MONOAMINE OXIDASE-A IN BORDERLINE PERSONALITY DISORDER AND ANTISOCIAL PERSONALITY DISORDER by Nathan J. Kolla A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy, Institute of Medical Science, University of Toronto © Copyright by Nathan J. Kolla (2015) Nathan J. Kolla Title: Monoamine Oxidase-A in Borderline Personality Disorder and Antisocial Personality Disorder Doctor of Philosophy, Institute of Medical Science, University of Toronto, 2015 ABSTRACT Monoamine oxidase A (MAO-A) is a brain enzyme that serves several physiologic functions, including metabolism of monoamine neurotransmitters and induction of pro-apoptotic signaling pathways. Increased brain MAO-A level is present in clinical disorders characterized by low mood states, whereas decreased brain MAO-A level is associated with higher trait impulsivity and aggression in healthy volunteers. Borderline personality disorder (BPD) and antisocial personality disorder (ASPD) are common psychiatric conditions that exact a high healthcare and societal burden. BPD is associated with acute episodes of severe dysphoria, and ASPD presents high levels of impulsivity and aggression. The overall aim of the thesis was to investigate MAO- A brain level in BPD and ASPD. The first experiment used [11C] harmine positron emission tomography (PET) to assess MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in females with BPD. Our results showed that MAO-A VT was elevated in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) of severe BPD compared to control groups. Greater PFC and ACC MAO-A VT was additionally associated with more severe mood symptoms and suicidality in BPD. 11 The second experiment applied [ C] harmine PET to examine MAO-A VT in ii impulsive, violent male offenders with ASPD. We found that orbitofrontal cortex and ventral striatum (VS) MAO-A VT were lower in ASPD compared to controls. Behavioral, self-report, and clinician-rated measures of impulsivity were also negatively correlated with VS MAO-A VT. The third experiment employed functional magnetic resonance imaging to measure VS resting state functional connectivity (FC) in ASPD. Our results demonstrated functional coupling between superior VS and bilateral dorsomedial prefrontal cortex that was correlated with VS MAO-A VT, and functional coupling between inferior VS and right hippocampus that was anti- correlated with VS MAO-A VT. The observed FC patterns were additionally associated with measures of impulsivity. Taken together, this body of research implicates abnormal brain MAO-A level in the pathophysiology of two related yet distinct personality disorders and their symptom clusters. Novel interventions targeting abnormal brain MAO-A level could emerge as potential new therapeutics for these disorders. iii ACKNOWLEDGEMENTS AND CONTRIBUTIONS I owe a tremendous debt of gratitude to the many individuals who offered me their steadfast support throughout graduate school. Much like the fiduciary obligation a physician has toward his patients, the PhD supervisor is entrusted with no less a responsibility in mentoring his students. I offer a very heartfelt thanks to my PhD supervisor, Dr. Jeffrey Meyer, for the undeniably positive influence he has been to me. When I reflect on all that Jeff has taught me about research and how to get the money to do it, I know that I have truly learned from a master. I would like to thank my PhD supervisory committee members, Drs. Michael Bagby and Paul Links, for their perceptive guidance throughout my degree. Paul, I have thoroughly enjoyed working together since I met you as a medical student. Mike, I hope that we are able to collaborate in the future. I wish to acknowledge all the personnel, fellows, and students in Dr. Meyer’s laboratory who contributed to my success in countless ways. In particular, I would like to thank Laura Miler for her boundless patience and helpfulness in troubleshooting laboratory issues that allowed my experiments to run all the more smoother. iv I was very fortunate to have supervised several undergraduate co-op students from the University of Toronto at Scarborough who completed consecutive work term placements at Dr. Meyer’s laboratory: Malcolm (Alex) Blagrove, Amanda Brijmohan, Charis Kellow, Jalpa Patel, Amina Hussain, and Fawn Rasquinha. This incredibly talented group of individuals was critical to the day-to-day success of the research operation and inspired me with their enthusiasm. I would like to thank Dr. Jonathan Downar and his graduate student, Katie Dunlop, who provided advice and guidance on the processing and analysis of resting state functional magnetic resonance imaging data. The emotional support I received from my parents, Ray and Val Kolla, during the tenure of my degree is just another example