical questions emphasized in RFA: DA-03-007. These include the impact of treating MDD (and of specific treatments) on subsequent substance use outcomes, the identification of moderators and mediators of successful outcome in the affective and substance use domains, and the longitudinal relationship between adolescent MDD and substance use or abuse in a clinical sample. Approximately 300 adolescents will be followed and assessed every six months. Selfreport, parent-report and diagnostic interview measures will be collected. The major hypothesis, that successful treatment of MDD will reduce subsequent substance use problems, and additional questions, will be tested using chi-square, logistic regression, and structural equation modeling. SOFTAD will be coordinated by the Duke Clinical Research Institute (DCRI), the same organization coordinating TADS, thus realizing substantial efficiencies and cost savings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STUDY OF YOUNG CHILDREN AT RISK FOR DEPRESSION AND ADHD Principal Investigator & Institution: Hirshfeld-Becker, Dina R.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 25-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Clinical and epidemiological studies document a substantial overlap of at least 30 percent between attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MD). Moreover, children comorbid for ADHD and MD are at heightened risk for morbidity and dysfunction. Clearly the ability to identify early the children most at risk for this comorbid presentation would be of the highest clinical and public health importance. To study early risk factors, it is necessary to choose a population known to be at especially high risk. Since parental MD has been shown to increase a child's risk for both MD and ADHD, and familial ADHD has been shown to increase risk for both MD and ADHD, a useful approach to studying early risk factors for these disorders in non-clinical samples is to focus on children at risk for MD and/or ADHD. Our work and that of others indicate that the temperamental trait "Behavioral Disinhibition" (BD) may be a powerful predictor of ADHD and externalizing symptoms and specifically of comorbid ADHD+MD. BD, which can be

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measured via laboratory observations in children ages 2 to 5 yrs, reflects the extreme tendency to seek out novelty, approach unfamiliar stimuli, and display disinhibition of speech and action. These responses may indicate a predisposition to develop ADHD+MD that can be measured before the disorders can be assessed accurately with standard psychiatric instruments. We therefore propose a 5-year longitudinal study of laboratory-observed BD in 2-5-year-old children and its psychiatric and functional outcomes (at age 6) in 100 offspring of parents with MD and 100 offspring of parents with ADHD, compared with 100 children of parents with neither disorder. We propose to examine BD as a predictor of (a) ADHD and (b) comorbid ADHD+MD. To examine the specificity of BD for these conditions, we will also examine rates of the broader categories of persistent disruptive behavior disorders, including oppositional-defiant disorder and conduct disorder, and of comorbid behavior disorders+MD. This study will form the foundation of a long-term follow-up study aimed at testing the usefulness of BD as a predictor of ADHD, comorbid ADHD+MD and of persistent disruptive behavior disorders in children at risk growing-up into later childhood and adolescence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SUBSTANCE DEPENDENT TEENS--IMPACT OF TREATING DEPRESSION Principal Investigator & Institution: Riggs, Paula D.; Associate Professor of Psychiatry; Psychiatry; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: (Applicant's Abstract) Adolescents with substance use disorders (SUD) and conduct disorder (CD) have high rates of comorbid depression. Despite the high prevalence of depression in such youth, little is known about effective treatment of such depressions. Moreover, the effects of treating depression on substance use and other problem behaviors in such youth are not known. Only serotonergic agents, fluoxetine (FLX) and paroxetine, with most support for FLX, have empirical support in the treatment of depression in adolescents without serious comorbidity. It is not known whether FLX (or paroxetine) are effective in treating the depressions of adolescents with SUD and CD. The proposed study is a randomized, placebo-controlled trial comparing placebo to fluoxetine for major depressive disorder (MDD) in 120 adolescents with SUD and CD. Adolescents with DSM-1V SUD, CD, and MDD assessed both clinically and with structured assessment instruments, will be randomized to one of these two treatment cells for 16 weeks. All subjects will also receive standardized, manual-driven cognitive behavior treatment for adolescent SUD for the duration of the trial as the background "treatment as usual" Medication compliance will be electronically monitored. Adverse side effects will be monitored weekly. The specific aims of this study are to test the following hypotheses: 1. Fidoxeline + CBT will be more effective in treating unipolar depression in adolescents with SUD and CD than placebo + CBT. 2. The treatment of depression with RX + CBT, in depressed adolescents with SUD and CD will be more effective than placebo + CBT in reducing substance use and improving conduct symptoms. 3. The treatment of depression with RX will result in greater retention in, and compliance with substance treatment (CBT) and reduction in both substance use and conduct problems than treatment with placebo. This research will contribute important knowledge regarding effective treatment of depression in conductdisordered adolescents with SUD and provide information about the effects of treating depression on substance and other behavioral outcomes as well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TELEPHONE PSYCHOTHERAPY--TREATMENT OF DEPRESSION IN MS Principal Investigator & Institution: Mohr, David C.; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2002; Project Start 08-SEP-2000; Project End 31-JUL-2005 Summary: (Adapted from the Applicant's Abstract): Rates of depression in multiple sclerosis (MS) have been estimated at between 14% and 54%, and have been shown to be higher than rates in the general population or in other chronic illnesses. While untreated depression in MS is likely to worsen over time, it has been shown to respond well to treatment with cognitive behavioral therapy (CBT). Nevertheless, many patients with MS remain untreated. This may be due in part to common symptoms of MS, which can interfere with regular office visits. We are proposing to test a model of CBT, administered over the telephone, designed to treat depression in MS. While the use of telephone counseling and support services is increasing, empirical evidence on the efficacy of such services for the treatment of depression is scant at best. A patient workbook and therapist CBT treatment manual were developed by the PI and tested in an uncontrolled pilot study. In the 8-week pilot, 32 MS patients were randomly assigned to either telephone CBT or standard care (SC) in an HMO. Patients receiving telephone CBT showed improvement, as compared to patients receiving SC as measured by the Profile of Mood States Depression-Dejection scale (p=.01). This study proposed to enroll 128 patients in a randomized treatment study. Patients will be selected from the diverse population of patients in the Northern California Kaiser Permanente Medical Care Group (KPMC). Patients who meet inclusion criteria, including definite MS, activity limitation (disability) criteria, and DSM-IV diagnosis of Major Depressive Disorder (MDD), will be randomized into one of two treatment groups: 1) Coping with MS (CMS) telephone psychotherapy, which is a 16 week, 18 session, manualized form of telephone CBT that focuses on depression and adjustment to illness; or 2) a non-directive (ND) therapy contrast condition that controls for the nonspecific effects of psychotherapy. Outcomes include dichotomous and continuous measures of MDD, Quality of Life, and activity limitations. Patients will be followed for one year after the end of treatment. If the treatment proves efficacious, it will result in a validated form of telephone CBT for the treatment of depression that can be provided to MS patients independent of their mobility status or geographic location. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TESTING COGNITIVE BEHAVIORAL THERAPY IN A PUBLIC SYSTEM Principal Investigator & Institution: Lopez, Molly Ann.; Psychologist; Texas State Dept of Mental Health & Mr Box 12668, 909 W 45Th St Austin, Tx 78711 Timing: Fiscal Year 2003; Project Start 05-AUG-2003; Project End 31-DEC-2004 Summary: The Texas Department of Mental Health and Mental Retardation (TDMHMR) is committed to incorporating empirically-supported interventions into a service array designed to meet the needs of the citizens of Texas with severe or persistent mental illness. As a part of this on-going effort, TDMHMR proposes to undergo a project designed to identify and implement an empirically-validated cognitive behavioral therapeutic approach for adults diagnosed with major depressive disorder. There is compelling research evidence that cognitive behavioral therapies are as effective as pharmacotherapy in improving depressive symptomatology and may be more effective in preventing relapse. The department has the long-range goal of identifying and

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implementing one or more validated psychotherapies throughout all community mental health centers in Texas. The current application has three primary aims: (1) to review empirically-validated, manualized, cognitive behavioral therapies for the treatment of major depression in adults and select a therapeutic approach that can best be transported into a community mental health system; (2) to create an implementation plan that includes a training module to maximize implementation and fidelity to the treatment model and addresses methods for reducing common barriers to implementation; and (3) to conduct a brief pilot study utilizing four to eight masterslevel clinicians currently employed within community mental health clinics to provide the manualized treatment to consumers deemed appropriate for the service. Providers will undergo training and supervision by an expert consultant. Adults with major depression referred for counseling will be recruited for the study. Changes in symptom severity during treatment will be measured, as well as each therapists' level of competence with the selected therapeutic approach. This small pilot study will provide preliminary information on the feasibility of implementing this approach within community mental health clinics and provide guidance for the future planning of a more comprehensive implementation effort. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE COLLABORATIVE STUDY OF MAJOR DEPRESSION Principal Investigator & Institution: Crowe, Raymond R.; Professor; Psychiatry; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: (Adapted from investigator's abstract) Major depressive disorder (MDD) has at least a 5-10% lifetime population prevalence and causes severe morbidity and mortality including suicide. Heritability in twins is 0.4-0.70. Mapping of susceptibility genes may be feasible with the recurrent, early-onset subtype (MDD-RE) which demonstrates a three- to eight-fold increase in risk to first-degree relatives of probands, vs. twofold for all MDD. The complex pattern of transmission suggests multigenic transmission and/or locus heterogeneity, so that large samples may be required. We propose a four-year, six-site project to collect an estimated 770 pedigrees which contain 1,000 independent affected sibling pairs (ASPs), extended by first-degree relationships to include additional affected relatives, plus unaffected relatives (parents and sibs) for genetic phase information. All sites will have identical inclusion criteria, clinical assessment DIGS and FIGS interviews and the NEO personality inventory), interviewer training and reliability monitoring, consensus diagnostic procedures, data management system, and administrative oversight including a quality assurance program. Permanent cell line specimens will be created and DNA extracted at the NIMH-sponsored cell repository. A 10 cM genome scan will be completed on all affected subjects at the Center for Inherited Disease Research (CIDR), which has approved this project for CIDR access. A three-stage design is proposed: regions with maximum lod scores (MLS) exceeding a liberal simulation-based threshold will be identified in a genome scan of the affected individuals from the first half of the sample, and candidate regions selected which continue to meet this threshold after unaffected individuals are typed in these regions and added to the analysis. Evidence for linkage in these regions will then be tested in the entire sample with parametric and non-parametric analyses using stringent simulation-based thresholds for 5% genome-wide significance. In the four-year project period, genetic analyses can be completed on 80% of the sample (over 600 pedigrees, 800 ASPs), with the remaining families to be available by the end of the project period for immediate completion of the genome scan on these pedigrees at CIDR. A timetable is

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proposed for rapid sharing of all biological materials, blinded clinical data, genotypes and linkage analyses with the scientific community through the NIMH-sponsored Center for Genetic Studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE EPIDEMIOLOGY OF NEWLY DIAGNOSED PSYCHOTIC DISORDERS Principal Investigator & Institution: Bromet, Evelyn J.; Professor; Psychiatry and Behavioral Scis; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2003; Project Start 01-MAY-1989; Project End 30-NOV-2007 Summary: (provided by applicant): This renewal application seeks support to complete the 10-year follow-up of the Suffolk County Mental Health Project (SCMHP). This firstadmission cohort was recruited between September 1989 and December 1995 primarily from the public, community, and private hospitals of Suffolk County, Long Island (population 1.3 million), diagnosed at baseline, 6- and 24-month follow-up using a longitudinal consensus procedure, and reassessed on multiple occasions over a 4-year period. The three largest DSM-IV diagnostic groups were schizophrenia, bipolar disorder with psychotic features, and major depressive disorder with psychotic features. In reevaluating the cohort at the 10-year point, the study extends our understanding of the stability of diagnosis, course of illness, quality of life, and treatment patterns by wedding clinical and epidemiological methods in a single, longitudinal study. A total of 581 members of the SCMHP cohort are being targeted for the 10-year follow-up. Follow-up assessments are being conducted by master's level mental health professionals trained on the SCID and other instruments used for the study. The respondent interview is conducted in two sessions. Session I focuses on interval episodes of illness, quality of life, trauma exposure and PTSD, social support and risk behavior. Session II focuses on finances, treatment, neuropsychological functioning, co morbid disorders, family history, physical health, and personality. A single interview is conducted with a significant other and addresses respondent's current symptoms, family history of mental illness, psychosocial functioning, family burden, perceptions of stigma, and perception of the adequacy of mental health services received by the respondent and by the significant other. Standard clinical ratings and a narrative are, completed by he interviewer after all inpatient and outpatient records are obtained. The diagnostic information is reviewed by, the project psychiatrist, and conferences are held to confirm the diagnosis, formulate consensus ratings of illness course, trauma and PTSD. As before, most interviews are conducted in respondents' homes. A number of substantive and methodological papers have been published from the study in collaboration with researchers from several institutions. As we enter the new era of molecular epidemiology, it is our hope that our sample, which is the only current epidemiological sample in North America, will prove to be a rich resource on which to build future studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TMS TREATMENT OF MAJOR DEPRESSION Principal Investigator & Institution: Avery, David H.; Professor; Psychiatry and Behavioral Scis; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-JUL-2004 Summary: Repetitive Transcranial Magnetic Stimulation (Rtms) is a promising new treatment Major Depressive Disorder: some small controlled studies of high frequency

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rTMS electrical current is induced in the cortext of the brain by the magnetic field of a small electromagnetic coil placed on the scalp. Unlike electroconvulsive therapy (ETC), one of the most effective treatment for severe depression, rTMS gives a much smaller, subconvulsive stimulus and is more focal in its localization. Preliminary data suggest no disorientation, confusion, or memory disturbance associated with Rtms. We propose to study 86 drug-free patients with Major Depressive Disorder who have failed at least two trials of antidepressant medication either because of medication resistance and/or medication intolerance. The subjects will be randomized into one of two stimulations to the left DLPFC: 1) Rtms at 110 percent of motor threshold intensity at 10 Hz with 5 second trains (rTMS) or 2) Sham stimulation (the electromagnetic coil angled at 90 degrees so that the cortex is not stimulated) at 110 percent motor threshold intensity at 10 Hz for 5 seconds. Each subject will be given 10 sessions with 32 trains per session over a period of two weeks. Blind assessment of the depression will take place before the 1st Rtms session, after the 5th and 10th rTMS sessions and 1 week and 2 weeks after the 10 rTMS session. Neuropsychological measures fo attention, memory, language production, psychomotor speed, visual motor sequencing, cognitive flexibility, information processing speed and executive functioning will be administered by a trained examiner blind to treatment conditions at screening. Baseline, and following the last rTMS session. Additionally, measures of orientation, attention, and memory to monitor for post-rTMS confusion will be administered following each Rtms treatment session. We hypothesize that the rTMS stimulations will be significantly more efficacious than the sham stimulations. Ultimately, if Rtms is shown efficacious, safe and free from cognitive disturbance, rTMS could be an alternative treatment for depressed patients who have failed to respond to antidepressant medication trials. In a second phase of the study, we will place responders on maintenance antidepressant medication two weeks after the last rTMS session and evaluate them at follow-up visits 1 month, 2 month, 3 months, 4 months, 5 months, and 6 months after the last rTMS session. Nonresponders to sham stimulation will be offered rTMS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRAIT DEPRESSION

AND

STATE

FRONTAL

BRAIN

ASYMMETRY

IN

Principal Investigator & Institution: Allen, John J.; Professor; Psychology; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Asymmetrical frontal brain activity holds promise as a marker of risk for depression. Over 40 studies suggest that resting frontal electroencephalographic (EEG) asymmetry may serve as an indicator of a trait-like diathesis to respond to emotional situations with a pattern of emotional negativity and behavioral withdrawal. Moreover, resting frontal EEG asymmetry distinguishes depressed individuals -- those currently symptomatic as well those as in remission -from never-depressed individuals. These findings suggest that frontal EEG asymmetry is more than a correlate of a depressive episode, potentially serving as a liability marker for the development of depression. Such a marker could have prognostic and etiological value, but superimposed on the trait-like stability are fluctuations that vary as a function of occasion of assessment or experimentally manipulated emotion. Estimates of the stability of frontal EEG asymmetry are in the range of.60, suggesting that trait factors are substantial, but that variation across assessments may limit the utility of asymmetrical frontal brain activity as a trait-like risk indicator for depression. Such factors may underlie the few inconsistent findings in this literature. The present proposal represents

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a necessary step in the programmatic investigation of frontal EEG asymmetry as a potential risk indicator for depression, by evaluating three distinct sources of variability in frontal EEG asymmetry: 1) Stable trait consistency across multiple assessments; 2) Occasion-specific fluctuations from one assessment to the next; and, 3) State-dependent changes within a single assessment. During four visits, trait resting as well as state manipulated frontal EEG asymmetry will be assessed in depressed and nondepressed subjects. This design will allow us to address several specific aims, including: 1) To assess the relative contributions of trait, occasion, and state variance in frontal EEG asymmetry; 2) To assess whether frontal EEG asymmetry has characteristics that suggest it may profitably serve as a marker of risk for major depressive disorder; and, 3) To assess the acute impact of a widely used selective serotonin reuptake inhibitor on frontal EEG asymmetry, as medication effects have been largely unexplored. Secondary aims address methodological and treatment-related questions, as well as assessing gender and menstrual cycle effects that may moderate the relationship between frontal EEG asymmetry and depression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TREATING ASTHMA PATIENTS WITH MAJOR DEPRESSIVE DISORDER Principal Investigator & Institution: Brown, E Sherwood.; Assistant Professor; Psychiatry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2004 Summary: (provided by applicant): Asthma is a common, severe, and debilitating general medical condition. Data suggest that the prevalence of asthma and asthmarelated morbidity and mortality are increasing in the United States particularly in minority, inner-city, and low socioeconomic status populations. These populations, which are traditionally underrepresented by medical research, have experienced a relative epidemic of asthma during the past decade, for reasons that are poorly understood. Data suggest depressive symptoms are common in asthma patients, and may even be a risk factor for death from asthma. We have initiated a research program on the interactions between asthma and clinical depression in a primarily low income, minority community served by a county-operated asthma clinic. Pilot data from this project reveal high rates of both depressive symptoms and current major depressive disorder which are generally unrecognized and untreated. We found a strong association between severity of depressive symptoms and measures of mental and physical disability in this population. Literature on patients with other general medical conditions suggest that antidepressant therapy is frequently associated with improvement in mood, medical symptoms, and functioning. However, no controlled trials of antidepressants have been reported in depressed asthma patients. This is an important population in which to examine the effects of antidepressant therapy as (1) asthma prevalence and deaths are increasing, (2) depression is common and has been suggested as a risk factor for mortality in this population, and (3) asthma has traditionally been considered an illness in which mood may contribute to symptom exacerbations. We propose a randomized, double blind, placebo-controlled, 12-week acute phase trial of citalopram in a group of primarily low income and minority adult asthma outpatients with nonpsychotic major depressive disorder. Symptoms of depression and asthma will be the primary outcome measures. This project will be a pilot study to determine effect size for the outcome measures. If the results of this study suggest improvement in depression and/or asthma symptoms following antidepressant therapy, we anticipate a larger and longer antidepressant trial examining mood and

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asthma symptoms, as well as utilization of medical services in patients receiving active drug versus placebo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TREATMENT OF DEPRESSION IN PARENTS--IMPACT ON CHILDREN Principal Investigator & Institution: Diamond, Guy S.; Assistant Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 15-SEP-1998; Project End 31-MAY-2005 Summary: (Adapted from applicant's abstract): The proposed project will study the impact of treating parental depression on children's socio-emotional adjustment. This project will interface with two newly funded NIMH treatment studies of adults diagnosed with major depressive disorder. The first is a two-site study being conducted at Vanderbilt University (PI, Steve Hollon, Ph.D.) and at the University of Pennsylvania (PI, Rob DeRubeis, Ph.D.). The second study will be at the University of Washington (PI, Neil Jacobson, Ph.D.). Across the three sites, 640 adults will receive cognitive therapy, pharmacotherapy, or placebo (plus a behavioral cell at UW). Based on preliminary data collected in the last four months, we estimate that about 25% of the patients will have children between 8 and 16 years old and will agree to participate. These preliminary data provide evidence of the feasibility and acceptability of the project, and showed that the targeted children of currently depressed parents were experiencing significant levels of symptoms and dysfunction. The proposed project will involve a comprehensive assessment of an index child with regard to psychopathology and functioning at the time the parent enters the treatment study and again at 2,4,8,12,18, and 24 months. A comparison group of children whose parents are lifetime-free of psychiatric and medical disorders also will be included. The primary aims of the study are: (a) to examine the relation between decreases in parent's depression and changes in children's functioning;(b) to explore possible mediators of these changes including the parent-child relationship, marital functioning, stressors, and cognitions; and (c) to test whether changes in child adaptation, the hypothesized mediators, and the relation between parent and child symptoms differ as a function of the type of treatment the parent received. Data analysis will involve traditional methods of repeated measures multivariate analyses of variance and a more general and innovative approach of individual growth curve modeling using covariance structure analysis. This study represents a truly unique opportunity to further our theoretical understanding of the link between parent and child psychopathology that can serve as a guide for the development of preventive interventions for high risk populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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TREATMENT

