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A longitudinal comparison of the metabolic characteristics of outpatients with first episode psychosis… Whitney, Zachary 2015

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 i A LONGITUDINAL COMPARISON OF THE METABOLIC CHARACTERISTICS OF OUTPATIENTS WITH FIRST EPISODE PSYCHOSIS TAKING SECOND GENERATION ANTIPSYCHOTICS; AN INTERIM ANALYSIS    by  Zachary Whitney B.Sc. (Nursing), RN, Dalhousie University, 2012 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pharmacology and Therapeutics)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2015   © Zachary Whitney, 2015         ii Abstract Background. Second generation antipsychotics (SGAs) are used widely for the treatment of schizophrenia and other psychotic disorders. Despite the efficacy of these compounds, they have been associated with a number of adverse events such as weight gain and type II diabetes.   Methods. In this study we have performed an interim analysis of a four-month long clinical trial to evaluate the effects of SGA drugs on weight gain in patients with first episode psychosis. A completer’s analysis was performed approximately mid-way through the trial. Anthropometric measures were collected at baseline and again at four months. Physical activity and eating patterns were measured through the international physical activity questionnaire (IPAQ) and three factor eating questionnaire (TFEQ). Secondary outcomes that were investigated include the effects on psychopathology using the positive and negative syndromes scale (PANSS) and the Calgary depression scale (CDS), effects on global functioning through the social and occupational functioning scale (SOFAS), quality of life as assessed by the short-form 36 (SF-36). Adherence to medication was assessed through the medication adherence rating scale (MARS). A simple t-test (p=<.05)  was used to detect differences in anthropometric data, the PANSS, and the CDS. Repeated measures one-way analysis of variance (ANOVA) (p=<.05) was utilized for analysis of SF-36, TFEQ, IPAQ, and MARS.  Findings. At baseline, patients taking antipsychotics weighed significantly more than the control group. Significant increases in waist circumference were observed in patients taking antipsychotics at four months. Significant differences in BMI and heart rate were detected between groups at four months. Significantly lower SF-36 summary  iii scores were detected between groups with significant improvements in mental health summary scores in the antipsychotic group. CDS scores also improved significantly. Conclusion. At four months of treatment with SGAs, patients may show measurable changes in metabolic parameters that could eventually lead to metabolic syndrome.                  iv Preface 	  Ethics approval for this study was obtained from the University of British Columbia Children’s and Women’s Research Ethics Board (UBC C&W REB) REB number H12-01611 approval date Nov 19th 2012 which was required for conducting research at the C&W facility.  Ethics approval was also obtained from Vancouver Coastal Health Research Institute (VCHRI) CREB REB number V12-01611 that was required for the recruitment of patients from the Vancouver/Richmond Early Psychosis Intervention (EPI) program.   The author’s specific contributions to the identification of the research study, involvement, and analysis of the research are discussed later.  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	   v Table of Contents Abstract	  ..................................................................................................................................................	  ii	  Preface	  ...................................................................................................................................................	  iv	  Table of Contents	  .................................................................................................................................	  v List of Tables	  .....................................................................................................................................	  viii	  List of Figures	  .....................................................................................................................................	  ix	  Acknowledgements	  ............................................................................................................................	  x	  Dedication	  ............................................................................................................................................	  xii	  Chapter 1: Introduction	  ....................................................................................................................	  1	  1.1 Metabolic Syndrome	  .....................................................................................................................	  1	  1.1.1 Definition	  .......................................................................................................................................	  1	  1.1.2 Prevalence	  ....................................................................................................................................	  2	  1.1.4 Prediabetes	  ..................................................................................................................................	  5	  1.1.5 Type II Diabetes mellitus	  ..........................................................................................................	  5	  1.1.6 Impaired glucose tolerance	  .....................................................................................................	  6	  1.1.7 Insulin resistance	  ........................................................................................................................	  7	  1.1.8 Obesity and Weight Gain	  .........................................................................................................	  7	  1.1.8.1 Definition	  ....................................................................................................................................	  7	  1.1.8.2 Prevalence	  ..............................................................................................................................	  10	  1.1.8.3 Attributing Factors	  .................................................................................................................	  10	  1.2 Summary of Schizophrenia and Psychotic Disorders	  .......................................................	  11	  1.2.1 Definition	  .....................................................................................................................................	  11	  1.2.2 Epidemiology	  .............................................................................................................................	  12	  1.2.3 Clinical Diagnosis and Treatment	  ........................................................................................	  12	  1.1.4 Diagnostic and Statistical Manual of Mental Disorders (DSM)	  ...................................	  14	  1.3 Second Generation Antipsychotics	  .........................................................................................	  14	  1.3.1 Pharmacology of Second Generation Antipsychotics	  ....................................................	  14	  1.3.2 Clinical Indications of Second Generation Antipsychotics	  ............................................	  15	  1.3.3 Safety and Tolerability	  ............................................................................................................	  15	  1.3.3.1 Antipsychotic Induced Metabolic Syndrome	  .................................................................	  15	  1.3.3.2 Mechanisms of Antipsychotic Induced Weight Gain	  ..................................................	  16	   vi 1.3.3.2.1 Dopamine Hypothesis	  ......................................................................................................	  16	  1.3.3.2.2 Serotonin hypothesis	  ........................................................................................................	  17	  1.3.3.2.3 Histamine hypothesis	  .......................................................................................................	  17	  1.4 Significance of Study	  ..................................................................................................................	  18	  1.4.1 Role of Visceral Fat	  ..................................................................................................................	  19	  1.5 Hypotheses and Specific Aims	  .................................................................................................	  19	  Chapter 2: Methods	  ..........................................................................................................................	  21	  2.1 Trial Design	  ....................................................................................................................................	  21	  2.1.1 Data Collection	  ..........................................................................................................................	  23	  2.1.2 Initial Contact	  .............................................................................................................................	  23	  2.1.3 Baseline Assessment	  ..............................................................................................................	  24	  2.1.4 Second Assessment (in person clinical interview)	  ..........................................................	  25	  2.1.5 Ongoing Assessments (monthly telephone questionnaires)	  .......................................	  26	  2.1.6 Third Assessment (Four-month follow up)	  ........................................................................	  26	  2.1.7 Final Assessment (second clinical interview)	  ...................................................................	  27	  2.2 Study Population and Characteristics	  ....................................................................................	  27	  2.3 Data Collection Protocol	  ............................................................................................................	  29	  2.3.1 Consent Process	  ......................................................................................................................	  29	  2.3.2 Anthropometric Measures and Vital Signs	  ........................................................................	  29	  2.3.3 Psychiatric Scales (clinical Interviews) and Questionnaires	  ........................................	  30	  2.3.3.1 Mini International Neuropsychiatric Interview (MINI)	  ..................................................	  31	  2.3.3.2 Three-factor Eating Questionnaire (TFEQ)	  ...................................................................	  32	  2.3.3.3 Short Form 36 (SF-36)	  ........................................................................................................	  32	  2.3.3.4 International Physical Activity Questionnaire (IPAQ)	  .................................................	  33	  2.3.3.5 Medication Adherence Rating Scale (MARS)	  ..............................................................	  33	  2.3.3.6 Positive and Negative Syndromes Scale (PANSS)	  ....................................................	  33	  2.3.3.7 Calgary Depression Scale  (CDS)	  ...................................................................................	  34	  2.3.3.8 Social and Occupational Functioning Scale (SOFAS)	  ...............................................	  34	  2.3.5 Honorarium	  .................................................................................................................................	  35	  2.4 Primary Outcome: Assessing Weight Gain Over Time	  .....................................................	  35	  2.5 Secondary Outcomes	  .................................................................................................................	  36	  2.6 Statistical Analysis	  .......................................................................................................................	  37	   vii Chapter 3: Results	  ............................................................................................................................	  39	  3.1 Anthropometric measures at baseline	  ...................................................................................	  51	  3.2 Anthropometric measures at four months	  .............................................................................	  51	  3.3 Within-subjects at baseline and four months	  .......................................................................	  52	  3.4 Weight gain over time	  .................................................................................................................	  52	  3.5 Short Form 36 (SF-36) Mental and Physical Health Summary	  ......................................	  53	  3.6 Three Factor Eating Questionnaire (TFEQ)	  .........................................................................	  54	  3.7 International Physical Activity Questionnaire (IPAQ)	  ........................................................	  54	  3.8 Positive and Negative Syndromes Scale (PANSS)	  ...........................................................	  54	  3.9 Calgary Depression Scale (CDS)	  ............................................................................................	  55	  3.10 Social and Occupational Functioning Scale (SOFAS)	  ....................................................	  55	  Chapter 4: Discussion	  ....................................................................................................................	  56	  4.1 Findings	  ..........................................................................................................................................	  56	  4.2 Limitations	  ......................................................................................................................................	  61	  4.3 Future Directions	  ..........................................................................................................................	  62	  4.4 Conclusion	  .....................................................................................................................................	  62	  References	  ...........................................................................................................................................	  63	  Appendix I: Mechanism of action of common SGAs	  .........................................................	  72	  Appendix II: Consent form	  ............................................................................................................	  75	  Appendix III: Short Form 36 (SF-36)	  ..........................................................................................	  89	  Appendix IV: International Physical Activity Questionnaire (IPAQ)	  ............................	  92	  Appendix V: Three Factor Eating Questionnaire (TFEQ)	  .................................................	  95	  Appendix VI: Medication Adherence rating Scale (MARS)	  ..............................................	  99	  Appendix VII: Positive and Negative Syndromes Scale (PANSS)	  ..............................	  100	  Appendix IX:  Calgary Depression Scale (CDS)	  ................................................................	  101	  Appendix X: Social and Occupational Functioning Scale (SOFAS)	  .........................	  102	    	  	  	  	  	   viii List of Tables 	  Table 1.1 NIH Diagnostic criteria for metabolic syndrome………………………..….…….4 Table 1.2 CDA diagnostic criteria for prediabetes…………………………….…….………5 Table 1.3 2006 Health Canada weight classification system………………………………8 Table 1.4 Health Canada Body Mass Index (BMI) health risk classification………….….8 Table 1.5 DSM-5 Diagnostic criteria for schizophrenia……………………………………12 Table 1.6 Study Hypotheses………………………………………………………………….19 Table 3.1 Complete list of variables included in statistical analysis……………...………39 Table 3.2 Anthropometric measures at baseline and four months………………….……40 Table 3.3 Blood pressure and pulse measurements at baseline and four months.…….47 Table 3.4 Mean scores for the Short Form 36 (SF-36)………...………………………….48 Table 3.5 Mean scores for the International Physical Activity Questionnaire (IPAQ)….49 Table 3.6 Mean scores for the Three Factor Eating Questionnaire (TFEQ)…………….50 Table 3.7 Mean scores from the Medication Adherence Rating Scale (MARS).............50 Table 3.8 Mean scores for the Positive and Negative Syndromes Scale (PANSS) subscales........................................................................................................................51 Table 3.9 Mean Calgary Depression Scale scores and statistical analysis……………..51 Table 3.10 Mean scores from the Social and Occupational Functioning scale (SOFAS)……………………………………..........................………………….…………….51      ix List of Figures Figure 1 Estimation of BMI chart………………………………………………..………..……9 Figure 2 Trial design diagram…………………………….……………………………..……22 Figure 3 Mean weight (kg) at baseline and four month follow up…………………….…..41 Figure 4 Mean WC at baseline and four month follow-up…………………………..…….43 Figure 5 Weight gain between baseline and four month follow-up……………………….44  Figure 6 SF-36 Physical Health Summary…………………………………………....…….45 Figure 7 SF-36 Mental Health Summary………………………………………....…………46        	  	  	  	  	  	  	   x Acknowledgements • First and foremost I would like to thank my supervisor Dr Alasdair Barr, for his dedication to my success in this program. My journey in this program has not been easy. Through the highs and lows Dr Barr has supported me consistently with encouragement, hope, and support. I consider him not just a supervisor but also a mentor and a friend and will forever be grateful to him for his contributions to my academic success.  • Secondly, I would like to thank Dr Ric Procyshyn. In addition to serving as a member of my committee, he has helped me through this program thought being a mentor and teacher. I consider him a role model both professionally and personally. • Dr Heidi Boyda has served as a fellow graduate student and later a postdoctoral fellow in the lab. I had the honor of working alongside Heidi in this study where we served as members of the research team. In addition to providing me with the required training to complete this project, she has given me encouragement and support through teaching and education in all aspects of this degree. I am forever grateful to her hard work and patience.  • Lurdes Tse, a graduate of the program and current medical student worked in collaboration with, Heidi and myself, to undertake and carry out the study. In addition to serving as a vital member of the research team, she has provided me with much encouragement and wisdom. I owe her special thanks for her mentoring and patience in teaching. Conducting this highly sophisticated,  xi complex clinical trial would not have been possible without such strong team collaborations between Heidi, Lurdes, and myself.  • Committee members Dr Sastry Bhagavatula (Chair), and Dr Bernard Macleod, I would like to thank for through ongoing support, assistance, and feedback in this program.  • Others I would like to acknowledge are fellow graduate students Hyun-Kyoung Koo, Tim Fung, Wynne Leung, program secretary, and friends Jane Hambley and Primo Villanueva for your ongoing social support.                xii Dedication     To my Grandmother, Myrtle A. Whitney 1931-2014               1 Chapter 1: Introduction 1.1 Metabolic Syndrome 1.1.1 Definition Metabolic Syndrome is defined as a group of physical symptoms that together predispose patients and lead to chronic health conditions such as type II diabetes mellitus, stroke, coronary heart disease (CHD), and other cardiovascular diseases and health problems (National Institutes of Health (NIH), 2014). Metabolic syndrome has also been referred a syndrome X, dysmetabolic syndrome, obesity syndrome, insulin resistance syndrome, and hypertriglyceridemic waist (NIH, 2014).   There are different definitions of metabolic syndrome according to different institutions. The World Health Organization (WHO) in 1999 defined metabolic syndrome as having glucose intolerance, impaired glucose tolerance, or diabetes mellitus and/or insulin resistance in addition to two or more of the following: (1) impaired glucose regulation or diabetes (2) insulin resistance which is defined as: under hyperinsulinemic euglycemia, or glucose uptake which is below the lowest quartile of the population that is being investigated) (3) arterial blood pressure greater than or equal to 140/90 mmHg, (4) increased triglyceride levels (greater than or equal to 1.7 mmol) and or low HDL cholesterol levels (less than 0.9 mmol in men and 1.0 mmol in women), (5) abdominal obesity (defined as a waist-hip ratio greater than 0.9 in men and 0.85 in women) and or a BMI greater than 30. (6) microalbuminemia (defined as a urinary albumin excretion  2 rate of greater than or equal to 20 micrograms/min or and albumin-creatinine ratio greater than or equal 30mg/gram (WHO, 1999).  1.1.2 Prevalence  According to the Canadian Health Measures Survey (CHMS) (2009-2011), 1 in 5 Canadians between the ages of 18-79 had metabolic syndrome (Statistics Canada, 2014). This prevalence rate is consistent with a 2011 survey of the Canadian Medical Association (Riediger & Clara, 2011). According to this CHMS survey, 22% of Canadians meet the criteria for metabolic syndrome (Statistics Canada, 2014). The prevalence of metabolic syndrome in Canada was found to increase with age; 10% of Canadians ages 18-39 were found to meet the criteria for metabolic syndrome compared to 40% of Canadians ages 60-79 (Statistics Canada, 2014). The rates of metabolic syndrome in Canada were found to be similar in males and females (Statistics Canada, 2014).   Although exact mechanisms of metabolic syndrome have not completely understood (Riediger & Clara, 2011), studies have shown that the prevalence of metabolic syndrome tends to be higher in people with mental illness than the general population, regardless of their specific diagnosis (Mackin et. al., 2007). Specifically, the study by Mackin et. al. (2007) that surveyed 90 subjects with mental illness and 92 control subjects found that patients with mental illness had higher BMIs (average of 29.9 which indicates overweight), higher rates of dylipidemias, glucose homeostasis disorders, higher waist circumference, and waist hip ratios (that indicate higher visceral adiposity) (Mackin et. al.,2007).   3   Decreased physical activity combined with poor dietary intake may be contributing factors to the higher risk of cardiovascular disease seen in patients with schizophrenia (Hert et. al., 2009). In addition, the use of antipsychotic medications may increase risk factors of cardiovascular disease, including, weight gain (Hert et. al., 2009). After diagnosis of metabolic syndrome is made, treatment should begin with a risk assessment for cardiovascular disease and type 2 diabetes (Alberti et. al., 2006). Treatment regimens primarily involve lifestyle modifications such as (1) increased physical activity and (2) diet modification that decreases saturated fat, sodium, increase fiber, and decrease caloric intake with a goal of 5-10% loss of total body weight in 12 months (Alberti et. al., 2006). Hert et. al. (2009) suggests a focus on prevention, which target weight gain, diet, and lifestyle as soon as antipsychotic therapy is initiated. See appendix I for further information on treatment for clozapine associated weight gain.  1.1.3 Diagnostic Criteria and Symptomology  Diagnosis of metabolic syndrome is based on a set of specific criteria. Although each symptom may occur on its own, they are more commonly found together (NIH, 2014). In order to be diagnosed with metabolic syndrome, 3 or more of the following risk factors must be presenting the individual (see table 1).        4 Table 1.1 Diagnostic Criteria of Metabolic Syndrome according to National Institutes of Health (2014)  Diagnostic Criteria for Metabolic Syndrome ≥3 of the following risk factors indicate Metabolic Syndrome Abdominal Obesity ≥35 inches for women ≥40 inches for men Hypertriglyceridemia  ≥150mg/dL  or  taking lipid lowering agents Low HDL <50mg/dL for women <40mg/dL for men Hypertension or High Blood Pressure ≥130/85mmHg  or   taking antihypertensive medication   *Note, single systolic or diastolic elevation still places patients’ at risk for metabolic syndrome Hyperglycemia (Fasting) ≥100mg/dL or taking antidiabetic medication Source: (NIH, 2014)      5 1.1.4 Prediabetes  The Canadian Diabetes Association (CDA) (2013) defines prediabetes as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or an gylcated hemoglobin (A1C) value of 6.0-6.4% (CDA, 2013) (see table 1.2). These risk factors place individuals at a higher risk for developing diabetes than the general population (CDA, 2013).  According to a 2005-2008 U.S. survey over a third (35%) of Americans over the age of 20 and half (50%) of those over the age of 65 were found to have prediabetes (Center for Disease Control (CDC), 2011).   Table 1.2 Canadian Diabetes Association Clinical Practice Guidelines Expert Committee (2013) criteria for the diagnosis of prediabetes.    Source: (CDA, 2013) 1.1.5 Type II Diabetes mellitus  Diabetes is defined as a disease whereby the body is unable to produce functional insulin (Canadian Diabetes Association (CDA), 2014). Insulin is a hormone produced by beta cells in the pancreas that is integral to the regulation and utilization of glucose levels in the blood. Insufficient or non-functioning insulin results in abnormally high levels of glucose in the blood that result in a number of acute and chronic negative  6 effects on body systems (CDA, 2014). There are three major types of diabetes; type 1, 2, and gestational (CDA, 2014).   Type 1 diabetes is defined as a type of diabetes that occurs when the body is unable to produce insulin (CDA, 2014). Type 2 diabetes is defined as that in which insulin is produced but in insufficient amounts or is produced but is non-functional (CDA, 2014). Gestational diabetes is a type of diabetes that can temporarily affect pregnant women during their pregnancy (CDA, 2014). Of those diagnosed with diabetes, approximately 10-15% of persons have type 1 diabetes and approximately 85-90% have type 2 (Smith et. al., 2008).  Although disturbances in blood glucose have been reported in patients with schizophrenia prior to the use of antipsychotic medications (Haupt & Newcomer, 2001). Various SGAs have been linked to the incidence of type II diabetes (Gianfrancesco et. al., 2002). Patients taking SGAs have been identified as a high-risk group for developing type two diabetes (Lean & Pajonk, 2003). Fortunately, antipsychotic  induced diabetes us usually revisable if them medication is stopped.  1.1.6 Impaired glucose tolerance Impaired glucose tolerance is a condition whereby the glucose levels in the blood remain high to levels that are above normal but not high enough to constitute diagnosis of diabetes (Nathan et. al., 2007). An individual is said to have impaired glucose tolerance if their plasma glucose concentration (between 140-200 mg/dl) for two hours after the administration of a 75-gram oral glucose tolerance test (OGTT) in the presence of fasting plasma glucose of less than 126 mg/dl (Nathan et. al., 2007).   7 1.1.7 Insulin resistance Insulin resistance is a condition that results in abnormally high glucose levels in the blood due to a decrease in the uptake of circulating glucose by cells (National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 2014).  This lack of glucose uptake occurs because the cells do not respond normally to insulin.  1.1.8 Obesity and Weight Gain  1.1.8.1 Definition The World Health Organization (WHO) (2014) defines obesity (and overweight) as “abnormal or excessive fat accumulation that presents a risk to health”. Specifically, WHO (2013) classifies a person as obese if they have a BMI of greater than or equal to 30 (WHO, 2013). Those whom have a BMI of greater than or equal to 25 but less than 30 are defined as overweight (WHO, 2013). Obesity places persons at risk for many comorbid conditions including coronary heart disease, stroke, hypertension or high blood pressure, diabetes type II, gallbladder disease, breast, colon, and endometrial cancer, sleep apnea and psychological issues such as low self esteem and depression (Health Canada, 2006). Obesity is also associated with various metabolic abnormalities such as insulin resistance, diabetes, dyslipidemia, and cardiovascular disease (Newcomer, 2005).     8     Table 1.3. Weight Classification System   Source: (Health Canada, 2006)  Table 1.4. Health Risk Classification According to Body Mass Index (BMI).       Source: Health Canada. Canadian Guidelines for Body Weight Classification in Adults. Ottawa: Minister of Public Works and Government Services Canada; 2003 Health Canada (2006) Weight Classification System (Body Mass Index Underweight (≤18.4) Normal weight (18.5-24.5) Overweight (between 25 and 29.9) Obese (≥30) Classification BMI Category (kg/m2) Risk of developing health problems Underweight < 18.5 Increased Normal Weight 18.5 - 24.9 Least Overweight 25.0 - 29.9 Increased Obese class I 30.0 - 34.9 High Obese class II 35.0 - 39.9 Very high Obese class III >= 40.0 Extremely high  9 Figure 1. Estimation of BMI Chart  Figure 1. Estimation of BMI Chart. The above chart (Fig. 1) is used to estimate BMI. In order to estimate BMI, find the location where weight (y-axis) and height (x-axis) intersect (Health Canada, 2003). The number on the dashed line closest to the intersection point is the estimated BMI (Health Canada, 2003). BMI can also be calculated by dividing weight in kilograms by height in meters: BMI = Weight (Kg) / Height (m)2 (Health Canada, 2003).  10 Source: Health Canada. Canadian Guidelines for Body Weight Classification in Adults. Ottawa: Minister of Public Works and Government Services Canada; 2003.  1.1.8.2 Prevalence  High rates of obesity are seen in both Canada and the U.S. In 2008, over 1/3 of Canadians were found to be overweight (see Table 1.3) and ¼ of those surveyed were found to be obese (Statistics Canada, 2014). The rates of obesity have increased 1% from a 2005 survey (Statistics Canada, 2014). In a 2011 survey of obesity and overweight rates within British Columbia, Canada was found to have the lowest rates of overweightness (30%) and obesity (14%) and Newfoundland and Labrador had the highest overweight (40%) and obesity (29%) (Statistics Canada, 2014).  Internationally, among G7 countries, Canada was ranked as having the third highest rates of obesity with the U.S. having the highest and France having the lowest (Statistics Canada, 2014). In a 2010 study of prevalence rates in the U.S. between 1999-2000, 68% of the U.S. population was found to be overweight (BMI ≥ 25) and 35% were found to be obese (BMI ≥ 30) (Flegal et. al., 2010). Rates of overweight and obesity tend to be higher in those with advanced age (ages 45-54) than younger populations (Statistics Canada, 2014).  1.1.8.3 Attributing Factors   According to the National Institutes of Health (NIH) (2014), obesity occurs when the caloric intake exceeds the calories that are utilized over time (NIH, 2014). Caloric intake usually fluctuates from  day to day, however, if overtime calorie input (food)  11 exceeds caloric output (e.g. exercise, day to day activities) than weight gain will result.  When an individuals’ caloric intake is below that which is required by the body, over time, the person may lose weight (NIH, 2014). When the caloric intake of the individual is in balance, over time, than the persons weight will usually stay the same (NIH, 2014).   In addition to the imbalance of caloric intake and output described, other factors also play a role in weight gain and obesity. These include, but are not limited to decreased physical activity, environmental factors, medical conditions, genetic influences, medication, insufficient rest, age, emotional influences (Wright & Aronne, 2012). 1.2 Summary of Schizophrenia and Psychotic Disorders   1.2.1 Definition Psychotic disorders are defined as a group of mental disorders that includes abnormal changes in thinking and perceptions and a loss of touch with reality (American Psychiatric Association (APA), 2013; NIH, 2014). Primary symptoms include delusions (false beliefs) and hallucinations (false perceptions) (NIH, 2014). Schizophrenia is type of psychotic disorder (APA, 2013). According to the DSM-5, schizophrenia belongs to a larger group of psychotic disorders known as schizophrenia spectrum and other psychotic disorders that include schizophrenia, schizotypal (personality) disorder, and other psychotic disorders (APA, 2013). There are a variety of psychotic disorders and disorders that may lead to psychotic symptoms (APA, 2013). For the purposes of this thesis, only schizophrenia will be explored in greater detail.  12 1.2.2 Epidemiology  Schizophrenia is the most common type of psychotic disorder that effects approximately 1% of the Canadian population (Public Health Agency of Canada (PHAC), 2014) and 0.7% of the population worldwide (Saha et. al., 2005).  Approximately 20-30% of all patients treated for schizophrenia may be resistant to treatment (Conley & Kelly, 2001). In a Finnish population survey study of the prevalence of psychotic disorders in the general population, schizophrenia was found to be the most common followed by schizoaffective disorder, schizophreniform, delusional disorder, bipolar I disorder, psychotic symptoms related to major depressive disorder, substance induced psychosis, and psychotic symptoms secondary to a medical condition respectively (Perälä et. al., 2007). 1.2.3 Clinical Diagnosis and Treatment  Diagnosis of schizophrenia is based on specific criteria of symptoms in the Diagnostic and Statistical Manual of Mental Disorders version 5 (table 3.) Table 1.5. Diagnostic criteria for Schizophrenia (DSM-5, 2013)  DSM-V Diagnostic criteria for schizophrenia  1. ≥ 2 of the following symptoms present during a considerable amount of time in  1-month unless successfully treated. ≥ must be I), II), or III).  I) Delusions II) Hallucinations III) Disorganized speech IV) Grossly disorganized  13 DSM-V Diagnostic criteria for schizophrenia  V) Negative Symptoms 2. Decreased level of functioning (e.g. in work, relationships, self care) compared to the level prior to the onset of symptoms or compared to the expected level of functioning.  3. Symptoms of disturbance must be present for at least 6 months. Within the 6-month window, the individual must have experienced symptoms from criteria 1.  and may include prodromal or residual symptoms. The prodromal/residual periods maybe observed as negative symptoms or  ≥2 of the symptoms listed in section 1. in an “attenuated” form (e.g. odd beliefs , unusual perceptual experience).  4. Bipolar disorder with psychotic features and schizoaffective disorder have been ruled out due to the following 2 reasons I) the absence of any manic or major depressive episode occurring together with active-phase symptoms, or II) if episodes of mood abnormalities have occurred during active phase symptoms, than they have only been present for a small amount of the total active and residual periods.  5. Symptoms are not secondary to a medical condition (e.g. brain tumor) or substance (e.g. LSD, anesthetics).   6. If the patient has been diagnosed with a communication disorder or autism spectrum disorder where the onset was in childhood than a diagnosis of schizophrenia can be given only if marked delusions, hallucinations, are present in addition to the other diagnostic criteria of schizophrenia are also present for ≥1 month or <1 month if the symptoms have been treated successfully. *Note, there are further specifies for schizophrenia (e.g. first episode, with catatonia). See the DSM-V for greater detail on diagnoses  __________________________________________________________________ Table 3 has been adapted from the American Psychiatric Association: DSM-V. 2013. Diagnostic Criteria for Schizophrenia. Source: (APA, 2013)  14 1.1.4 Diagnostic and Statistical Manual of Mental Disorders (DSM) The DSM is a manual used by health care professionals and researchers in Canada and the United States that provides information and specific guidelines on the diagnosis of psychiatric disorders (American Psychiatric Association (APA), 2014). The DSM provides definitions, diagnostic criteria, symptomology that define types of psychiatric disorders (APA, 2014). The DSM provides guidelines on assessment and diagnoses of psychiatric disorders but not instructions on treatments (APA, 2014). Treatments for psychiatric disorders are specific to the individual diagnoses, therefore, the DSM does provide information required to make accurate psychiatric diagnoses that will then determine which treatments are administered (APA, 2014). The most recent version of the manual is the DSM-5 (APA, 2014). 