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Sophie Legge Examining Treatment Response and Adverse Effects of Clozapine Thesis submitted for the degree of Doctor of Philosophy at Cardiff University by Sophie Legge 2015 Supervisors: Dr James Walters Dr Marian Hamshere Prof Michael Owen i Declaration and Statements DECLARATION This work has not been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 1 This thesis is being submitted in partial fulfilment of the requirements for the degree of PhD. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. The views expressed are my own. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available online in the University’s Open Access repository and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available online in the University’s Open Access repository and for inter-library loans after expiry of a bar on access previously approved by the Academic Standards & Quality Committee. Signed ………………………………………… (candidate) Date ………………………… ii Acknowledgements I would like to express my sincere gratitude to James Walters, whose guidance made my studies both rewarding and enjoyable. It was James who encouraged me to embark on this PhD and I am privileged to have had him as a supervisor. I have learnt an incredible amount from him and his vast knowledge, encouragement and patience made this thesis possible. I particularly thank him for motivating me to persist through each reanalysis and redraft, and for his on-going support in the next stages of my career. I thank Marian Hamshere for all her help and support over the last three years. She patiently taught and guided me through the intricacies of conducting genetic association studies and provided invaluable statistical and methodological advice throughout my PhD. I would also like to express my thanks to Michael Owen and Michael O’Donovan for the invaluable advice provided throughout my studies and for their comments and suggestions on the manuscripts. I am also very grateful to my other colleagues and in particular Leon, Elliott, Jun and Antonio at Cardiff University for their help, support and for enduring my incessant questions. I would also like to extend my thanks to external collaborators that have contributed to this research. I am grateful for the valuable input from Dan Rujescu, Patrick Sullivan and Stephan Ripke for Chapter 2. As part of this PhD I was fortunate enough to spend some time at King’s College London. I thank James MacCabe for this opportunity, and for his on- going direction and guidance. I would also like to thank Johnny Downs and Richard Hayes for their suggestions and advice for Chapters 4 and 5. This work was supported by the Medical Research Council (MRC) and CRESTAR. I thank them not only for providing the funding which allowed me to undertake this research, but also for giving me the opportunity to attend inspiring conferences and valuable training courses. I am grateful to all my friends and family who experienced all of the ups and downs of the last three years. I cannot thank my Mum and Dad (Jenny and Mark) enough for their constant encouragement, incredible support and unwavering belief in me, I am extremely lucky to have them. I am very grateful to my Dad for the many hours spent reading this thesis and for his valuable comments. My sisters, Cathy, Amy and Annabelle have provided invaluable support and encouragement. I would like to thank my sister Cathy and her husband Gareth for generously giving me a home from home in London. Finally, I would like to thank my best friend and husband Mark. Every day he inspires and encourages me to pursue my ambitions and I couldn’t wish for a more supportive partner. iii Thesis Summary The antipsychotic clozapine is uniquely effective in the management of treatment- resistant schizophrenia (TRS), but its use is limited by its potential to induce agranulocytosis. A substantial proportion of patients discontinue clozapine treatment, which carries a poor prognosis, and only 30-60% of patients with TRS will respond to clozapine. The causes of clozapine-associated agranulocytosis, and of its precursor neutropenia, are largely unknown although genetic factors contribute. To examine the genetic susceptibility to clozapine-associated neutropenia, I conducted a multifaceted genetic analysis in the largest combined sample studied to date. Using GWAS, I identified a novel genome-wide significant association with rs149104283 (OR = 4.32, P = 1.79x10-8), a SNP intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes involved in drug uptake. Furthermore, I replicated a previously reported association between neutropenia and a variant in HLA-DQB1 (OR = 15.6, P = 0.015). I investigated clozapine discontinuation and clinical response in a two-year retrospective cohort study of 316 patients with TRS receiving their first course of clozapine. By studying the reasons for discontinuations due to a patient decision, I found that adverse drug reactions accounted for over half of clozapine discontinuations. High levels of deprivation in the neighbourhood where the patient lived were associated with increased risk of clozapine discontinuation (HR = 2.12, 95% CI 1.30-3.47). Female gender (HR = 0.63, 95% CI 0.41-0.96) and clinical improvement after one month of treatment (HR = 0.56, 95% CI 0.44- 0.71) were significantly associated with a good response to clozapine. However, I found that up to six months of treatment may be required to determine non-response. This thesis implicates variants that may increase susceptibility to clozapine-associated neutropenia and contributes to our current understanding of the causes of clozapine discontinuation and treatment response. iv Structure of Thesis This thesis is divided into six chapters. Chapter 1 provides an overview of schizophrenia and the use of clozapine in its management. The focus then turns to the literature base of clozapine-associated agranulocytosis and neutropenia, all-cause discontinuation, and clinical response to clozapine. Chapters 2, 4 and 5 are presented as results chapters, each with their own introduction, method, results and discussion sections. Chapter 3 provides details of methods relevant for both Chapters 4 and 5. Finally, Chapter 6 provides an overall discussion of the principal findings of the thesis in the context of the existing literature, the strengths and weaknesses of the studies, and provides indications for future research. v Publications resulting from work in this thesis Legge, S.E., Hamshere, M.L., Ripke, S., Pardinas, A.F., Goldstein, J.I., Rees, E., Richards, A.L., Leonenko, G., Jorskog, L.F., Clozapine-Induced Agranulocytosis Consortium, Chambert, K.D., Collier, D.A., Genovese, G., Giegling, I., Holmans, P., Jonasdottir, A., Kirov, G., McCarroll, S.A., MacCabe, J.H., Mantripragada, K., Moran, J.L., Neale, B.M., Stefansson, H., Rujescu, D., Daly, M.J., Sullivan, P.F., Owen, M.J., O’Donovan, M.C., Walters, J.T. (2016). Genome-wide common and rare variant analysis provides novel insights into clozapine- associated neutropenia. Molecular Psychiatry (In press). Legge, S.E., Hamshere, M.L., Hayes, R.D., Downs, J., O’Donovan, M.C., Owen, M.J., Walters, J.T., MacCabe, J.H. (2016). Schizophrenia Research (Epub ahead of print). doi: 10.1016/j.schres.2016.05.002. vi Table of Contents Chapter 1 Background Literature .............................................................................. 1 1.1. Introduction .............................................................................................................. 1 1.2. Schizophrenia ........................................................................................................... 1 1.3. Treatment-resistant schizophrenia ........................................................................ 19 1.4. Clozapine ................................................................................................................ 27 1.5. Clozapine-induced agranulocytosis and neutropenia ............................................ 38 1.6. Discontinuation of clozapine .................................................................................. 49 1.7. Clozapine response ................................................................................................ 56 1.8. Summary and limitations of existing literature ...................................................... 67 1.9. Aims and objectives ................................................................................................ 69 Chapter 2 Clozapine-associated Neutropenia ......................................................... 71 2.1. Summary ................................................................................................................ 71 2.2. Introduction ............................................................................................................ 72 2.3. Method ..................................................................................................................
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