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Advances in Biological Psychiatry Editors: W.P. Kaschka, W.F. Gattaz Vol. 30 Biological Aspects of Suicidal Behavior Editors W.P. Kaschka D. Rujescu Biological Aspects of Suicidal Behavior Advances in Biological Psychiatry Vol. 30 Series Editors W.P. Kaschka Ulm/Ravensburg W.F. Gattaz São Paulo Biological Aspects of Suicidal Behavior Volume Editors W.P. Kaschka Ulm/Ravensburg D. Rujescu Halle 4 figures, 4 in color, and 6 tables, 2016 Basel · Freiburg · Paris · London · New York · Chennai · New Delhi · Bangkok · Beijing · Shanghai · Tokyo · Kuala Lumpur · Singapore · Sydney Advances in Biological Psychiatry Prof. Dr. Wolfgang P. Kaschka Prof. Dr. Dan Rujescu Department of Psychiatry I Klinik und Poliklinik für Psychiatrie, University of Ulm Psychotherapie und Psychosomatik ZfP Südwürttemberg der Martin-Luther Universität Weingartshofer Strasse 2 Halle-Wittenberg DE–88190 Ravensburg (Germany) Julius-Kühn-Strasse 7 DE–06112 Halle/Saale (Germany) Library of Congress Cataloging-in-Publication Data Biological aspects of suicidal behavior / volume editors, W.P. Kaschka, D. Rujescu. p. ; cm. -- (Advances in biological psychiatry, ISSN 0378-7354 ; vol. 30) Includes bibliographical references and index. ISBN 978-3-318-05583-2 (hard cover : alk. paper) -- ISBN 978-3-318-05584-9 (electronic version) I. Kaschka, Wolfgang P., editor. II. Rujescu, D. (Dan), editor. III. Series: Advances in biological psychiatry ; v. 30. 0378-7354 [DNLM: 1. Depression--drug therapy. 2. Suicide--psychology. 3. Adrenergic Neurons--physiology. 4. Mental Disorders--genetics. W1 AD44 v.30 2016 / WM 165] RC569 362.28--dc23 2015032176 Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and Index Medicus. Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2016 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Germany on acid-free and non-aging paper (ISO9706) by Kraft Druck, Ettlingen ISSN 0378–7354 e-ISSN 1662–2774 ISBN 978–3–318–05583–2 e-ISBN 978–3–318–05584–9 Contents VII Preface Kaschka, W.P. (Ulm/Ravensburg); Rujescu, D. (Halle) Epidemiology 1 Global Suicide Värnik, P. (Tallinn); Wasserman, D. (Stockholm/Strasbourg) Neurotransmitters 11 Suicidal Ideation, Suicide Attempts and Completed Suicide in Adolescents: Neurobiological Aspects Sarchiapone, M.; D’Aulerio, M.; Iosue, M. (Campobasso) 21 Serotonergic and Noradrenergic Neurotransmitter Systems in Suicide Dwivedi, Y. (Birmingham, Ala.) 37 GABA, Depression and Suicide Pabba, M.; Sibille, E. (Toronto, Ont.) Genetics 51 Genetics of Suicidal Behavior Giegling, I.; Rujescu, D. (Halle) 63 Gene-Environment Interaction Studies in Suicidal Behaviour Mandelli, L.; Serretti, A. (Bologna) 75 Epigenetics of Suicidal Behaviour Turecki, G. (Montreal, Que.) N europsychology/Physiology/Imaging 88 Neurocognitive Processes and Decision Making in Suicidal Behaviour Richard-Devantoy, S. (Montreal, Que./Angers); Courtet, P. (Montpellier/Créteil) 101 Electroencephalographic Risk Markers of Suicidal Behaviour Hodgkinson, S.; Steyer, J.; Kaschka, W.P. (Ulm/Ravensburg); Jandl, M. (Bern) 110 Neuroimaging of Suicidal Behavior Jollant, F. (Montreal, Que./Nîmes) V Immunology 123 Inflammation and Suicidal Behavior Postolache, T.T. (Baltimore, Md./Denver, Colo.); Manalai, P. (Washington, D.C.); Brenner, L.A. (Aurora, Colo.); Brundin, L. (Grand Rapids, Mich.) Treatment 145 The Contributions of Lithium and Clozapine for the Prophylaxis and Treatment of Suicidal Behavior Müller-Oerlinghausen, B. (Berlin); Lewitzka, U. (Dresden) Outlook 161 Challenges for Future Research and Closing Remarks Rujescu, D. (Halle); Kaschka, I.N. (Erlangen); Kaschka, W.P. (Ulm/Ravensburg) 164 Author Index 165 Subject Index VI Contents Preface According to a definition of the Institute of Medicine of the National Academies of the USA [1] , suicide is ‘a fatal self-inflicted destructive act with explicit or inferred intent to die’. Globally, year by year, approximately one million people die by suicide, which corresponds to a rate of 16 per 100,000. In the year 2012, suicide accounted for 1.4% of all deaths worldwide, making it the fifteenth leading cause of death through- out the lifespan and the second leading cause