1.3 Second Generation Antipsychotics SGAs, also referred to as atypical antipsychotics are a group of newer antipsychotic drugs that are claimed to have a broader efficacy, lower propensity to induce EPS, and benefit in the treatment of negative symptoms and depression (Leucht et. al., 2009).   1.3.1 Pharmacology of Second Generation Antipsychotics Mechanism of action of SGAs is generally understood to involve an interaction between the antagonism of serotonin 5-HT2A receptors and dopamine D2 receptors  15 (Kuroki et. al., 2008). Most new SGAs share the common mechanism of having a higher degree of antagonism for 5HT2A receptors than D2 receptors (Kuroki et. al., 2008). See appendix II for specific pharmacology of common SGAs.  1.3.2 Clinical Indications of Second Generation Antipsychotics  SGAs are used for a multitude of psychiatric disorders including Tourette’s disorder, bipolar disorder, conduct disorder, attention deficit hyperactivity disorder (ADHD), eating disorders, disruptive behavior disorder (DBD), anxiety disorders, sleep disorders, and depression (Linton et. al. 2013, Procyshyn et. al., 2014, Whitney et. al., 2015). 1.3.3 Safety and Tolerability 1.3.3.1 Antipsychotic Induced Metabolic Syndrome  Rates of obesity, glucose disregulation, cardiovascular disease, and diabetes have been found to be present more frequently in patients with schizophrenia than the general population (Meyer et. al., 2005).  These could be related to negative symptoms of schizophrenia (e.g. lack of motivation) or psychotic symptoms resulting in an inability to work and a sedentary lifestyle. Weight Gain may be related to lower income and consumption of fast food (Beebe, 2008).  In addition to the preexisting risk factors for metabolic syndrome that is seen in schizophrenia, the use of antipsychotic medications have also been associated with an increased risk of metabolic disturbances  16 (Newcomer, 2005). The prevalence of metabolic syndrome is said to be 35-40% in patients with schizophrenia. As previously mentioned, the use of SGAs places patients in a high-risk category for developing type 2 diabetes (Lean & Pajonk, 2003). In addition, the use of SGAs increase patients’ risk of weight gain which is a risk factor for type 2 diabetes and increases the likelihood of ones chances of developing metabolic syndrome (Lean & Pajonk, 2003). 1.3.3.2 Mechanisms of Antipsychotic Induced Weight Gain Antipsychotic induced weight gain is a complex process that may have multiple causal mechanisms (Rege, 2008). As discussed, antipsychotic medications act on a variety of receptors including dopamine histamine, and serotonin of which, all may result in weight gain (Reynold et. al., 2006; Baptista et. al., 1999). There is still no clear understanding of the exact causal mechanisms behind antipsychotic induced weight gain, however many theories exist. It is suspected that there are multiple pathways and that each may contribute to the metabolic disregulation and weight gain. Theories of antipsychotic induced weight gain can be explained though describing their effects at these various receptors.  1.3.3.2.1 Dopamine Hypothesis In a review article by Goudie et. al. (2005), the authors describe a dopaminergic hypothesis of antipsychotic induced weight gain and suggest that, in light of research that obese people may have a “dopamine deficiency” which may lead to a  17 compensation by excess food intake.  There is evidence that the antagonistic effects at dopamine receptors could contribute to weight gain (Baptista et. al., 1987). For example, sulpride, a potent D2 and D3 antagonist showed a linear relationship with the dose of the drug and weight gain in rats (Baptista et. al., 1987).  1.3.3.2.2 Serotonin hypothesis There is evidence that SGAs effects on serotonergic systems may contribute to weight gain. For example, when mice were mutated to express nonfunctional 5-HT2C receptors they become obese as a result of uncontrolled feeding behavior (Tecott et. al., 1995). Experiments in rats have shown that olanzapine and 5-HT2C-receptor antagonist result in significant increases in weight (Kirk et. al., 2009). Goudie et. al. (2005), described that the serotonergic hypothesis insufficient at explaining the marked weight gain seen in SGAs because olanzapine is known to have a low affinity for 5-HT2C. 1.3.3.2.3 Histamine hypothesis The role of histamine receptors in antipsychotic induced weight gain is well described in the literature (Kroez et. al., 2003). Experiments in mice have shown large increases in the activity of the enzyme AMPK, a hypothalamic orexigenic-stimulating enzyme with the largest increases in response to clozapine and olanzapine. The stimulation of this enzyme was linked to the antagonism at histaminergic receptor H1R (Kim et. al., 2006). Wirshing and colleagues showed a correlated between short-term weight gain and affinity of antipsychotic to histamine H1 receptors with the greatest weight gain seen in clozapine and olanzapine (Wirshing et. al., 1999). Goudie et. al.  18 (2005), suggests this is an incomplete hypothesis because ziprasidone has a high affinity for H1 yet has a lower propensity to induce weight gain (Richelson & Souder, 2000). 1.4 Significance of Study Numerous studies have discussed antipsychotic induce weight gain (Bai et. al., 2011; Hummer et. al., 1995; Kroez et. al., 2003), however, this is the first ever study that has looked at the distribution of visceral versus subcutaneous fat using MRI. The primary goal of the clinical trial is to look at the distribution of visceral versus subcutaneous fat.  For the purposes of this interim analysis, data analysis will consist only of anthropometric measures, physical assessments, questionnaires, and psychiatric tests. This valued information will form as an interim analysis to gain insight into the progression of the entire clinical trial that will utilize MRI and blood work in addition to data utilized for this thesis. Interim analyses are an important part of a clinical trial as it provides useful insight into the progression into the outcome of the clinical trial. In addition to providing useful insight into the progression of the clinical trial, this data will also be useful to see where differences exist. For example it will be useful to note any major differences in waist circumference as this will indicate a change in visceral fat. Recently published literature has suggested that visceral fat magnitude may be a much more accurate predictor of insulin resistance and glucose intolerance than subcutaneous fat (Usui et. al., 2009). It is therefore vital that research exploring this  19 connection between antipsychotic induced metabolic disregulation and visceral fat distribution is carried out.  1.4.1 Role of Visceral Fat It is well documented in the literature that rates of obesity, diabetes mellitus, and insulin resistance are higher in patients with schizophrenia than the general population (Ryan & Thakore, 2002). The side effect of weight gain is arguably the most discussed component of metabolic disregulation in the literature and is also the most pronounced.   It is well documented that second generation antipsychotics are associated with marked weight gain (Newcomer, 2005). Interestingly, it has also been reported that patients with schizophrenia, both drug naive and those treated with antipsychotics, have been shown to have a large increases in visceral fat when compared healthy controls (Thakore et. al., 2002). It is therefore pertinent that research investigating the association between visceral fat and SGA use is carried out.  1.5 Hypotheses and Specific Aims The purpose of this study was to explore the metabolic changes over four months in a group of patients with first episode psychosis in the early stages of treatment with SGAs. In addition, changes in psychopathology would be evaluated in response to drug treatment over time, as well as subjective perceptions of mental and physical health, eating patterns, physical activity, and overall social and occupational functioning, and compare the results to those seen in a group of healthy control participants.   20 Table 1.6 Study Hypotheses Study Hypotheses  I) Hypothesis I. There will be no significant differences between participants taking antipsychotics and those not taking antipsychotics at baseline.  II) Hypothesis 2. At four months, significant increases in weight, WC, and BMI will be seen in participants taking antipsychotics.  III) Hypothesis 3. At four months, participants taking antipsychotics will show significant decreases in physical activity and significant changes in eating patterns. IV) Hypothesis 4.  At four months, participants taking antipsychotics will show significant improvements in psychopathology, global functioning, and quality of life.  V) Hypothesis 5. At four months, there will be no significant changes in control participants.   It was hypothesized that there will be no significant differences between groups in any variables at baseline. This is because participants in the antipsychotic group were newly started on SGAs so metabolic effects may not yet be measurable. Moreover, it was hypothesized that a significant increase in weight, WC, and BMI at the four month follow up as well as decreased levels of physical activity, changes in eating patterns in the antipsychotic group with no significant differences in the control group. Furthermore, it was hypothesized that significant improvements in quality of life, global  21 functioning, and psychopathology would be seen in the antipsychotic group with no changes in the control group. Chapter 2: Methods 2.1 Trial Design The study that was conducted was part of a larger clinical trial that looked at comparing high metabolic risk second-generation antipsychotic drugs and a low metabolic risk drug aripiprazole. This thesis will consist of an interim analysis of a clinical trial but will not include MRI or blood work data. Specifically, a comparison between all second-generation antipsychotics with controls has been done and an analysis only of the questionnaires (TFEQ, IPAQ), psychiatric scales (PANSS, CDS), and anthropometric measures (blood pressure, weight etc.) were carried out.   The clinical trial is titled “A longitudinal comparison of Aripiprazole vs. Higher Metabolic Risk Antipsychotic Drugs on Adiposity Using MRI”, abbreviated “the CALM study”. This is a longitudinal study with naturalistic intake. It is a four-month long clinical trial whereby participants receive MRI scans and interviews at the beginning of the study and again after 4 months. Interviews are conducted throughout the study at regular time points.  In addition to MRI, participants also received magnetic resonance spectroscopy (MRS) scans which to evaluate hepatic lipid content. In addition, relevant blood work has been conducted on both treatment groups and controls at baseline and again at four months to supplement the MRI/MRS imaging.   22      Figure 2. Trial Design Diagram.     Source: (Retrieved from CALM study protocol version 2.0 Sept 2 2014.)     23   2.1.1 Data Collection As discussed, this was a four-month long study whereby a series of clinical assessments were conducted with human participants. In this section, the schedule of assessments beginning with the first contact with a participant and ending with the last contact will be discussed.  In the following section the “graduate student” and  “researcher” refer to myself, the author. I, as the graduate student, was part of an interdisciplinary team who carried out this clinical trial. I was responsible for the data collection used in this thesis. As a registered nurse with foundations in psychiatry, this provided me with unique qualifications to carry out data collection procedures that would not have been possible without intense training and education by other individuals.  2.1.2 Initial Contact  The initial contact between the graduate student and the potential participant begins when the individual is referred to the study by one of the following means: 1) the individual contacts the graduate student after hearing about the study from a flyer, co patient, friend, family member, or other means 2) the individual has implied interest in the study to one of the psychiatrists at their community mental health team (Vancouver/Richmond early psychosis intervention (EPI) program). Once the individual has consented to the study, the participant is then scheduled for the initial set of baseline assessments.  24 2.1.3 Baseline Assessment The first assessment was termed the “first visit” and was done after the consented participant had been determined to meet the inclusion and exclusion criteria. This initial baseline assessment was completed as soon as possible after the consent process was complete. The purpose of the baseline assessment was to review the informed consent process once again, perform baseline anthropometric measures (height, weight, waste circumference), vital signs (blood pressure (orthostatic), heart rate), MRI and MRS, blood work (oral glucose tolerance test (OGTT), lipids, leptin, adiponectin, insulin, and glucagon like peptide 1 (GLP-1), medical history, and questionnaires (short form-36 (SF-36), international physical activity questionnaire (IPAQ), three factor eating questionnaire (TFEQ)).   All baseline and four-month follow up assessments were conducted at the University of British Columbia (UBC) Hospital. Physical assessments, medical history and questionnaires were conducted in a designated research room in the department of psychiatry. MRI/MRS were conducted at the MRI 3T research center connected to UBC hospital. Blood collection/phlebotomy was carried out by the graduate student or by technicians at UBC hospital laboratory services.  Processing of blood work, which includes centrifugation of samples and separation into aliquots, was conducted in secure facilities at UBC department of anesthesiology, pharmacology, and therapeutics medical sciences block C. After the plasma had been separated and the samples had been placed into separate vials, they were then stored in a -80 degrees Celsius freezer in secure laboratory at the same location.   25  Baseline assessments were conducted in the morning and lasted approximately six hours from beginning to end (0700-1300). Participants were asked to begin fasting approximately ten to twelve hours prior to the baseline assessments, blood work, and MRI/MRS. Specifically, the participant is asked to have only water after midnight the night prior.  Baseline anthropometric measures and vital signs were done initially followed by blood collection or MRI/MRS scans.  2.1.4 Second Assessment (in person clinical interview) In the second assessment, an approximately three-hour long clinical interview was conducted whereby a series of psychiatric scales that evaluate the mental health and psychiatric symptoms of patients were administered. The graduate student, along with other members of the research team was responsible for conducting the clinical interviews. Second assessments were scheduled approximately 7-10 days after the baseline assessments. The second assessment was for participants taking antipsychotic medications only. The psychiatric scales administered in the second visit include the mini international neuropsychiatric interview (MINI), positive and negative syndromes scale (PANSS), social and occupational functioning scale, and the Calgary depression scale (CDS). The interviews were conducted in a place of the participants choice, usually a coffee shop or the participants home, wherever they would feel most comfortable. Furthermore, answers to the psychiatric scales were also interpreted and reviewed by two individuals to ensure inter rater reliability and accuracy.   26 2.1.5 Ongoing Assessments (monthly telephone questionnaires) At three time points throughout the 4 months, participants were contacted via telephone for three 20-30 minute telephone interviews. These interviews were conducted at approximately one month, two months, and again at three months from the baseline assessment. The purpose of the telephone interviews was to assess any changes in overall health, physical activity, medication adherence, and eating patterns over the course of the study. Questionnaires that were administered as part of the telephone interviews were the SF-36, TFEQ, IPAQ, and the MARS. MARS were not administered to those in the control group.  2.1.6 Third Assessment (Four-month follow up) At approximately four months from the baseline assessment, participants were asked to meet for the second clinical assessment involving MRI, anthropometric assessments, vital signs, and blood work. All participants (patients and controls) undergo the third assessment. The third assessment is nearly identical in structure to the baseline assessment. Contrasting from the baseline assessment, participants taking antipsychotics were asked to provide an additional vial of blood collected with the regular blood work in order to assess medication adherence. Furthermore, participants were invited to participate in an optional biobanking component of the study, if informed consent is obtained, the participant is asked to provide an additional three milliliters of blood which was stored in the -80 freezer and be used for future studies.  