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H-MRS and Neurocognitive Analysis of Psychotic Symptoms in Stimulant Dependence

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H-MRS and Neurocognitive Analysis of Psychotic Symptoms in Stimulant Dependence University of Alberta A 1H-MRS and Neurocognitive Analysis of Psychotic Symptoms in Stimulant Dependence by Bonnie June Lakusta A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Psychiatry ©Bonnie June Lakusta Spring 2012 Edmonton, Alberta Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission. DEDICATION This thesis is dedicated to my husband, Sean, for his patience, for always being understanding and for providing the voice of reason; and to my family, my parents Wendy and Evan and brother Stephen, for their never-ending support and encouragement, and for fostering a love of learning. ABSTRACT The association between stimulant drug use and the presence of a psychotic disorder raises questions about causation. Substance-induced psychosis may differ etiologically from schizophrenia despite similar phenotypic presentation. It is possible that stimulant drug users who develop symptoms of psychosis have a pre-existing vulnerability to schizophrenia. A recent theory building on the neurodevelopmental hypothesis of schizophrenia proposes that a second insult in conjunction with a pre-existing vulnerability may be necessary to trigger the onset of psychosis. Stimulant dependence may be one of these exogenous triggers for psychosis. This study investigated the possibility that stimulant dependence can trigger psychosis biologically by using proton magnetic resonance spectroscopy, and cognitively by using a battery of cognitive assessments. It was hypothesized the stimulant drug users who develop psychotic symptoms have a pre-existing vulnerability to psychosis that manifests when the substance use triggers abnormal neuropathological development. Evidence of this pathology should be found biologically in proton magnetic resonance spectroscopy measures of N- acetylaspartate, glutamate and choline, and cognitively in measures of processing speed and executive functioning. Abstinent stimulant-dependent users were recruited from the community and compared to a healthy control group and a group of non-substance-induced first episode psychosis patients. Results of this study provide support for the association between methamphetamine use and psychosis. The stimulant-dependent group had worse performance on measures of executive function and processing speed compared to healthy controls, but only processing speed was related to the presence of psychotic symptoms, providing support for processing speed as a potential endophenotype for psychosis. The stimulant-dependent group also had abnormal neurochemical profiles as measured by N-acetylaspartate and glutamate. Finally, in comparison between stimulant- dependent users with symptoms of psychosis and a de novo schizophrenia, the factors predicting severity of psychotic symptoms differed substantially between groups. These results suggest that the cognitive and biological correlates of a substance-induced psychosis differ from a non-substance-induced psychosis, suggesting that a vulnerability to substance-induced psychosis may differ from the neurodevelopomental pathology associated with schizophrenia. ACKNOWLEDGEMENT I would like to thank everyone who has assisted me in reaching my goals. To Dr. Philip Tibbo, thank-you for your support and mentorship, to Dr. Cameron Wild, thank-you for being an outstanding educator, to Dr. Scot Purdon thank-you for sharing your expertise. I would like to thank all members of the Peter S. Allen MR Research Centre, particularly Dr. Chris Hanstock for your willingness to educate patiently, and Peter Seres for your hard work and guidance. I would also like to thank members of the Department of Psychiatry. Thank-you to Tara Checknita for always having an answer and a solution, and especially to Dr. Glen Baker for such dedication to learning. Finally, a special thank-you to all the collaborating drug treatment centres in the Edmonton area. Without your interest in recognizing the need for research in addictions and mental health, this project would never have been successful. Table of Contents Introduction ............................................................................................................. 1 Chapter 1: Literature Review .................................................................................. 4 Schizophrenia .......................................................................................................... 4 Neurobiology of schizophrenia. ....................................................................... 6 Relevant neurochemistry. ................................................................................ 7 Dopamine hypothesis. ................................................................................. 7 Glutamate hypothesis. ................................................................................. 8 Neurodevelopmental hypothesis. .............................................................. 11 Substance Abuse and Dependence ........................................................................ 14 Methamphetamine. ........................................................................................ 15 Neurobiology of substance dependence. ....................................................... 19 Comorbidity of Substance Dependence and Mental Illness.................................. 23 Theories of comorbidity between substance dependence and mental illness 26 Stimulant dependence and schizophrenia. ..................................................... 30 Proton Magnetic Resonance Spectroscopy ........................................................... 34 Neurochemicals measured by 1H-MRS. ........................................................ 37 1H-MRS studies of schizophrenia. ................................................................. 39 1H-MRS studies of high-risk samples. ...................................................... 44 1H-MRS co-registered with cognitive performance. ................................. 46 1H-MRS and relationship to symptom presentation. ................................. 47 Summary of 1H-MRS and schizophrenia. ................................................. 48 1H-MRS studies of substance abuse and dependence. ................................... 49 Cognition ............................................................................................................... 52 Processing speed. ........................................................................................... 53 Executive functioning . .................................................................................... 54 Cognitive impairment in psychosis. ............................................................... 55 Processing speed. ...................................................................................... 59 Executive function..................................................................................... 61 Cognitive impairment in substance abuse and dependence. .......................... 62 Cognitive impairment in comorbid disorders. ............................................... 67 Chapter 2: Project Model and Hypotheses ............................................................ 69 Model .................................................................................................................... 69 Neurochemistry. ............................................................................................. 73 Cognition. ...................................................................................................... 75 Negative symptoms. ....................................................................................... 77 Medial prefrontal cortex. ............................................................................... 79 Rationale for samples. .................................................................................... 80 Summary. ....................................................................................................... 81 Research Objectives and Hypotheses .................................................................... 84 Research Objective 1: Drug use and severity of psychotic symptoms .......... 84 Research Objective 2: Neurochemical correlates of psychotic symptoms in stimulant-dependent users: N-acetylaspartate ........................................... 85 Research Objective 3: Neurochemical correlates of psychotic symptoms in stimulant-dependent users: Glutamate ....................................................... 85 Research Objective 4: Cognitive correlates of psychotic symptoms in stimulant-dependent users: Processing Speed ............................................... 86 Research Objective 5: Cognitive correlates of psychotic symptoms in stimulant-dependent users: Executive Functioning ....................................... 86 Research Objective 6: Predicting
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