WITH

EXERCISE

AUGMENTATION

FOR

Principal Investigator & Institution: Trivedi, Madhukar H.; Associate Professor; Psychiatry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): This study proposes to examine the efficacy of a public health dose (PHD) of exercise as an augmentation strategy in the treatment of Major Depressive Disorder (MDD). We will assess patients on SSRI treatment who still have significant residual symptoms of depression, defined by a Hamilton Rating Scale for Depression (17-item; HRSD17) score >14. Incomplete response with significant

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residual symptoms is common in MDD and is associated with an increased likelihood of relapse and poorer quality of life and function. Augmentation strategies are often implemented to alleviate residual symptoms. However, limitations of pharmacological augmentation, such as lack of overwhelming evidence for efficacy for most agents and increased risks of adverse side effects, often render this strategy undesirable. Exercise may be a viable augmenting strategy for the treatment of residual symptoms of depression since it is associated with a reduced risk of side effects, as well as many associated benefits, including increased longevity and reduced risks of many common medical conditions. Our recently completed randomized controlled trial, DOSE (Depression Outcomes Study of Exercise), revealed that a public health dose of exercise significantly reduced symptoms of depression, measured by the HRSD17, compared to a low dose of exercise or flexibility exercise control group. A logical next step in our investigation of the use of exercise in the treatment of depression is to assess its viability as an augmenting strategy in persons who responded to SSRI therapy, but still endorse significant residual depressive symptoms. The goal of our exercise intervention will be remission, defined as an HRSD17 score of 7 or less. Patients meeting DSM-IV criteria for Major Depressive Disorder, who have been taking an SSRI at an adequate dose for 8-12 weeks, will be randomized to a PHD or low dose of exercise for 12 weeks. The HRSD17 will serve as the primary outcome measure. In addition, the 30-item versions of the Inventory for Depressive Symptomatology, Clinician-Rated (IDS-C30) and Self-Report (IDS-SR30) will be assessed. Quality of life and satisfaction will also be evaluated. The primary aims of the study are to: 1) compare the effectiveness of PHD exercise augmentation to low dose augmentation in eliciting remission in responders to SSRI treatment who have significant residual symptoms of depression; 2) to compare functioning and quality of life between treatment groups; 3) to examine the extent to which symptom reduction mediates improvement in social function; and 4) to explore the pattern of symptom reduction that occurs over the course of exercise augmentation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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.3 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 major depressive disorder, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “major depressive disorder” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for major depressive disorder (hyperlinks lead to article summaries):

3

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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A history of major depressive disorder influences intent to die in violent suicide attempters. Author(s): Astruc B, Torres S, Jollant F, Jean-Baptiste S, Castelnau D, Malafosse A, Courtet P. Source: The Journal of Clinical Psychiatry. 2004 May; 65(5): 690-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15163257

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A naturalistic visual scanning approach to assess selective attention in major depressive disorder. Author(s): Eizenman M, Yu LH, Grupp L, Eizenman E, Ellenbogen M, Gemar M, Levitan RD. Source: Psychiatry Research. 2003 May 30; 118(2): 117-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798976

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A pharmacoeconomic evaluation of major depressive disorder. Author(s): Casciano R. Source: Manag Care Interface. 2003; Suppl B: 16-21. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12647609

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A preliminary open study of the tolerability and effectiveness of nefazodone in major depressive disorder: comparing patients who recently discontinued an SSRI with those on no recent antidepressant treatment. Author(s): Mischoulon D, Opitz G, Kelly K, Fava M, Rosenbaum JF. Source: Depression and Anxiety. 2004; 19(1): 43-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14978785

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A randomised study comparing escitalopram with venlafaxine XR in primary care patients with major depressive disorder. Author(s): Montgomery SA, Huusom AK, Bothmer J. Source: Neuropsychobiology. 2004; 50(1): 57-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15179022

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A randomized, placebo-controlled trial of sertraline for prophylactic treatment of highly recurrent major depressive disorder. Author(s): Lepine JP, Caillard V, Bisserbe JC, Troy S, Hotton JM, Boyer P. Source: The American Journal of Psychiatry. 2004 May; 161(5): 836-42. Erratum In: Am J Psychiatry. 2004 July; 161(7): 1320. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15121648

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Abnormal prefrontal and anterior cingulate activation in major depressive disorder during episodic memory encoding of sad stimuli. Author(s): Fahim C, Stip E, Mancini-Marie A, Mensour B, Leroux JM, Beaudoin G, Bourgouin P, Beauregard M. Source: Brain and Cognition. 2004 March; 54(2): 161-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15025051

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Achieving remission in major depressive disorder: the first step to long-term recovery. Author(s): Kelsey JE. Source: J Am Osteopath Assoc. 2004 March; 104(3 Suppl 3): S6-10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15083991

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Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. Author(s): DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR; Modafinil in Depression Study Group. Source: The Journal of Clinical Psychiatry. 2003 September; 64(9): 1057-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14628981

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Adjunctive modafinil at initiation of treatment with a selective serotonin reuptake inhibitor enhances the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue. Author(s): Ninan PT, Hassman HA, Glass SJ, McManus FC. Source: The Journal of Clinical Psychiatry. 2004 March; 65(3): 414-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15096082

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Adolescent twins discordant for major depressive disorder: shared familial liability to externalizing and other internalizing disorders. Author(s): Burcusa SL, Iacono WG, McGue M. Source: Journal of Child Psychology and Psychiatry, and Allied Disciplines. 2003 October; 44(7): 997-1005. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14531582

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Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients. Author(s): Gardner A, Johansson A, Wibom R, Nennesmo I, von Dobeln U, Hagenfeldt L, Hallstrom T. Source: Journal of Affective Disorders. 2003 September; 76(1-3): 55-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943934

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An open trial of reboxetine in HIV-seropositive outpatients with major depressive disorder. Author(s): Carvalhal AS, de Abreu PB, Spode A, Correa J, Kapczinski F. Source: The Journal of Clinical Psychiatry. 2003 April; 64(4): 421-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716244

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Anatomic evaluation of the orbitofrontal cortex in major depressive disorder. Author(s): Lacerda AL, Keshavan MS, Hardan AY, Yorbik O, Brambilla P, Sassi RB, Nicoletti M, Mallinger AG, Frank E, Kupfer DJ, Soares JC. Source: Biological Psychiatry. 2004 February 15; 55(4): 353-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14960287

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Anatomical MRI study of basal ganglia in major depressive disorder. Author(s): Lacerda AL, Nicoletti MA, Brambilla P, Sassi RB, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC. Source: Psychiatry Research. 2003 November 30; 124(3): 129-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623065

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Association between major depressive disorder and the -1438A/G polymorphism of the serotonin 2A receptor gene. Author(s): Choi MJ, Lee HJ, Lee HJ, Ham BJ, Cha JH, Ryu SH, Lee MS. Source: Neuropsychobiology. 2004; 49(1): 38-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14730199

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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842167

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Association of depression duration with reduction of global cerebral gray matter volume in female patients with recurrent major depressive disorder. Author(s): Lampe IK, Hulshoff Pol HE, Janssen J, Schnack HG, Kahn RS, Heeren TJ. Source: The American Journal of Psychiatry. 2003 November; 160(11): 2052-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14594756

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Association study of the interleukin-1 beta (C-511T) genetic polymorphism with major depressive disorder, associated symptomatology, and antidepressant response. Author(s): Yu YW, Chen TJ, Hong CJ, Chen HM, Tsai SJ. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2003 June; 28(6): 1182-5. Epub 2003 April 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12700687

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Axis III disorders in treatment-resistant major depressive disorder. Author(s): Papakostas GI, Petersen T, Iosifescu DV, Roffi PA, Alpert JE, Rosenbaum JF, Fava M, Nierenberg AA. Source: Psychiatry Research. 2003 May 30; 118(2): 183-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798983

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Baseline characteristics of major depressive disorder patients in clinical trials in Europe and United States: is there a transatlantic difference? Author(s): Niklson IA, Reimitz PE. Source: Journal of Psychiatric Research. 2001 March-April; 35(2): 71-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11377436

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Beclomethasone-induced vasoconstriction in women with major depressive disorder. Author(s): Coupland NJ, Hegadoren KM, Myrholm J. Source: Journal of Psychiatry & Neuroscience : Jpn. 2003 September; 28(5): 364-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517580

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Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder. Author(s): Coric V, Milanovic S, Wasylink S, Patel P, Malison R, Krystal JH. Source: Psychopharmacology. 2003 May; 167(2): 219-20. Epub 2003 March 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12658528

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Beta-adrenoceptors on lymphocytes of patients with major depressive disorder. Author(s): Carstens ME, Engelbrecht AH, Russell VA, Aalbers C, Gagiano CA, Chalton DO, Taljaard JJ. Source: Psychiatry Research. 1987 March; 20(3): 239-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3035597

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Biological heterogeneity of major depressive disorder: indications by sleep EEG and TRH stimulation test findings. Author(s): Pugnetti L, Scarone S, Brambilla F. Source: Neuropsychobiology. 1987; 17(3): 124-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3120030

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Bipolar disorder at prospective follow-up of adults who had prepubertal major depressive disorder. Author(s): Geller B, Zimerman B, Williams M, Bolhofner K, Craney JL. Source: The American Journal of Psychiatry. 2001 January; 158(1): 125-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11136645

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Bipolar II disorder and major depressive disorder: continuity or discontinuity? Author(s): Benazzi F. Source: World J Biol Psychiatry. 2003 October; 4(4): 166-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14608587

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Birth-cohort trends in rates of major depressive disorder among relatives of patients with affective disorder. Author(s): Klerman GL, Lavori PW, Rice J, Reich T, Endicott J, Andreasen NC, Keller MB, Hirschfield RM. Source: Archives of General Psychiatry. 1985 July; 42(7): 689-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4015310

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Blood levels of cytokines in elderly patients with major depressive disorder. Author(s): Brambilla F, Maggioni M. Source: Acta Psychiatrica Scandinavica. 1998 April; 97(4): 309-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9570493

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Bone mineral density in premenopausal women with major depressive disorder. Author(s): Yazici KM, Akinci A, Sutcu A, Ozcakar L. Source: Psychiatry Research. 2003 March 25; 117(3): 271-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12686369

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Brain metabolic changes associated with symptom factor improvement in major depressive disorder. Author(s): Brody AL, Saxena S, Mandelkern MA, Fairbanks LA, Ho ML, Baxter LR. Source: Biological Psychiatry. 2001 August 1; 50(3): 171-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11513815

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Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. Author(s): Brody AL, Saxena S, Silverman DH, Alborzian S, Fairbanks LA, Phelps ME, Huang SC, Wu HM, Maidment K, Baxter LR Jr. Source: Psychiatry Research. 1999 October 11; 91(3): 127-39. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10641577

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Brain output dysregulation induced by olfactory bulbectomy: an approximation in the rat of major depressive disorder in humans? Author(s): Jesberger JA, Richardson JS. Source: The International Journal of Neuroscience. 1988 February; 38(3-4): 241-65. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3286555

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Bupropion in tricyclic antidepressant nonresponders with unipolar major depressive disorder. Author(s): Ferguson J, Cunningham L, Merideth C, Apter J, Feighner J, Ionescu-Pioggia M, Samara B, Johnston JA, Ascher J. Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 1994 September; 6(3): 153-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7881495

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Citalopram treatment of major depressive disorder in Hispanic HIV and AIDS patients: a prospective study. Author(s): Currier MB, Molina G, Kato M. Source: Psychosomatics. 2004 May-June; 45(3): 210-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15123845

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Clinical efficacy of tandospirone augmentation in patients with major depressive disorder: a randomized controlled trial. Author(s): Yamada K, Yagi G, Kanba S. Source: Psychiatry and Clinical Neurosciences. 2003 April; 57(2): 183-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12667165

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Clinical recovery in cognitive functioning and self-image among adolescents with major depressive disorder and conduct disorder during psychiatric inpatient care. Author(s): Hintikka U, Viinamaki H, Pelkonen M, Hintikka J, Laukkanen E, Korhonen V, Lehtonen J. Source: The American Journal of Orthopsychiatry. 2003 April; 73(2): 212-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12769242

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Clinical results for patients with major depressive disorder in the Texas Medication Algorithm Project. Author(s): Trivedi MH, Rush AJ, Crismon ML, Kashner TM, Toprac MG, Carmody TJ, Key T, Biggs MM, Shores-Wilson K, Witte B, Suppes T, Miller AL, Altshuler KZ, Shon SP. Source: Archives of General Psychiatry. 2004 July; 61(7): 669-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15237079

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Combination therapy in the treatment of major depressive disorder complicated by fibromyalgia and menopause. Author(s): Clayton AH, Kaltsounis-Puckett J. Source: Psychosomatics. 2002 November-December; 43(6): 491-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12444233

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Common treatment of polycystic ovarian syndrome and major depressive disorder: case report and review. Author(s): Rasgon NL, Carter MS, Elman S, Bauer M, Love M, Korenman SG. Source: Current Drug Targets. Immune, Endocrine and Metabolic Disorders. 2002 April; 2(1): 97-102. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12477299

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Comorbid major depressive disorder as a prognostic factor in cocaine-abusing buprenorphine-maintained patients treated with desipramine and contingency management. Author(s): Gonzalez G, Feingold A, Oliveto A, Gonsai K, Kosten TR. Source: The American Journal of Drug and Alcohol Abuse. 2003 August; 29(3): 497-514. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14510037

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Comorbid obsessive compulsive and major depressive disorder. Author(s): Ninan PT. Source: Psychopharmacology Bulletin. 2001 Winter; 35(1): 77-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12397872

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Correlation between serum lipid, lipoprotein concentrations and anxious state, depressive state or major depressive disorder. Author(s): Huang TL, Wu SC, Chiang YS, Chen JF. Source: Psychiatry Research. 2003 May 30; 118(2): 147-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798979

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Course and outcome of child and adolescent major depressive disorder. Author(s): Birmaher B, Arbelaez C, Brent D. Source: Child Adolesc Psychiatr Clin N Am. 2002 July; 11(3): 619-37, X. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12222086

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CPT performance in major depressive disorder before and after treatment with imipramine or fluvoxamine. Author(s): Koetsier GC, Volkers AC, Tulen JH, Passchier J, van den Broek WW, Bruijn JA. Source: Journal of Psychiatric Research. 2002 November-December; 36(6): 391-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12393308

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Current comorbidity of psychiatric disorders among DSM-IV major depressive disorder patients in psychiatric care in the Vantaa Depression Study. Author(s): Melartin TK, Rytsala HJ, Leskela US, Lestela-Mielonen PS, Sokero TP, Isometsa ET. Source: The Journal of Clinical Psychiatry. 2002 February; 63(2): 126-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11874213

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CYP2C9 gene and susceptibility to major depressive disorder. Author(s): LLerena A, Berecz R, Dorado P, Gonzalez AP, Penas-LLedo EM, De La Rubia A. Source: The Pharmacogenomics Journal. 2003; 3(5): 300-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14583800

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Density and distribution of white matter neurons in schizophrenia, bipolar disorder and major depressive disorder: no evidence for abnormalities of neuronal migration. Author(s): Beasley CL, Cotter DR, Everall IP. Source: Molecular Psychiatry. 2002; 7(6): 564-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12140779

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Depression and memory in major depressive disorder. Author(s): Bornstein RA, Baker GB, Douglass AB. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 1991 Winter; 3(1): 78-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7580179

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Depressive personality in the relatives of outpatients with dysthymic disorder and episodic major depressive disorder and normal controls. Author(s): Klein DN. Source: Journal of Affective Disorders. 1999 September; 55(1): 19-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10512602

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Determinants of attrition from cessation treatment in smokers with a history of major depressive disorder. Author(s): Curtin L, Brown RA, Sales SD. Source: Psychology of Addictive Behaviors : Journal of the Society of Psychologists in Addictive Behaviors. 2000 June; 14(2): 134-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10860112

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Determinants of spontaneous extrapyramidal symptoms in elderly psychiatric inpatients diagnosed with Alzheimer's disease, major depressive disorder, or psychotic disorders. Author(s): Sweet RA, Akil M, Mulsant BH, Ulrich R, Pasternak RE, Zubenko GS. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 1998 Winter; 10(1): 68-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9547469

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Determination of the dose of agomelatine, a melatoninergic agonist and selective 5HT(2C) antagonist, in the treatment of major depressive disorder: a placebocontrolled dose range study. Author(s): Loo H, Hale A, D'haenen H. Source: International Clinical Psychopharmacology. 2002 September; 17(5): 239-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12177586

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Dexamethasone suppression test in children with major depressive disorder. Author(s): Birmaher B, Ryan ND, Dahl R, Rabinovich H, Ambrosini P, Williamson DE, Novacenko H, Nelson B, Lo ES, Puig-Antich J. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1992 March; 31(2): 291-7. Erratum In: J Am Acad Child Adolesc Psychiatry 1992 May; 31(3): 561. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1564032

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Diagnostic differences in social anhedonia: a longitudinal study of schizophrenia and major depressive disorder. Author(s): Blanchard JJ, Horan WP, Brown SA. Source: Journal of Abnormal Psychology. 2001 August; 110(3): 363-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11502079

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Differential responses to anxiogenic challenge studies in patients with major depressive disorder and panic disorder. Author(s): Targum SD. Source: Biological Psychiatry. 1990 July 1; 28(1): 21-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2375944

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Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Author(s): Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH. Source: Molecular Psychiatry. 2000 March; 5(2): 142-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10822341

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Diurnal variations in endocrine and psychological responses to 0.2 mg/kg naloxone administration in patients with major depressive disorder and matched controls. Author(s): Martin del Campo AF, Dowson JH, Herbert J, Paykel ES. Source: Journal of Affective Disorders. 2000 January-March; 57(1-3): 37-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10708814

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Diurnal variations of mood and sleep disturbances during phototherapy in major depressive disorder. Author(s): Volz HP, Mackert A, Stieglitz RD, Muller-Oerlinghausen B. Source: Psychopathology. 1991; 24(4): 238-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1754656

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Does early intervention increase latency to relapse in major depressive disorder? Reevaluation with cognitive behavior therapy. Author(s): Quiring JM, Monroe SM, Simons AD, Thase ME. Source: Journal of Affective Disorders. 2002 July; 70(2): 155-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12117627

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Double-blind, placebo-controlled study with reboxetine in inpatients with severe major depressive disorder. Author(s): Versiani M, Amin M, Chouinard G. Source: Journal of Clinical Psychopharmacology. 2000 February; 20(1): 28-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10653205

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Drug use and the risk of major depressive disorder, alcohol dependence, and substance use disorders. Author(s): Brook DW, Brook JS, Zhang C, Cohen P, Whiteman M. Source: Archives of General Psychiatry. 2002 November; 59(11): 1039-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12418937

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Dual monoamine modulation for improved treatment of major depressive disorder. Author(s): Tran PV, Bymaster FP, McNamara RK, Potter WZ. Source: Journal of Clinical Psychopharmacology. 2003 February; 23(1): 78-86. Review. Erratum In: J Clin Psychopharmacol. 2003 August; 23(4): 425. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12544378

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Duloxetine in the long-term treatment of major depressive disorder. Author(s): Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. Source: The Journal of Clinical Psychiatry. 2003 October; 64(10): 1237-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14658974

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Effect of reboxetine on major depressive disorder in breast cancer patients: an openlabel study. Author(s): Grassi L, Biancosino B, Marmai L, Righi R. Source: The Journal of Clinical Psychiatry. 2004 April; 65(4): 515-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15119914

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Effectiveness and outcome predictors of long-term lithium prophylaxis in unipolar major depressive disorder. Author(s): Baethge C, Gruschka P, Smolka MN, Berghofer A, Bschor T, MullerOerlinghausen B, Bauer M. Source: Journal of Psychiatry & Neuroscience : Jpn. 2003 September; 28(5): 355-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517579

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Effectiveness measures of major depressive disorder in pharmacoeconomic evaluations. Author(s): Casciano R. Source: Manag Care Interface. 2003; Suppl B: 14-5. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12647608

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Effects of adding cognitive therapy to fluoxetine dose increase on risk of relapse and residual depressive symptoms in continuation treatment of major depressive disorder. Author(s): Perlis RH, Nierenberg AA, Alpert JE, Pava J, Matthews JD, Buchin J, Sickinger AH, Fava M. Source: Journal of Clinical Psychopharmacology. 2002 October; 22(5): 474-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12352270

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Effects of daily events on mood states in major depressive disorder. Author(s): Peeters F, Nicolson NA, Berkhof J, Delespaul P, deVries M. Source: Journal of Abnormal Psychology. 2003 May; 112(2): 203-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12784829

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Effects of imipramine, fluvoxamine and depressive mood on autonomic cardiac functioning in major depressive disorder. Author(s): Volkers AC, Tulen JH, van den Broek WW, Bruyn JA, Passchier J, Pepplinkhuizen L. Source: Pharmacopsychiatry. 2004 January; 37(1): 18-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14750044

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Effects of recurrent major depressive disorder on behavior and cognitive function in female depressed patients. Author(s): Lampe IK, Sitskoorn MM, Heeren TJ. Source: Psychiatry Research. 2004 February 15; 125(2): 73-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15006430

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Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder. Author(s): Yehuda R, Halligan SL, Golier JA, Grossman R, Bierer LM. Source: Psychoneuroendocrinology. 2004 April; 29(3): 389-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644068