27   2.1.7 Final Assessment (second clinical interview) The second clinical interview was identical to the first clinical interview. Similar to the first clinical interview, the second clinical interview applied to participants taking antipsychotic medications only. Psychiatric scales that were administered in the second clinical interview were the PANSS, SOFAS, and CDS. The purpose of the second clinical interview was to evaluate the mental health and psychiatric symptoms at two time points, early in antipsychotic treatment (within twenty-four weeks) and after four months.  2.2 Study Population and Characteristics  The complete trial will consist of ninety participants of whom all will undergo assessment through magnetic resonance imaging (MRI) at baseline and again at 4 months. For the CALM study, thirty will be controls (age and gender matched), thirty will be treated with high metabolic risk atypical antipsychotic drugs, and thirty with aripiprazole (low risk metabolic group). Individuals were deemed eligible to participate in the study if they were (1) 12 years or older with a diagnosis of bipolar disorder or 15 years of age or older with a diagnosis of a non-affective psychosis, (2) the individual has experienced recent admission to hospital or enrollment in community based psychiatric treatment or follow up services related to first episode psychosis or first episode bipolar disorder (inpatient or outpatient) (3) the individual must be treated with some type of antipsychotic medication (4) at the time of consent the individual must have been under  28 treatment of the antipsychotic for 24 weeks or less (5) the individual had to have been able to give informed consent or assent thought informed parental consent. The individual was deemed ineligible to participate in the study if: (1) they had been taking antipsychotic medication for greater than 24 weeks or their total lifetime exposure to antipsychotic medication exceeds 24 weeks. (2) the individual was not eligible to receive an MRI. For example, if the individual may have any metal in their body e.g. from tattoos, piercings (that cannot be removed), recent surgery, metalwork etc. or if the individual had morbid obesity or claustrophobia. Patients who had surgery within the passed six months were not eligible enter the MRI scanner and participate in the study (3) the individual had been diagnosed previously with any of the following disorders/conditions: diabetes mellitus, mental retardation (specifically that with an IQ of less than seventy). (4) If the individual were pregnant or within three months postpartum (5) if the individual were not proficient in written, spoken, and comprehension of English (6) the individual had undergone chemotherapy within the previous four weeks preceding the baseline assessment or the sixteen week follow-up interview.  For the purposes of this interim analysis, the treatment group will be defined as participants in the study whom are currently taking antipsychotic medication. The control group is defined as participants who are not currently taking any antipsychotic medication.  29 2.3 Data Collection Protocol 2.3.1 Consent Process Individuals were screened either in person or over the phone to determine if they were eligible to enter the study. Prior to the baseline assessment visit, all participants must have had signed and dated the consent forms. No less than seven days prior to the baseline assessment visit the potential participant was met for an in-person meeting with a research associate. The purpose of this meeting is to ensure that the potential participant understands the protocol, expectations, risks and benefits of the study. This meeting also provides an opportunity for the individual to ask questions before deciding to enter the study. After the meeting, the individual was scheduled for another follow-up meeting whereby the individual may ask any further questions they may have had before entering the study. The follow-up meetings occured approximately 24 hours after the initial meetings. The participant, as well as the graduate student or research associate was required to sign and date the consent forms. Two copies of the consent were signed and one was given to the participant and the other kept in a secure location for record by the researchers.  2.3.2 Anthropometric Measures and Vital Signs During the initial baseline assessment visits and at the four-month follow-up visits, all participants including controls and those taking antipsychotic medications had the following assessments performed. Anthropometric and vital sign assessments began with measuring the patients’ height and weight. With shoes removed, the  30 participant was asked to stands tall on the scale while height and weight was measured. Height is measured to the nearest 0.1 centimeter and weight to the nearest 0.1 kilogram. Weight was taken at approximately the same time of day at each study visit to avoid fluctuations within subjects. Waist circumference was measured though measuring the median between the top of the iliac crest and the bottom of the costal margin in the mid-axillary line. To obtain orthostatic blood pressure and heart rate, the participant was asked to lay supine for five minutes before having the blood pressure and heart rate measures. The participant was then asked remain in the standing position for two minutes before having their blood pressure and heart rate measured again. The same automatic blood pressure and heart rate monitor was used for all participants.  2.3.3 Psychiatric Scales (clinical Interviews) and Questionnaires  At the baseline assessment, month one, month two, month three, the four-month follow-up visit, and the final clinical interview, a series of questionnaires and or psychiatric assessments were carried out.   Questionnaires were administered to all participants (patients and controls) at five time points throughout the study; the baseline assessment, month one, month two, and month three telephone interviews and at the four-month follow-up visit.  The first set of questionnaires took place at the baseline assessment during the two hour window between the first and second blood draw of the oral glucose tolerance test (OGTT), the questionnaires were then repeated over the phone at approximately one  31 month into the study, and again at two months, three months, and in person at the four-month follow up visit. The following is brief description of the questionnaires that were administered.  2.3.3.1 Mini International Neuropsychiatric Interview (MINI) The MINI was used at the two clinical interviews with participants who were taking antipsychotic medications only. The purpose of the MINI is to provide a guided clinical interview to establish if a participant meets the criteria for a spectrum of psychiatric diagnoses. It is an abbreviated, thirty-minute, structured clinical interview that allows for the diagnosis of DSM-IV and ICD-10 Axis I disorders. The MINI is divided into modules that correspond to a diagnostic category. For example, module A evaluates whether the individual meets criteria for a past or current major depressive episode (MDE), module B for suicidality, and module C for dysthymia etc. There are a total of twenty-four modules (A-X). Although the MINI is designed to take approximately thirty-minutes, the clinical interviews lasted approximately two to four hours. Length of the clinical interviews was dependent on the cognitive process and ability of the participant.  The MINI was the first psychiatric test that was administered during the clinical interviews because, depending on the outcome of the MINI, either the PANSS or the Y-MRS were administered.  32  2.3.3.2 Three-factor Eating Questionnaire (TFEQ) The three-factor eating questionnaire is a short test that evaluates three dimensions of eating behavior; cognitive restraint in eating (factor one), disinhibition of control (factor two), and susceptibility to hunger (factor three). The first factor, cognitive restraint in eating, measures the conscious mechanisms of limiting food intake. Factor two, disinhibition of control, evaluates disinhibition type behaviors in eating. Factor three, susceptibility to hunger, evaluates the general sensations of hunger and the associated behavioral consequences. The test is comprised of fifty-one questions that are a combination of true and false, and multiple choice scaled questions. Items of the questionnaire are scored as binary functions. Each of the 51 questions is scored as ordinal data and assigned zero or one). Maximum score for the TFEQ is 20-16-15 corresponding to factor one, two, and three respectively with a minimum score of 0-0-0.  2.3.3.3 Short Form 36 (SF-36) The SF-36 is a tool used to assess general physical and mental health as perceived by the individual. The SF-36 is structured to assess eight dimensions of health. The eight dimensions are: physical functioning (assesses limitations in performing physical activities), role-physical (assesses bodily pain), general health, vitality (assess general energy levels and fatigability), social functioning (assesses impact of physical and emotional problems on social functioning), role-emotional (assess the limitations in role act), and mental health (overall perceptions of mental health).   33 2.3.3.4 International Physical Activity Questionnaire (IPAQ) The IPAQ is a short questionnaire that quantifies the amount of physical activity performed by the individual. Levels of physical activity are calculated in terms of vigorous, moderate, mild physical (e.g. walking), and sedentary activities (sitting). There are two forms of the IPAQ that are available; the long form and the short form. The short form was used for this study.  2.3.3.5 Medication Adherence Rating Scale (MARS)  The MARS is short questionnaire composed of ten yes or no questions that is used to assess adherence to antipsychotic medications. The MARS evaluates three components of medication adherence; behaviors relate to medication adherence, attitudes about taking medications, and thirdly, adverse events associated with antipsychotic medication and their attitudes towards these effects. One point is given for each of the ten questions of the MARS. A score of five or greater indicates that the participant is likely adhering to their medication.  2.3.3.6 Positive and Negative Syndromes Scale (PANSS) The PANSS is a tool used in clinical practice and in research that measures the positive and negative symptoms of psychosis. The PANSS is composed of three separate rating subscales: positive scale, negative scale, and a general psychopathology scale. The positive and negative scale is composed of seven sections  34 that are rated on a scale of severity from one (absence of symptoms) to seven (extreme). The third subscale used to rate general psychopathology is composed of sixteen sections that are also rated on a scale of severity from one to seven. The thirty sections are then totaled to give total score for the PANSS with a minimum score of thirty and a maximum of two-hundred-ten. The information required to accurately score the PANSS was obtained through the structured clinical interview and information received from primary care staff and family members. The graduate student and research assistants, whom were trained by a licensed and practicing psychiatrist, were the ones who administered and score the PANSS.  2.3.3.7 Calgary Depression Scale  (CDS) The CDS is a tool used to evaluate depressive symptoms in patients with schizophrenia separate from the negative symptoms associated with schizophrenia. The CDS is a short, one-page questionnaire composed of nine symptoms associated with depression (for example, depression, hopelessness, self depreciation). Each section is rated on a scale of 0-3 from absent to severe respectively.  2.3.3.8 Social and Occupational Functioning Scale (SOFAS) The SOFAS is a scale that is used to measure limitations in functioning related to mental or physical limitations. The criteria will only apply if the participant is  35 experiencing limitations in functioning directly related to mental or physical health problems (maybe add more here) 2.3.5 Honorarium  Honorariums for participation in the study were allocated as follows; seventy-five dollars was given to all participants for compensation of the baseline assessment and four month follow up. Compensation was given at the end of each assessment. Fifty dollars was given to participants in the antipsychotic group after completion of each of the two clinical interviews. For all participants who complete the telephone interviews, ten dollars was given for the first and second telephone interview and fifteen dollars was allocated for the third.  2.4 Primary Outcome: Assessing Weight Gain Over Time  Weight gain was assessed manually though physical assessments at baseline and again at four months. A manual column scale was used to assess height and weight. Differences were calculated after the four-month follow up. WC was measured manually in centimeters using a standard measuring tape at baseline and four-month follow-up visits. BMI was calculated manually (weight in kilograms by height in meters: BMI = Weight (Kg) / Height (m)2 (see figure 1.) (Health Canada, 2003). A minimum of two individuals was required to perform physical assessments in both control and participants taking antipsychotics. Research assistants were required to have special training in both physical assessments and patient communication. The graduate student’s baccalaureate training and clinical experience in nursing have served as a  36 vital prerequisite for performing physical assessments and served as served as an important intellectual contribution to this aspect of the study. The graduate student was responsible for obtaining height, weight, and WC while other members of team would simultaneously be responsible for the processing of blood and urinalysis samples at the nearby UBC laboratory. The role of the graduate student and research assistants was interchanged depending on patient preference, knowledge base, participant rapport, and safety. 2.5 Secondary Outcomes Secondary outcomes that were investigated include orthostatic blood pressure and pulse measurements, which may be affected by antipsychotic treatment. Changes in psychopathology were assessed through the PANSS and CDS. Changes in physical activity and eating patterns were evaluated through the IPAQ and TFEQ respectively. Changes in subjective quality of life and perceptions of mental and physical health were measured through the SF-36. Lastly, adherence to medication was assessed though the MARS. The graduate student, along with other members of the research team, were responsible collecting secondary outcome data. The graduate student was responsible for the measurement of pulse and orthostatic blood pressure while another member of the research team would be responsible for processing samples at the nearby UBC laboratory. The graduate student was responsible for administration of the SF-36, TFEQ, IPAQ, and MARS during the baseline and four month follow-up assessments while another member of the team would be responsible for the processing of samples. As previously mentioned, roles may interchange depending on patient preference,  37 rapport, knowledge base, and safety. The graduate student and research team were responsible for administration and scheduling of telephone interviews throughout the study. The graduate student as well as another member of the research team was required to perform clinical interviews (MINI, PANSS assessment, CDS, and SOFAS) and for interpretation of the results to maintain inter-rater reliability.  Due to the frequency of telephone interview assessments (three per participant), consenting processes, clinical interview assessments and interpretation (two per participant in the antipsychotic group), baseline, and follow up assessments, telephone interview appointments would often conflict with clinical interviews, baseline/follow-up assessments, and consenting. In this case the graduate student or other members of the research team would be required to perform the telephone interview while the other members of the team (or graduate student) performed the other assessments.  2.6 Statistical Analysis  Statistical analysis was performed using IBM Statistics Package for the Social Sciences (SPSS) version 22.0. Age, height, weight, WC, BMI, PANSS scores, CDS scores, SOFAS scores, orthostatic blood pressure, and pulse measurements were analyzed using a students t-test (p ≤ 0.05). Independent samples t-test was used for analysis between groups and paired samples t-test used for within groups analysis. A chi-squared test was used to detect differences in gender (p ≤ 0.05). t-tests were used for statistical analysis because the type of data that was analyzed was continuous variables that show normality. Repeated measures one way analysis of variance (ANOVA) was used for analysis of the TFEQ, IPAQ, SF-36, and MARS (p ≤ 0.05). This  38 test was determined to be appropriate because it will show the differences over time as well as interaction effects between two groups (treatment and control). A completer’s analysis was utilized because it was an appropriate for interim analysis of a clinical trial that may take four years to complete. The completer’s analysis was also useful because results may change by the end of the trial, therefore further statistical tests may not be beneficial. The graduate student was responsible for learning to utilize SPSS software, running, analyzing, and interpreting the statistical analysis of the data. The graduate student contributed intellectually to statistical analysis through the choices of statistical tests in collaboration with Dr Barr. Further intellectual contributions include interpretation of data both raw and that which was generated though statistical analysis. Solely the graduate student drew data interpretation and conclusions.        	   39 Chapter 3: Results  	  Table 3.1 Complete list of variables included in statistical analysis.   