of death among 15- to 29-year-olds [2] . In Germany, the suicide rate as of 2013 is almost twice as high as the death rate from traffic accidents [3] . Therefore, effective and evidence-based interventions should be implemented at population, subpopulation, and individual levels to prevent suicides and suicide attempts. However, the reliable assessment of suicide risk in an individu- al person is a major scientific challenge. Although apparently relevant, psychological, psychosocial, and cultural factors offer merely weak predictive power with regard to suicidal behaviour, and even the clinical history of a patient, though extremely valu- able, can be non-specific. It is generally accepted that mental disorders per se repre- sent a risk factor for suicidal behaviour, but there appear to exist other causative fac- tors – environmental as well as dispositional – which are independent of psychiatric diseases. During recent years, an increasing amount of research has been dedicated to the analysis of the neurobiological basis of suicide, enabling the development of neuro-psycho-biological models which may help to improve our understanding of this complex behaviour. This book provides a comprehensive overview on the epide- miological, neurobiological, and psychopharmacological aspects of suicide and sui- cide attempts throughout the lifespan. Värnik and Wasserman present a meticulous review of the worldwide epidemiol- ogy of completed and attempted suicide. Mainly based on data from the World Health Organization, they draw our attention to the broad spectrum of factors influencing suicide rates, among which age and gender are only the most prominent ones. In ad- dition, among others, societal, cultural, socioeconomic, and geographic effects have been identified. Methodological problems involved in the recording of suicide and attempted suicide rates are also discussed. The important issue of suicidal ideation, suicide attempts, and completed suicide in adolescents is dealt with in the chapter by Sarchiapone, D’Aulerio and Iosue, with VII special emphasis on neurobiological aspects. The authors review alterations in major neurotransmitter and signalling systems found to be related to suicidal behaviour. Most interestingly, different results have been obtained in a number of parameters when groups of adolescents and adults were compared. In many cases, the biological significance of these differences has yet to be revealed. A great number of clinical as well as post-mortem brain studies have shown neu- robiological abnormalities associated with suicidal behaviour. Many of these were pointed out to be related to the serotonergic and noradrenergic neurotransmitter sys- tems. The role of these systems, their intracellular signalling pathways and down- stream effector molecules and their effects on the regulation of target genes in sui- cidal behaviour are discussed in the chapter by Dwivedi. Among neurotransmitter systems, special attention has focused on the role of GABA in depression and suicide. Pabba and Sibille review the current evidence – mainly from post-mortem studies – suggesting a dysfunction of GABAergic systems in suicide victims having suffered from major depressive disorder (MDD-related sui- cides) compared to those not having suffered from major depression (MDD-unrelat- ed suicides). Giegling and Rujescu focus on the genetic part of suicidal behaviour. Beside medical, psychological, psychosocial, social, cultural, and socioeconomic parameters, biological factors, especially genetic variants, were also shown to be risk factors for suicidal behav- iour. The heritability is about 55% assuming a polygenic risk model. The chapter gives an overview on first-candidate gene studies focusing mainly on the serotonergic sys- tem. Additionally, newly started genome-wide association studies are discussed. The relative contributions of heritable versus environmental risk factors to sui- cidal behaviour have become a more and more challenging question. In their chapter, Mandelli and Serretti provide a comprehensive overview on studies regarding the interaction between genes modulating brain functions and stressful life events in the aetiology