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Efficacy and tolerability of duloxetine, a novel dual reuptake inhibitor, in the treatment of major depressive disorder. Author(s): Schatzberg AF. Source: The Journal of Clinical Psychiatry. 2003; 64 Suppl 13: 30-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14552654

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Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder. Author(s): Spielmans GI. Source: Jama : the Journal of the American Medical Association. 2004 January 7; 291(1): 41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709570

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Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder. Author(s): Solyom AE. Source: Jama : the Journal of the American Medical Association. 2004 January 7; 291(1): 41-2; Author Reply 42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709569

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Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder. Author(s): Price D. Source: Jama : the Journal of the American Medical Association. 2004 January 7; 291(1): 40-1; Author Reply 42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709568

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Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder. Author(s): Bradley RH, Barkin RL, Jerome J, DeYoung K, Dodge CW. Source: American Journal of Therapeutics. 2003 September-October; 10(5): 318-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12975715

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Elderly patients with major depressive disorder and delusional disorder are at increased risk of subsequent dementia. Author(s): Leinonen E, Santala M, Hyotyla T, Santala H, Eskola MNSc N, Salokangas RK. Source: Nordic Journal of Psychiatry. 2004; 58(2): 161-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15204223

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Elevated cholesterol levels associated with nonresponse to fluoxetine treatment in major depressive disorder. Author(s): Sonawalla SB, Papakostas GI, Petersen TJ, Yeung AS, Smith MM, Sickinger AH, Gordon J, Israel JA, Tedlow JR, Lamon-Fava S, Fava M. Source: Psychosomatics. 2002 July-August; 43(4): 310-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12189257

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Examination of the temporal relationship between smoking and major depressive disorder among low-income women in public primary care clinics. Author(s): Scarinci IC, Thomas J, Brantley PJ, Jones GN. Source: American Journal of Health Promotion : Ajhp. 2002 July-August; 16(6): 323-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12192743

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Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Author(s): Hamidi M, Drevets WC, Price JL. Source: Biological Psychiatry. 2004 March 15; 55(6): 563-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15013824

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Growth hormone response to growth hormone releasing hormone and to clonidine stimulation in peripubertal patients with major depressive disorder. Author(s): Brambilla F, Guareschi-Cazzullo A, Tacchini C, Gerra G, Musetti C. Source: Biological Psychiatry. 1994 July 1; 36(1): 51-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8080904

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Growth hormone response to the GABAB agonist baclofen in major depressive disorder. Author(s): Davis LL, Trivedi M, Choate A, Kramer GL, Petty F. Source: Psychoneuroendocrinology. 1997 April; 22(3): 129-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9203224

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Growth hormone secretion in children and adolescents at high risk for major depressive disorder. Author(s): Birmaher B, Dahl RE, Williamson DE, Perel JM, Brent DA, Axelson DA, Kaufman J, Dorn LD, Stull S, Rao U, Ryan ND. Source: Archives of General Psychiatry. 2000 September; 57(9): 867-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10986550

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High delta sleep-inducing peptide-like immunoreactivity in plasma in suicidal patients with major depressive disorder. Author(s): Westrin A, Ekman R, Traskman-Bendz L. Source: Biological Psychiatry. 1998 May 15; 43(10): 734-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9606527

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High vitamin B12 level and good treatment outcome may be associated in major depressive disorder. Author(s): Hintikka J, Tolmunen T, Tanskanen A, Viinamaki H. Source: Bmc Psychiatry [electronic Resource]. 2003 December 02; 3(1): 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14641930

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Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up. Author(s): Frodl T, Meisenzahl EM, Zetzsche T, Hohne T, Banac S, Schorr C, Jager M, Leinsinger G, Bottlender R, Reiser M, Moller HJ. Source: The Journal of Clinical Psychiatry. 2004 April; 65(4): 492-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15119911

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Hormone pattern and post-treatment attitudes in patients with major depressive disorder given electroconvulsive therapy. Author(s): Aperia B. Source: Acta Psychiatrica Scandinavica. 1986 March; 73(3): 271-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3012951

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Identifying an abnormal electroencephalographic sleep profile to characterize major depressive disorder. Author(s): Thase ME, Kupfer DJ, Fasiczka AJ, Buysse DJ, Simons AD, Frank E. Source: Biological Psychiatry. 1997 May 1; 41(9): 964-73. Erratum In: Biol Psychiatry 2000 July 15; 48(2): Following 170. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9110102

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Importance of psychotic features to long-term course in major depressive disorder. Author(s): Coryell W, Leon A, Winokur G, Endicott J, Keller M, Akiskal H, Solomon D. Source: The American Journal of Psychiatry. 1996 April; 153(4): 483-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8599395

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Increased bone remodeling in first-episode major depressive disorder. Author(s): Herran A, Amado JA, Garcia-Unzueta MT, Vazquez-Barquero JL, Perera L, Gonzalez-Macias J. Source: Psychosomatic Medicine. 2000 November-December; 62(6): 779-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11138996

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Increased concentration of calcitonin gene-related peptide in cerebrospinal fluid of depressed patients. A possible trait marker of major depressive disorder. Author(s): Mathe AA, Agren H, Lindstrom L, Theodorsson E. Source: Neuroscience Letters. 1994 December 5; 182(2): 138-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7715797

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Increased prevalence of negative life events in subtypes of major depressive disorder. Author(s): Kohn Y, Zislin J, Agid O, Hanin B, Troudart T, Shapira B, Bloch M, Gur E, Ritsner M, Lerer B. Source: Comprehensive Psychiatry. 2001 January-February; 42(1): 57-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11154717

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Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder. Author(s): Tuglu C, Kara SH, Caliyurt O, Vardar E, Abay E. Source: Psychopharmacology. 2003 December; 170(4): 429-33. Epub 2003 August 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12955291

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Independent factors associated with major depressive disorder in a national sample of individuals with diabetes. Author(s): Egede LE, Zheng D. Source: Diabetes Care. 2003 January; 26(1): 104-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12502665

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Interleukin-1beta and tumor necrosis factor-alpha in children with major depressive disorder or dysthymia. Author(s): Brambilla F, Monteleone P, Maj M. Source: Journal of Affective Disorders. 2004 March; 78(3): 273-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15013254

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Intravenous dexamethasone for symptoms of major depressive disorder. Author(s): Arana GW. Source: The American Journal of Psychiatry. 1991 October; 148(10): 1401-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1897623

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Isokinetic muscle performance in major depressive disorder: alterations by antidepressant therapy. Author(s): Bilici M, Koroglu MA, Cakirbay H, Guler M, Tosun M, Aydin T, Tan U. Source: The International Journal of Neuroscience. 2001 August; 109(3-4): 149-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11699327

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Isokinetic muscle performance in major depressive disorder: alterations by antidepressant therapy. Author(s): Bilici M, Cakirbay H, Koroglu MA, Guler M, Tosun M, Aydin T, Tan U. Source: The International Journal of Neuroscience. 2001 September; 110(1-2): 9-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11697214

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Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder. Author(s): Clayton AH, Zajecka J, Ferguson JM, Filipiak-Reisner JK, Brown MT, Schwartz GE. Source: International Clinical Psychopharmacology. 2003 May; 18(3): 151-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702894

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Levels of monocyte reactive oxygen species are associated with reduced natural killer cell activity in major depressive disorder. Author(s): Frank MG, Hendricks SE, Bessette D, Johnson DR, Wieseler Frank JL, Burke WJ. Source: Neuropsychobiology. 2001; 44(1): 1-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11408785

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Life events and depression in adolescence: relationship loss as a prospective risk factor for first onset of major depressive disorder. Author(s): Monroe SM, Rohde P, Seeley JR, Lewinsohn PM. Source: Journal of Abnormal Psychology. 1999 November; 108(4): 606-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10609425

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Long-term treatment of major depressive disorder with paroxetine. Author(s): Duboff EA. Source: Journal of Clinical Psychopharmacology. 1993 December; 13(6 Suppl 2): 28S-33S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8106653

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Low basal levels of cortisol distinguish detoxified alcoholics with major depressive disorder from non-MDDs. Author(s): Halbreich U, Castaneda R, Galanter M. Source: Alcoholism, Clinical and Experimental Research. 1989 December; 13(6): 834-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2690668

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Lymphocyte function in major depressive disorder. Author(s): Schleifer SJ, Keller SE, Meyerson AT, Raskin MJ, Davis KL, Stein M. Source: Archives of General Psychiatry. 1984 May; 41(5): 484-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6609689

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Lytic effector cell activity and major depressive disorder in patients with breast cancer: a prospective study. Author(s): Sachs G, Rasoul-Rockenschaub S, Aschauer H, Spiess K, Gober I, Staffen A, Zielinski C. Source: Journal of Neuroimmunology. 1995 June; 59(1-2): 83-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7797623

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Major depressive disorder in a population of urban, African-American young adults: prevalence, correlates, comorbidity and unmet mental health service need. Author(s): Ialongo N, McCreary BK, Pearson JL, Koenig AL, Schmidt NB, Poduska J, Kellam SG. Source: Journal of Affective Disorders. 2004 April; 79(1-3): 127-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15023487

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Major depressive disorder in adolescence: a brief review of the recent treatment literature. Author(s): Milin R, Walker S, Chow J. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2003 October; 48(9): 600-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14631880

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Major depressive disorder in adolescents exposed to a friend's suicide. Author(s): Bridge JA, Day NL, Day R, Richardson GA, Birmaher B, Brent DA. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2003 November; 42(11): 1294-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14566166

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Major depressive disorder in Parkinson's disease: a register-based study. Author(s): Nilsson FM, Kessing LV, Sorensen TM, Andersen PK, Bolwig TG. Source: Acta Psychiatrica Scandinavica. 2002 September; 106(3): 202-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12197858

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Major depressive disorder in the general hospital: adaptation of clinical practice guidelines. Author(s): Voellinger R, Berney A, Baumann P, Annoni JM, Bryois C, Buclin T, Bula C, Camus V, Christin L, Cornuz J, de Goumoens P, Lamy O, Strnad J, Burnand B, Stiefel F. Source: General Hospital Psychiatry. 2003 May-June; 25(3): 185-93. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748031

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Major depressive disorder with anger: a bipolar spectrum disorder? Author(s): Benazzi F. Source: Psychotherapy and Psychosomatics. 2003 November-December; 72(6): 300-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14526132

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Major depressive disorder with psychotic features in an aviator after head trauma. Author(s): McLay RN, Drake A, Santiago PN, Kim CH. Source: Aviation, Space, and Environmental Medicine. 2004 February; 75(2): 175-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14960056

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Managing reboxetine-associated urinary hesitancy in a patient with major depressive disorder: a case study. Author(s): Kasper S. Source: Psychopharmacology. 2002 February; 159(4): 445-6. Epub 2001 December 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11823898

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Membrane Na(+)-K+ ATPase mediated cascade in bipolar mood disorder, major depressive disorder, and schizophrenia--relationship to hemispheric dominance. Author(s): Kurup AR, Kurup PA. Source: The International Journal of Neuroscience. 2002 August; 112(8): 965-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12448837

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Mental Health QUERI Initiative: expert ratings of criteria to assess performance for major depressive disorder and schizophrenia. Author(s): Owen RR, Cannon D, Thrush CR; Quality Enhancement Research Initiative. Source: American Journal of Medical Quality : the Official Journal of the American College of Medical Quality. 2003 January-February; 18(1): 15-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12583641

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Meta-analysis of placebo rates in major depressive disorder trials. Author(s): Stolk P, Ten Berg MJ, Hemels ME, Einarson TR. Source: The Annals of Pharmacotherapy. 2003 December; 37(12): 1891-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14632596

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Monoamine oxidase: A gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder. Author(s): Yoshida K, Naito S, Takahashi H, Sato K, Ito K, Kamata M, Higuchi H, Shimizu T, Itoh K, Inoue K, Tezuka T, Suzuki T, Ohkubo T, Sugawara K, Otani K. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2002 December; 26(7-8): 1279-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12502014

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Mood disorders. Effective management of major depressive disorder in the geriatric patient. Author(s): Evers MM, Marin DB. Source: Geriatrics. 2002 October; 57(10): 36-40; Quiz 41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12391798

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Morning and evening plasma melatonin and dexamethasone suppression test in patients with nonseasonal major depressive disorder from northern Greece (latitude 40-41.5 degrees ). Author(s): Fountoulakis KN, Karamouzis M, Iacovides A, Nimatoudis J, Diakogiannis J, Kaprinis G, Demitriadou A, Bech P. Source: Neuropsychobiology. 2001; 44(3): 113-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11586048

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Motor activity and autonomic cardiac functioning in major depressive disorder. Author(s): Volkers AC, Tulen JH, van den Broek WW, Bruijn JA, Passchier J, Pepplinkhuizen L. Source: Journal of Affective Disorders. 2003 September; 76(1-3): 23-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943930

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Motorcortical excitability after electroconvulsive therapy in patients with major depressive disorder. Author(s): Bajbouj M, Gallinat J, Lang UE, Neu P, Niehaus L. Source: Suppl Clin Neurophysiol. 2003; 56: 433-40. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14677419

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Natural course of adolescent major depressive disorder in a community sample: predictors of recurrence in young adults. Author(s): Lewinsohn PM, Rohde P, Seeley JR, Klein DN, Gotlib IH. Source: The American Journal of Psychiatry. 2000 October; 157(10): 1584-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11007711

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Natural course of adolescent major depressive disorder: I. Continuity into young adulthood. Author(s): Lewinsohn PM, Rohde P, Klein DN, Seeley JR. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1999 January; 38(1): 56-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9893417

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Negative mood, depressive symptoms, and major depression after smoking cessation treatment in smokers with a history of major depressive disorder. Author(s): Kahler CW, Brown RA, Ramsey SE, Niaura R, Abrams DB, Goldstein MG, Mueller TI, Miller IW. Source: Journal of Abnormal Psychology. 2002 November; 111(4): 670-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12428781

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Negative symptoms in patients with major depressive disorder: a preliminary report. Author(s): Galynker II, Cohen LJ, Cai J. Source: Neuropsychiatry, Neuropsychology, and Behavioral Neurology. 2000 July; 13(3): 171-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10910087

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Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Author(s): Neumeister A, Nugent AC, Waldeck T, Geraci M, Schwarz M, Bonne O, Bain EE, Luckenbaugh DA, Herscovitch P, Charney DS, Drevets WC. Source: Archives of General Psychiatry. 2004 August; 61(8): 765-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15289275

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Neuroendocrine response to 5-hydroxy-L-tryptophan in prepubertal children at high risk of major depressive disorder. Author(s): Birmaher B, Kaufman J, Brent DA, Dahl RE, Perel JM, al-Shabbout M, Nelson B, Stull S, Rao U, Waterman GS, Williamson DE, Ryan ND. Source: Archives of General Psychiatry. 1997 December; 54(12): 1113-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9400347

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No gender differences in placebo responses of patients with major depressive disorder. Author(s): Casper RC, Tollefson GD, Nilsson ME. Source: Biological Psychiatry. 2001 January 15; 49(2): 158-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11164762

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Nocturnal urinary excretion of 6-hydroxymelatonin sulfate in prepubertal major depressive disorder. Author(s): Waterman GS, Ryan ND, Perel JM, Dahl RE, Birmaher B, Williamson DE, Thomas CR, Puig-Antich J. Source: Biological Psychiatry. 1992 March 15; 31(6): 582-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1581437

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Noradrenergic function and hypothalamic-pituitary-adrenal axis activity in adolescents with major depressive disorder. Author(s): de Villiers AS, Russell VA, Carstens ME, Searson JA, van Zyl AM, Lombard CJ, Taljaard JJ. Source: Psychiatry Research. 1989 February; 27(2): 101-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2710859

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Noradrenergic function and hypothalamic-pituitary-adrenal axis activity in primary unipolar major depressive disorder. Author(s): de Villiers AS, Russell VA, Carstens ME, Aalbers C, Gagiano CA, Chalton DO, Taljaard JJ. Source: Psychiatry Research. 1987 October; 22(2): 127-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3120204

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Noradrenergic function in generalized anxiety disorder, major depressive disorder, and healthy subjects. Author(s): Sevy S, Papadimitriou GN, Surmont DW, Goldman S, Mendlewicz J. Source: Biological Psychiatry. 1989 January 15; 25(2): 141-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2539200

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Observational measurement of symptoms responsive to treatment of major depressive disorder in children and adolescents. Author(s): Kaminer Y, Seifer R, Mastrian A. Source: The Journal of Nervous and Mental Disease. 1992 October; 180(10): 639-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1402842

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Obsessive-compulsive disorder and the five-factor model of personality: distinction and overlap with major depressive disorder. Author(s): Rector NA, Hood K, Richter MA, Bagby RM. Source: Behaviour Research and Therapy. 2002 October; 40(10): 1205-19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12375729

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Obstetrician-gynecologists' attitudes towards premenstrual dysphoric disorder and major depressive disorder. Author(s): Hill LD, Greenberg BD, Holzman GB, Schulkin J. Source: Journal of Psychosomatic Obstetrics and Gynaecology. 2001 December; 22(4): 241-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11840578

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Occipital brain perfusion deficits in children with major depressive disorder. Author(s): Bonte FJ, Trivedi MH, Devous MD Sr, Harris TS, Payne JK, Weinberg WA, Haley RW. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2001 July; 42(7): 1059-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11438629

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Olfactory sensitivity in major depressive disorder and obsessive compulsive disorder. Author(s): Gross-Isseroff R, Luca-Haimovici K, Sasson Y, Kindler S, Kotler M, Zohar J. Source: Biological Psychiatry. 1994 May 15; 35(10): 798-802. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8043710

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On the nature and pattern of neurocognitive function in major depressive disorder. Author(s): Zakzanis KK, Leach L, Kaplan E. Source: Neuropsychiatry, Neuropsychology, and Behavioral Neurology. 1998 July; 11(3): 111-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9742509

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Onset of major depressive disorder among adolescents. Author(s): Hoffmann JP, Baldwin SA, Cerbone FG. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2003 February; 42(2): 217-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12544182

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Open study of the catechol-O-methyltransferase inhibitor tolcapone in major depressive disorder. Author(s): Fava M, Rosenbaum JF, Kolsky AR, Alpert JE, Nierenberg AA, Spillmann M, Moore C, Renshaw P, Bottiglieri T, Moroz G, Magni G. Source: Journal of Clinical Psychopharmacology. 1999 August; 19(4): 329-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10440460

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Open trial of buspirone in the treatment of major depressive disorder. Author(s): Schweizer EE, Amsterdam J, Rickels K, Kaplan M, Droba M. Source: Psychopharmacology Bulletin. 1986; 22(1): 183-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2873610

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Pain thresholds as a putative functional test for cerebral laterality in major depressive disorder and panic disorder. Author(s): Spernal J, Krieg JC, Lautenbacher S. Source: Neuropsychobiology. 2003; 48(3): 146-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14586165

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Parents concordant for major depressive disorder and the effect of psychopathology in offspring. Author(s): Nomura Y, Warner V, Wickramaratne P. Source: Psychological Medicine. 2001 October; 31(7): 1211-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11681547

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Paroxetine treatment of major depressive disorder. Author(s): Keller MB. Source: Psychopharmacology Bulletin. 2003 Spring; 37 Suppl 1: 42-52. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14566200

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Partial validation of the atypical features subtype of major depressive disorder. Author(s): Posternak MA, Zimmerman M. Source: Archives of General Psychiatry. 2002 January; 59(1): 70-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11779285

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Patient compliance with enteric-coated weekly fluoxetine during continuation treatment of major depressive disorder. Author(s): de Klerk E. Source: The Journal of Clinical Psychiatry. 2001; 62 Suppl 22: 43-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11599648

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Personality changes in adult subjects with major depressive disorder or obsessivecompulsive disorder treated with paroxetine. Author(s): Brody AL, Saxena S, Fairbanks LA, Alborzian S, Demaree HA, Maidment KM, Baxter LR Jr. Source: The Journal of Clinical Psychiatry. 2000 May; 61(5): 349-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10847309

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Platelet glutamate receptor supersensitivity in major depressive disorder. Author(s): Berk M, Plein H, Ferreira D. Source: Clinical Neuropharmacology. 2001 May-June; 24(3): 129-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11391122

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Possible association between -G308A tumour necrosis factor-alpha gene polymorphism and major depressive disorder in the Korean population. Author(s): Jun TY, Pae CU, Hoon-Han, Chae JH, Bahk WM, Kim KS, Serretti A. Source: Psychiatric Genetics. 2003 September; 13(3): 179-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12960751

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Posttraumatic stress disorder and major depressive disorder: investigating the role of overlapping symptoms in diagnostic comorbidity. Author(s): Franklin CL, Zimmerman M. Source: The Journal of Nervous and Mental Disease. 2001 August; 189(8): 548-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11531207

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Predicting recurrence of major depressive disorder in young adults: a prospective study. Author(s): Hart AB, Craighead WE, Craighead LW. Source: Journal of Abnormal Psychology. 2001 November; 110(4): 633-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11727952

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Premenstrual dysphoric disorder and risk for major depressive disorder: a preliminary study. Author(s): Hartlage SA, Arduino KE, Gehlert S. Source: Journal of Clinical Psychology. 2001 December; 57(12): 1571-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11745598