Baseline assessment  First clinical interview Telephone interview I Telephone interview II Telephone interview III Four month follow-up Second clinical interview Height Weight BMI Waist circumference Orthostatic blood pressure laying HR laying systolic  laying diastolic standing HR laying systolic standing diastolic  SF-36 Physical functioning Role physical Bodily pain Gen health Vitality Social functioning Role emotional Mental health MH summary Physical health summary   IPAQ  Mild PA Moderate PA Vigorous PA Total PA   TFEQ Level of cognitive restraint  Level of disinhibition  Susceptibility to hunger  MARS (antipsychotic group)  PANSS CDS SOFAS SF-36 Physical functioning Role physical Bodily pain Gen health Vitality Social functioning Role emotional Mental health MH summary Physical health summary  IPAQ  Mild PA Moderate PA Vigorous PA Total PA   TFEQ Level of cognitive restraint  Level of disinhibition  Susceptibility to hunger  MARS (antipsychotic group) SF-36 Physical functioning Role physical Bodily pain Gen health Vitality Social functioning Role emotional Mental health MH summary Physical health summary  IPAQ Mild PA Moderate PA Vigorous PA Total PA   TFEQ Level of cognitive restraint  Level of disinhibition  Susceptibility to hunger  MARS (antipsychotic group) SF-36 Physical functioning Role physical Bodily pain Gen health Vitality Social functioning Role emotional Mental health MH summary Physical health summary  IPAQ Mild PA Moderate PA Vigorous PA Total PA   TFEQ Level of cognitive restraint  Level of disinhibition  Susceptibility to hunger  MARS (antipsychotic group) Height Weight BMI Waist circumference Orthostatic blood pressure laying HR laying systolic  laying diastolic standing HR laying systolic standing diastolic  SF-36 Physical functioning Role physical Bodily pain Gen health Vitality Social functioning Role emotional Mental health MH summary Physical health summary   IPAQ Mild PA Moderate PA Vigorous PA Total PA   TFEQ Level of cognitive restraint  Level of disinhibition  Susceptibility to hunger  MARS (antipsychotic group) PANSS CDS SOFAS    40 Table 3.2 Mean (SD) values, sample sizes (n), and statistical analysis of anthropometric data at baseline and four months. P-values are given for between subjects at baseline, at four months, and longitudinally for both groups.  Variable   Mean (SD) Baseline Assessment Four month follow-up Control Group (n=20) Antipsychotic  Group (n=34) P Value Control Group (n=15) Antipsychotic  Group (n=21) P Value Age (Years) 23.7(2.9) 22.8(3.8) .2*    Sex, Male N(%) 11(55) 21(63.6) .5 9(60) 12(57) .9 Weight (kg) 68.7(10.1) 73.4(14.6) .02*  70.4(8.8) 79.3(17.7) .03* .5**  .001*** Height (m) 1.7(0.11) 1.71(0.10)  .68*  1.7(0.9) 1.71(0.11) .8* .10** .4*** Body Mass Index (BMI) (kg/m2) 23.5(3.1) 25(4.3) .13* 24.2(2.8) 26.2(6.7) .04* .17** .005*** Waist Circumference (cm) 82.8(8.7) 90.3(11.6) .09* 84.6(7.8) 96.3(13) .08* .38** .01***  a	  Significance	  values:	  Independent	  samples	  t	  test=*,	  Paired	  samples	  t	  test:	  Controls=**,	  antipsychotic	  group=***.         41 Figure 3. Mean weight (Kg) at baseline and four month follow-up.   	                                 -­‐5	  25	  55	  85	  Baseline	   Follow-­‐up	  Control	  Antipsychotic	  Time 	  Weight (kg) 	  	  	  *	  	  	  	  	  	  	  	  *	  aValues	  represent	  group	  means	  ±	  standard	  error	  of	  the	  mean	  (SEM).	  *P<.05	  	   42           Figure 4. Mean WC at baseline and four month follow-up.                               0	  30	  60	  90	  Baseline	   Follow-­‐up	  Control	  Antipsychotic	  Time WC (cm) 	  	  	  	  	  	  	  	  	  *	  	  aValues	  represent	  group	  means	  ±	  standard	  error	  of	  the	  mean	  (SEM).	  *P<.05	  	   43 Figure 5. Weight gain between baseline and four month follow-up.      a Graph depicts weight in kilograms (Kg) of control participants and those taking antipsychotic medication. Only participants who completed the baseline assessment and four month follow-up were included in the illustration.               0	  20	  40	  60	  80	  100	  120	  140	  Baseline	   4	  months	  Weight	  [kg]	   Weight	  [kg]	         Weight (kg)  44  Figure 6. SF-36 Physical Health Summary.                            70	  75	  80	  85	  90	  95	  100	  Baseline	   T1	   T2	   T3	   Follow-­‐up	  Contol	  Antipsychotic	  Time Mean score  aT1	  =	  Telephone	  interview	  1;	  T2	  =	  Telephone	  interview	  2,	  T3	  =	  Telephone	  interview	  3;	  aValues	  represent	  group	  means	  ±	  standard	  error	  of	  the	  mean	  (SEM).	  *P<.05	  	  *	   45 Figure 7. SF-36 Mental Health Summary.                          50	  55	  60	  65	  70	  75	  80	  85	  90	  95	  Baseline	   T1	   T2	   T3	   Follow-­‐up	  Contol	  Antipsychotic	  aT1	  =	  Telephone	  interview	  1;	  T2	  =	  Telephone	  interview	  2,	  T3	  =	  Telephone	  interview	  3;	  aValues	  represent	  group	  means	  ±	  standard	  error	  of	  the	  mean	  (SEM).	  *P<.05	  Time Mean score  	  *	   46 Table 3.3 Mean (SD) data and sample sizes (N) of orthostatic blood pressure and pulse measurements of control and antipsychotic participants at baseline and at four months.  Baseline Four-month follow-up  Variable Mean(SD) Controls (n=20) Antipsychotic group (n=33-34) P Value Controls (n=14-15) Antipsychotic group (n=20) P Value Supine        Systolic BP (mmHg) 111.1(16.4) 112.8(10.9) .41* 110.1(13) 112(13.6) .52* .86** .79*** Diastolic BP 71.5(9.5) 69.7(8.4) .59* 72.9(8.4) 69.9(10.4) .55* .96** .85*** Pulse (BPM) 63.5(12.4) 64(12.1) .95*  58.6(8.4) 61.5(13.3) .07* .08** .3*** Standing       Systolic BP 119.1(16.4) 112(14.9) .42* 114.6(11.3) 110.6(16.6) .24* .13** .25*** Diastolic BP 85.4(16.6) 78.6(13.2) .49* 79.4(7.6) 75.3(8.5) .85* .11** .6*** Pulse 79.9(13.6) 85.8(17.8) .14* 77.1(7.4) 82.8(17.4) .005* .14** .04*** a P values are given for between subjects at baseline and at four months, and longitudinally for both groups. Significance values: Independent samples t test=*, Paired samples t test: Controls=**, antipsychotic group=***.   47 Table 3.4 Mean (SD) values and sample sized (n) of the Short Form 36 (SF-36) in the control group (C) and antipsychotic group (A) and at baseline, month one, two, and three telephone interviews, and four-month follow up visit.  	  Variable Baseline Month I Month II Month III Four-month follow-up Mean (SD) C (n=13) A (n=11) C (n=13) A (n=11) C (n=13) A (n=11) C (n=13) A (n=11) C (n=13) A (n=11) P value Physical Functioning 96.9  (6) 92.7 (14.9) 98.1  (4.8) 83.6 (20.9) 96.5  (5.6) 91.8  (15.2) 98.5 (5.5) 90.9 (14.8) 98.5 (4.3) 89.6 (15.7)  Role -Physical 95.2  (8.5) 71.6 (28.6) 96.6  (5.5) 80.7 (16.2) 91.3  (10.7) 90.9  (11.6) 92.8 (10.5) 86.4 (17.2) 97.1  (6) 80.1 (17.4) Pain 94.2 (9.5) 85.2 (14.1) 92.7  (11.1) 87.7 15.3 88.8  (9.3) 92.3  (9.5) 91.9 (13.1) 93.1  (13) 96  (8.1) 97  (7.1) General Health 75 (16.3) 71.8 (14) 74.2 (13) 74.1 (13.9) 73.9 (15.2) 68.2 (14) 75.8 (14) 71.4 (16.1) 75 (13.8) 71.8 (15.2) Role Emotional 96.2 (6.5) 69.7 (22.4) 91 (14.2) 78.8 (18.4) 94.9 (8.7) 90.9 (16) 96.2 (8.1) 84.1 (19.9) 96.2 (11.6) 81.8 (18.9) Vitality 66.8 (18.1) 54 (17.5) 67.3 (11.7) 63.1 (13.2) 68.3 (9.7) 51.7 (18.1) 70.2 (14.9) 59.7 (12) 68.8 (13.5) 58 (12.2) Social Functioning 93.3 (13.1) 61.4 (16.3) 97.1 (7.4) 86.4 (13.1) 94.2 (11) 87.5 (15.5) 96.2 (93.4) 83 (20.4) 94.2 (11) 73.9 (22) Mental Health 82.7 (12) 69.6 (16.8) 81.5 (9) 77.7 (11) 85.8 (8.9) 73.6 (16.4) 85.4 (11.8) 78.2 (11) 84.2 (10.8) 70 (16.1) Physical Health Summary 90.6 (3.1) 78.1 (3.4) 90.1 (2.2) 83.9 (2.4) 87.6 (2.1) 85.8 (2.3) 89.8 (2.9) 85.5 (3.1) 91.6 (2.4)  84.6 (2.6) .42* .03** Mental Health Summary 84.7 (3.2) 63.6 (3.5) 84.2 (2.5) 76.5 (2.8) 85.8 (3) 75.9 (3.7) 89 (2.8) 76.2 (3) 85.8 (3.5) 71 (3.8) .04*  .09g* .00** a Significance values: Repeated measures ANOVA significance values: within subjects*, between subjects**. Interaction effects: group = g, time = t. C = control group, A = antipsychotic group.       48  Table 3.5 Mean (SD) values of the international physical activity questionnaire (IPAQ) in the control group at baseline, month one, two, and three telephone interviews, and four-month follow-up visit.   Variable Mean (SD) Baseline (n=13) Month I (n=13) Month II (n=13) Month III (n=13) Four month follow-up (n=13) C A C A C A C A C A P Walking 1524.7 (1737.2) 2760.8 (2501.3) 1306.3 (1950.6) 1320 (1644.1) 1182.9 (1121.3) 941.8 (775.2) 2293.5 (3254.1) 2009.2 (2780.6) 1863.2 (2433.5) 1756.6 (2520.1)  Moderate physical activity 341.5 (253.8) 266.2 (401.1) 498.5 (477.1) 696.9 (867.9) 678.5 (508.8) 495.4 (547.9) 700 (627.1) 927.7 (1304.6) 696.9 (560.5) 646.2 (603.7)  Vigorous physical activity 566.2 (381.2) 926.2 (1543.1) 830.8 (616.7) 600 (1104.2) 1680 (992.9) 923.1 (891.8) 1240 (973.7) 1163.1 (1232) 1181.5 (689.1) 935.4 (1246.7)  Total physical activity  2432.4 (554.1) 3952.9 (554.1) 2635.5 (572.8) 2616.9 (572.8) 3541.4 (456.75) 2360.2 (456.75) 4233.5 (1023.8) 4099.96 (1023.8) 3741.7 (456.1) 3338.2 (756.1)  0.1* 0.9**   a Repeated measures ANOVA significance values: within subjects=*, between subjects=**. C = control group, A = antipsychotic group.      49 Table 3.6 Mean (SD) values and statistical analysis of the Three Factor Eating Questionnaire (TFEQ) the in the control group at baseline, month one, two, and three telephone interviews, and four-month follow up visit.   Factor Mean (SD) Baseline Month I Month II Month III Four month follow-up C (n=13) A (n=12) C (n=13) A (n=12) C (n=13) A (n=12) C (n=13) A (n=12) C (n=13) A (n=12) P Value I-Cognitive restraint 7.1 (1.3) 8.9 (1.4) 7.5 (1.2) 8.7 (1.3) 6.6 (1.0) 6.5 (1.0) 7.3 (1.4) 9  (1.5) 7.385 (1.4) 9.8 (1.5) .06* .4** II-Disinhibion 4.8 (3) 5.9 (2.2) 4.2 (3.5) 6.1 (4.4) 3.5 (2.5) 4.8 (3.5) 3.8 (3.3) 4.3 (2.8) 3.5 (2.8) 5.8 (3.3) .09*  .2** III-Susceptibility to hunger 3.6 (2.4) 5.4 (4) 3.6 (2.8) 5.6 (3.7) 4 (2.6) 4.6 (3.1) 3.6 (2.7) 4.4 (3.4) 3.2 (3) 5 (3.6) .8* .2** a Repeated measures ANOVA significance values: within subjects=*, between subjects=**. C = control group, A = antipsychotic group.  Table 3.7 Mean (SD) values for the Medication Adherence Rating Scale (MARS) of participants in the antipsychotic group at month one, two, and three telephone interviews, and four-month follow-up visit.   Month I Month II Month III Four-month follow up P Value MARS Score Mean (SD) (n=13) 8 (2) 8 (2) 8 (2) 8 (2) .8         	   50 Table 3.8 Mean (SD) values for the positive scale, negative subscale, and general psychopathology subscale and total scored Positive and Negative Syndromes Scale for participants taking antipsychotics at the first and second clinical interview.   Clinical Interview I (n=17) Clinical Interview II (n=17) P value Positive Scale 17 (6) 14(5)  Negative Subscale 20(7) 33(11)  General Psychopathology Subscale 41(9) 35(13)  Total PANSS Score Mean (SD)   77 (18) 68 (23) .2  Table 3.9 Mean (SD) values Calgary Depression Scale (CDS) in the antipsychotic group at the first and second clinical interview.    Variable  Clinical Interview I Mean (SD)  Clinical Interview II P Value Total Score 4.45(4.22) 2.65(2.64) .05  Table 3.10 Mean (SD) values for the Social and Occupational Functioning Scale (SOFAS) of participants in the antipsychotic group at the first and second clinical interview.    Clinical Interview I Mean (SD) Clinical Interview II  P Value SOFAS Score 60(13.9) 62(14.8) 0.7  51 3.1 Anthropometric measures at baseline At the baseline assessment, a significant difference in weight was seen between control participants (68.7±10.1) and antipsychotic drug treated participants (73.4±14.6), t(52) = 5.91, p=0.02 (Table 3.2, Figure 3). At baseline, participants taking antipsychotic medications weighed on average 4.6 kilograms (kg) more than control participants. A trend difference was also seen in waist circumference (WC) at baseline. Antipsychotic treated participants (90.3±11.6) had greater waist WCs than control participants (82.8±8.7), t(52) = 2.9, p = .09. Age, height, BMI, sitting and standing blood pressures and pulse measurements were not significantly different between control participants and participants taking antipsychotic medications at baseline.  3.2 Anthropometric measures at four months At the four month follow-up a significant difference in weight was seen between control participants (70.4±8.8) and participants taking antipsychotics (79.3±17.7), t(34) = -1.784, p < .05. At four months, participants taking antipsychotic medications weighed an average of 8.9 kg more than control participants. A significant difference in BMI was found between control participants (24.2±2.8) and participants taking antipsychotics (27±5.4) at four months t(34) = -1.9, p=.04. On average, participants taking antipsychotic medications had a 2-point higher (8.2%) BMI than control participants. A trend in WC was seen at four months between controls (84.6±7.8) and antipsychotic participants (96.3±13), t(34) =3.243, p=0.08. On average, control participants had 11.7 cm smaller WCs than participants taking antipsychotic medications. Standing pulse measurements were found to be significantly different at four months between control  52 participants (77.1±7.4) and those taking antipsychotics (82.8±17.4), t(32) = 8.903, p=.005. On average, participants taking antipsychotic medications had 5.6 beats per minute (BPM) higher pulse measurements than control participants.  Furthermore, a trend was seen in supine pulse measurements at four months between control participants (58.6±8.4) and those taking antipsychotics (61.5±13.3) t(32) =3.608, p=.07. Participants in the control group had slightly higher pulse measurements, although not statistically significant.  3.3 Within-subjects at baseline and four months Significant differences in WC were seen within participants taking antipsychotics at baseline (90.3±11.6) and at four months (96±13), t(20) = -2.937, p = .08 (see Figure 4). On average, antipsychotic treated participants showed a 5.6 cm increase in waist circumference at the four month follow up. A significant difference was seen between standing pulse measurements in the antipsychotic group (85.8±17.8) and four months (82.8±17.4), t(18) = 2.219, p = .04. Lastly, a significant difference was seen when comparing baseline weight (73.4±15.7) with weight at four months (79.3±17.7), t(20) = -3.732, p < .005 in the antipsychotic group. Over the course of four months, participants taking antipsychotic medications gained an average of 5.5 kg.  3.4 Weight gain over time To test for the presence of weight gain over time, the difference in weight between four months and baseline was calculated (weight at four months – weight at baseline). Gain in BMI and WC was also calculated. Only participants who had  53 completed both the baseline assessment and the four-month follow-up were included in the analysis. A t-test was used to detect significance between the control group (n=15) and those taking antipsychotics (n=21). We found that the weight gain in participants taking antipsychotics was significantly greater than the control participants (t(34) = -3.56, p < .05). In addition, we found significantly greater BMI (t(34) = -2.96, p = .005) in participants taking antipsychotics compared to control participants. Gain in WC did not reach statistical significance.  When the weight gain was normalized it was also found to be statistically significant (t(34) = -3.53, p < .05).  3.5 Short Form 36 (SF-36) Mental and Physical Health Summary  Between subjects analysis revealed significant differences between control participants (n=13) and participants taking antipsychotics (n=11) in physical health summary results of the SF-36 (Table 3.4, Figure 6) F(1, 22) = 5.54, p < .05. Patients taking antipsychotics reported lower physical health scores than participants not on antipsychotics. No other significant differences in physical heath summary results were found. Significant differences in the mental health summary were found through within subjects analysis over time F(4, 88) = 2.657, p < 0.05. A significant increase in mental health summary scores over time was seen in participants taking antipsychotic medication (Figure 7). A trend was seen though within subjects analysis by group F(4, 88) = 2.657, p = 0.09. Furthermore, significant differences were also found through between subjects analysis of the mental health summary when comparing control participants (n=13) and those taking antipsychotics (n=11) F(1,22) = 17.83, p < .05.  54 Control subjects had significantly higher mental health summary scores than those taking antipsychotics.  No other significant differences were found in mental health summary scores.  3.6 Three Factor Eating Questionnaire (TFEQ)  Within subjects analysis of factor one revealed a trend differences by time F(4,92) = 2.347, p = 0.06 (Table 3.6). Within subjects analysis revealed a trend differences over time of factor two of the TFEQ F(4, 92) = 2.088, p = 0.09 (Table 3.6). No further significant differences were found though analysis of the TFEQ through within or between subjects analysis of the TFEQ in either group.  3.7 International Physical Activity Questionnaire (IPAQ) 	   No significant differences were found through analysis of the IPAQ in either group over time. A trend, however, was seen through within subjects analysis over time F(4, 96) = 2.018, p = .1 (Table 3.5).  3.8 Positive and Negative Syndromes Scale (PANSS)  For analysis of the PANSS a paired samples t-test was used to test for differences within the same group at two time points, clinical interview one at the beginning of the study and the second four months later. No significant differences were found though analysis of the PANSS (Table 3.8).   55 3.9 Calgary Depression Scale (CDS)   Again, paired samples t test was used to test for differences within the CDS. Significantly lower CDS scores were found at the second clinical interview (4.5±4.42) compared to clinical interview one (2.7±2.6) t(19) = 2.1, p = 0.05 (Table 3.9). 3.10 Social and Occupational Functioning Scale (SOFAS) A paired samples t test was also used to test for significance between clinical interview one (60±13.9) and clinical interview two (62±14.8). No significant differences were seen in the SOFAS scores. Analysis of the SOFAS, did, however, reveal a trend increase in SOFAS score at the second clinical interview t(19) = -.358, p = 0.07 (Table 3.10).       56 Chapter 4: Discussion  4.1 Findings In this study we have undertaken an interim analysis of a four month long clinical trial. A completers analysis was used for statistical analysis.  