of suicide. A great number of studies have confirmed an association between early-life adver- sity and increased suicide risk. Turecki describes how epigenetic mechanisms in- duced by early-life adversity are able to mediate altered behavioural development, resulting in increased vulnerability toward psychopathology in general and suicidal behaviour in particular. In an analysis of what might predispose individuals to make a suicide attempt or completed suicide, neurocognitive processes appear to play a crucial role. Richard- Devantoy and Courtet review evidence from the current literature showing that, in addition to impulsive aggression and persistent hopelessness, impairments in cogni- tive domains may increase the vulnerability to suicidal behaviour. Clinical electrophysiology, although mostly neglected in earlier reviews, has also contributed to our knowledge on the neurobiological basis of suicide. For example, it was shown that the habituation of P300, an event-related potential, differed between patients with MDD and a history of suicidal behaviour and MDD patients without VIII Kaschka · Rujescu such a history. Hodgkinson, Steyer, Kaschka, and Jandl summarize recent electro- physiological studies and discuss their implications for suicide risk assessment and suicide prophylaxis. The rapid development of neuroimaging techniques during the last decades has provided us with tools that allow the investigation of suicidal behaviour in vivo. Re- sults obtained using the different methods of structural and functional neuroimaging are reviewed by Jollant. Derived from the data presented in the context of the current literature, the author proposes a neurocognitive model of suicidal behaviour which could stimulate the development of interventions for the prevention of suicide. In recent years, evidence has accumulated indicating that inflammatory processes and alterations within the immune system may contribute to the pathophysiology not only of depression but also of suicidal behaviour. Postolache, Manalai, Brenner, and Brundin give a comprehensive overview of the available data and delineate novel strategies of intervention, targeting immune dysregulation and aiming at the im- provement of suicide risk assessment and suicide prevention. The topic of pharmacological influences on suicidal ideation and behaviour is ad- dressed by Müller-Oerlinghausen and Lewitzka. Whereas a large variety of pharmaco- logically different compounds is able to induce depressive states, suicidal ideation and suicidal behaviour, pharmaceutical agents that effectively counteract suicidality are surprisingly rare. Over the years, satisfactory evidence of an antisuicidal efficacy has been presented for lithium salts and clozapine only. The authors provide a comprehen- sive review of the literature, also covering the question of possible mechanisms of ac- tion. As for lithium, in addition to studies based on the use of lithium salts as pharma- ceutical drugs, some studies have been published on the potential antisuicidal effects of lithium as a trace element in drinking water. These are also critically discussed. Rujescu, Kaschka and Kaschka outline possible further directions of research which might be promising to improve our understanding of the neurobiological foun- dations of suicidal behaviour. It is suggested that biological parameters should be in- tegrated into algorithms for the assessment of suicide risk in individual persons. Thereby, neurobiological research can be expected to make a significant contribution to personalized medicine in general and to suicide prevention in particular. Wolfgang P. Kaschka, Ulm/Ravensburg Dan Rujescu, Halle References 1 The Institute of Medicine of the National Acade- 3 Statistisches Bundesamt: Todesursachenstatistik. mies of the USA. http://www.nap.edu/author/IOM/ http://www.gbe-bund.de (Suizid-Tabellen-Sterbe- institute-of-medicine (accessed March 10, 2015). fälle; accessed March 10, 2015). 2 World Health Organization: Suicide Prevention (SUPRE). http://www.who.int/mental_health/ prevention/suicide/suicideprevent/en/ (accessed March 10, 2015). Preface IX

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