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Preschool major depressive disorder: preliminary validation for developmentally modified DSM-IV criteria. Author(s): Luby JL, Heffelfinger AK, Mrakotsky C, Hessler MJ, Brown KM, Hildebrand T. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2002 August; 41(8): 928-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12162628

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Prevalence and incidence of major depressive disorder in Alzheimer's disease: findings from two databases. Author(s): Weiner MF, Doody RS, Sairam R, Foster B, Liao TY. Source: Dementia and Geriatric Cognitive Disorders. 2002; 13(1): 8-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11731709

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Prevalence of major depressive disorder among Chinese-Americans in primary care. Author(s): Yeung A, Chan R, Mischoulon D, Sonawalla S, Wong E, Nierenberg AA, Fava M. Source: General Hospital Psychiatry. 2004 January-February; 26(1): 24-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14757299

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Psychiatric comorbidity as a predictor of clinical response to nortriptyline in treatment-resistant major depressive disorder. Author(s): Papakostas GI, Petersen TJ, Farabaugh AH, Murakami JL, Pava JA, Alpert JE, Fava M, Nierenberg AA. Source: The Journal of Clinical Psychiatry. 2003 November; 64(11): 1357-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14658951

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Psychopathology in the adolescent and young adult offspring of parents with dysthymic disorder and major depressive disorder. Author(s): Lizardi H, Klein DN, Shankman SA. Source: The Journal of Nervous and Mental Disease. 2004 March; 192(3): 193-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15091300

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Psychopharmacological treatment of major depressive disorder in children and adolescents. Author(s): Varley CK. Source: Jama : the Journal of the American Medical Association. 2003 August 27; 290(8): 1091-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12941683

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Psychosocial disability during the long-term course of unipolar major depressive disorder. Author(s): Judd LL, Akiskal HS, Zeller PJ, Paulus M, Leon AC, Maser JD, Endicott J, Coryell W, Kunovac JL, Mueller TI, Rice JP, Keller MB. Source: Archives of General Psychiatry. 2000 April; 57(4): 375-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10768699

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Psychosocial functioning in youths at high risk to develop major depressive disorder. Author(s): Birmaher B, Bridge JA, Williamson DE, Brent DA, Dahl RE, Axelson DA, Dorn LD, Ryan ND. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 July; 43(7): 839-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15213585

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Psychosocial functioning of young adults who have experienced and recovered from major depressive disorder during adolescence. Author(s): Lewinsohn PM, Rohde P, Seeley JR, Klein DN, Gotlib IH. Source: Journal of Abnormal Psychology. 2003 August; 112(3): 353-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943014

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Quality assessment of meta-analyses of RCTs of pharmacotherapy in major depressive disorder. Author(s): Hemels ME, Vicente C, Sadri H, Masson MJ, Einarson TR. Source: Current Medical Research and Opinion. 2004 April; 20(4): 477-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15119985

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Quality of life assessments in major depressive disorder: a review of the literature. Author(s): Papakostas GI, Petersen T, Mahal Y, Mischoulon D, Nierenberg AA, Fava M. Source: General Hospital Psychiatry. 2004 January-February; 26(1): 13-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14757297

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Quantitative electroencephalography (qEEG) to discriminate primary degenerative dementia from major depressive disorder (depression). Author(s): Deslandes A, Veiga H, Cagy M, Fiszman A, Piedade R, Ribeiro P. Source: Arquivos De Neuro-Psiquiatria. 2004 March; 62(1): 44-50. Epub 2004 April 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15122432

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Randomized, double-blind comparison of venlafaxine and sertraline in outpatients with major depressive disorder. Venlafaxine 631 Study Group. Author(s): Mehtonen OP, Sogaard J, Roponen P, Behnke K. Source: The Journal of Clinical Psychiatry. 2000 February; 61(2): 95-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10732656

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Reboxetine, a unique selective NRI, prevents relapse and recurrence in long-term treatment of major depressive disorder. Author(s): Versiani M, Mehilane L, Gaszner P, Arnaud-Castiglioni R. Source: The Journal of Clinical Psychiatry. 1999 June; 60(6): 400-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10401920

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Reboxetine: a double-blind comparison with fluoxetine in major depressive disorder. Author(s): Massana J, Moller HJ, Burrows GD, Montenegro RM. Source: International Clinical Psychopharmacology. 1999 March; 14(2): 73-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10220121

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Recollection memory deficits in patients with major depressive disorder predicted by past depressions but not current mood state or treatment status. Author(s): MacQueen GM, Galway TM, Hay J, Young LT, Joffe RT. Source: Psychological Medicine. 2002 February; 32(2): 251-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11866320

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Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Author(s): Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W, Warshaw M, Maser JD. Source: The American Journal of Psychiatry. 1999 July; 156(7): 1000-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10401442

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Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Author(s): Cotter D, Mackay D, Landau S, Kerwin R, Everall I. Source: Archives of General Psychiatry. 2001 June; 58(6): 545-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11386983

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Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Author(s): Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP. Source: Cerebral Cortex (New York, N.Y. : 1991). 2002 April; 12(4): 386-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11884354

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Reduced phosphorylation of cyclic AMP-responsive element binding protein in the postmortem orbitofrontal cortex of patients with major depressive disorder. Author(s): Yamada S, Yamamoto M, Ozawa H, Riederer P, Saito T. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2003 June; 110(6): 67180. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12768362

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Relationships among alexithymia, adverse childhood experiences, sociodemographic variables, and actual mood disorder: a 2-year clinical follow-up study of patients with major depressive disorder. Author(s): Honkalampi K, Koivumaa-Honkanen H, Antikainen R, Haatainen K, Hintikka J, Viinamaki H. Source: Psychosomatics. 2004 May-June; 45(3): 197-204. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15123843

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Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general population study. Author(s): Carpenter KM, Hasin DS, Allison DB, Faith MS. Source: American Journal of Public Health. 2000 February; 90(2): 251-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10667187

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Remission as the goal of treatment in major depressive disorder. Author(s): Kelsey JE. Source: Manag Care Interface. 2003; Suppl B: 4-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12647606

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Remission in major depressive disorder: a comparison of pharmacotherapy, psychotherapy, and control conditions. Author(s): Casacalenda N, Perry JC, Looper K. Source: The American Journal of Psychiatry. 2002 August; 159(8): 1354-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12153828

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Respiratory sinus arrhythmia as a predictor of outcome in major depressive disorder. Author(s): Rottenberg J, Wilhelm FH, Gross JJ, Gotlib IH. Source: Journal of Affective Disorders. 2002 September; 71(1-3): 265-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12167527

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Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitors, or placebo. Author(s): Entsuah AR, Huang H, Thase ME. Source: The Journal of Clinical Psychiatry. 2001 November; 62(11): 869-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11775046

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Response in relation to baseline anxiety levels in major depressive disorder treated with bupropion sustained release or sertraline. Author(s): Rush AJ, Trivedi MH, Carmody TJ, Donahue RM, Houser TL, Bolden-Watson C, Batey SR, Ascher JA, Metz A. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2001 July; 25(1): 131-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11377926

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Response style, interpersonal difficulties and social functioning in major depressive disorder. Author(s): Lam D, Schuck N, Smith N, Farmer A, Checkley S. Source: Journal of Affective Disorders. 2003 August; 75(3): 279-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12880940

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Response to depression and anxiety Stroop stimuli in posttraumatic stress disorder, obsessive-compulsive disorder, and major depressive disorder. Author(s): McNeil DW, Tucker P, Miranda R Jr, Lewin MR, Nordgren JC. Source: The Journal of Nervous and Mental Disease. 1999 August; 187(8): 512-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10463070

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Sadness and amusement reactivity differentially predict concurrent and prospective functioning in major depressive disorder. Author(s): Rottenberg J, Kasch KL, Gross JJ, Gotlib IH. Source: Emotion (Washington, D.C.). 2002 June; 2(2): 135-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899187

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Selective serotonin reuptake inhibitor treatment of major depressive disorder in children and adolescents. Author(s): Newcorn JH. Source: Current Psychiatry Reports. 2004 April; 6(2): 85-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15038909

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Severity and comorbidity predict episode duration and recurrence of DSM-IV major depressive disorder. Author(s): Melartin TK, Rytsala HJ, Leskela US, Lestela-Mielonen PS, Sokero TP, Isometsa ET. Source: The Journal of Clinical Psychiatry. 2004 June; 65(6): 810-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15291658

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Somatic symptoms as predictors of time to onset of response to fluoxetine in major depressive disorder. Author(s): Papakostas GI, Petersen TJ, Iosifescu DV, Summergrad P, Sklarsky KG, Alpert JE, Nierenberg AA, Fava M. Source: The Journal of Clinical Psychiatry. 2004 April; 65(4): 543-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15119918

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Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. Author(s): Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, Biggs MM, O'Connor K, Rasmussen K, Litle M, Zhao W, Bernstein HJ, Smith G, Mueller M, McClintock SM, Bailine SH, Kellner CH. Source: The Journal of Clinical Psychiatry. 2004 April; 65(4): 485-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15119910

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Subthreshold depression as a risk indicator for major depressive disorder: a systematic review of prospective studies. Author(s): Cuijpers P, Smit F. Source: Acta Psychiatrica Scandinavica. 2004 May; 109(5): 325-31. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15049768

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Suicidal ideation and attempts among psychiatric patients with major depressive disorder. Author(s): Sokero TP, Melartin TK, Rytsala HJ, Leskela US, Lestela-Mielonen PS, Isometsa ET. Source: The Journal of Clinical Psychiatry. 2003 September; 64(9): 1094-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14628986

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Sustained efficacy of gepirone-IR in major depressive disorder: a double-blind placebo substitution trial. Author(s): Amsterdam JD, Brunswick DJ, Gibertini M. Source: Journal of Psychiatric Research. 2004 May-June; 38(3): 259-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15003431

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Switching to reboxetine: an efficacy and safety study in patients with major depressive disorder unresponsive to fluoxetine. Author(s): Fava M, McGrath PJ, Sheu WP; Reboxetine Study Group. Source: Journal of Clinical Psychopharmacology. 2003 August; 23(4): 365-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12920412

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Symptoms and circuits, part 1: major depressive disorder. Author(s): Stahl SM. Source: The Journal of Clinical Psychiatry. 2003 November; 64(11): 1282-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14658940

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The association of the D2S2944 124 bp allele with recurrent early onset major depressive disorder in women. Author(s): Philibert R, Caspers K, Langbehn D, Troughton EP, Yucuis R, Sandhu HK, Cadoret RJ. Source: American Journal of Medical Genetics. 2003 August 15; 121B(1): 39-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12898573

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The Diagnostic Inventory for Depression: a self-report scale to diagnose DSM-IV major depressive disorder. Author(s): Zimmerman M, Sheeran T, Young D. Source: Journal of Clinical Psychology. 2004 January; 60(1): 87-110. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14692011

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The effects of anxiety, substance use and conduct disorders on risk of major depressive disorder. Author(s): Hettema JM, Prescott CA, Kendler KS. Source: Psychological Medicine. 2003 November; 33(8): 1423-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14672251

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The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). Author(s): Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS; National Comorbidity Survey Replication. Source: Jama : the Journal of the American Medical Association. 2003 June 18; 289(23): 3095-105. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12813115

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The impact of medical comorbidity on acute treatment in major depressive disorder. Author(s): Iosifescu DV, Nierenberg AA, Alpert JE, Smith M, Bitran S, Dording C, Fava M. Source: The American Journal of Psychiatry. 2003 December; 160(12): 2122-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638581

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The symptomatic expression of major depressive disorder in adolescents and young adults. Author(s): Lewinsohn PM, Pettit JW, Joiner TE Jr, Seeley JR. Source: Journal of Abnormal Psychology. 2003 May; 112(2): 244-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12784834

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Trait and state aspects of harm avoidance and its implication for treatment in major depressive disorder, dysthymic disorder, and depressive personality disorder. Author(s): Abrams KY, Yune SK, Kim SJ, Jeon HJ, Han SJ, Hwang J, Sung YH, Lee KJ, Lyoo IK. Source: Psychiatry and Clinical Neurosciences. 2004 June; 58(3): 240-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15149288

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Treatment of major depressive disorder in children and adolescents. Author(s): Ramchandani P. Source: Bmj (Clinical Research Ed.). 2004 January 3; 328(7430): 3-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14703522

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Treatment-related adverse events and outcome in a clinical trial of fluoxetine for major depressive disorder. Author(s): Papakostas GI, Petersen T, Denninger JW, Montoya HD, Nierenberg AA, Alpert JE, Fava M. Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 2003 September-December; 15(3-4): 187-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14971864

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Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density. Author(s): Chana G, Landau S, Beasley C, Everall IP, Cotter D. Source: Biological Psychiatry. 2003 June 15; 53(12): 1086-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12814860

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Unaltered 24 h serum PRL levels and PRL response to TRH in contrast to decreased 24 h serum TSH levels and TSH response to TRH in major depressive disorder. Author(s): Unden F, Ljunggren JG, Kjellman BF, Beck-Friis J, Wetterberg L. Source: Acta Psychiatrica Scandinavica. 1987 February; 75(2): 131-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3105251

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Update on "open study of the catechol-O-methyltransferase inhibitor tolcapone in major depressive disorder". Author(s): Moroz G, Magni G, Fava M. Source: Journal of Clinical Psychopharmacology. 2000 April; 20(2): 285. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10770481

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Urinary mhpg in anorexia nervosa patients with and without a concomitant major depressive disorder. Author(s): Biederman J, Herzog DB, Rivinus TM, Ferber RA, Harper GP, Orsulak PJ, Harmatz JS, Schildkraut JJ. Source: Journal of Psychiatric Research. 1984; 18(2): 149-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6747913

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Use of the five-factory inventory in characterizing patients with major depressive disorder. Author(s): Petersen T, Bottonari K, Alpert JE, Fava M, Nierenberg AA. Source: Comprehensive Psychiatry. 2001 November-December; 42(6): 488-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11704941

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Usefulness of EQ-5D in assessing health status in primary care patients with major depressive disorder. Author(s): Sapin C, Fantino B, Nowicki ML, Kind P. Source: Health and Quality of Life Outcomes [electronic Resource]. 2004 May 05; 2(1): 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15128456

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Validity of the Depression-Arkansas (D-ARK) Scale: a tool for measuring major depressive disorder. Author(s): Smith GR, Kramer TL, Hollenberg JA, Mosley CL, Ross RL, Burnam A. Source: Mental Health Services Research. 2002 September; 4(3): 167-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12385569

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Valproate as an antidepressant in major depressive disorder. Author(s): Davis LL, Kabel D, Patel D, Choate AD, Foslien-Nash C, Gurguis GN, Kramer GL, Petty F. Source: Psychopharmacology Bulletin. 1996; 32(4): 647-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8993086

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Variability and severity of depression and anxiety in post traumatic stress disorder and major depressive disorder. Author(s): Golier JA, Yehuda R, Schmeidler J, Siever LJ. Source: Depression and Anxiety. 2001; 13(2): 97-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11301926

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Venlafaxine versus sertraline for major depressive disorder. Author(s): Wise TN, Sheridan MJ. Source: The Journal of Clinical Psychiatry. 2000 November; 61(11): 873-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11105744

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Verbal learning by major depressive disorder patients during treatment with fluoxetine or amitriptyline. Author(s): Richardson JS, Keegan DL, Bowen RC, Blackshaw SL, Cebrian-Perez S, Dayal N, Saleh S, Shrikhande S. Source: International Clinical Psychopharmacology. 1994 Spring; 9(1): 35-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8195581

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Weight loss, cortisol levels, and dexamethasone suppression in major depressive disorder. Author(s): Casper RC, Swann AC, Stokes PE, Chang S, Katz MM, Garver D. Source: Acta Psychiatrica Scandinavica. 1987 March; 75(3): 243-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3473911

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Well-being and life satisfaction in generalized anxiety disorder: comparison to major depressive disorder in a community sample. Author(s): Stein MB, Heimberg RG. Source: Journal of Affective Disorders. 2004 April; 79(1-3): 161-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15023490

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What characteristics of primary anxiety disorders predict subsequent major depressive disorder? Author(s): Bittner A, Goodwin RD, Wittchen HU, Beesdo K, Hofler M, Lieb R. Source: The Journal of Clinical Psychiatry. 2004 May; 65(5): 618-26, Quiz 730. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15163247

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What is new in bipolar disorder and major depressive disorder in children and adolescents. Author(s): Carlson GA, Kashani JH. Source: Child Adolesc Psychiatr Clin N Am. 2002 July; 11(3): Xv-Xxii. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12222089

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When are psychotherapy and pharmacotherapy combinations the treatment of choice for major depressive disorder? Author(s): Thase ME. Source: The Psychiatric Quarterly. 1999 Winter; 70(4): 333-46. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10587988

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World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Acute and continuation treatment of major depressive disorder. Author(s): Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ; World Federation of Societies Biological Psychiatry Task Force on Treatment Guidelines for Unipolar Depressive Disorders. Source: World J Biol Psychiatry. 2002 January; 3(1): 5-43. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12479086

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World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. Author(s): Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ; World Federation of Societies of Biological Psychiatry (WFSBF) Task Force on Treatment Guidelines for Unipolar Depressive Disorders. Source: World J Biol Psychiatry. 2002 April; 3(2): 69-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12479080

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Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. Author(s): Papakostas GI, Petersen TJ, Nierenberg AA, Murakami JL, Alpert JE, Rosenbaum JF, Fava M. Source: The Journal of Clinical Psychiatry. 2004 February; 65(2): 217-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15003076

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CHAPTER 2. NUTRITION AND MAJOR DEPRESSIVE DISORDER Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and major depressive disorder.

Finding Nutrition Studies on Major Depressive Disorder The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.4 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “major depressive disorder” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

4 Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following information is typical of that found when using the “Full IBIDS Database” to search for “major depressive disorder” (or a synonym): •

Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. Author(s): Department of Psychiatry and Biobehavioral Science, University of California, Los Angeles, USA. Source: Rasgon, Natalie L Altshuler, Lori L Fairbanks, Lynn A Dunkin, Jennifer J Davtyan, Camelia Elman, Shana Rapkin, Andrea J J-Clin-Psychiatry. 2002; 63 Suppl 7: 45-8 0160-6689

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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Google: http://directory.google.com/Top/Health/Nutrition/

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Healthnotes: http://www.healthnotes.com/

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Open Directory Project: http://dmoz.org/Health/Nutrition/

Nutrition

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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

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WebMDHealth: http://my.webmd.com/nutrition

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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The following is a specific Web list relating to major depressive disorder; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

Minerals Fluoxetine Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. ALTERNATIVE MEDICINE AND MAJOR DEPRESSIVE DISORDER Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to major depressive disorder. At the conclusion of this chapter, we will provide additional sources.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to major depressive disorder and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “major depressive disorder” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to major depressive disorder: •

“Diet pills” and major depression in the Canadian population. Author(s): Patten SB. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2001 June; 46(5): 438-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11441784

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A comparative mental health literacy survey of psychiatrists and other mental health professionals in Singapore. Author(s): Parker G, Chen H, Kua J, Loh J, Jorm AF. Source: The Australian and New Zealand Journal of Psychiatry. 2000 August; 34(4): 62736. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10954394

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A holistic approach to the psychoses: I. The affective psychoses. Author(s): Rubins JL. Source: American Journal of Psychoanalysis. 1968; 28(2): 139-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5682822

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A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Author(s): Berman RM, Narasimhan M, Sanacora G, Miano AP, Hoffman RE, Hu XS, Charney DS, Boutros NN. Source: Biological Psychiatry. 2000 February 15; 47(4): 332-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10686268

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A randomized controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic stimulation in severe and resistant nonpsychotic major depression. Author(s): Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN. Source: Biological Psychiatry. 2003 February 15; 53(4): 324-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12586451

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Acute mood and thyroid stimulating hormone effects of transcranial magnetic stimulation in major depression. Author(s): Szuba MP, O'Reardon JP, Rai AS, Snyder-Kastenberg J, Amsterdam JD, Gettes DR, Wassermann E, Evans DL. Source: Biological Psychiatry. 2001 July 1; 50(1): 22-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11457420

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Acute phase proteins in major depression. Author(s): Berk M, Wadee AA, Kuschke RH, O'Neill-Kerr A. Source: Journal of Psychosomatic Research. 1997 November; 43(5): 529-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9394269

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Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Author(s): Nemets B, Stahl Z, Belmaker RH. Source: The American Journal of Psychiatry. 2002 March; 159(3): 477-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11870016

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Affective startle modulation in clinical depression: preliminary findings. Author(s): Allen NB, Trinder J, Brennan C. Source: Biological Psychiatry. 1999 August 15; 46(4): 542-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10459405

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Altered habituation in the auditory cortex in a subgroup of depressed patients by functional magnetic resonance imaging. Author(s): Michael N, Ostermann J, Soros P, Schwindt W, Pfleiderer B. Source: Neuropsychobiology. 2004; 49(1): 5-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14730193

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Alternative medicine use by individuals with major depression. Author(s): Wang JL, Patten SB, Russell ML. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2001 August; 46(6): 528-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11526809

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Alternative treatment modalities in human immunodeficiency virus/acquired immune deficiency syndrome. Author(s): Ernst J. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003; 37 Suppl 2: S150-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942390

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An open-label pilot study of St. John's wort in juvenile depression. Author(s): Findling RL, McNamara NK, O'Riordan MA, Reed MD, Demeter CA, Branicky LA, Blumer JL. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2003 August; 42(8): 908-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12874492

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Anguish and despair in adolescents with eating disorders--helping to manage suicidal ideation and impulses. Author(s): Manley RS, Leichner P. Source: Crisis. 2003; 24(1): 32-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12809151

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Applications of TMS to therapy in psychiatry. Author(s): Lisanby SH, Kinnunen LH, Crupain MJ. Source: Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society. 2002 August; 19(4): 344-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12436089

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Are all cognitive therapies alike? A comparison of cognitive and noncognitive therapy process and implications for the application of empirically supported treatments. Author(s): Malik ML, Beutler LE, Alimohamed S, Gallagher-Thompson D, Thompson L.