This interim analysis shows that patients with first episode psychosis newly started on a SGA tend to weigh more than people with no history of psychiatric illness and SGA treatment. This is contrary to the hypothesis that at baseline there would be no significant differences in weight. In addition to weighing more, patients with first episode psychosis on SGAs tend to have greater waist circumferences at the beginning of the study.   Although this contrasts to our hypothesis that there would be no significant differences in weight or waist circumference at baseline, it is not unexpected that a sample of patients with mental illness would greater weight and waist circumferences than those with no history of psychiatric illness. As such, there are a number of factors, in addition to antipsychotic drug treatment, that place those with mental illness at a greater risk of weight gain than those without (Thakore et. al., 2002; Hennekens et. al., 2005). The disease process of schizophrenia can result in a number of symptoms that lead to weight gain. For example, poor diet, smoking, and decreased physical activity have been found to be more prevalent in people with schizophrenia (Brown et. al., 1999), increasing their risk of obesity. At four month follow-up, patients taking antipsychotics appeared to gain weight over the course of the study. This is consistent  57 with the hypothesis and is an expected finding given the potential of SGAs to induce weight gain.  Changes in heart rate were also noted at four months with slightly significant differences between controls and those taking antipsychotics. Given that there were no significant differences at baseline, we can conclude that that this is related to the effects of antipsychotic medications. Moreover, heart rate variability has been reported as an effect of antipsychotics (Silke et. al., 2002).  At four month follow up, a trend difference was seen in WC with slightly greater WC observed in patients taking antipsychotics compared to controls. We hypothesize that, by completion of the entire clinical trial (n=90), differences in WC between groups will reach statistical significance. Although WC differences were not significantly different than controls at four months, participants taking antipsychotics did show a significant increase in WC from their measurements at baseline. Given that WC is an indicator of visceral fat deposition (Thakore et. al., 2002), this is consistent with our hypothesis that the weight gain seen in patients taking antipsychotics could be largely visceral. Given these findings, the benefit of analysis through abdominal MRI is especially useful in exploring the locality and magnitude of visceral fat deposition in patients taking antipsychotic medications. Although a significant difference in weight was expected to be seen within the antipsychotic group, the weight gain seen over the course of four months did not reach statistical significance. A trend difference in weight was seen in the antipsychotic group with a mean weight gain of 2.5 kg. We hypothesize that, by the end of the clinical trial, which would create a larger sample size, significant differences in weight will be seen in the antipsychotic group.   58 In order to assess weight gain over time, the difference in weight at baseline and four months was calculated in participants who had completed the baseline assessment and four-month follow-up. We found that participants taking antipsychotics had significantly more weight gain at four months of the study than did control participants. Furthermore, we found an overall weight loss in control participants at four months of the study. Additionally, a corresponding gain in BMI was also found in BMI at four months.  Gain in WC was also calculated, however, it was not statistically significant. Overall, we found that, after four months of the study, participants taking antipsychotic medication gained an average of 5.5 kg.   There are a number of confounders that may have affected the significant gain in weight in participants taking antipsychotics. These include, starting weight, duration of antipsychotic treatment. Participants who had a lower BMI at the beginning of the study may have had a higher likelihood of weight gain than participants who were already at a high BMI. In order to be eligible for the study, the duration of antipsychotic treatment was limited to no longer than twenty-four weeks (six months) of initial treatment with the drug. Based on our results that significant weight gain was found over four months of the study, it is likely that the length of time that the participant has been on the antipsychotic may be a confounder. Specifically, participants that have been on the antipsychotic for longer may experience less weight gain than those who are in earlier stages of antipsychotic treatment.  The results of the study found significant differences in subjective quality of life assessed by the SF-36. Patients taking antipsychotic medications rated their physical and mental heath as lower than the control participants. The SF-36 has been shown to  59 be an accurate tool to measure quality of life in patients with schizophrenia (Meijer et. al., 2003). In this study we were able to see that the summary scores of the SF-36 were lower in patients on antipsychotic medication compared to those that are not. It is not surprising that patients with psychotic disorders would have rated their physical and mental health as lower than that of control subjects regardless of antipsychotic treatment. There are a number of factors that are related to the disease pathology of schizophrenia and other psychotic disorders that may decrease the subjective quality of life. Such factors include its impact on of social relationships (Gupta et. al., 1998), depression (Siris, 2000), and adverse effects related to treatment may all contribute to lowering ones self described feelings of physical and mental health. Although the mental and physical health of people on antipsychotics were lower than that of the control group, improvements in subjective mental health were seen at the four month follow up in patients taking antipsychotics. This is not unexpected as the effects of antipsychotics may be improving symptoms in this group. Although mean PANSS scores did improve slightly by the second clinical interview, the improvements were not significantly different. This suggests that patients taking antipsychotics are feeling as if their mental health has improved after four months of treatment. This is consistent with the findings of Awad et. al. (2012) who found a general trend of SGAs to have a positive impact on quality of life of patients. We conclude that, by completion of the clinical trial or with longer duration of study, significant differences in PANNS scores may be seen. Lastly, we conclude that the lack of significant improvements in physical health of patients taking antipsychotics were related to the adverse events related to antipsychotic medication such as weight gain (Robson & Gray, 2007).   60 No significant differences were detected though analysis of the TFEQ. Trend differences were seen over time in factor one and two. Consistently patients taking antipsychotic medications scored higher than control participants in all three factors of the TFEQ however they did not reach statistical significance. Although no significant differences were detected in mean MARS, IPAQ, or PANSS scores, a significant improvement was seen in CDS scores at the second clinical interview in participants taking antipsychotic medication. Similar to the findings reported in Innamorati et. al. (2013) SGAs have been shown to decrease depressive symptoms in patients with schizophrenia, regardless of the type of SGA used. In this study we found that over the course of four months a significant improvement in depressive symptoms were seen in patients taking antipsychotic medications. In this study we reported no significant improvements in psychotic symptoms in light of significant improvements in depressive symptoms. We hypothesize that the CDS may be a more sensitive measure to test for initial improvements in symptomology in the early stages of antipsychotic treatment. This may prove a useful tool for clinicians wishing to assess the efficacy of antipsychotic treatment if a patient does not appear to be responding to treatment. Further research is needed to determine if the CDS could be used as a clinical tool to determine efficacy of SGAs in the early stages of treatment.  Lastly, a trend increase was observed in SOFAS scores at the second clinical interview. It is not unexpected that slight improvements in SOFAS scored would be seen after four months of antipsychotic treatment. By completion of the trial, significant improvements in SOFAS scored could be detected. Other hypotheses for why significant improvements in SOFAS scores could not be detected with the present  61 sample is that the population of participants taking antipsychotics is already at a relatively high level of functioning. In order to consent to the study and to participate in all aspects of the trial the individual was required to be at a higher level of functioning, as such, their baseline may be too high to detect differences. Moreover, in future studies it may be useful to utilize more sensitive questionnaires that are more sensitive at detecting improvements in global functioning.  4.2 Limitations This study may have benefited though randomized method of participant recruitment. Method of recruitment for the treatment group was primarily though physician referral at a community based mental health treatment center in Vancouver, Canada. Although obtaining an adequate sample size would be difficult to achieve, It could be suggested that a degree of biases may have had impact on metabolic characteristics of the treatment group. Various, geographic, cultural, and socioeconomic factors may have played a roll in creating bias. Although significant differences in weight, WC, and CDS scores were reported, a high level of variance limits the strength. Longitudinal data was limited by participant retention. A number of participants in the antipsychotic group suffered relapses or exacerbation in psychotic symptoms and had to withdraw from the study or were unable to participate various assessments. Future studies may benefit though defining a set of criteria at the time of consent that will assess the likelihood of stability on ones chronic condition.   62 4.3 Future Directions In this study we have performed an interim analysis of a four-month long clinical trial that has shown promising results. In future analysis, it will be beneficial to compare analysis of MRI data and waist circumferences. Given the findings in this study, it will be beneficial to perform analysis on high and low metabolic risk drugs over time. With large sample sizes it is likely that trend differences may reach statistical significance.   4.4 Conclusion  Consistent with previous studies, we have also found that patients with mental illness may benefit from health promotion and lifestyle coaching (Brown et. al., 1999).  The results of this study are consistent with previous work (Mackin et. al., 2007) who found that patients with mental illness tend to have greater waist circumferences and higher BMIs than the general population. The results of this study suggest that individuals taking antipsychotics may benefit from regular monitoring of WC, weight and pulse measurements. SGAs may have a positive effect on mental health of patients with psychotic disorders. Given the results seen in this sample of drug naive patients, careful monitoring may be especially important in the initial phase of antipsychotic treatment.  	  	  	  	  	  	  	  	  	   63 References Alberti, K. G. M. M., Zimmet, P., & Shaw, J. (2006). Metabolic syndrome—a new  world‐wide definition. A consensus statement from the international diabetes federation. Diabetic Medicine, 23(5), 469-480. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental  disorders (5th ed.). 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(Accepted   for publication, pending revisions) Wirshing, D. A., Wirshing, W. C., Kysar, L., Berisford, M. A., Goldstein, D., Pashdag, J.,  ... & Marder, S. R. (1999). Novel antipsychotics: comparison of weight gain  liabilities. Journal of Clinical Psychiatry. World Health Organization. (1999). Definition, Diagnosis, and Classification of Diabetes  Mellitus and its Complications. A report of WHO Consultation. Part 8. The  Metabolic Syndrome.  World Health Organization. (2013). Obesity and overweight. Fact sheet N°311.  Retrieved online May 12, 2014 from   http://www.who.int/mediacentre/factsheets/fs311/en/ Wright, S. M., & Aronne, L. J. (2012). Causes of obesity. Abdominal imaging, 37(5),  730-732.     72 Appendix I: Mechanism of action of common SGAs Appendix I has been adapted from a published manuscript by Whitney et. al. (2015). Appendix II: Mechanism of action of common SGAs  Aripiprazole. The pharmacological mechanism of action of aripiprazole is somewhat different from all other SGAs in that it provides partial agonism at dopaminergic receptors. This partial agonistic effect decreases neuronal transmission in areas of hyperdopaminergic activity and increases neuronal transmission in areas of hypodopaminergic activity (Mailman, Murthy 2010). Aripiprazole has high affinity for the dopamine D2 and D3 receptors and moderate affinity for D4 receptors. Partial agonism occurs with the D2 receptors. Clozapine. Clozapine was the first SGA to have been used widely in the clinic (Crilly 2007). It has moderate-to-low affinity for D1 receptors, low affinity for D2 and D3 receptors, but high affinity for D4 receptors (Ashby, Wang 1996). Clozapine has been shown to possess high affinity to both 5-HT2A and 5-HT2C receptors and moderate affinity to 5-HT3 receptors. Clozapine is unique among SGAs because it is known to be beneficial in patients with treatment resistant schizophrenia, and for persistent psychotic symptoms for which other antipsychotic agents have proven ineffective (Meltzer 2013). Risperidone. Similar to other SGAs, it occupies more than 80% of cortical 5- 73 Appendix II: Mechanism of action of common SGAs  HT2A receptors and over 70% of D2 receptors at therapeutic dosages (Miyamoto, et al. 2005). Quetiapine. The pharmacological mechanism of action of quetiapine is slightly different than other SGAs. Quetiapine exhibits weaker antagonistic effects at dopamine D2 and serotonin 5-HT2 receptors, stronger antagonistic effects at alpha-1 receptors, and modest histaminergic effects (Nasrallah 2008). This combination of receptor antagonism is thought to be responsible for its therapeutic effects and low risk of EPS. Olanazpine. Like other SGAs, olanzapine produces antipsychotic effects through the antagonism of dopamine at D2 receptors and serotonin at 5-HT2A receptors (Kantrowitz, Citrome 2008). In addition, olanzapine also has antagonistic effects at 5HT-2C, 5HT3, 5HT6. D1-4, histamine H1, alpha1-adrenoreceptors, GABAa, beta-adrenoreceptors, and muscarinic M1-5 receptors (ibid). Olanzapine’s effects at these other receptors have been hypothesized to be responsible for its adverse effects (ibid). Studies have indicated that olanzapine may be associated with significant pharmacokinetic inter-individual variability, due to induction and inhibition of its primary metabolizing enzyme CYP1A2. One study found that patients who smoked cleared olanzapine 55% faster than nonsmokers, men cleared olanzapine 38% faster than women, and black patients cleared olanzapine 26% faster than other ethnicities (Bigos, et al. 2008). Ziprasidone. Ziprasidone is a newer SGA that has pharmacological properties distinct from other SGAs. Ziprasidone is understood to have high affinity for 5- 74 Appendix II: Mechanism of action of common SGAs  HT2A, 5-HT2C, 5-HT1A and 5-HT1B and 1D receptors (Schmidt et. al., 2001). Ziprasidone is also understood to possess high affinity for D2 receptors (Stahl, Shayegan 2003).                	  	  	  	  	   75 Appendix II: Consent form  If	  you	  are	  a	  parent	  or	  legal	  guardian	  of	  a	  child	  who	  may	  take	  part	  in	  this	  study,	  permission	  from	  you	  and	  the	  assent	  (agreement)	  of	  your	  child	  may	  be	  required.	  	  When	  we	  say	  “you”	  or	  “your”	  in	  this	  consent	  form,	  we	  mean	  you	  and/or	  your	  child;	  “we”	  means	  the	  doctors	  and	  other	  staff.	  	  1.	  	  INVITATION	  	  	  You	  are	  being	  invited	  to	  take	  part	  in	  this	  research	  study	  because you	  are	  being	  seen	  by	  one	  of	  the	  psychiatrists	  within	  the	  Mental	  Health	  Program	  in	  one	  of	  the	  Child	  and	  Adolescent	  Psychiatric	  Units	  at	  British	  Columbia’s	  Children’s	  Hospital,	  or	  in	  the	  Vancouver/Richmond	  EPI	  Early	  Psychosis	  Intervention	  Clinic	  on	  East	  Hastings	  Street	  in	  Vancouver	  (EPI	  Clinic).	  	  	  	  We	  are	  asking	  male	  or	  female	  subjects	  who	  are	  at	  least	  12	  years	  old	  who	  are	  healthy	  or	  who	  have	  first-­‐episode	  bipolar	  disorder,	  to	  take	  part	  in	  the	  study,	  as	  well	  as	  subjects	  who	  are	  at	  least	  15	  years	  old	  and	  who	  have	  first-­‐episode	  psychosis.	  	  In	  addition,	  subjects	  with	  bipolar	  disorder	  or	  psychosis	  must	  be	  taking	  “aripiprazole”	  (ABILIFY®),	  “risperidone”	  (Risperdal®)	  or	  “quetiapine”	  (Seroquel®)	  for	  treatment.	  	   	  2.	  YOUR	  PARTICIPATION	  IS	  VOLUNTARY	  	  	  	  Your	  participation	  is	  voluntary.	  You	  have	  the	  right	  to	  refuse	  to	  participate	  in	  this	  study.	  If	  you	  decide	  to	  participate,	  you	  may	  still	  choose	  to	  withdraw	  from	  the	  study	  at	  any	  time	  without	  any	  negative	  consequences	  to	  the	  medical	  care,	  education,	  or	  other	  services	  to	  which	  you	  are	  entitled	  or	  are	  presently	  receiving.	  	  Before	  you	  decide,	  it	  is	  important	  for	  you	  to	  understand	  what	  the	  research	  involves.	  	  This	  consent	  form	  will	  tell	  you	  about	  the	  study,	  why	  the	  research	  is	  being	  done,	  what	  will	  happen	  to	  you	  during	  the	  study	  and	  the	  possible	  benefits,	  risks	  and	  discomforts.	  	  	  