University of Groningen The Dysregulated Brain Haarman, Bartholomeus Cornelius Maria IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Haarman, B. C. M. (2017). The Dysregulated Brain: A psychoimmunological approach to bipolar disorder. University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. 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Haarman The Dysregulated Brain A psychoimmunological approach to bipolar disorder Illustration cover Alan Flemming Layout Marieke van der Vliet / dit-s.nl Printed by Pumbo.nl The studies described in this thesis were performed at the Department of Psychiatry, University Medical Center Groningen, Groningen, The Netherlands; Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; and Radiology Morphological Solutions, Berkel en Rodenrijs, The Netherlands. The studies were financially supported by the European Commission EU-FP7-HEALTH-222963 ‘MOODINFLAME’ and ­­ EU-FP7-PEOPLE- 286334 ‘PSYCHAID’. ISBN 978-90-824638-1-1 (printed version) 978-90-824638-2-8 (digital version) © 2017 B.C.M. Haarman. All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system, without written permission from the author. The Dysregulated Brain A psychoimmunological approach to bipolar disorder PhD thesis to obtain the degree of PhD at the University of Groningen on the authority of the Rector Magnificus Prof. E. Sterken and in accordance with the decision by the College of Deans. This thesis will be defended in public on 1 March 2017 at 16:15 hours by Bartholomeus Cornelius Maria Haarman born on 7 August 1978 in Raalte Supervisor(s) Prof. W.A. Nolen Prof. H.A. Drexhage Co-supervisor(s) Dr. R.F. Riemersma – Van der Lek Dr. H. Burger Assessment committee Prof. A. Aleman Prof. V. Arolt Prof. J.D. Laman Table of Contents CHAPTER 1 General background 7 PART 1 Peripheral immune system 25 CHAPTER 2 Relationship between clinical features and inflammation related monocyte gene expression in bipolar disorder 27 CHAPTER 3 Feature-expression heat maps 51 CHAPTER 4 Inflammatory monocyte gene expression 67 CHAPTER 5 Does CRP predict outcome in bipolar disorder in regular outpatient care? 81 PART 2 Neuroimmune system 99 CHAPTER 6 PET and SPECT in bipolar disorders 101 CHAPTER 7 Neuroinflammation in bipolar disorder 121 CHAPTER 8 Volume, metabolites and neuroinflammation of the hippocampus in bipolar disorder 141 CHAPTER 9 Diffusion tensor imaging in euthymic bipolar disorder 171 CHAPTER 10 Summary and general discussion 195 Dutch summary 223 List of publications 243 Acknowledgements 247 Curriculum vitae 253 CHAPTER 1 General background Bartholomeus C.M. Haarman Adapted from Haarman BCM, Riemersma - Van der Lek RF, Ruhé HG, Groot JC, Nolen WA, Doorduin J. Bipolar Disorders. In: Dierckx RAJO, Otte A, de Vries EFJ, Waarde A, den Boer JA, editors. PET and SPECT in Psychiatry. Heidelberg: Springer Berlin Heidelberg; 2014. p. 223–51. Introduction Bipolar disorder: diagnostic description Bipolar disorder (BD)1 is a mood disorder characterized by episodic pathologic distur- bances in mood: (hypo)manic episodes and depressive episodes which alternate with euthymic periods, i.e. with normal mood. BD has to be distinguished from (unipolar) major depressive disorder (MDD), which is characterized by only depressive episodes. According to DSM-IV, the core criterion of a (hypo)manic episode is the occurrence of a pathologically elated (euphoria), expansive or irritable mood. DSM-5 added increased energy or activity to this list. In addition to these core criteria, there are other symptoms such as inflated self-esteem or grandiosity, decreased need for sleep, being more talkative than usual, flight of ideas, distractibility, increase in goal-directed activity or psychomotor agitation and excessive involvement in plea- surable activities that have a high potential for painful consequences. A depressive episode consists of at least one of the core symptoms: depressed mood and loss of interest or pleasure, completed with symptoms such as sleep problems, psychomotor changes, fatigue or loss of energy, feelings of worthlessness or excessive feelings of guilt, difficulty concentrating or making decisions and recurrent thoughts of death1. Two types of BD are recognized: bipolar I disorder (BD-I) and bipolar II disorder (BD-II), characterized by the occurrence of manic episode(s) or by only hypomanic episode(s), respectively. The difference between manic and hypomanic episodes (and thus between BD-I and BD-II) is that manic episodes are associated with marked impairment in occupational, relational or social functioning, which can lead to hospitalization, while hypomanic episodes do not have this marked impairment and do not lead to hospitalization. When manic and depressive symptoms co-occur (or alternate very quickly) in the same episode, in DSM-IV it is labeled as a mixed episode and in DSM-5 as a bipolar disorder, manic or depressive episode with mixed features. Manic, depressive and mixed episodes can also be complicated by the presence of concurrent psychotic symptoms. Besides the mood symptoms, many patients with BD also show cognitive dysfunctions which may persist during euthymic periods, and which involve disturbances in various domains such as attention, verbal memory and executive functioning2,3. 8 Epidemiology and burden of disease The lifetime prevalence of BD is about 2% across different countries, women being affected as frequently as men4,5. Across the world, the disorder is sixth among all 1 health conditions in terms of causing disability6 with poor clinical and functional 7 8 9 outcome , increased risk for suicidality and significant societal costs . It has been General background calculated that in the United States the average cost per case ranged from $11,720 to $624,785, based on the severity of the illness9. In the European countries societal costs for managing BD are considered to be high as well10–12. Risk factors Established risk factors for BD include history of BD, and interestingly also other psychiatric disorders, in parents or siblings; severe childhood adversities; and excessive alcohol use, although the last two are viewed as triggers rather than causes in the presence of biological vulnerability13,14. A recent systematic review concluded that it is still unclear whether perinatal infection has a role in the etiology of BD15. This is particularly relevant in view of the present thesis. Diagnostic and treatment complications Although the clinical picture seems clear at first glance, making the diagnosis is more complicated in practice. On average, there is a time lag of about 6 years between the first episode and the making of the right diagnosis, and another six years before the start of adequate treatment. This is in most cases partly impeded by the precedence of depressive episodes without obvious (hypo)manic symptoms at the beginning of the disease16. Because antidepressants appear less effective for the treatment of bipolar depressive episodes than for unipolar MDD17, delayed diagnosis often leads to prolonged illness and dysfunction. Current pathophysiological models It is generally accepted that the cause of BD is multifactorial, with multiple genes making someone vulnerable, and with psychological and social factors causing the genes to be expressed. Moreover, somatic factors are assumed to play a role. To unravel the complex interplay between genotype and phenotype researchers have tried to find intermediary processes that are related to both the underlying geno- type and the ultimate phenotype. Over the last 50 years several pathophysiological theories have been proposed for BD. Of these, we will shortly address the monoamine theory, the neuroinflammation theory, the white matter tract integrity disruption theory and the mitochondrial dysfunction theory. 9 Monoamine theory Since the 1960s, after the discovery of the first antipsychotic and antidepressant drugs, the monoamine theory has been the leading pathophysiological theory for various psychiatric disorders, including MDD and BD18–20. Based on the working mechanism of these drugs, disruption of serotonergic