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Source: Journal of Consulting and Clinical Psychology. 2003 February; 71(1): 150-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12602435 •

Association of depression, CD8+ T lymphocytes, and natural killer cell activity: implications for morbidity and mortality in Human immunodeficiency virus disease. Author(s): Cruess DG, Douglas SD, Petitto JM, Leserman J, Ten Have T, Gettes D, Dube B, Evans DL. Source: Current Psychiatry Reports. 2003 December; 5(6): 445-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609499

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Auditory event-related potential indices of increased distractibility in children with major depression. Author(s): Lepisto T, Soininen M, Ceponiene R, Almqvist F, Naatanen R, Aronen ET. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2004 March; 115(3): 620-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15036058

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Auditory startle response in trauma survivors with posttraumatic stress disorder: a prospective study. Author(s): Shalev AY, Peri T, Brandes D, Freedman S, Orr SP, Pitman RK. Source: The American Journal of Psychiatry. 2000 February; 157(2): 255-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10671396

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Bach flower therapy in the treatment of chronic major depressive disorder. Author(s): Masi MP. Source: Alternative Therapies in Health and Medicine. 2003 November-December; 9(6): 112, 108-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14618865

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Cellular immunity in depressed, conduct disorder, and normal adolescents: role of adverse life events. Author(s): Birmaher B, Rabin BS, Garcia MR, Jain U, Whiteside TL, Williamson DE, alShabbout M, Nelson BC, Dahl RE, Ryan ND. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1994 June; 33(5): 671-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8056730

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Cerebral blood flow changes in depressed patients after treatment with repetitive transcranial magnetic stimulation: evidence of individual variability. Author(s): Nadeau SE, McCoy KJ, Crucian GP, Greer RA, Rossi F, Bowers D, Goodman WK, Heilman KM, Triggs WJ.


Source: Neuropsychiatry, Neuropsychology, and Behavioral Neurology. 2002 September; 15(3): 159-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12218709 •

Charles Bonnet syndrome with major depression in a Chinese middle-aged man. Author(s): Fong SY, Wing YK. Source: The Australian and New Zealand Journal of Psychiatry. 1997 October; 31(5): 76971. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9400886

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Circulating lymphocyte subsets in major depression and dysthymia with typical or atypical features. Author(s): Ravindran AV, Griffiths J, Merali Z, Anisman H. Source: Psychosomatic Medicine. 1998 May-June; 60(3): 283-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9625215

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Clinical observation on needling extrachannel points in treating mental depression. Author(s): Yang X, Liu X, Luo H, Jia Y. Source: J Tradit Chin Med. 1994 March; 14(1): 14-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8196410

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Cognitive behavior therapy, relaxation training, and tricyclic antidepressant medication in the treatment of depression. Author(s): Murphy GE, Carney RM, Knesevich MA, Wetzel RD, Whitworth P. Source: Psychological Reports. 1995 October; 77(2): 403-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8559866

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Cognitive change in patients undergoing hypnotherapy for irritable bowel syndrome. Author(s): Gonsalkorale WM, Toner BB, Whorwell PJ. Source: Journal of Psychosomatic Research. 2004 March; 56(3): 271-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15046962

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Correlation of cerebral blood flow and treatment effects of repetitive transcranial magnetic stimulation in depressed patients. Author(s): Mottaghy FM, Keller CE, Gangitano M, Ly J, Thall M, Parker JA, PascualLeone A. Source: Psychiatry Research. 2002 August 20; 115(1-2): 1-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12165364

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Course and severity of substance abuse among patients with comorbid major depression. Author(s): Westermeyer J, Kopka S, Nugent S.

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Source: The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 1997 Fall; 6(4): 284-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9398926 •

Cultural scripts, memories of childhood abuse, and multiple identities: a study of role-played enactments. Author(s): Stafford J, Lynn SJ. Source: Int J Clin Exp Hypn. 2002 January; 50(1): 67-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11778708

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Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. Author(s): Hypericum Depression Trial Study Group. Source: Jama : the Journal of the American Medical Association. 2002 April 10; 287(14): 1807-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11939866

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Magnetic motor threshold and response to TMS in major depressive disorder. Author(s): Dolberg OT, Dannon PN, Schreiber S, Grunhaus L. Source: Acta Psychiatrica Scandinavica. 2002 September; 106(3): 220-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12197860

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Major depressive disorder and health care costs in multiple sclerosis. Author(s): Patten SB, Jacobs P, Petcu R, Reimer MA, Metz LM. Source: International Journal of Psychiatry in Medicine. 2002; 32(2): 167-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12269597

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Neuropsychological impairment in patients with major depressive disorder: the effects of feedback on task performance. Author(s): Murphy FC, Michael A, Robbins TW, Sahakian BJ. Source: Psychological Medicine. 2003 April; 33(3): 455-67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12701666

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Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Author(s): Su KP, Huang SY, Chiu CC, Shen WW. Source: European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 2003 August; 13(4): 267-71. Erratum In: Eur Neuropsychopharmacol. 2004 March; 14(2): 173. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888186


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Omega-3 fatty acids, homocysteine, and the increased risk of cardiovascular mortality in major depressive disorder. Author(s): Severus WE, Littman AB, Stoll AL. Source: Harvard Review of Psychiatry. 2001 November-December; 9(6): 280-93. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11600487

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Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. Author(s): Grunhaus L, Dannon PN, Schreiber S, Dolberg OH, Amiaz R, Ziv R, Lefkifker E. Source: Biological Psychiatry. 2000 February 15; 47(4): 314-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10686266

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Repetitive transcranial magnetic stimulation is effective following repeated courses in the treatment of major depressive disorder--a case report. Author(s): Dannon PN, Grunhaus L. Source: Human Psychopharmacology. 2003 June; 18(4): 313-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766937

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The Effectiveness of St. John's Wort in Major Depressive Disorder: A Naturalistic Phase 2 Follow-Up in Which Nonresponders Were Provided Alternate Medication. Author(s): Gelenberg AJ, Shelton RC, Crits-Christoph P, Keller MB, Dunner DL, Hirschfeld RM, Thase ME, Russell JM, Lydiard RB, Gallop RJ, Todd L, Hellerstein DJ, Goodnick PJ, Keitner GI, Stahl SM, Halbreich U, Hopkins HS. Source: The Journal of Clinical Psychiatry. 2004 August; 65(8): 1114-1119. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15323598

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Ventromedial prefrontal cortex and amygdala dysfunction during an anger induction positron emission tomography study in patients with major depressive disorder with anger attacks. Author(s): Dougherty DD, Rauch SL, Deckersbach T, Marci C, Loh R, Shin LM, Alpert NM, Fischman AJ, Fava M. Source: Archives of General Psychiatry. 2004 August; 61(8): 795-804. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15289278

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

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Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMDHealth: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to major depressive disorder; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Depression Source: Healthnotes, Inc.; www.healthnotes.com Depression Source: Integrative Medicine Communications; www.drkoop.com

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Herbs and Supplements Melatonin Source: Healthnotes, Inc.; www.healthnotes.com

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON MAJOR DEPRESSIVE DISORDER Overview In this chapter, we will give you a bibliography on recent dissertations relating to major depressive disorder. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “major depressive disorder” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on major depressive disorder, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Major Depressive Disorder ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to major depressive disorder. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

Examination of the efficacy of behavioral activation in the treatment of comorbid major depressive disorder and post-traumatic stress disorder by Mulick, Patrick Sean, PhD from WESTERN MICHIGAN UNIVERSITY, 2003, 141 pages http://wwwlib.umi.com/dissertations/fullcit/3080104

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Physician demographics and decision making in the diagnosis and treatment of major depressive disorder and premenstrual dysphoric disorder by Hill, Lauren Diane, PhD from THE AMERICAN UNIVERSITY, 2003, 126 pages http://wwwlib.umi.com/dissertations/fullcit/3085558

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Specific depressive symptoms as risk factors for the onset of major depressive disorder in adolescence by Hadjiyannakis, Katholiki Kathy, PhD from UNIVERSITY OF OREGON, 2003, 146 pages http://wwwlib.umi.com/dissertations/fullcit/3080587

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Treating major depressive disorder with a holistic and integrative approach by Borden, Constance R., PsyD from REGENT UNIVERSITY, 2003, 88 pages http://wwwlib.umi.com/dissertations/fullcit/3120702

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. PATENTS ON MAJOR DEPRESSIVE DISORDER Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.5 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “major depressive disorder” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on major depressive disorder, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Major Depressive Disorder By performing a patent search focusing on major depressive disorder, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. 5Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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The following is an example of the type of information that you can expect to obtain from a patent search on major depressive disorder: •

Use of NK-1 receptor antagonists for treating major depressive disorders with anxiety Inventor(s): Baker; Raymond (Dursley, GB), Curtis; Neil Roy (Puckeridge, GB), Elliott; Jason Matthew (Felsted, GB), Harrison; Timothy (Great Dunmow, GB), Hollingworth; Gregory John (Basildon, GB), Jackson; Philip Stephen (Harlow, GB), Kulagowski; Janusz Jozef (Sawbridgeworth, GB), Rupniak; Nadia Melanie (Bishops Stortford, GB), Seward; Eileen Mary (Bishops Stortford, GB), Swain; Christopher John (Duxford, GB), Williams; Brian John (Great Dunmow, GB) Assignee(s): Merck Sharp & Dohme Ltd. (Hoddesdon, GB) Patent Number: 6,114,315 Date filed: June 11, 1998 Abstract: The present invention provides methods for the treatment or prevention of major depressive disorder with anxiety without concomitant therapy with other antidepressant or anti-anxiety agents which comprises oral administration of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist and pharmaceutical compositions comprising such a NK-1 receptor antagonist. Excerpt(s): This invention relates to the treatment or prevention of certain depressive disorders when present with anxiety by the administration of a specific class of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities. The individual may also experience changes in appetite or weight, sleep and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating or making decisions; and recurrent thoughts of death or suicidal ideation, plans or attempts. One or more major depressive episodes may give rise to a diagnosis of major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatric Association, 1994). Unfortunately, the condition of an individual suffering from a major depressive disorder is sometimes complicated by the fact that the individual is also suffering from anxiety. Thus in addition to the symptoms of their depressive illness, the patient may show signs of excessive or uncontrolled worry, irritability, feelings of tension, fears, restlessness and insomnia, difficulty in concentrating, and multiple somatic complaints such as pains and aches, twitching, stiffness, myoclonic jerks, tinnitus, blurred vision, hot and cold flushes, etc., all of which add to the individual's social and occupational impairment. Web site: http://www.delphion.com/details?pn=US06114315__

Patent Applications on Major Depressive Disorder As of December 2000, U.S. patent applications are open to public viewing.6 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to major depressive disorder: 6

This has been a common practice outside the United States prior to December 2000.

Patents 125

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Gene signature of electroshock therapy and methods of use Inventor(s): Altar, C. Anthony; (Garrett Park, MD), Charles, Vinod D.; (Silver Spring, MD), Laeng, Pascal; (Washington, DC), Young, Theresa A.; (Germantown, MD) Correspondence: Darby & Darby P.C.; P. O. Box 5257; New York; NY; 10150-5257; US Patent Application Number: 20040152107 Date filed: September 18, 2003 Abstract: Gene signatures associated with electroconvulsive therapy (ECT) and/or electroconvulsive seizures (ECS) are disclosed. Such "signatures" are useful, e.g., for diagnosing and treating neuropsychiatric disorders such as major depressive disorder (MDD), bipolar affective disorder (BAD) and psychotic depression. Such methods are therefore also provided here. The invention additionally provides screening methods that use gene signatures of the invention to identify new therapeutic compounds for treating these disorders. Excerpt(s): Priority is claimed under 35 U.S.C. 119(e) to U.S. provisional application Serial Nos. 60/411,718; 60/431,882; and 60/479,970 filed on Sep. 18, 2002; Dec. 9, 2002; and Jun. 18, 2003, respectively. The contents of these priority applications are hereby incorporated by reference in their entireties. The invention relates to methods and compositions for the diagnosis and treatment of neuropsychiatric disorders, including major depressive disorder (MDD), bipolar affective disorder (BAD), schizophrenia and psychotic depression. More specifically, the invention relates to gene signatures, that are associated with electroshock therapy and are useful for diagnosing and treating such neuropsychiatric disorders. Current treatments for the psychiatric depression, such as that associated with major depressive disorder (MDD), bipolar affective disorder (BAD), and psychotic depression, comprise several classes of antidepressant drugs. Unfortunately, many patients with these forms of depression fail to respond to such drug therapies. In such cases, electroconvulsive therapy (ECT) may be the only avaiable treatment. Indeed, ECT does produce a high level of success in patients where other pharmacological treatment regimens have failed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods of determining susceptibility to or presence of schizophrenia, or a disorder related thereto Inventor(s): Gogos, Joseph A.; (New York, NY), Karayiorgou, Maria; (New York, NY) Correspondence: Klauber & Jackson; 411 Hackensack Avenue; Hackensack; NJ; 07601 Patent Application Number: 20020193581 Date filed: April 10, 2002 Abstract: Variations in the DNA sequence of the human proline dehydrogenase gene (PRODH) which correlate to an increased susceptibility to, or presence of schizophrenia or a disease or disorder related thereto, such as obsessive compulsive disorder (OCD), bipolar disorder (BP), or major depressive disorder (MDD) are provided, along with assays to diagnosing schizophrenia or a disease or disorder related thereto, and evaluating potential drugs or agents for using in treating such diseases or disorders. Excerpt(s): This Application is a continuation-in-part of copending U.S. application Ser. No. 09/229,530 entitled "Methods of Determining Susceptibility to or presence of schizophrenia, or a disorder related thereto", which is hereby incorporated by reference

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in its entirety. The present invention relates to isolated nucleic acid molecules which encode human and murine proline dehydrogenase, and methods for determining susceptibility to, or the presence of schizophrenia or a disease or disorder related thereto, such as obsessive compulsive disorder, bipolar disorder (BP), or major depressive disorder in a subject by determining levels of proline dehydrogenase (PRODH) in a bodily sample. Furthermore, the present invention comprises polymorphisms of the human proline dehydrogenase (PRODH) gene which correlate to a phenotype closely related to schizophrenia or a disease or disorder related thereto. The present invention also relates to various assays for drugs or agents that can treat schizophrenia or a disease or disorder related thereto. It has been posited that the amino acid proline serves as a modulator of synaptic transmission in the mammalian brain, due to the selective expression of a brain specific high affinity proline transporter in a subset of glutamatergic pathways (Fremeau et al., 1996). Proline transporter is modulated by enckephalins, the expression of which may be decreased in the brains of patients with schizophrenia and elevated proline concentration. Furthermore, recent analysis indicates that endogenous extracellular proline may regulate the basal function of some glutamate synapses by maintaining them in a partially potentiated state. Also, elevated proline concentration has also been previously associated with behavioral and neurological effects. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with major depressive disorder, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “major depressive disorder” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on major depressive disorder. You can also use this procedure to view pending patent applications concerning major depressive disorder. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 6. PERIODICALS AND NEWS ON MAJOR DEPRESSIVE DISORDER Overview In this chapter, we suggest a number of news sources and present various periodicals that cover major depressive disorder.

News Services and Press Releases One of the simplest ways of tracking press releases on major depressive disorder is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “major depressive disorder” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to major depressive disorder. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “major depressive disorder” (or synonyms). The following was recently listed in this archive for major depressive disorder: •

Rate of major depressive disorder high among HIV-positive women Source: Reuters Medical News Date: May 10, 2002

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•


Recovery From Major Depressive Disorder Still Possible After 5 Years Source: Reuters Medical News Date: September 23, 1996 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “major depressive disorder” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “major depressive disorder” (or synonyms). If you know the name of a company that is relevant to major depressive disorder, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “major depressive disorder” (or synonyms).

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Academic Periodicals covering Major Depressive Disorder Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to major depressive disorder. In addition to these sources, you can search for articles covering major depressive disorder that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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APPENDICES

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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute7: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

7

These publications are typically written by one or more of the various NIH Institutes.

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•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.8 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:9 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

8

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 9 See http://www.nlm.nih.gov/databases/databases.html.

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•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

The NLM Gateway10 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.11 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “major depressive disorder” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 6819 31 452 22 44 7368

HSTAT12 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.13 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.14 Simply search by “major depressive disorder” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

10

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

11

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 12 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 13 14

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

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Coffee Break: Tutorials for Biologists15 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.16 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.17 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

15 Adapted 16

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 17 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on major depressive disorder can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to major depressive disorder. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to major depressive disorder. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “major depressive disorder”:

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Bipolar Disorder http://www.nlm.nih.gov/medlineplus/bipolardisorder.html Mental Health http://www.nlm.nih.gov/medlineplus/mentalhealth.html Suicide http://www.nlm.nih.gov/medlineplus/suicide.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on major depressive disorder. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Depression in children and adolescents: A fact sheet for physicians Source: Bethesda, MD: National Institute of Mental Health. 2000. 9 pp. Contact: Available from National Institute of Mental Health, 6001 Executive Boulevard, Bethesda, MD 20892-9663. Telephone: (301) 443-4513 or (301) 443-8431 TDD or (301) 4435158 (faxed information) / fax: (301) 443-4279 / e-mail: [email protected] / Web site: http://www.nimh.nih.gov. Available from the Web site at no charge. Summary: This fact sheet, which is intended for physicians, summarizes some of the latest scientific findings on child and adolescent depression and lists resources where physicians can obtain more information. It discusses the scope of the problem, clinical characteristics, screening, risk factors, treatment, and talking with parents. A sidebar provides symptoms of major depressive disorder common to adults, children, and adolescents; signs that may be associated with depression in children and adolescents; bipolar disorder: manic symptoms; and bipolar disorder: a warning about antidepressants and psychostimulants. The National Guideline Clearinghouse™

The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “major depressive disorder” (or synonyms). The following was recently posted:

Patient Resources

•

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VHA/DOD clinical practice guideline for the management of major depressive disorder in adults Source: Department of Defense - Federal Government Agency [U.S.]; 1997 (updated 2000); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2585&nbr=1811&a mp;string=major+AND+depressive+AND+disorder The NIH Search Utility

The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to major depressive disorder. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •


•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMDHealth: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to major depressive disorder. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with major depressive disorder. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about major depressive disorder. For more

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information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “major depressive disorder” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “major depressive disorder”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “major depressive disorder” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “major depressive disorder” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.18

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

18

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)19: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

19

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

Finding Medical Libraries

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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

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Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

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On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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MAJOR DEPRESSIVE DISORDER DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Absenteeism: Chronic absence from work or other duty. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH]

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Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Aggressiveness: The quality of being aggressive (= characterized by aggression; militant; enterprising; spreading with vigour; chemically active; variable and adaptable). [EU] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Agoraphobia: Obsessive, persistent, intense fear of open places. [NIH] Akathisia: 1. A condition of motor restlessness in which there is a feeling of muscular quivering, an urge to move about constantly, and an inability to sit still, a common extrapyramidal side effect of neuroleptic drugs. 2. An inability to sit down because of intense anxiety at the thought of doing so. [EU] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration.

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Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amitriptyline: Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the re-uptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antaganize cholinergic and alpha-1 adrenergic responses to bioactive amines. [NIH] Amnestic: Nominal aphasia; a difficulty in finding the right name for an object. [NIH] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [NIH]

Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anomalies: Birth defects; abnormalities. [NIH]

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Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea. [NIH]

Anti-Anxiety Agents: Agents that alleviate anxiety, tension, and neurotic symptoms, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. Some are also effective as anticonvulsants, muscle relaxants, or anesthesia adjuvants. Adrenergic beta-antagonists are commonly used in the symptomatic treatment of anxiety but are not included here. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticholinergic: An agent that blocks the parasympathetic nerves. Called also parasympatholytic. [EU] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]

Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting.