You	  also	  need	  to	  know	  that	  there	  are	  important	  differences	  between	  being	  in	  a	  research	  study	  and	  being	  cared	  for	  by	  your	  family	  doctor	  or	  psychiatrist.	  When	  you	  participate	  in	  a	  research	  study,	  the	  main	  goal	  is	  to	  learn	  things	  to	  help	  other	  patients	  in	  the	  future.	  Outside	  a	  research	  study,	  your	  doctor’s	  sole	  goal	  is	  to	  care	  for	  your	  health.	  Nevertheless,	  the	  scientists	  have	  a	  duty	  of	  care	  to	  all	  subjects	  and	  will	  inform	  you	  of	  any	  information	  that	  may	  affect	  your	  willingness	  to	  remain	  in	  the	  study.	  	  If	  you	  wish	  to	  participate	  in	  this	  study,	  you	  will	  be	  asked	  to	  sign	  this	  form.	  	  If	  you	  do	  decide	  to	  take	  part	  in	  this	  study,	  you	  are	  still	  free	  to	  withdraw	  from	  the	  study	  at	  any	  time	  and	  without	  giving	  any	  reasons	  for	  your	  decision.	  	  	  	  If	  you	  do	  not	  wish	  participate,	  you	  do	  not	  have	  to	  provide	  any	  reason	  for	  your	  decision	  nor	  will	  you	  lose	  the	  benefit	  of	  any	  medical	  care	  to	  which	  you	  are	  entitled	  or	  are	   76 presently	  receiving.	  	  Please	  take	  time	  to	  read	  the	  following	  information	  carefully	  and	  to	  discuss	  it	  with	  your	  family,	  friends,	  and	  psychiatrist	  before	  you	  decide.	  	  	  3.	  	  WHO	  IS	  CONDUCTING	  THE	  STUDY?	  	  	  This	  study	  is	  an	  investigator-­‐driven	  study	  conducted	  by	  Drs.	  Barr	  and	  Kopala	  from	  the	  University	  of	  British	  Columbia	  (UBC).	  	  The	  Principal	  Investigators	  have	  received	  financial	  compensation	  from	  Bristol	  Myers	  Squibb	  (BMS)	  for	  the	  work	  required	  to	  do	  this	  clinical	  research.	  Bristol	  Myers	  Squibb	  is	  the	  company	  that	  produces	  ABILIFY®	  (“aripiprazole”).	  	  4.	  	  BACKGROUND	  	  	  Fifteen	  percent	  of	  BC’s	  youth	  suffer	  from	  psychiatric	  disorders;	  many	  of	  these	  individuals	  will	  be	  treated	  with	  atypical	  antipsychotics,	  such	  as	  “aripiprazole”	  (ABILIFY®),	  “risperidone”	  (Risperidal®)	  or	  “quetiapine”	  (Seroquel®).	  Over	  the	  past	  few	  years,	  prescription	  of	  atypical	  antipsychotics	  to	  youth	  has	  increased	  substantially	  with	  little	  evaluation	  of	  the	  potential	  side	  effects	  these	  medications	  may	  have	  on	  individuals	  who	  are	  still	  growing	  and	  developing.	  In	  adults,	  atypical	  antipsychotics	  have	  been	  shown	  to	  cause	  significant	  weight	  gain	  and	  other	  biological	  changes,	  leading	  to	  an	  increased	  risk	  of	  type	  2	  diabetes.	  Importantly,	  nothing	  is	  known	  about	  how	  atypical	  antipsychotics	  affect	  the	  storage	  of	  fat	  in	  the	  body:	  some	  fat	  (“subcutaneous”,	  i.e.	  the	  fat	  just	  under	  the	  skin)	  is	  considered	  less	  harmful	  than	  other	  types	  of	  fat	  (“visceral”,	  i.e.	  the	  fat	  that	  surrounds	  the	  internal	  organs).	  Also,	  it	  is	  uncertain	  whether	  all	  atypical	  antipsychotics	  affect	  fat	  storage	  in	  the	  same	  way.	  	  This	  will	  be	  the	  first	  ever	  study	  to	  use	  MRI	  to	  look	  at	  the	  levels	  and	  distribution	  of	  fat	  in	  subjects	  taking	  aripiprazole.	  	  A	  total	  of	  60	  subjects	  with	  first-­‐episode	  psychosis	  or	  first-­‐episode	  bipolar	  disorder	  will	  be	  recruited	  for	  the	  study.	  	  In	  addition,	  another	  30	  healthy	  subjects	  will	  also	  be	  recruited	  as	  study	  controls.	  	  Recruitment	  will	  take	  place	  at	  BC	  Children’s	  Hospital,	  as	  well	  as	  from	  the	  Vancouver/Richmond	  EPI	  Early	  Psychosis	  Intervention	  clinic	  on	  East	  Hastings	  Street	  in	  Vancouver,	  British	  Columbia	  (EPI	  Clinic).	  	  5.	  	  WHAT	  IS	  THE	  PURPOSE	  OF	  THE	  STUDY?	  	  The	  purpose	  of	  this	  study	  is	  to	  determine	  if	  treatment	  with	  the	  antipsychotic	  medications	  aripiprazole,	  risperidone	  or	  quetiapine	  causes	  an	  increase	  in	  both	  types	  of	  fat	  in	  the	  abdomen,	  or	  whether	  one	  type	  of	  fat	  or	  the	  other	  is	  more	  affected.	  We	  will	  also	  determine	  if	  these	  atypical	  (otherwise	  known	  as	  ‘second	  generation’)	  antipsychotics	  cause	  an	  increase	  in	  liver	  fat	  content,	  as	  this	  could	  increase	  the	  risk	  of	  developing	  type	  2	  diabetes	  in	  the	  future.	  	  	  We	  are	  also	  interested	  in	  comparing	  the	  levels	  of	  glucose,	  cholesterol,	  fats,	  and	  hormones	  in	  our	  subjects’	  blood	  to	  see	  if	  there	  are	  any	  differences	  depending	  on	  what	  medication	  you	  are	  taking.	  	  Finally,	  we	  will	  be	  gathering	  information	  on	  mental	  health,	   77 physical	  growth,	  eating	  behaviours	  and	  activity	  levels	  to	  see	  if	  we	  can	  observe	  between	  subjects	  taking	  aripiprazole,	  risperidone,	  or	  quetiapine,	  and	  subjects	  who	  are	  not	  taking	  any	  antipsychotics.	  	  6.	  WHO	  CAN	  PARTICIPATE	  IN	  THIS	  STUDY?	  	  You	  may	  be	  able	  to	  participate	  in	  this	  study	  if	  you:	  • Are	  male	  or	  female	  • Have	  bipolar	  disorder	  and	  you	  are	  at	  least	  12	  years	  old;	  or	  if	  you	  are	  healthy	  and	  you	  are	  at	  least	  12	  years	  old;	  or	  if	  you	  are	  at	  least	  15	  years	  old	  and	  have	  psychosis	  • Have	  recently	  been	  admitted	  to	  the	  hospital	  or	  community	  care	  for	  first-­‐episode	  psychosis	  or	  for	  first-­‐episode	  bipolar,	  or	  if	  you	  are	  completely	  healthy	  • Are	  taking	  aripiprazole,	  risperidone,	  quetiapine,	  olanzapine,	  or	  paliperidone	  principally	  for	  psychosis	  or	  bipolar.	  	  	  • Have	  received	  no	  more	  than	  6	  months	  lifetime	  total	  of	  treatment	  with	  antipsychotic	  medication	  at	  the	  time	  of	  consent.	  	  7.	  WHO	  SHOULD	  NOT	  PARTICIPATE	  IN	  THE	  STUDY?	  	  You	  cannot	  participate	  in	  this	  study	  if	  you:	  • Have	  diabetes	  mellitus,	  seizure	  disorders,	  mental	  retardation	  (IQ	  <70),	  or	  pregnancy	  (current	  or	  within	  3	  months	  postpartum). Because	  we	  do	  not	  know	  if	  or	  how	  an	  unborn	  baby/fetus	  could	  be	  harmed,	  you	  should	  avoid	  becoming	  pregnant.	  	  Talk	  to	  your	  study	  family	  doctor	  or	  psychiatrist	  about	  the	  risks	  to	  your	  unborn	  baby/fetus	  if	  you	  do	  get	  pregnant.	  	  Work	  with	  the	  study	  doctor	  to	  find	  the	  best	  solution	  to	  make	  sure	  you	  do	  not	  get	  pregnant,	  if	  you	  wish	  to	  be	  in	  the	  study.	  	  	  • Received	  chemotherapy	  in	  the	  4	  weeks	  prior	  to	  baseline	  or	  16-­‐week	  follow-­‐up	  interview.	  • Are	  not	  able	  to	  fluently	  communicate	  in	  English.	  • Have	  any	  of	  the	  criteria	  that	  exclude	  you	  from	  having	  an	  MRI	  scan	  (i.e.,	  if	  you	  have	  had	  major	  surgery	  in	  the	  last	  6	  months,	  are	  morbidly	  obese,	  have	  claustrophobia,	  have	  metal	  in	  your	  body	  from	  a	  surgical	  intervention	  or	  from	  doing	  metalwork,	  are	  experiencing	  fever/dizziness/nausea/coughing/agitation,	  or	  have	  uncontrolled	  seizures).	  	  8.	  WHAT	  DOES	  THE	  STUDY	  INVOLVE?	  	   If	  you	  decide	  to	  take	  part	  in	  this	  study,	  you	  may	  be	  in	  one	  of	  three	  groups:	  the	  aripiprazole	  group,	  the	  risperidone/quetiapine/olanzapine/paliperidone	  group,	  or	  the	  control	  (healthy)	  group.	  	  Which	  group	  you	  belong	  to	  will	  depend	  on	  what	  type	  of	  medication	  your	  psychiatrist	  has	  prescribed	  for	  you.	   78 	  Overview	  of	  the	  Study	  	  If	  you	  are	  taking	  antipsychotics,	  you	  will	  need	  to	  come	  to	  4	  study	  visits.	  	  All	  of	  these	  appointments	  will	  take	  place	  at	  UBC	  Hospital.	  	  The	  first	  2	  visits	  will	  occur	  approximately	  10	  days	  apart,	  followed	  by	  a	  3	  month	  period	  where	  there	  will	  be	  no	  visits,	  and	  then	  you	  will	  have	  your	  third	  visit,	  and	  approximately	  10	  days	  after	  that,	  your	  fourth	  visit.	  	  During	  the	  3	  month	  period	  where	  there	  will	  be	  no	  visits,	  you	  will	  receive	  one	  telephone	  call	  each	  month	  and	  we	  will	  be	  asking	  you	  some	  questions	  about	  your	  eating	  habits,	  exercise	  level,	  and	  general	  health.	  	  For	  the	  first	  and	  third	  study	  visit,	  you	  will	  need	  to	  come	  to	  UBC	  Hospital	  in	  the	  morning	  to	  have	  your	  weight,	  height,	  blood	  pressure	  and	  heart	  rate	  measured,	  have	  an	  MRI	  scan,	  get	  some	  blood	  taken,	  and	  answer	  some	  questionnaires.	  These	  visits	  will	  take	  no	  more	  than	  4	  hours	  each	  to	  complete.	  One	  of	  the	  things	  you	  will	  be	  asked	  to	  do	  in	  preparation	  for	  these	  visits	  is	  to	  eat	  at	  least	  150	  grams	  of	  carbohydrates	  a	  day	  for	  the	  3	  days	  prior	  to	  your	  first	  and	  third	  visits	  without	  increasing	  your	  total	  calorie	  intake	  (this	  means	  you	  may	  have	  to	  cut	  back	  on	  the	  amount	  of	  fat	  in	  your	  food	  by	  an	  equivalent	  amount).	  This	  is	  approximately	  equal	  to	  one	  portion	  of	  pasta,	  plus	  a	  bowl	  of	  breakfast	  cereal,	  plus	  a	  sub	  sandwich	  every	  day	  for	  3	  days.	  We	  also	  ask	  that	  you	  maintain	  your	  regular	  level	  of	  activity,	  but	  refrain	  from	  heavy	  exercise,	  smoking	  or	  drinking	  alcohol.	  The	  reason	  we	  ask	  you	  to	  do	  this	  is	  to	  prepare	  you	  for	  one	  of	  the	  blood	  tests	  that	  we	  will	  be	  doing.	  However,	  you	  do	  not	  have	  to	  do	  this	  if	  this	  is	  too	  challenging.	  On	  the	  second	  and	  fourth	  visits,	  we	  will	  be	  evaluating	  your	  mental	  health	  by	  asking	  you	  some	  more	  questions.	  	  These	  visits	  may	  take	  place	  at	  UBC	  Hospital,	  but	  it	  is	  also	  possible	  to	  meet	  you	  in	  a	  private	  location	  of	  your	  choice	  (such	  as	  your	  home),	  and	  will	  take	  between	  3	  to	  4	  hours	  each.	  	  If	  you	  are	  a	  healthy	  individual,	  we	  will	  ask	  you	  to	  come	  to	  UBC	  Hospital	  for	  the	  first	  and	  third	  visit	  only.	  	  At	  these	  two	  visits,	  we	  will	  take	  your	  weight,	  height,	  blood	  pressure	  and	  heart	  rate,	  give	  you	  an	  MRI	  scan,	  take	  some	  blood,	  and	  ask	  you	  some	  questionnaires.	  	  These	  two	  visits	  will	  take	  approximately	  4	  hours	  each	  to	  complete.	  	  You	  will	  not	  be	  required	  to	  come	  to	  the	  second	  and	  fourth	  visits	  because	  these	  assessments	  only	  apply	  to	  people	  with	  mental	  health	  conditions.	  	  	  	  	  We	  also	  ask	  that	  you	  allow	  us	  to	  access	  your	  Pharmanet	  records.	  	  Pharmanet	  is	  a	  computer-­‐based	  electronic	  record	  of	  all	  the	  prescriptions	  that	  you	  have	  filled	  through	  a	  pharmacy.	  	  The	  reason	  we	  ask	  for	  your	  permission	  to	  look	  at	  your	  Pharmanet	  records	  is	  so	  that	  we	  may	  gather	  accurate	  data	  on	  the	  medications	  that	  you	  have	  taken	  over	  the	  past	  year	  to	  see	  if	  any	  of	  these	  other	  medications	  affect	  weight	  gain.	  	  	  	  Descriptions	  of	  Each	  Visit	  	  First	  Visit:	  Everyone	  comes	  to	  this	  first	  study	  visit.	  	  For	  the	  first	  study	  visit,	  you	  will	  start	  the	  day	  by	  receiving	  a	  magnetic	  resonance	  imaging	  (MRI)	  scan,	  which	  will	  last	  approximately	  45	   79 minutes.	  	  The	  MRI	  scan	  will	  help	  us	  to	  measure	  the	  effects	  of	  atypical	  antipsychotics	  on	  fat	  in	  your	  abdomen	  by	  obtaining	  a	  three	  dimensional	  image	  of	  the	  inside	  of	  your	  abdomen.	  MRI	  scans	  are	  completely	  non-­‐invasive	  and	  work	  by	  use	  of	  powerful	  magnets,	  so	  they	  do	  not	  involve	  exposure	  to	  radiation	  or	  x-­‐rays.	  However,	  if	  you	  have	  ever	  worked	  with	  metal	  (e.g.,	  welding,	  metalworking)	  and/or	  you	  suspect	  the	  presence	  of	  metal	  in	  your	  eye,	  you	  will	  be	  required	  to	  complete	  an	  orbital	  x-­‐ray	  (x-­‐ray	  for	  your	  eyes).	  The	  x-­‐ray	  will	  help	  us	  to	  determine	  whether	  or	  not	  it	  is	  safe	  for	  us	  to	  perform	  an	  MRI	  scan.	  If	  an	  orbital	  x-­‐ray	  is	  required,	  it	  will	  be	  done	  in	  the	  same	  building	  as	  the	  MRI	  scan.	  The	  MRI	  scan	  itself	  occurs	  in	  a	  small	  space	  (approximately	  1	  metre	  in	  width)	  and	  the	  scanner	  generates	  a	  loud	  sound	  when	  it	  is	  active.	  You	  will	  be	  provided	  with	  ear	  protection	  during	  your	  scan.	  If	  you	  suffer	  from	  a	  fear	  of	  small	  spaces	  you	  may	  find	  the	  MRI	  scan	  uncomfortable,	  however	  you	  will	  not	  suffer	  any	  harm	  as	  a	  result	  of	  this	  scan.	  	  After	  your	  scan,	  you	  will	  be	  taken	  to	  get	  your	  blood	  drawn	  for	  some	  blood	  tests.	  	  Please	  note	  that	  if	  you	  are	  female,	  we	  will	  also	  ask	  you	  to	  do	  a	  urine	  (pee)	  pregnancy	  test.	  	  We	  will	  take	  no	  more	  than	  2	  teaspoons	  (8	  mL)	  of	  blood	  to	  measure	  for	  sugars,	  fats,	  cholesterol,	  and	  hormones.	  	  We	  will	  also	  perform	  a	  blood	  test	  on	  you	  called	  an	  oral	  glucose	  tolerance	  test.	  	  For	  this	  test,	  you	  will	  need	  to	  drink	  a	  sugary	  beverage	  that	  is	  made	  from	  sugar,	  water,	  and	  flavoring.	  	  We	  will	  be	  taking	  blood	  from	  your	  once	  before	  you	  drink	  the	  beverage,	  and	  once	  2	  hours	  later.	  	  This	  test	  will	  require	  1	  mL	  of	  blood.	  	  Thus,	  this	  means	  that	  in	  total,	  we	  will	  take	  no	  more	  than	  2	  teaspoons	  (9	  mL)	  of	  blood	  for	  the	  first	  visit.	  	  	  	  During	  the	  oral	  glucose	  tolerance	  test,	  while	  you	  are	  waiting	  for	  the	  2	  hours	  to	  pass,	  we	  will	  ask	  you	  to	  answer	  4	  or	  5	  questionnaires	  about	  your	  physical	  growth,	  your	  medications,	  your	  eating	  behaviour	  and	  your	  daily	  activity	  levels.	  	  One	  of	  these	  questionnaires	  will	  be	  ‘self-­‐reported’	  (meaning	  that	  you	  will	  read	  the	  questionnaire	  yourself	  and	  write	  in	  your	  answer);	  but	  the	  rest	  will	  be	  verbally	  asked	  to	  you	  by	  the	  Research	  Coordinator.	  You	  are	  not	  required	  to	  answer	  any	  question	  that	  you	  are	  uncomfortable	  answering.	  	  	  	  The	  entire	  visit	  will	  last	  approximately	  4	  hours.	  	  Second	  Visit:	  People	  who	  are	  taking	  antipsychotic	  medications	  will	  be	  asked	  to	  come	  for	  a	  second	  study	  visit	  about	  1	  week	  after	  the	  first	  visit.	  	  This	  visit	  will	  also	  be	  at	  UBC	  Hospital,	  or	  it	  can	  be	  at	  a	  private	  location	  that	  is	  convenient	  for	  you	  (such	  as	  your	  home).	  	  For	  the	  second	  visit,	  we	  will	  ask	  you	  some	  questions	  to	  evaluate	  your	  mental	  health.	  	  The	  entire	  visit	  will	  last	  approximately	  4	  hours.	  	  Telephone	  Interviews	  (once	  a	  month	  for	  3	  months):	  After	  these	  visits,	  there	  will	  be	  3	  months	  where	  you	  will	  not	  be	  required	  to	  come	  in	  for	  the	  study.	  	  However,	  for	  each	  of	  these	  months,	  you	  will	  receive	  a	  telephone	  call	  from	  the	  Research	  Coordinator,	  and	  she	  will	  be	  asking	  you	  the	  same	  questionnaires	  that	  you	   80 answered	  at	  your	  first	  visit	  about	  your	  medications,	  your	  eating	  behaviour	  and	  your	  daily	  activity	  levels.	  	  In	  other	  words,	  you	  will	  be	  completing	  3	  telephone	  interviews	  between	  your	  visits	  (i.e.,	  1	  month	  after	  first	  visit,	  2	  months	  after	  first	  visit,	  and	  3	  months	  after	  first	  visit;	  at	  4	  months	  after	  first	  visit,	  you	  will	  come	  in	  for	  your	  second	  visit).	  	  Each	  call	  will	  last	  no	  more	  than	  30	  minutes.	  	  	  Third	  Visit:	  A	  third	  visit	  will	  be	  scheduled	  4	  months	  (or	  16	  weeks)	  after	  the	  first	  visit.	  	  Again,	  everyone	  will	  come	  to	  UBC	  Hospital	  for	  this	  third	  visit.	  	  If	  you	  are	  a	  healthy	  volunteer,	  this	  will	  be	  the	  last	  visit	  you	  will	  have	  to	  make	  for	  the	  study.	  	  Everyone	  will	  repeat	  all	  of	  the	  same	  procedures	  that	  you	  were	  asked	  to	  do	  for	  the	  first	  visit	  (MRI	  scan,	  blood	  tests,	  questionnaires).	  The	  only	  difference	  is	  that	  for	  the	  third	  visit,	  we	  will	  take	  1	  additional	  teaspoon	  of	  blood	  (for	  a	  total	  of	  3	  teaspoons,	  or	  16	  mL)	  from	  people	  who	  are	  taking	  antipsychotic	  medications	  to	  measure	  for	  the	  levels	  of	  medication	  in	  your	  blood.	  	  	  If	  you	  wish,	  there	  will	  also	  be	  an	  optional	  blood	  test	  that	  anyone	  may	  receive	  during	  your	  third	  visit	  that	  involves	  taking	  another	  1	  teaspoon	  of	  blood	  (6	  mL)	  from	  your	  arm	  to	  look	  for	  potential	  genes	  that	  may	  play	  a	  role	  in	  antipsychotic-­‐induced	  weight	  gain.	  	  There	  is	  a	  separate	  consent	  form	  for	  this	  part	  of	  the	  study	  if	  you	  wish	  to	  participate.	  	  	  