of the positive affirmation that has been consistently afforded to me by them. Although my parents may not have initially appreciated the reasons for my wanting to pursue a PhD, especially since in their estimation I already possessed a perfectly fine doctorate, I am very grateful for their constant encouragement and the genuine interest that they take in my work. Finally, I extend the deepest thanks to my husband, Brian G. Bachand, whose utter selflessness, irrepressible optimism, and unconditional love made completion of this work possible. Brian, I dedicate my thesis to you. v I would also like to acknowledge the following programs and/or organizations for their support: Canadian Institutes of Health Research Clinician Scientist Program, American Psychiatric Institute for Research and Education Psychiatric Research Fellowship Program, Physicians’ Services Incorporated Foundation Resident Research Grant Program, and the University of Toronto Department of Psychiatry Clinician Scientist Program. This research was funded by an operating grant from the Canadian Institutes of Health Research with support from the above agencies. vi ABSTRACT ii ACKNOWLEDGEMENTS/CONTRIBUTIONS iv TABLE OF CONTENTS viii LIST OF TABLES xv LIST OF FIGURES xvi ABBREVIATIONS xvii vii CHAPTER I ................................................................................................................. 1 1.1 Introduction .......................................................................................................... 2 1.2 General Characteristics of Monoamine Oxidase-A.............................................. 3 1.2.1 Substrate Selectivity of Monoamine Oxidase-A....................................... 3 1.2.1.1 Serotonin ............................................................................................. 4 1.2.1.2 Norepinephrine .................................................................................. 4 1.2.1.3 Dopamine ........................................................................................... 6 1.2.2 Inhibition Sensitivity of Monoamine Oxidase-A ...................................... 7 1.2.3 Distribution of Monoamine Oxidase-A In Human Brain ....................... 10 1.2.3.1 Fetal and Postnatal Levels of Monoamine Oxidase-A ..................... 10 1.2.3.2 Adult Levels of Monoamine Oxidase-A ........................................... 10 1.2.4 Physiological Functions of Monoamine Oxidase-A in Human Brain .... 11 1.2.4.1 Amine Degradation and Production of Hydrogen Peroxide ............. 11 1.2.4.2 Induction of Apoptotic Pathways...................................................... 13 1.2.5 Transcription Regulation of the Monoamine Oxidase-A Gene .............. 14 1.2.5.1 Specificity Protein 1 and R1 ............................................................. 14 1.2.5.2 Sex-determining Region Y ............................................................... 15 1.2.5.3 Glucocorticoids ................................................................................ 15 1.2.6 Monoamine Oxidase-A Genetic Polymorphisms ................................... 16 1.3. Monoamine Oxidase-A and Psychiatric Symptoms ......................................... 17 1.3.1 Monoamine Oxidase-A in Depression and Dysphoria ........................... 18 1.3.1.1 Human Studies of Monoamine Oxidase-A, Depression, and Dysphoria .......................................................................................... 18 1.3.1.1.1 Clinical Studies Linking Elevated Monoamine Oxidase-A to viii Depression................................................................................... 18 1.3.1.1.2 Postmortem Studies of Monoamine Oxidase-A ......................... 20 1.3.1.1.3 Molecular Imaging Studies of Monoamine Oxidase-A in Depression................................................................................... 20 1.3.1.1.3.1 [11C] Harmine Positron Emission Tomography .................... 21 1.3.1.1.3.2 Monoamine Oxidase-A Total Distribution Volume ............. 26 1.3.1.1.4 Genetic Studies of Monoamine Oxidase-A and Depressive Illness .......................................................................................... 28 1.3.1.2 Animal Studies of Monoamine Oxidase-A and Depressive Symptoms ......................................................................................... 29 1.3.1.2.1 Preclinical Studies of Monoamine Oxidase-A and Depressive Symptoms ................................................................................... 29 1.3.2 Monoamine Oxidase-A in Impulsivity and Aggression ......................... 31 1.3.2.1 Human Studies of Monoamine Oxidase-A, Impulsivity, and Aggression .......................................................................................