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Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [EU] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiety Disorders: Disorders in which anxiety (persistent feelings of apprehension, tension, or uneasiness) is the predominant disturbance. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Approximate: Approximal [EU] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arteries: The vessels carrying blood away from the heart. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Aspiration: The act of inhaling. [NIH] Astringent: Causing contraction, usually locally after topical application. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Auditory Cortex: Area of the temporal lobe concerned with hearing. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU]

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Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Back Pain: Acute or chronic pain located in the posterior regions of the trunk, including the thoracic, lumbar, sacral, or adjacent regions. [NIH] Baclofen: A GABA derivative that is a specific agonist at GABA-B receptors. It is used in the treatment of spasticity, especially that due to spinal cord damage. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal metabolic rate: Represents the minimum energy expenditure required for the maintenance of vital functions; normally the amount of energy expended, measured in calories, per unit of time at rest; measured after 14-18 hours of rest. [NIH] Behavior Therapy: The application of modern theories of learning and conditioning in the treatment of behavior disorders. [NIH] Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning

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technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bipolar Disorder: A major affective disorder marked by severe mood swings (manic or major depressive episodes) and a tendency to remission and recurrence. [NIH] Bladder: The organ that stores urine. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is most frequently measured by photon absorptiometry or x-ray computed tomography. [NIH] Bone Remodeling: The continuous turnover of bone matrix and mineral that involves first, an increase in resorption (osteoclastic activity) and later, reactive bone formation (osteoblastic activity). The process of bone remodeling takes place in the adult skeleton at discrete foci. The process ensures the mechanical integrity of the skeleton throughout life and plays an important role in calcium homeostasis. An imbalance in the regulation of bone remodeling's two contrasting events, bone resorption and bone formation, results in many of the metabolic bone diseases, such as osteoporosis. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Buprenorphine: A derivative of the opioid alkaloid thebaine that is a more potent and longer lasting analgesic than morphine. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use. [NIH] Bupropion: A unicyclic, aminoketone antidepressant. The mechanism of its therapeutic actions is not well understood, but it does appear to block dopamine uptake. The hydrochloride is available as an aid to smoking cessation treatment. [NIH] Buspirone: An anxiolytic agent and a serotonin receptor agonist belonging to the azaspirodecanedione class of compounds. Its structure is unrelated to those of the benzodiazepines, but it has an efficacy comparable to diazepam. [NIH] Calcitonin: A peptide hormone that lowers calcium concentration in the blood. In humans,

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it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. [NIH] Calcitonin Gene-Related Peptide: Calcitonin gene-related peptide. A 37-amino acid peptide derived from the calcitonin gene. It occurs as a result of alternative processing of mRNA from the calcitonin gene. The neuropeptide is widely distributed in neural tissue of the brain, gut, perivascular nerves, and other tissue. The peptide produces multiple biological effects and has both circulatory and neurotransmitter modes of action. In particular, it is a potent endogenous vasodilator. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carcinogenic: Producing carcinoma. [EU] Cardiac: Having to do with the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Catechol: A chemical originally isolated from a type of mimosa tree. Catechol is used as an astringent, an antiseptic, and in photography, electroplating, and making other chemicals. It can also be man-made. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Caudate Nucleus: Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cellular Structures: Components of a cell. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon

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differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemoreceptor: A receptor adapted for excitation by chemical substances, e.g., olfactory and gustatory receptors, or a sense organ, as the carotid body or the aortic (supracardial) bodies, which is sensitive to chemical changes in the blood stream, especially reduced oxygen content, and reflexly increases both respiration and blood pressure. [EU] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH]

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Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Citalopram: A selective neuronal serotonin reuptake inhibitor and a clinically effective antidepressant with tolerable side effects. The drug is also effective in reducing ethanol uptake in alcoholics and is used in depressed patients who also suffer from tardive dyskinesia (TD) in preference to tricyclic antidepressants, which aggravate this condition. [NIH]

Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clomipramine: A tricyclic antidepressant similar to imipramine that selectively inhibits the uptake of serotonin in the brain. It is readily absorbed from the gastrointestinal tract and demethylated in the liver to form its primary active metabolite, desmethylclomipramine. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Cochlear: Of or pertaining to the cochlea. [EU] Cochlear Diseases: Diseases of the cochlea, the part of the inner ear that is concerned with hearing. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Cognitive behavior therapy: A system of psychotherapy based on the premise that distorted or dysfunctional thinking, which influences a person's mood or behavior, is common to all psychosocial problems. The focus of therapy is to identify the distorted thinking and to replace it with more rational, adaptive thoughts and beliefs. [NIH] Cognitive Therapy: A direct form of psychotherapy based on the interpretation of situations (cognitive structure of experiences) that determine how an individual feels and behaves. It is

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based on the premise that cognition, the process of acquiring knowledge and forming beliefs, is a primary determinant of mood and behavior. The therapy uses behavioral and verbal techniques to identify and correct negative thinking that is at the root of the aberrant behavior. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Community Mental Health Centers: Facilities which administer the delivery of psychologic and psychiatric services to people living in a neighborhood or community. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH]

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Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Compulsions: In psychology, an irresistible urge, sometimes amounting to obsession to perform a particular act which usually is carried out against the performer's will or better judgment. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Concomitant: Accompanying; accessory; joined with another. [EU] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The

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comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Convulsive: Relating or referring to spasm; affected with spasm; characterized by a spasm or spasms. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Disease: Disorder of cardiac function due to an imbalance between myocardial function and the capacity of the coronary vessels to supply sufficient flow for normal function. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronary Vessels: The veins and arteries of the heart. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cost Savings: Reductions in all or any portion of the costs of providing goods or services. Savings may be incurred by the provider or the consumer. [NIH] Cost-benefit: A quantitative technique of economic analysis which, when applied to radiation practice, compares the health detriment from the radiation doses concerned with the cost of radiation dose reduction in that practice. [NIH] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Cribriform: Pierced with small holes as in a sieve. Refers to the appearance of a tumor when

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viewed under a microscope. The tumor appears to have open spaces or small holes inside. [NIH]

Curative: Tending to overcome disease and promote recovery. [EU] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cytokines: Non-antibody proteins secreted by inflammatory leukocytes and some nonleukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Dangerous Behavior: Actions which have a high risk of being harmful or injurious to oneself or others. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Decision Making: The process of making a selective intellectual judgment when presented with several complex alternatives consisting of several variables, and usually defining a course of action or an idea. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Delirium: (DSM III-R) an acute, reversible organic mental disorder characterized by reduced ability to maintain attention to external stimuli and disorganized thinking as manifested by rambling, irrelevant, or incoherent speech; there are also a reduced level of consciousness, sensory misperceptions, disturbance of the sleep-wakefulness cycle and level of psychomotor activity, disorientation to time, place, or person, and memory impairment. Delirium may be caused by a large number of conditions resulting in derangement of cerebral metabolism, including systemic infection, poisoning, drug intoxication or withdrawal, seizures or head trauma, and metabolic disturbances such as hypoxia, hypoglycaemia, fluid, electrolyte, or acid-base imbalances, or hepatic or renal failure. Called also acute confusional state and acute brain syndrome. [EU] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [NIH] Delta Sleep-Inducing Peptide: A nonapeptide that is found in neurons, peripheral organs, and plasma. This neuropeptide induces mainly delta sleep in mammals. In addition to sleep, the peptide has been observed to affect electrophysiological activity, neurotransmitter levels in the brain, circadian and locomotor patterns, hormonal levels, psychological performance, and the activity of neuropharmacological drugs including their withdrawal. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU]

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Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]

Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Dentists: Individuals licensed to practice dentistry. [NIH] Deoxyglucose: 2-Deoxy-D-arabino-hexose. An antimetabolite of glucose with antiviral activity. [NIH] Depersonalization: Alteration in the perception of the self so that the usual sense of one's own reality is lost, manifested in a sense of unreality or self-estrangement, in changes of body image, or in a feeling that one does not control his own actions and speech; seen in depersonalization disorder, schizophrenic disorders, and schizotypal personality disorder. Some do not draw a distinction between depersonalization and derealization, using depersonalization to include both. [EU] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Derealization: Is characterized by the loss of the sense of reality concerning one's surroundings. [NIH] Desipramine: A tricyclic dibenzazepine compound that potentiates neurotransmission. Desipramine selectively blocks reuptake of norepinephrine from the neural synapse, and also appears to impair serotonin transport. This compound also possesses minor anticholingeric activity, through its affinity to muscarinic receptors. [NIH] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU]

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Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Drinking Behavior: Behaviors associated with the ingesting of water and other liquids; includes rhythmic patterns of drinking (time intervals - onset and duration), frequency and satiety. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Duct: A tube through which body fluids pass. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dysphoric: A feeling of unpleasantness and discomfort. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Eating Disorders: A group of disorders characterized by physiological and psychological

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disturbances in appetite or food intake. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electroacupuncture: A form of acupuncture using low frequency electrically stimulated needles to produce analgesia and anesthesia and to treat disease. [NIH] Electroconvulsive Therapy: Electrically induced convulsions primarily used in the treatment of severe affective disorders and schizophrenia. [NIH] Electroencephalography: Recording of electric currents developed in the brain by means of electrodes applied to the scalp, to the surface of the brain, or placed within the substance of the brain. [NIH] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Electroplating: Coating with a metal or alloy by electrolysis. [NIH] Electroshock: Induction of a stress reaction in experimental subjects by means of an electrical shock; applies to either convulsive or non-convulsive states. [NIH] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous)

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production. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enteric-coated: A term designating a special coating applied to tablets or capsules which prevents release and absorption of their contents until they reach the intestines. [EU] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithalamus: The dorsal posterior subdivision of the diencephalon. The epithalamus is generally considered to include the habenular nuclei (habenula) and associated fiber bundles, the pineal body, and the epithelial roof of the third ventricle. The anterior and posterior paraventricular nuclei of the thalamus are included with the thalamic nuclei although they develop from the same pronuclear mass as the epithalamic nuclei and are sometimes considered part of the epithalamus. [NIH] ERV: The expiratory reserve volume is the largest volume of gas that can be expired from the end-expiratory level. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethmoid: An unpaired cranial bone which helps form the medial walls of the orbits and contains the themoidal air cells which drain into the nose. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH]

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Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Expiratory: The volume of air which leaves the breathing organs in each expiration. [NIH] Expiratory Reserve Volume: The extra volume of air that can be expired with maximum effort beyond the level reached at the end of a normal, quiet expiration. Common abbreviation is ERV. [NIH] Extracellular: Outside a cell or cells. [EU] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fetal Heart: The heart of the fetus of any viviparous animal. It refers to the heart in the postembryonic period and is differentiated from the embryonic heart (heart/embryology) only on the basis of time. [NIH] Fetal Monitoring: Physiologic or biochemical monitoring of the fetus. It is usually done during labor and may be performed in conjunction with the monitoring of uterine activity. It may also be performed prenatally as when the mother is undergoing surgery. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fluoxetine: The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants. [NIH]

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Fluvoxamine: A selective serotonin reuptake inhibitor. It is effective in the treatment of depression, obsessive-compulsive disorders, anxiety, panic disorders, and alcohol amnestic disorders. [NIH] Focus Groups: A method of data collection and a qualitative research tool in which a small group of individuals are brought together and allowed to interact in a discussion of their opinions about topics, issues, or questions. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition, blood flow, or both. [NIH]

Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gland: An organ that produces and releases one or more substances for use in the body.

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Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glial Fibrillary Acidic Protein: An intermediate filament protein found only in glial cells or cells of glial origin. MW 51,000. [NIH] Glomeruli: Plural of glomerulus. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Gyrus Cinguli: One of the convolutions on the medial surface of the cerebral hemisphere. It surrounds the rostral part of the brain and interhemispheric commissure and forms part of the limbic system. [NIH] Habituation: Decline in response of an organism to environmental or other stimuli with repeated or maintained exposure. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when

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coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Hepatic: Refers to the liver. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Home Care Services: Community health and nursing services providing coordinated multiple service home care to the patient. It includes home-offered services provided by a visiting nurse, home health agencies, hospitals, or organized community groups using professional staff for care delivery. It differs from home nursing which is provided by nonprofessionals. [NIH] Home Nursing: Nursing care given to an individual in the home. The care may be provided by a family member or a friend. Home nursing as care by a non-professional is differentiated from home care services provided by professionals: visiting nurse, home health agencies, hospital, or other organized community group. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH]

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Homicide: The killing of one person by another. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypnotherapy: Sleeping-cure. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Imipramine: The prototypical tricyclic antidepressant. It has been used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. It has less sedative effect than some other members of this therapeutic group. [NIH]

Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of

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neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which

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activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Intervention Studies: Epidemiologic investigations designed to test a hypothesized causeeffect relation by modifying the supposed causal factor(s) in the study population. [NIH] Intervertebral: Situated between two contiguous vertebrae. [EU] Intervertebral Disk Displacement: An intervertebral disk in which the nucleus pulposus has protruded through surrounding fibrocartilage. This occurs most frequently in the lower lumbar region. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestines: The section of the alimentary canal from the stomach to the anus. It includes the large intestine and small intestine. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratolytic: An agent that promotes keratolysis. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lactation: The period of the secretion of milk. [EU] Latency: The period of apparent inactivity between the time when a stimulus is presented

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and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Laterality: Behavioral manifestations of cerebral dominance in which there is preferential use and superior functioning of either the left or the right side, as in the preferred use of the right hand or right foot. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Ligaments: Shiny, flexible bands of fibrous tissue connecting together articular extremities of bones. They are pliant, tough, and inextensile. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipid: Fat. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]

Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH]

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Localized: Cancer which has not metastasized yet. [NIH] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Lod: The lowest analyte content which, if actually present, will be detected with reasonable statistical certainty and can be identified according to the identification criteria of the method. If both accuracy and precision are constant over a concentration range. [NIH] Lod Score: The total relative probability, expressed on a logarithmic scale, that a linkage relationship exists among selected loci. Lod is an acronym for "logarithmic odds." [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Low Back Pain: Acute or chronic pain in the lumbar or sacral regions, which may be associated with musculo-ligamentous sprains and strains; intervertebral disk displacement; and other conditions. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphocyte Subsets: A classification of lymphocytes based on structurally or functionally different populations of cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mania: Excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behaviour, and elevation of mood. [EU]

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Manic: Affected with mania. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Man-made: Ionizing radiation emitted by artificial or concentrated natural, radioactive material or resulting from the operation of high voltage apparatus, such as X-ray apparatus or particle accelerators, of nuclear reactors, or from nuclear explosions. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Health Services: Organized services to provide mental health care. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesolimbic: Inner brain region governing emotion and drives. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH]

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Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoamine: Enzyme that breaks down dopamine in the astrocytes and microglia. [NIH] Monocyte: A type of white blood cell. [NIH]

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Mononuclear: A cell with one nucleus. [NIH] Monotherapy: A therapy which uses only one drug. [EU] Mood Disorders: Those disorders that have a disturbance in mood as their predominant feature. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Mother-Child Relations: Interaction between the mother and the child. [NIH] Motility: The ability to move spontaneously. [EU] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle relaxant: An agent that specifically aids in reducing muscle tension, as those acting at the polysynaptic neurons of motor nerves (e.g. meprobamate) or at the myoneural junction (curare and related compounds). [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Naltrexone: Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of naloxone. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction. The FDA has approved naltrexone for the treatment of alcohol dependence. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasm: A new growth of benign or malignant tissue. [NIH]

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Neostriatum: The phylogenetically newer part of the corpus striatum consisting of the caudate nucleus and putamen. It is often called simply the striatum. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Endings: Specialized terminations of peripheral neurons. Nerve endings include neuroeffector junction(s) by which neurons activate target organs and sensory receptors which transduce information from the various sensory modalities and send it centrally in the nervous system. Presynaptic nerve endings are presynaptic terminals. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuroanatomy: Study of the anatomy of the nervous system as a specialty or discipline. [NIH]

Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neuropil: A dense intricate feltwork of interwoven fine glial processes, fibrils, synaptic terminals, axons, and dendrites interspersed among the nerve cells in the gray matter of the central nervous system. [NIH] Neurosciences: The scientific disciplines concerned with the embryology, anatomy, physiology, biochemistry, pharmacology, etc., of the nervous sytem. [NIH] Neurosis: Functional derangement due to disorders of the nervous system which does not affect the psychic personality of the patient. [NIH] Neurotic: 1. Pertaining to or characterized by neurosis. 2. A person affected with a neurosis. [EU]

Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU]

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Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nonverbal Communication: Transmission of emotions, ideas, and attitudes between individuals in ways other than the spoken language. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nortriptyline: A metabolite of amitryptyline that is also used as an antidepressive agent. Nortriptyline is used in major depression, dysthymia, and atypical depressions. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nursing Services: A general concept referring to the organization and administration of nursing activities. [NIH] Obsessive-Compulsive Disorder: An anxiety disorder characterized by recurrent, persistent obsessions or compulsions. Obsessions are the intrusive ideas, thoughts, or images that are experienced as senseless or repugnant. Compulsions are repetitive and seemingly purposeful behavior which the individual generally recognizes as senseless and from which the individual does not derive pleasure although it may provide a release from tension. [NIH] Occult: Obscure; concealed from observation, difficult to understand. [EU] Olfactory Bulb: Ovoid body resting on the cribriform plate of the ethmoid bone where the olfactory nerve terminates. The olfactory bulb contains several types of nerve cells including the mitral cells, on whose dendrites the olfactory nerve synapses, forming the olfactory glomeruli. The accessory olfactory bulb, which receives the projection from the vomeronasal organ via the vomeronasal nerve, is also included here. [NIH] Olfactory Nerve: The 1st cranial nerve. The olfactory nerve conveys the sense of smell. It is formed by the axons of olfactory receptor neurons which project from the olfactory epithelium (in the nasal epithelium) to the olfactory bulb. [NIH] Omega-3 fatty acid: A type of fat obtained in the diet and involved in immunity. [NIH]

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Opacity: Degree of density (area most dense taken for reading). [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Panic Disorder: A type of anxiety disorder characterized by unexpected panic attacks that last minutes or, rarely, hours. Panic attacks begin with intense apprehension, fear or terror and, often, a feeling of impending doom. Symptoms experienced during a panic attack include dyspnea or sensations of being smothered; dizziness, loss of balance or faintness; choking sensations; palpitations or accelerated heart rate; shakiness; sweating; nausea or other form of abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest discomfort or pain; fear of dying and fear of not being in control of oneself or going crazy. Agoraphobia may also develop. Similar to other anxiety disorders, it may be inherited as an autosomal dominant trait. [NIH] Parent-Child Relations: The interactions between parent and child. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paresthesias: Abnormal touch sensations, such as burning or prickling, that occur without an outside stimulus. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Paroxetine: A serotonin uptake inhibitor that is effective in the treatment of depression. [NIH]

Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Partial response: A decrease in the size of a tumor, or in the extent of cancer in the body, in

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response to treatment. [NIH] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perennial: Lasting through the year of for several years. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perimenopausal: The time of a woman's life when menstrual periods become irregular. Refers to the time near menopause. [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Peripheral vision: Side vision; ability to see objects and movement outside of the direct line of vision. [NIH] Perivascular: Situated around a vessel. [EU] Personality Disorders: A major deviation from normal patterns of behavior. [NIH] Personality Inventory: Check list, usually to be filled out by a person about himself, consisting of many statements about personal characteristics which the subject checks. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacology, Clinical: The branch of pharmacology that deals directly with the effectiveness and safety of drugs in humans. [NIH] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood

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and appetite. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phobia: A persistent, irrational, intense fear of a specific object, activity, or situation (the phobic stimulus), fear that is recognized as being excessive or unreasonable by the individual himself. When a phobia is a significant source of distress or interferes with social functioning, it is considered a mental disorder; phobic disorder (or neurosis). In DSM III phobic disorders are subclassified as agoraphobia, social phobias, and simple phobias. Used as a word termination denoting irrational fear of or aversion to the subject indicated by the stem to which it is affixed. [EU] Phobic Disorders: Anxiety disorders in which the essential feature is persistent and irrational fear of a specific object, activity, or situation that the individual feels compelled to avoid. The individual recognizes the fear as excessive or unreasonable. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorous: Having to do with or containing the element phosphorus. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorus Compounds: Inorganic compounds that contain phosphorus as an integral part of the molecule. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Phototherapy: Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH]

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Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Post-traumatic stress disorder: A psychological disorder that develops in some individuals after a major traumatic experience such as war, rape, domestic violence, or accident. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prefrontal Cortex: The rostral part of the frontal lobe, bounded by the inferior precentral fissure in humans, which receives projection fibers from the mediodorsal nucleus of the thalamus. The prefrontal cortex receives afferent fibers from numerous structures of the diencephalon, mesencephalon, and limbic system as well as cortical afferents of visual, auditory, and somatic origin. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH]

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Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or

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vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychometric testing: Psychological and mental testing and quantitative analysis of an individual's psychological traits or attitudes or mental processes. [NIH] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychopathology: The study of significant causes and processes in the development of mental illness. [NIH] Psychopharmacology: The study of the effects of drugs on mental and behavioral activity. [NIH]

Psychophysiology: The study of the physiological basis of human and animal behavior. [NIH]

Psychosis: A mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of his behaviour; the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g. manic-depressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH] Psychotomimetic: Psychosis miming. [NIH] Psychotropic: Exerting an effect upon the mind; capable of modifying mental activity; usually applied to drugs that effect the mental state. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pyramidal Tracts: Fibers that arise from cells within the cerebral cortex, pass through the

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medullary pyramid, and descend in the spinal cord. Many authorities say the pyramidal tracts include both the corticospinal and corticobulbar tracts. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radioactive: Giving off radiation. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Randomized Controlled Trials: Clinical trials that involve at least one test treatment and one control treatment, concurrent enrollment and follow-up of the test- and control-treated groups, and in which the treatments to be administered are selected by a random process, such as the use of a random-numbers table. Treatment allocations using coin flips, odd-even numbers, patient social security numbers, days of the week, medical record numbers, or other such pseudo- or quasi-random processes, are not truly randomized and trials employing any of these techniques for patient assignment are designated simply controlled clinical trials. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH]

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Reimbursement Mechanisms: Processes or methods of reimbursement for services rendered or equipment. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Research Support: Financial support of research activities. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Riluzole: A glutamate antagonist that has reported anticonvulsant activity. It has been shown to prolong the survival of patients with amyotrophic lateral sclerosis and has been approved in the United States to treat patients with ALS. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of person he/she is. [EU] Risperidone: A selective blocker of dopamine D2 and serotonin-5-HT-2 receptors that acts as an atypical antipsychotic agent. It has been shown to improve both positive and negative symptoms in the treatment of schizophrenia. [NIH] Rod: A reception for vision, located in the retina. [NIH] Role-play: In this method, a conflict is artificially constructed, and the trainee is given a strategic position in it. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or

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computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Secular trends: A relatively long-term trend in a community or country. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septal Nuclei: Neural nuclei situated in the septal region. They have afferent and cholinergic efferent connections with a variety of forebrain and brainstem areas including the hippocampus, the lateral hypothalamus, the tegmentum, and the amygdala. Included are the dorsal, lateral, medial, and triangular septal nuclei, septofimbrial nucleus, nucleus of diagonal band, nucleus of anterior commissure, and the nucleus of stria terminalis. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH]

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Sertraline: A selective serotonin uptake inhibitor that is used in the treatment of depression. [NIH]

Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoking Cessation: Discontinuation of the habit of smoking, the inhaling and exhaling of tobacco smoke. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Security: Government sponsored social insurance programs. [NIH] Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a

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subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Sprains and Strains: A collective term for muscle and ligament injuries without dislocation or fracture. A sprain is a joint injury in which some of the fibers of a supporting ligament are ruptured but the continuity of the ligament remains intact. A strain is an overstretching or overexertion of some part of the musculature. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may

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be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Supraspinal: Above the spinal column or any spine. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules.

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Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Synaptosomes: Pinched-off nerve endings and their contents of vesicles and cytoplasm together with the attached subsynaptic area of the membrane of the post-synaptic cell. They are largely artificial structures produced by fractionation after selective centrifugation of nervous tissue homogenates. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Temporal Lobe: Lower lateral part of the cerebral hemisphere. [NIH] Teratogenicity: The power to cause abnormal development. [NIH] Thalamus: Paired bodies containing mostly gray substance and forming part of the lateral wall of the third ventricle of the brain. The thalamus represents the major portion of the diencephalon and is commonly divided into cellular aggregates known as nuclear groups. [NIH]

Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thoracic: Having to do with the chest. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for

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increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]

Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [NIH] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] Trigger zone: Dolorogenic zone (= producing or causing pain). [EU] Trophic: Of or pertaining to nutrition. [EU] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for

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nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tryptophan Hydroxylase: An enzyme that catalyzes the hydroxylation of tryptophan to 5hydroxytryptophan in the presence of NADPH and molecular oxygen. It is important in the biosynthesis of serotonin. EC 1.14.16.4 [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Umbilical cord blood: Blood from the placenta (afterbirth) that contains high concentrations of stem cells needed to produce new blood cells. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]

Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] VE: The total volume of gas either inspired or expired in one minute. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venlafaxine: An antidepressant drug that is being evaluated for the treatment of hot flashes in women who have breast cancer. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH]

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Vestibulocochlear Nerve: The 8th cranial nerve. The vestibulocochlear nerve has a cochlear part (cochlear nerve) which is concerned with hearing and a vestibular part (vestibular nerve) which mediates the sense of balance and head position. The fibers of the cochlear nerve originate from neurons of the spiral ganglion and project to the cochlear nuclei (cochlear nucleus). The fibers of the vestibular nerve arise from neurons of Scarpa's ganglion and project to the vestibular nuclei. [NIH] Vestibulocochlear Nerve Diseases: Diseases of the vestibular and/or cochlear (acoustic) nerves, which join to form the vestibulocochlear nerve. Vestibular neuritis, cochlear neuritis, and acoustic neuromas are relatively common conditions that affect these nerves. Clinical manifestations vary with which nerve is primarily affected, and include hearing loss, vertigo, and tinnitus. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visual field: The entire area that can be seen when the eye is forward, including peripheral vision. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Vomeronasal Organ: A specialized part of the olfactory system located anteriorly in the nasal cavity within the nasal septum. Chemosensitive cells of the vomeronasal organ project via the vomeronasal nerve to the accessory olfactory bulb. The primary function of this organ appears to be in sensing pheromones which regulate reproductive and other social behaviors. While the structure has been thought absent in higher primate adults, data now suggests it may be present in adult humans. [NIH] War: Hostile conflict between organized groups of people. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Xenograft: The cells of one species transplanted to another species. [NIH]

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Xerostomia: Decreased salivary flow. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH]

201

INDEX A Abdominal, 151, 175, 183 Abdominal Pain, 151, 175 Aberrant, 151, 161 Absenteeism, 18, 151 Acetylcholine, 151, 159, 181 Acidity, 151, 184 Adaptation, 33, 54, 62, 90, 151, 186 Adenosine, 151, 185 Adipocytes, 151, 176 Adjustment, 41, 57, 62, 151 Adolescence, 10, 37, 56, 81, 87, 88, 89, 99, 121, 151 Adrenal Cortex, 151, 163, 187 Adrenal Medulla, 151, 158, 168, 182 Adrenergic, 151, 153, 154, 155, 166, 168, 194 Adverse Effect, 151, 192 Aerobic, 152, 169 Afferent, 152, 176, 186, 191 Affinity, 126, 152, 155, 165 Aggressiveness, 84, 152 Agonist, 73, 83, 152, 156, 157, 166, 182 Agoraphobia, 152, 173, 183, 185 Akathisia, 152, 155 Alertness, 8, 152 Algorithms, 152, 157 Alimentary, 152, 175, 183 Alkaloid, 152, 157, 160, 180, 182 Alleles, 152, 172, 176 Alpha-1, 152, 153 Alternative medicine, 22, 51, 115, 128, 152 Amenorrhea, 152, 154 Amino acid, 126, 152, 153, 154, 155, 158, 170, 171, 178, 181, 184, 186, 187, 191, 194, 196, 197 Amino Acid Sequence, 153, 154, 170 Amitriptyline, 107, 153 Amnestic, 153, 170 Amphetamine, 20, 153, 165 Amygdala, 19, 40, 82, 84, 88, 119, 153, 176, 191 Anaesthesia, 153, 174 Anal, 38, 54, 153, 177 Analgesic, 153, 157, 180 Analogous, 46, 153, 196 Anaphylatoxins, 153, 161

Anatomical, 66, 153, 159, 162, 167, 173, 179, 191 Anesthesia, 153, 154, 167 Anesthetics, 4, 153, 168 Animal model, 6, 8, 153 Anomalies, 8, 153 Anorexia, 106, 154 Anorexia Nervosa, 106, 154 Anti-Anxiety Agents, 124, 154 Antibacterial, 154, 193 Antibiotic, 154, 193 Antibodies, 46, 154, 172, 173, 177, 185 Antibody, 46, 152, 154, 161, 164, 172, 173, 174, 178, 193 Anticholinergic, 153, 154 Anticonvulsant, 154, 190 Antiemetic, 154, 155 Antigen, 152, 154, 161, 173, 174, 178, 179 Antigen-Antibody Complex, 154, 161 Anti-inflammatory, 154, 165, 171 Antimetabolite, 154, 165 Antipsychotic, 46, 154, 181, 190 Antiseptic, 155, 158 Antiviral, 155, 165 Anus, 153, 155, 161, 175 Anxiety Disorders, 15, 16, 24, 48, 79, 81, 107, 155, 183 Anxiolytic, 155, 157 Apolipoproteins, 155, 176 Approximate, 25, 155 Arginine, 18, 153, 155 Arrhythmia, 32, 101, 155 Arteries, 155, 157, 163, 177, 178, 180, 197 Artery, 9, 155, 157, 163, 188, 197 Aspiration, 37, 155 Astringent, 155, 158 Astrocytes, 31, 155, 179 Asymptomatic, 40, 155 Atrophy, 6, 31, 155 Atypical, 20, 96, 117, 155, 182, 190 Auditory, 115, 116, 155, 186 Auditory Cortex, 115, 155 Autoimmune disease, 155, 180 Autonomic, 32, 34, 43, 75, 91, 151, 155, 156, 182, 194 Autonomic Nervous System, 156, 194 Axons, 156, 165, 181, 182

202


B Back Pain, 51, 156 Baclofen, 83, 156 Bacteria, 154, 156, 165, 178, 179, 189, 193, 196, 197 Bacterial Physiology, 151, 156 Bacteriophage, 156, 196 Basal Ganglia, 10, 66, 155, 156, 159, 176 Basal metabolic rate, 8, 156 Behavior Therapy, 156 Benzodiazepines, 156, 157 Bewilderment, 156, 162 Binding Sites, 85, 156 Biochemical, 46, 152, 154, 156, 169, 191 Biopsy, 156, 184 Biosynthesis, 156, 197 Biotechnology, 63, 128, 135, 156 Bipolar Disorder, 30, 33, 36, 59, 72, 74, 105, 107, 125, 126, 140, 157 Bladder, 157, 162, 180, 197 Bloating, 157, 175 Blood Platelets, 157, 191 Blood pressure, 157, 158, 159, 173, 179 Blood vessel, 157, 158, 159, 175, 176, 184, 194, 197 Blot, 30, 157 Body Composition, 18, 157 Bone Density, 6, 157 Bone Remodeling, 86, 157 Bone Resorption, 157 Bone scan, 157, 190 Bowel, 153, 157, 193 Buprenorphine, 71, 157 Bupropion, 12, 69, 102, 157 Buspirone, 96, 157 C Calcitonin, 86, 157, 158 Calcitonin Gene-Related Peptide, 86, 158 Calcium, 157, 158, 161 Capsules, 158, 168 Carbohydrate, 158, 171 Carcinogenic, 158, 174, 193 Cardiac, 9, 75, 91, 158, 163, 168, 169, 180, 193 Cardiovascular, 9, 32, 33, 54, 119, 153, 158, 169, 191 Cardiovascular disease, 33, 158 Case report, 70, 119, 158, 160 Catechol, 96, 105, 158 Catecholamine, 158, 166, 184 Caudate Nucleus, 36, 158, 181 Causal, 158, 175

Cell Adhesion, 31, 158 Cellular Structures, 158, 179 Central Nervous System, 151, 153, 156, 158, 160, 165, 170, 171, 179, 180, 181, 191 Centrifugation, 158, 195 Cerebral, 22, 23, 39, 40, 42, 66, 96, 100, 116, 117, 156, 159, 163, 164, 168, 169, 170, 171, 176, 188, 192, 195 Cerebral hemispheres, 22, 156, 159, 195 Cerebrospinal, 86, 159 Cerebrospinal fluid, 86, 159 Cerebrovascular, 158, 159 Cerebrum, 159, 195 Character, 159, 164 Chemoreceptor, 155, 159 Chemotactic Factors, 159, 161 Chin, 117, 159, 178 Cholesterol, 77, 159, 160, 163, 176, 177, 193 Cholesterol Esters, 159, 176 Choline, 10, 35, 159 Cholinergic, 153, 155, 159, 182, 191 Chorea, 154, 159 Chromosome, 82, 159, 176 Chronic, 8, 23, 45, 51, 53, 57, 77, 78, 108, 116, 151, 156, 157, 160, 168, 174, 177, 186 Chronic Disease, 23, 160 Chronic renal, 160, 186 Chylomicrons, 160, 176 Circadian, 160, 164 Citalopram, 7, 17, 61, 69, 80, 160 Clamp, 18, 160 Clinical study, 160, 162 Clinical trial, 5, 17, 35, 45, 67, 105, 135, 160, 162, 163, 166, 180, 187, 189 Clomipramine, 86, 160 Cloning, 156, 160 Coca, 160 Cocaine, 24, 34, 41, 71, 79, 160 Cochlear, 160, 195, 198 Cochlear Diseases, 160, 195 Cognition, 22, 65, 160, 161, 181 Cognitive behavior therapy, 55, 74, 117, 160 Cognitive Therapy, 13, 48, 62, 75, 160 Colitis, 161, 175 Collagen, 153, 161, 187 Colon, 161, 175 Community Mental Health Centers, 47, 50, 58, 161 Comorbidity, 35, 41, 49, 52, 56, 71, 81, 89, 97, 98, 102, 104, 161 Complement, 26, 153, 161, 162

203

Complementary and alternative medicine, 113, 120, 161 Complementary medicine, 113, 162 Compliance, 7, 53, 56, 96, 162 Compulsions, 162, 182 Computational Biology, 135, 162 Computed tomography, 157, 162, 190 Computerized axial tomography, 162, 191 Computerized tomography, 20, 162 Concomitant, 7, 34, 106, 124, 162 Confusion, 60, 162, 166, 181 Congestion, 155, 162 Congestive heart failure, 45, 162 Consciousness, 153, 154, 162, 164, 166, 188 Constipation, 155, 162, 175 Constriction, 162, 175, 197 Constriction, Pathologic, 162, 197 Consultation, 11, 51, 162 Contraindications, ii, 162 Control group, 14, 25, 40, 54, 63, 162 Controlled clinical trial, 33, 162, 189 Controlled study, 7, 21, 42, 44, 65, 74, 163 Conventional therapy, 163 Conventional treatment, 22, 163 Convulsions, 154, 163, 167 Convulsive, 163, 167 Coordination, 163, 180 Coronary, 9, 158, 163, 178, 180 Coronary Disease, 9, 163 Coronary heart disease, 158, 163 Coronary Thrombosis, 163, 178, 180 Coronary Vessels, 163 Cortex, 10, 19, 36, 40, 52, 60, 66, 74, 100, 105, 163, 168, 169, 186, 188 Cortical, 10, 46, 163, 169, 186, 191 Cortisol, 6, 18, 25, 40, 52, 53, 71, 76, 83, 88, 107, 163 Cortisone, 163, 165 Cost Savings, 55, 163 Cost-benefit, 39, 163 Craniocerebral Trauma, 163, 195 Cribriform, 163, 182 Curative, 164, 182, 195 Cyclic, 100, 164, 191 Cytokines, 9, 68, 164, 179 Cytoplasm, 164, 168, 195 D Dangerous Behavior, 26, 164 Data Collection, 164, 170 Decision Making, 121, 164 Degenerative, 99, 164 Delirium, 154, 164

Delivery of Health Care, 164, 172 Delta Sleep-Inducing Peptide, 83, 164 Dementia, 77, 98, 99, 154, 164 Dendrites, 164, 165, 181, 182 Dendritic, 31, 164 Density, 6, 31, 68, 72, 100, 105, 157, 159, 165, 176, 183 Dental Caries, 4, 165 Dentate Gyrus, 165, 172 Dentists, 4, 165 Deoxyglucose, 39, 165 Depersonalization, 165, 183, 191 Derealization, 165, 183 Desipramine, 18, 71, 165 Dexamethasone, 73, 76, 83, 87, 91, 107, 165 Dextroamphetamine, 153, 165 Diabetes Mellitus, 18, 165, 171 Diagnostic procedure, 27, 28, 29, 58, 123, 128, 165 Diarrhea, 165, 175 Diathesis, 60, 165 Diencephalon, 166, 168, 173, 186, 195 Direct, iii, 10, 19, 20, 38, 43, 52, 54, 160, 166, 184, 189, 194 Discrete, 32, 54, 157, 166 Disorientation, 60, 162, 164, 166 Dissociation, 152, 166 Dizziness, 166, 183 Dominance, 90, 166, 176 Dopamine, 20, 153, 155, 157, 160, 165, 166, 179, 181, 190 Dorsal, 40, 166, 168, 186, 191 Dorsum, 166 Double-blind, 13, 20, 42, 43, 44, 50, 53, 65, 74, 99, 100, 103, 118, 166 Drinking Behavior, 11, 166 Drug Interactions, 166 Duct, 166, 190 Dyskinesia, 155, 160, 166 Dysphoric, 95, 97, 121, 165, 166 Dyspnea, 166, 183 E Eating Disorders, 115, 166 Effector, 89, 151, 161, 167 Effector cell, 89, 167 Elective, 102, 167 Electroacupuncture, 22, 167 Electroconvulsive Therapy, 22, 60, 84, 92, 103, 114, 119, 125, 167 Electroencephalography, 99, 167 Electrons, 167, 177, 189 Electrophysiological, 40, 164, 167

204


Electroplating, 158, 167 Electroshock, 125, 167 Elementary Particles, 167, 177, 188 Embryo, 167, 174, 197 Embryology, 167, 169, 181 Empirical, 11, 13, 31, 56, 57, 167 Enamel, 165, 167 Endocrine System, 167, 181 Endocrinology, 23, 167 Endogenous, 126, 158, 166, 167 Endotoxins, 161, 168 End-stage renal, 160, 168, 186 Energy balance, 168, 176 Enteric-coated, 96, 168 Entorhinal Cortex, 168, 172 Environmental Health, 134, 136, 168 Enzymatic, 153, 158, 161, 165, 168, 172 Enzyme, 167, 168, 178, 179, 187, 195, 197 Epidemic, 61, 168 Epidemiological, 8, 31, 45, 55, 59, 168 Epinephrine, 151, 166, 168, 181, 182, 197 Epithalamus, 166, 168, 176 ERV, 136, 168, 169 Estrogen, 6, 110, 168, 187 Ethanol, 160, 168 Ethmoid, 168, 182 Ethnic Groups, 72, 168 Eukaryotic Cells, 168, 174 Evoke, 169, 193 Excitability, 92, 169 Excitatory, 156, 169, 171 Exercise Test, 24, 169 Exogenous, 167, 169 Expiratory, 168, 169 Expiratory Reserve Volume, 168, 169 Extracellular, 126, 155, 169 Extraction, 19, 169 Extrapyramidal, 73, 152, 155, 166, 169 F Family Planning, 135, 169 Fat, 151, 157, 163, 169, 176, 180, 182, 190 Fatigue, 4, 65, 169, 172 Fetal Heart, 25, 169 Fetal Monitoring, 37, 169 Fetus, 169, 185, 197 Fibrinogen, 9, 169, 195 Fissure, 165, 169, 186 Fluoxetine, 13, 18, 42, 48, 55, 56, 75, 77, 79, 80, 96, 100, 103, 105, 107, 111, 169 Fluvoxamine, 71, 75, 91, 170 Focus Groups, 5, 170 Fold, 27, 28, 29, 58, 169, 170

Fractionation, 170, 195 Frontal Lobe, 170, 186 Functional magnetic resonance imaging, 5, 115, 170 G Ganglia, 151, 170, 181, 194 Gap Junctions, 170, 194 Gas, 168, 170, 173, 175, 182, 197 Gastrin, 170, 173 Gastrointestinal, 160, 168, 170, 191, 194 Gastrointestinal tract, 160, 168, 170, 191 Gene, 26, 30, 31, 66, 69, 72, 91, 97, 125, 126, 152, 157, 158, 166, 170, 173, 186 Gene Expression, 30, 31, 170 Genetic Code, 170, 182 Genetic testing, 5, 170 Genetics, 20, 24, 26, 69, 82, 97, 104, 166, 170, 179 Genotype, 170, 185 Geriatric, 91, 98, 170 Germ Cells, 170, 178, 192 Gestation, 25, 49, 170, 185 Gland, 151, 163, 170, 183, 191, 193, 195 Glial Fibrillary Acidic Protein, 31, 171 Glomeruli, 171, 182 Glucocorticoid, 6, 52, 82, 89, 165, 171 Glucose, 18, 40, 52, 165, 171, 174 Glucose Intolerance, 165, 171 Glucose tolerance, 18, 171 Glucose Tolerance Test, 18, 171 Glutamate, 97, 126, 171, 190 Glutamic Acid, 171, 181, 187 Glycine, 152, 171, 181 Glycoprotein, 169, 171, 197 Gonad, 171 Gonadal, 23, 171, 193 Governing Board, 171, 186 Grade, 9, 171 Gyrus Cinguli, 171, 176 H Habituation, 115, 171 Haptens, 152, 171 Health Care Costs, 118, 172 Health Expenditures, 172 Health Services, 45, 164, 172 Health Status, 4, 12, 32, 54, 106, 172 Heart attack, 158, 172 Heart failure, 172 Hemostasis, 172, 191 Hepatic, 164, 171, 172 Heredity, 170, 172 Heterogeneity, 27, 28, 29, 58, 67, 152, 172

205

Heterozygotes, 166, 172 Hippocampus, 31, 52, 165, 172, 176, 191, 194 Histamine, 153, 155, 172 Home Care Services, 39, 172 Home Nursing, 172 Homeostasis, 157, 172 Homicide, 55, 173 Homologous, 152, 172, 173, 194 Homozygotes, 166, 173 Hormonal, 25, 84, 155, 164, 173 Hormone, 83, 84, 93, 114, 157, 163, 168, 170, 173, 174, 176, 187, 190, 191, 195 Hydrogen, 151, 158, 173, 179, 184, 188 Hydrophobic, 173, 176 Hydroxylation, 173, 197 Hydroxyproline, 153, 161, 173 Hypersensitivity, 173, 190 Hypertension, 158, 173, 175 Hypnotherapy, 117, 173 Hypotension, 155, 163, 173 Hypothalamic, 8, 23, 53, 94, 173 Hypothalamus, 156, 166, 173, 176, 191 I Imipramine, 71, 75, 80, 85, 160, 173 Immune response, 154, 155, 163, 171, 173, 194, 198 Immune system, 9, 167, 173, 177, 180, 198 Immunodeficiency, 115, 116, 173 Immunohistochemistry, 46, 173 Immunology, 84, 152, 173 Immunosuppressive, 171, 173 Impairment, 4, 12, 14, 15, 16, 22, 49, 93, 118, 124, 156, 164, 166, 173, 178, 188 In situ, 30, 173 In Situ Hybridization, 30, 174 In vitro, 174 In vivo, 10, 40, 43, 174 Induction, 43, 119, 154, 167, 174, 187 Infarction, 163, 174, 178, 180 Infection, 159, 164, 173, 174, 177, 190, 194, 198 Inflammation, 9, 154, 161, 174, 186, 190 Informed Consent, 5, 174 Ingestion, 171, 174 Initiation, 65, 174 Inotropic, 166, 174 Inpatients, 73, 74, 174 Insight, 40, 174 Insomnia, 7, 8, 124, 174 Insulator, 174, 180 Insulin, 18, 171, 174

Insulin-dependent diabetes mellitus, 174 Interleukin-1, 66, 87, 174 Interleukin-2, 175 Intermittent, 9, 175 Intervention Studies, 50, 175 Intervertebral, 175, 177 Intervertebral Disk Displacement, 175, 177 Intestinal, 171, 175 Intestines, 151, 168, 170, 175 Intoxication, 164, 175, 198 Intracranial Hypertension, 175, 195 Intramuscular, 175, 183 Intravenous, 87, 175, 183 Intrinsic, 152, 175 Invasive, 175, 177 Involuntary, 159, 175, 180 Ion Channels, 155, 175, 194 Irritable Bowel Syndrome, 117, 175 Ischemia, 155, 175 K Kb, 134, 175 Keratolytic, 165, 175 L Labile, 161, 175 Lactation, 175, 187 Latency, 7, 9, 74, 175 Latent, 38, 176, 186 Laterality, 96, 176 Leptin, 18, 176 Lesion, 40, 176, 195 Leukocytes, 159, 164, 176, 197 Ligaments, 163, 176 Limbic, 10, 19, 30, 153, 171, 176, 186 Limbic System, 30, 153, 171, 176, 186 Linkage, 27, 28, 29, 58, 69, 82, 176, 177 Linkage Disequilibrium, 69, 176 Lipid, 71, 155, 159, 174, 176, 180 Lipoprotein, 71, 176, 177 Lithium, 36, 66, 75, 154, 176 Liver, 151, 160, 171, 172, 176, 190 Liver scan, 176, 190 Localization, 60, 173, 176 Localized, 10, 165, 174, 177, 185 Locomotor, 164, 177 Lod, 27, 28, 29, 58, 177 Lod Score, 27, 28, 29, 58, 177 Longitudinal study, 17, 18, 38, 54, 56, 59, 73, 177 Low Back Pain, 51, 177 Low-density lipoprotein, 176, 177 Lumbar, 156, 175, 177

206


Lutein Cells, 177, 187 Lymphocyte, 9, 88, 89, 117, 154, 177, 178 Lymphocyte Count, 9, 177 Lymphocyte Subsets, 117, 177 Lymphoid, 154, 177 M Macrophage, 175, 177 Magnetic Resonance Imaging, 17, 24, 177, 191 Magnetic Resonance Spectroscopy, 10, 17, 35, 80, 177 Malnutrition, 155, 177 Mania, 177, 178 Manic, 140, 154, 157, 176, 178, 188 Manifest, 9, 178 Man-made, 158, 178 Mediate, 11, 37, 54, 166, 178 Mediator, 175, 178, 191 MEDLINE, 135, 178 Meiosis, 178, 194 Membrane, 90, 155, 161, 168, 169, 175, 178, 180, 185, 194, 195, 196 Memory, 20, 31, 60, 65, 69, 72, 100, 154, 164, 178 Menopause, 70, 178, 184, 186 Menstruation, 152, 178 Mental Disorders, 36, 46, 54, 124, 178, 188 Mental Health Services, iv, 4, 33, 36, 38, 59, 106, 136, 178 Mental Processes, 166, 178, 188 Mentors, 11, 178 Mesolimbic, 155, 178 Metabolite, 160, 178, 182 Methionine, 20, 43, 50, 178, 194 Methyltransferase, 96, 105, 178 MI, 33, 149, 178 Microbe, 178, 196 Microbiology, 84, 151, 155, 179 Microglia, 46, 155, 179 Microorganism, 179, 184 Micro-organism, 165 Micro-organism, 179 Migration, 72, 179 Milliliter, 157, 179 Mitochondrial Swelling, 179, 180 Mobility, 57, 179 Modeling, 19, 23, 25, 38, 49, 55, 62, 179 Modification, 153, 179, 189 Modulator, 126, 179 Molecular, 23, 25, 59, 72, 74, 135, 137, 156, 162, 165, 169, 179, 187, 189, 196, 197 Molecular Probes, 26, 179

Molecular Structure, 179, 196 Molecule, 31, 154, 156, 161, 166, 167, 179, 185, 189, 197 Monitor, 26, 35, 39, 50, 60, 179, 182 Monoamine, 74, 91, 153, 165, 179 Monocyte, 88, 179 Mononuclear, 180, 197 Monotherapy, 10, 180 Mood Disorders, 13, 30, 36, 37, 40, 44, 49, 180 Morphine, 157, 180 Mother-Child Relations, 47, 180 Motility, 180, 191 Mucins, 180, 190 Mucosa, 180, 187 Multicenter study, 22, 180 Multiple sclerosis, 57, 118, 180 Muscle relaxant, 154, 180 Myelin, 180 Myocardial Ischemia, 163, 180 Myocardium, 32, 178, 180 N Naltrexone, 53, 180 Narcotic, 180 Nausea, 154, 180, 183 Necrosis, 97, 174, 178, 180 Neonatal, 8, 180 Neoplasm, 180, 197 Neostriatum, 158, 181 Nerve, 31, 151, 153, 156, 159, 164, 178, 180, 181, 182, 186, 191, 193, 195, 196, 198 Nerve Endings, 181, 195 Nervous System, 152, 153, 156, 158, 178, 181, 194 Neural, 30, 31, 34, 92, 100, 152, 158, 165, 179, 181, 191 Neuroanatomy, 39, 176, 181 Neuroendocrine, 52, 93, 181 Neuroleptic, 152, 154, 181 Neurologic, 154, 181 Neuronal, 6, 31, 46, 51, 72, 100, 105, 160, 181 Neurons, 9, 31, 46, 72, 160, 164, 165, 169, 170, 180, 181, 182, 194, 198 Neuropeptide, 158, 164, 181 Neurophysiology, 40, 115, 116, 181 Neuropil, 31, 181 Neurosciences, 5, 70, 72, 73, 105, 181 Neurosis, 181, 185 Neurotic, 154, 181 Neurotransmitter, 151, 153, 158, 164, 166, 171, 172, 175, 181, 182, 191, 194

207

Niacin, 182, 197 Nicotine, 24, 182 Nitrogen, 152, 182, 197 Nonverbal Communication, 182, 188 Norepinephrine, 21, 151, 153, 165, 166, 181, 182 Nortriptyline, 98, 182 Nuclear, 85, 95, 156, 167, 168, 176, 178, 180, 182, 195 Nuclei, 35, 153, 167, 168, 177, 182, 188, 191, 198 Nucleic acid, 126, 170, 174, 182 Nucleus, 36, 156, 164, 167, 168, 175, 178, 180, 182, 186, 187, 188, 191, 198 Nursing Services, 172, 182 O Obsessive-Compulsive Disorder, 39, 67, 97, 102, 170, 182 Occult, 4, 182 Olfactory Bulb, 68, 182, 198 Olfactory Nerve, 182 Omega-3 fatty acid, 44, 114, 118, 119, 182 Opacity, 165, 183 Oral Health, 183 Oral Hygiene, 4, 183 Orthostatic, 155, 183 Osteoclasts, 158, 183 Osteoporosis, 157, 183 Outpatient, 23, 33, 36, 59, 183 Ovum, 170, 183, 187 Oxygen Consumption, 169, 183, 190 P Palliative, 183, 195 Pancreas, 151, 174, 183 Panic, 73, 96, 170, 173, 183 Panic Disorder, 73, 96, 170, 173, 183 Parent-Child Relations, 62, 183 Parenteral, 20, 43, 183 Paresthesias, 183 Parkinsonism, 155, 183 Paroxetine, 10, 39, 56, 68, 80, 88, 96, 97, 183 Partial remission, 183, 190 Partial response, 7, 183 Particle, 178, 184, 196 Parturition, 184, 187 Pathogen, 9, 184 Pathogenesis, 8, 10, 40, 184 Pathologic, 156, 163, 173, 184, 190 Pathophysiology, 10, 17, 30, 35, 42, 43, 184 Patient Education, 140, 144, 146, 149, 184

Peptide, 152, 157, 158, 164, 176, 184, 186, 187 Perception, 5, 32, 59, 165, 184, 191 Percutaneous, 9, 184 Perennial, 184, 196 Perfusion, 95, 184 Perimenopausal, 110, 184 Periodontal disease, 4, 184 Peripheral vision, 184, 198 Perivascular, 158, 179, 184 Personality Disorders, 13, 15, 16, 184 Personality Inventory, 27, 28, 29, 58, 184 PH, 20, 157, 184 Pharmacologic, 11, 49, 153, 184, 196 Pharmacology, Clinical, 11, 184 Pharmacotherapy, 13, 22, 35, 39, 48, 52, 57, 62, 87, 91, 99, 101, 107, 184 Phenotype, 70, 126, 185 Phobia, 20, 26, 185 Phobic Disorders, 185 Phospholipids, 169, 176, 185 Phosphorous, 35, 185 Phosphorus, 17, 158, 185 Phosphorus Compounds, 17, 185 Phosphorylation, 100, 185 Phototherapy, 74, 185 Physiologic, 43, 152, 156, 169, 178, 185, 189, 190 Physiology, 53, 167, 181, 185 Pilot study, 7, 14, 22, 42, 47, 57, 58, 61, 115, 185 Placenta, 185, 187, 197 Plants, 152, 159, 160, 171, 182, 185, 196 Plasma, 12, 18, 40, 83, 91, 154, 158, 159, 164, 169, 171, 172, 185, 198 Plasma cells, 154, 185 Plasticity, 31, 186 Platelets, 85, 186, 195 Pneumonia, 162, 186 Polycystic, 70, 186 Polymorphism, 66, 91, 97, 186 Polypeptide, 153, 161, 169, 186, 187 Posterior, 153, 156, 166, 168, 183, 186 Postnatal, 25, 186, 193 Postsynaptic, 186, 194 Post-synaptic, 186 Post-synaptic, 195 Post-traumatic, 24, 121, 186 Post-traumatic stress disorder, 24, 121, 186 Potentiates, 165, 175, 186 Potentiating, 153, 186

208


Practicability, 186, 196 Practice Guidelines, 90, 136, 140, 186 Precursor, 159, 166, 167, 168, 182, 186, 197 Predisposition, 56, 186 Prefrontal Cortex, 19, 40, 52, 82, 100, 119, 186 Premenopausal, 68, 186 Presynaptic, 181, 187, 194, 195 Prevalence, 4, 6, 8, 20, 23, 27, 28, 29, 31, 37, 43, 49, 56, 58, 61, 86, 89, 95, 98, 187 Progesterone, 187, 193 Prognostic factor, 71, 187 Progression, 9, 33, 153, 187, 198 Progressive, 160, 164, 180, 187, 197 Projection, 182, 186, 187 Prolactin, 83, 187 Proline, 125, 126, 161, 173, 187 Prophase, 187, 194 Prophylaxis, 44, 75, 187 Prospective Studies, 103, 187 Prospective study, 18, 69, 89, 97, 116, 177, 187 Protein C, 153, 155, 156, 176, 187 Protein S, 157, 170, 187 Proteolytic, 152, 161, 169, 187 Protocol, 11, 14, 18, 34, 44, 50, 187 Protons, 173, 177, 188, 189 Psychic, 178, 181, 188, 191 Psychoactive, 188, 198 Psychometric testing, 24, 188 Psychomotor, 60, 124, 164, 181, 188 Psychopathology, 3, 11, 24, 37, 41, 46, 48, 55, 62, 74, 96, 98, 188 Psychophysiology, 43, 188 Psychosis, 154, 188 Psychotherapy, 7, 21, 22, 33, 46, 57, 87, 90, 101, 107, 160, 188 Psychotomimetic, 153, 165, 188 Psychotropic, 10, 25, 36, 50, 188 Public Health, 14, 17, 34, 41, 48, 50, 54, 55, 62, 101, 136, 188 Public Policy, 135, 188 Pulmonary, 45, 157, 169, 188, 197 Pulse, 32, 179, 188 Pyramidal Tracts, 169, 188 Q Quality of Life, 3, 9, 21, 22, 24, 39, 44, 45, 57, 59, 63, 106, 189 R Race, 25, 179, 189 Radiation, 163, 167, 170, 178, 189, 191, 199

Radioactive, 157, 173, 176, 178, 179, 182, 189, 191 Radiological, 184, 189 Randomized clinical trial, 13, 21, 38, 44, 48, 114, 189 Randomized Controlled Trials, 77, 189 Reactive Oxygen Species, 88, 189 Receptor, 20, 23, 40, 46, 52, 66, 82, 89, 97, 124, 151, 154, 157, 159, 166, 182, 189, 191 Receptors, Serotonin, 189, 191 Recurrence, 4, 13, 21, 47, 48, 49, 92, 97, 99, 100, 102, 157, 189 Refer, 1, 161, 166, 176, 181, 188, 189 Refraction, 189, 193 Refractory, 13, 14, 17, 39, 50, 79, 189 Regimen, 36, 167, 184, 189 Reimbursement Mechanisms, 38, 190 Relapse, 7, 13, 14, 21, 24, 47, 48, 49, 52, 57, 63, 74, 75, 78, 99, 190 Reliability, 27, 28, 29, 58, 190 Remission, 7, 14, 21, 40, 44, 45, 48, 60, 63, 65, 101, 103, 157, 189, 190 Research Support, 40, 190 Resorption, 157, 183, 190 Respiration, 159, 179, 190 Response rate, 51, 190 Rheumatism, 190 Rheumatoid, 17, 190 Rheumatoid arthritis, 17, 190 Riluzole, 67, 190 Risk factor, 10, 27, 32, 37, 41, 52, 55, 61, 88, 121, 140, 187, 190 Risk patient, 13, 48, 190 Risperidone, 39, 190 Rod, 160, 190 Role-play, 118, 190 S Saliva, 4, 25, 190 Salivary, 4, 25, 40, 190, 199 Salivary glands, 190 Scans, 42, 190 Schizoid, 191, 198 Schizophrenia, 36, 46, 59, 72, 73, 74, 78, 84, 90, 91, 105, 125, 167, 190, 191, 198 Schizotypal Personality Disorder, 165, 191, 198 Sclerosis, 180, 190, 191 Screening, 60, 125, 140, 160, 191 Second Messenger Systems, 191 Secretion, 52, 83, 93, 172, 174, 175, 179, 180, 191 Secretory, 191, 194

209

Secular trends, 10, 191 Sedative, 153, 173, 191 Seizures, 125, 164, 191 Septal, 176, 191 Septal Nuclei, 176, 191 Sequencing, 60, 191 Sertraline, 21, 24, 52, 64, 76, 77, 80, 89, 99, 102, 106, 192 Serum, 71, 85, 86, 94, 105, 153, 161, 177, 192, 197 Sex Characteristics, 151, 192 Shock, 167, 192, 196 Side effect, 20, 24, 43, 56, 63, 151, 152, 155, 160, 192, 196 Signs and Symptoms, 4, 190, 192 Skeletal, 160, 192 Skeleton, 157, 192 Skull, 163, 192, 195 Small intestine, 160, 173, 175, 192 Smoking Cessation, 92, 157, 192 Social Environment, 189, 192 Social Security, 189, 192 Social Support, 49, 59, 192 Social Work, 39, 192 Soma, 31, 192 Somatic, 52, 103, 124, 151, 176, 178, 186, 192 Spastic, 175, 192 Specialist, 142, 192 Species, 168, 178, 179, 189, 192, 198 Specificity, 38, 56, 70, 152, 193 Spectroscopic, 36, 177, 193 Spectrum, 90, 179, 193 Sperm, 159, 193 Spinal cord, 155, 156, 158, 159, 181, 189, 193, 194 Sprains and Strains, 177, 193 Staging, 190, 193 Statistically significant, 50, 193 Steel, 160, 193 Stem Cells, 193, 197 Steroid, 163, 193 Stimulant, 6, 153, 165, 172, 193 Stimulus, 22, 34, 60, 167, 175, 183, 185, 193, 195 Stomach, 151, 170, 171, 173, 175, 180, 192, 193 Stool, 161, 175, 193 Stroke, 134, 158, 193 Subclinical, 5, 174, 191, 194 Subcutaneous, 151, 183, 194 Subiculum, 172, 194

Substance P, 178, 191, 194 Sulfur, 178, 194 Suppression, 32, 73, 86, 91, 107, 194 Supraspinal, 156, 194 Sympathetic Nervous System, 8, 156, 194 Sympathomimetic, 153, 165, 166, 168, 182, 194 Symptomatic, 20, 22, 31, 40, 60, 104, 154, 194 Symptomatic treatment, 154, 194 Symptomatology, 14, 46, 47, 57, 63, 66, 194 Synapse, 151, 165, 187, 194, 196 Synaptic, 31, 126, 181, 182, 194 Synaptic Transmission, 126, 182, 194 Synaptic Vesicles, 194 Synaptosomes, 12, 195 Synergistic, 14, 35, 187, 195 T Tardive, 155, 160, 195 Telencephalon, 156, 195 Temporal, 9, 77, 153, 155, 172, 195 Temporal Lobe, 153, 155, 195 Teratogenicity, 8, 195 Thalamus, 166, 168, 176, 186, 195 Therapeutics, 77, 195 Thoracic, 156, 195, 198 Threshold, 27, 28, 29, 58, 60, 118, 169, 173, 195 Thrombin, 169, 187, 195 Thrombocytes, 186, 195 Thyroid, 114, 158, 195, 197 Tinnitus, 124, 195, 198 Tolerance, 157, 171, 195 Tomography, 20, 23, 39, 41, 43, 52, 119, 177, 196 Tone, 9, 183, 196 Tonus, 196 Tooth Preparation, 151, 196 Toxic, iv, 182, 196 Toxicity, 6, 8, 166, 196 Toxicology, 136, 196 Trachea, 195, 196 Traction, 160, 196 Transduction, 35, 196 Transfection, 156, 196 Translation, 152, 196 Translational, 22, 196 Transmitter, 151, 155, 166, 175, 178, 182, 194, 196 Trauma, 59, 76, 90, 116, 164, 180, 196 Treatment Outcome, 10, 20, 42, 83, 196 Trees, 31, 196

210


Tricyclic, 6, 20, 43, 69, 79, 80, 117, 153, 160, 165, 173, 196 Trigger zone, 155, 196 Trophic, 46, 196 Tryptophan, 69, 91, 92, 93, 161, 191, 196, 197 Tryptophan Hydroxylase, 69, 91, 197 Tumor Necrosis Factor, 86, 87, 197 Tumour, 97, 197 Tyrosine, 166, 197 U Umbilical Arteries, 197 Umbilical Cord, 25, 197 Umbilical cord blood, 25, 197 Unconscious, 153, 197 Urethra, 197 Urinary, 9, 53, 90, 94, 106, 197 Urine, 25, 157, 197 V Vaccines, 197, 198 Vascular, 24, 174, 185, 197 Vasoconstriction, 67, 168, 197 Vasodilator, 158, 166, 172, 197 VE, 53, 197 Vector, 196, 197 Vein, 175, 182, 197 Venlafaxine, 21, 35, 41, 64, 77, 78, 99, 101, 106, 197

Ventricle, 153, 158, 168, 172, 173, 188, 195, 197 Vestibulocochlear Nerve, 195, 198 Vestibulocochlear Nerve Diseases, 195, 198 Veterinary Medicine, 135, 198 Viral, 12, 196, 198 Viral Load, 12, 198 Virulence, 196, 198 Virus, 115, 116, 156, 196, 198 Viscera, 192, 198 Visceral, 156, 176, 198 Visual field, 22, 198 Vivo, 43, 198 Vomeronasal Organ, 182, 198 W War, 186, 198 White blood cell, 154, 176, 177, 179, 185, 198 Windpipe, 195, 198 Withdrawal, 14, 60, 164, 198 X Xenograft, 153, 198 Xerostomia, 4, 199 X-ray, 157, 162, 178, 182, 191, 199 Y Yeasts, 185, 199

211

212


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