Fourth	  Visit:	  For	  people	  who	  are	  taking	  antipsychotic	  medications,	  this	  is	  the	  last	  visit	  you	  will	  have	  to	  make	  to	  UBC	  Hospital	  (or	  this	  meeting	  can	  also	  occur	  at	  a	  private	  location	  of	  your	  choice).	  	  This	  visit	  will	  be	  scheduled	  1	  week	  after	  your	  third	  visit.	  	  Like	  the	  second	  visit,	  we	  will	  ask	  you	  some	  questions	  to	  evaluate	  your	  mental	  health.	  	  This	  visit	  will	  be	  shorter	  than	  the	  second	  visit	  and	  will	  last	  about	  3	  hours.	   81 If	  You	  Decide	  to	  Join	  This	  Study:	  	  Specific	  Procedures	  	  	  Study	  Visit	   When?	   Who	  Comes?	   Preparing	  for	  the	  Visit	   What	  We	  Do	  at	  This	  Visit…	   Visit	  Location	   Visit	  Length	  First	  Visit	   Week	  0	   • Subjects	  who	  are	  taking	  antipsychotics	  	  • Healthy	  subjects	  Eat	  at	  least	  150	  grams	  of	  carbs	  for	  3	  days;	  fast	  for	  12	  hours	  before	  your	  visit	  • Measure	  weight,	  height,	  blood	  pressure,	  heart	  rate	  • Take	  2	  teaspoons	  of	  blood	  (including	  glucose	  tolerance	  test)	  • Urine	  pregnancy	  test	  for	  females	  • Questionnaires	  o Three-­‐Factor	  Eating	  Questionnaire(TFEQ)	  o Schematic	  Tanner	  Scale	  o Short-­‐Form	  36	  (SF-­‐36)	  o International	  Physical	  Activity	  Questionnaire	  (IPAQ)	  • MRI	  scan	  (45-­‐60	  min)	  UBC	  Hospital	   4	  hours	  Second	  Visit	   <	  10	  days	  after	  First	  Visit	  • Subjects	  taking	  antipsychotics	   None	   • Mental	  health	  assessments	  o Mini	  International	  Neuropsychiatric	  Interview	  for	  Children	  and	  Adolescents	  (MINI	  KID)	  o Positive	  and	  Negative	  Syndrome	  Scale	  (PANSS)	  for	  psychosis,	  or	  the	  Young	  Mania	  Rating	  Scale	  (Y-­‐MRS)	  for	  bipolar	  o Social	  and	  Occupational	  Functioning	  Scale	  (SOFAS)	  o Calgary	  Depression	  Scale	  (CDS)	  UBC	  Hospital,	  or	  a	  private	  location	  of	  your	  choice	   4	  hours	  Telephone	  Interviews	   Once	  a	  month	  after	  First	  Visit,	  for	  a	  total	  of	  3	  phone	  calls	  • Subjects	  who	  are	  taking	  antipsychotics	  	  • Healthy	  subjects	  None	   • Questionnaires	  o TFEQ	  o SF-­‐36	  o IPAQ	  o MARS	  (for	  subjects	  taking	  antipsychotics)	  Phone	  call	   30	  minutes	  each	  Third	  Visit	   4	  months	  after	  first	  visit	  • Subjects	  who	  are	  taking	  antipsychotics	  	  • Healthy	  subjects	  (last	  visit)	  Eat	  at	  least	  150	  grams	  of	  carbs	  for	  3	  days;	  fast	  for	  12	  hours	  before	  your	  visit	  • Measure	  weight,	  height,	  blood	  pressure,	  heart	  rate	  • Take	  2	  teaspoons	  of	  blood	  from	  healthy	  subjects;	  3	  teaspoons	  of	  blood	  from	  subjects	  who	  are	  taking	  antipsychotics	  (including	  glucose	  tolerance	  test)	  • Urine	  pregnancy	  test	  for	  females	  • Questionnaires	  o TFEQ	  o SF-­‐36	  o Schematic	  Tanner	  Scale	  o IPAQ	  o MARS	  (for	  subjects	  taking	  antipsychotics	  only)	  • MRI	  scan	  (approximately	  45-­‐60	  min)	  	  UBC	  Hospital	   4	  hours	  Fourth	  Visit	   <	  10	  days	  after	  Third	  Visit	  • Subjects	  who	  are	  taking	  antipsychotics	  (last	  visit)	  None	   • Mental	  health	  assessments	  o PANSS/Y-­‐MRS	  o SOFAS	  o CDS	  UBC	  Hospital,	  or	  a	  private	  location	  of	  your	  choice	   3	  hours	   82 Optional	  Blood	  Collection	  for	  Genetic	  Testing	  and	  Biobanking	  	  There	  is	  an	  optional	  part	  of	  the	  study	  that	  will	  also	  be	  available	  to	  you.	  	  You	  do	  not	  have	  to	  do	  this	  optional	  part	  of	  the	  study	  in	  order	  to	  be	  a	  part	  of	  this	  main	  study.	  	  This	  optional	  part	  of	  the	  study	  involves	  taking	  some	  blood	  and	  storing	  it	  for	  genetic	  testing.	  You	  will	  be	  provided	  with	  a	  separate	  consent	  form	  for	  this	  optional	  study	  that	  describes	  the	  details	  to	  you.	  	  You	  will	  be	  required	  to	  sign	  this	  separate	  consent	  form	  if	  you	  wish	  to	  participate	  in	  the	  optional	  study.	  	  If	  you	  decide	  not	  to	  take	  part	  in	  the	  optional	  study	  your	  care	  will	  not	  be	  affected.	  	  Please	  refer	  to	  the	  separate	  consent	  form	  for	  details	  regarding	  this	  part	  of	  the	  study.	  	  	  	  	  	  	  	  9.	  	  WHAT	  ARE	  MY	  RESPONSIBILITIES?	  	  	  We	  ask	  that	  all	  subjects	  who	  agree	  to	  participate	  try	  their	  best	  to	  make	  it	  to	  their	  study	  visits	  and	  complete	  the	  telephone	  interviews	  between	  visits.	  	  If	  you	  consent	  to	  the	  study	  and	  you	  take	  antipsychotic	  medications,	  you	  should	  take	  the	  medications	  prescribed	  to	  you	  by	  your	  psychiatrist(s).	  	  	  	  	  In	  addition,	  we	  ask	  that	  you	  do	  your	  best	  to	  avoid	  pregnancy	  by	  taking	  the	  necessary	  birth	  control	  precautions	  or	  by	  abstaining	  for	  the	  duration	  of	  your	  participation	  in	  the	  study.	  	  10.	  	  WHAT	  ARE	  THE	  POSSIBLE	  HARMS	  AND	  DISCOMFORTS?	  	  Medications	  The	  scientists	  will	  not	  be	  giving	  any	  subjects	  any	  experimental	  medications	  or	  drugs	  for	  you	  to	  take.	  	  If	  you	  have	  a	  mental	  health	  condition,	  the	  only	  medications	  you	  will	  be	  taking	  will	  be	  the	  ones	  that	  your	  psychiatrist	  has	  prescribed.	  	  The	  risks	  and	  side-­‐effects	  of	  these	  usual	  treatments	  for	  first-­‐episode	  psychosis	  or	  bipolar	  disorder	  will	  be	  explained	  to	  you	  by	  your	  psychiatrist	  as	  part	  of	  your	  standard	  care.	  	  If	  you	  experience	  any	  discomfort	  or	  side-­‐effects	  from	  your	  medications,	  you	  should	  immediately	  contact	  your	  psychiatrist.	  	  The	  care	  that	  you	  receive	  from	  your	  psychiatrist	  will	  remain	  the	  same,	  regardless	  of	  whether	  or	  not	  you	  decide	  to	  do	  the	  study.	  	  If	  your	  doctor	  has	  prescribed	  aripiprazole,	  and	  you	  experience	  an	  adverse	  event	  or	  serious	  adverse	  event	  which	  may	  or	  may	  not	  be	  related	  to	  taking	  aripiprazole,	  we	  are	  obligated	  to	  report	  this	  problem	  to	  our	  financial	  supporter,	  BMS	  Canada.	  	  	  	  Blood	  Tests	  The	  amount	  of	  blood	  that	  we	  will	  be	  taking	  in	  this	  study	  is	  well	  below	  the	  safe	  amount	  of	  blood	  loss	  for	  human	  beings.	  	  However,	  some	  people	  may	  be	  uncomfortable	  with	  needles	  and/or	  the	  sight	  of	  blood.	  	  The	  main	  risk	  of	  getting	  a	  blood	  test	  is	  pain	  or	   83 bruising	  in	  the	  arm	  where	  the	  needle	  is	  inserted.	  	  This	  is	  usually	  minor,	  and	  the	  bruising	  goes	  away	  shortly	  after	  the	  procedure.	  	  Urine	  Pregnancy	  Test	  All	  female	  subjects	  will	  have	  a	  urine	  pregnancy	  test	  before	  performing	  the	  MRI	  scans.	  	  Because	  the	  effects	  of	  MRI	  scanning	  on	  an	  unborn	  child	  are	  not	  fully	  understood,	  we	  want	  to	  avoid	  performing	  an	  MRI	  scan	  on	  you	  if	  you	  are	  pregnant.	  	  If	  you	  find	  out	  that	  you	  are	  unexpectedly	  pregnant,	  it	  may	  potentially	  be	  psychologically	  or	  emotionally	  difficult	  for	  you	  to	  inform	  your	  partner	  or	  your	  family,	  and	  it	  may	  be	  difficult	  deciding	  what	  to	  do.	  	  Ask	  the	  study	  doctor	  or	  Research	  Coordinator	  about	  counselling	  and	  more	  information	  on	  pregnancy	  crises	  services	  if	  you	  require	  help,	  and	  we	  will	  provide	  you	  with	  the	  appropriate	  contact	  information.	  	  In	  addition,	  we	  will	  encourage	  you	  to	  contact	  your	  primary	  care	  physician.	  	  If	  you	  become	  pregnant	  while	  you	  are	  on	  this	  study,	  you	  should	  notify	  the	  study	  doctors.	  	  	  Psychiatric	  Testing	  and	  Questionnaires	  Some	  of	  the	  questionnaires	  that	  we	  will	  be	  doing	  with	  you	  will	  ask	  personal	  information	  that	  you	  may	  not	  feel	  like	  sharing	  with	  us.	  	  If	  you	  are	  not	  happy	  with	  sharing	  this	  information,	  you	  do	  not	  have	  to	  answer.	  	  	  	  MRI	  Scan	  The	  MRI	  scan	  is	  a	  well-­‐established	  and	  safe	  procedure,	  with	  no	  major	  side-­‐effects.	  The	  scan	   requires	   lying	   still	   for	   between	   45-­‐60	   minutes.	   About	   1	   in	   100	   people	   will	   feel	  anxious	  or	  claustrophobic	  (a	  feeling	  of	  fear	  when	  in	  a	  closed	  or	  narrow	  space)	  during	  the	  scan.	  You	  will	  be	  asked	  questions	  prior	  to	  the	  scan	  regarding	  any	  metal	  you	  may	  have	  in	  your	  body.	   If	   you	  are	  unsure,	   you	  will	   have	   to	  be	  discontinued	   from	   the	   study.	   If	   you	  have	   metal	   in	   your	   body,	   the	   MRI	   scan	   is	   dangerous	   and	   cannot	   be	   done	   in	   this	  situation.  	  Orbital	  X-­‐Ray	  If	  you	  have	  done	  any	  metalworking	  in	  the	  past,	  you	  will	  require	  an	  x-­‐ray	  for	  your	  eyes	  before	  going	  into	  the	  MRI	  scanner.	  This	  will	  be	  done	  using	  a	  very	  low	  level	  of	  radiation.	  You	  will	  be	  exposed	  to	  x-­‐rays	  for	  only	  a	  few	  seconds.	  There	  is	  always	  a	  slight	  risk	  of	  damage	  to	  your	  cells/tissues	  from	  being	  exposed	  to	  radiation,	  even	  at	  the	  low	  levels	  required	  for	  this	  x-­‐ray.	  The	  entire	  x-­‐ray	  procedure	  will	  take	  no	  more	  than	  10-­‐15	  minutes.	  	  11.	  WHAT	  ARE	  THE	  POTENTIAL	  BENEFITS	  OF	  PARTICIPATING?	  	  Benefits	  to	  You	  No	  one	  knows	  whether	  or	  not	  you	  will	  benefit	  from	  this	  study.	  	  There	  may	  or	  may	  not	  be	  direct	  benefits	  to	  you	  from	  taking	  part	  in	  this	  study.	  	  One	  potential	  benefit	  is	  that	  you	  can	  receive	  a	  copy	  of	  your	  MRI	  scans	  on	  a	  CD	  at	  the	  end	  of	  the	  study.	  	  However,	  a	  radiologist	  will	  not	  be	  reviewing	  your	  MRI	  scan,	  which	  means	  that	  we	  will	  not	  be	   84 diagnosing	  any	  new	  medical	  conditions,	  and	  we	  will	  not	  be	  telling	  you	  the	  ‘results’	  of	  your	  MRI	  scan.	  	  The	  scans	  are	  for	  research	  purposes	  only.	  	  	  Benefits	  to	  Others	  We	  hope	  that	  the	  information	  learned	  from	  this	  study	  can	  be	  used	  in	  the	  future	  to	  benefit	  other	  people	  with	  a	  similar	  condition.	  The	  results	  of	  this	  study	  will	  help	  scientists	  understand	  how	  antipsychotics	  affect	  obesity,	  and	  if	  certain	  medications	  are	  worse	  than	  others.	  In	  the	  future,	  the	  results	  of	  this	  study	  may	  help	  psychiatrists	  to	  use	  antipsychotics	  to	  treat	  patients	  more	  effectively.	  	  12.	  	  WHAT	  HAPPENS	  IF	  I	  DECIDE	  TO	  WITHDRAW	  MY	  CONSENT	  TO	  PARTICIPATE?	  	  	  Your	  participation	  in	  this	  research	  is	  entirely	  voluntary.	  	  You	  may	  withdraw	  from	  this	  study	  at	  any	  time	  without	  giving	  reasons	  –	  just	  let	  us	  know.	  	  If	  you	  decide	  to	  withdraw	  at	  any	  time	  in	  the	  future,	  there	  will	  be	  no	  penalty	  or	  loss	  of	  benefits	  to	  which	  you	  are	  otherwise	  entitled,	  and	  your	  future	  medical	  care	  will	  not	  be	  affected.	  	  However,	  if	  you	  decide	  to	  drop	  out,	  we	  ask	  that	  you	  come	  in	  to	  complete	  all	  the	  procedures	  of	  the	  THIRD	  VISIT	  (i.e.,	  blood	  tests,	  questionnaires,	  MRI	  scan)	  before	  you	  leave,	  if	  possible.	  	  	  	  	  If	  you	  choose	  to	  enter	   the	  study	  and	  then	  decide	  to	  withdraw	  at	  a	   later	   time,	  all	  data	  collected	   about	   you	   during	   the	   study	  will	   be	   retained	   for	   analysis.	   	   By	   law,	   this	   data	  cannot	  be	  destroyed.	  	  You	  will	  also	  be	  advised	  of	  any	  new	  information	  that	  becomes	  available	  that	  may	  affect	  your	  willingness	  to	  remain	  in	  this	  study.	  	  13.	  	  CAN	  I	  BE	  ASKED	  TO	  LEAVE	  THE	  STUDY?	  	  	  If	  you	  are	  not	  able	  to	  follow	  the	  requirements	  of	  the	  study	  or	  for	  any	  other	  reason,	  the	  scientists	  may	  take	  you	  out	  of	  the	  study	  and	  will	  arrange	  for	  your	  medical	  care	  to	  continue.	  	  You	  may	  also	  be	  withdrawn	  from	  the	  study	  at	  any	  time	  if	  your	  psychiatrist	  feels	  that	  it	  is	  in	  your	  best	  interests	  to	  do	  so,	  or	  if	  they	  feel	  that	  it	  would	  be	  better	  for	  your	  health.	  	  	  14.	  WILL	  MY	  TAKING	  PART	  IN	  THIS	  STUDY	  BE	  KEPT	  CONFIDENTIAL?	  	  	  Your	  and	  your	  child’s	  or	  your	  ward’s	  confidentiality	  will	  be	  respected.	  	  However,	  research	  records	  and	  health	  or	  other	  source	  records	  identifying	  you	  may	  be	  inspected	  in	  the	  presence	  of	  the	  Investigator	  or	  his	  or	  her	  designate	  by	  representatives	  of	  Health	  Canada,	  or	  the	  University	  of	  British	  Columbia’s	  Research	  Ethics	  Board,	  for	  the	  purpose	  of	  monitoring	  the	  research.	  	  No	  information	  or	  records	  that	  disclose	  your	  identity	  will	  be	  published	  without	  your	  consent,	  nor	  will	  any	  information	  or	  records	  that	  disclose	  your	  identity	  be	  removed	  or	  released	  without	  your	  consent	  unless	  required	  by	  law.	  	  	   85 You	  will	  be	  assigned	  a	  unique	  study	  number	  as	  a	  subject	  in	  this	  study.	  	  Only	  this	  number	  will	  be	  used	  on	  any	  research-­‐related	  information	  collected	  about	  you	  during	  the	  course	  of	  this	  study,	  so	  that	  your	  identity	  (i.e.	  your	  name	  or	  any	  other	  information	  that	  could	  identify	  you)	  as	  a	  subject	  in	  this	  study	  will	  be	  kept	  confidential.	  	  	  Information	  that	  contains	  your	  identity	  will	  remain	  only	  with	  the	  Principal	  Investigator	  and/or	  designate.	  	  The	  list	  that	  matches	  your	  name	  to	  the	  unique	  study	  number	  that	  is	  used	  on	  your	  research-­‐related	  information	  will	  not	  be	  removed	  or	  released	  without	  your	  consent	  unless	  required	  by	  law.	  	  Your	  rights	  to	  privacy	  are	  legally	  protected	  by	  federal	  and	  provincial	  laws	  that	  require	  safeguards	  to	  insure	  that	  your	  privacy	  is	  respected	  and	  also	  give	  you	  the	  right	  of	  access	  to	  the	  information	  about	  you	  that	  has	  been	  provided	  to	  the	  sponsor	  and,	  if	  need	  be,	  an	  opportunity	  to	  correct	  any	  errors	  in	  this	  information.	  	  Further	  details	  about	  these	  laws	  are	  available	  on	  request	  to	  your	  study	  doctor.	  	  Primary	  Care	  Physican(s)	  /Specialist(s)	  Notification	  	  Please	  indicate,	  by	  checking	  the	  applicable	  box,	  whether	  you	  want	  us	  to	  notify	  your	  primary	  care	  physician(s)	  or	  specialist(s)	  of	  your	  participation	  in	  this	  study.	  This	  is	  not	  a	  consent	  to	  release	  medical	  information.	  	  	  ___Yes,	  I	  want	  the	  study	  investigator	  to	  advise	  my	  primary	  care	  physician(s)	  or	  specialist(s)	  of	  my	  participation	  in	  this	  study.	  My	  primary	  care	  physician(s)	  and/or	  specialist(s)	  name(s)	  is/are:	  	  ____________________________________	  The	  name	  of	  the	  medical	  clinic	  I	  attend	  is:	  ____________________________	   Subject	  Initials:	  _______	   ____No,	  I	  do	  not	  want	  the	  study	  investigator	  to	  advise	  my	  primary	  care	  physician(s)	  or	  specialist(s)	  of	  my	  participation	  in	  this	  study.	  	  Subject	  Initials:	  _______	  	  ____I	  do	  not	  have	  a	  primary	  care	  physician	  or	  specialist.	  	  	  Subject	  Initials:	  _______	  	  I	  understand	  that	  if	  I	  choose	  not	  to	  advise	  my	  primary	  care	  physician(s)	  or	  specialist(s)	  of	  my	  participation	  in	  this	  study,	  there	  may	  be	  potential	  medical	  consequences	  which	  may	  affect	  my	  comprehensive	  medical	  care	  or	  treatment.	  I	  understand	  that	  the	  study	  investigator	  may	  not	  be	  responsible	  for	  these	  consequences.	  	  You	  may	  wish	  to	  discuss	  the	  consequences	  of	  your	  decision	  with	  the	  study	  staff.	  	  Disclosure	  of	  Race/Ethnicity	   86 Studies	  involving	  humans	  now	  routinely	  collect	  information	  on	  race	  and	  ethnic	  origin	  as	  well	  as	  other	  characteristics	  of	  individuals	  because	  these	  characteristics	  may	  influence	  how	  people	  respond	  to	  different	  medications.	  Providing	  information	  on	  your	  race	  or	  ethnic	  origin	  is	  voluntary.	  	  15.	  	  WHAT	  IF	  SOMETHING	  GOES	  WRONG?	  	  Signing	  this	  consent	  form	  in	  no	  way	  limits	  your,	  or	  your	  child’s,	  or	  your	  ward’s,	  legal	  rights	  against	  the	  sponsor,	  investigators,	  or	  anyone	  else,	  and	  you	  do	  not	  release	  the	  study	  doctors	  or	  participating	  institutions	  from	  their	  legal	  and	  professional	  responsibilities.	  	  	  16.	  	  AFTER	  THE	  STUDY	  IS	  FINISHED	  	  The	  results	  of	  the	  study	  will	  be	  presented	  at	  medical	  conferences,	  and	  will	  be	  published	  in	  medical	  journals,	  but	  you	  will	  not	  be	  named	  in	  these	  presentations	  or	  publications.	  Future	  Contact	  We	  would	  like	  to	  be	  able	  to	  contact	  you	  in	  the	  future	  to	  let	  you	  know	  about	  our	  other	  studies	  that	  require	  participants.	  	  Please	  let	  us	  know	  below	  if	  you	  are	  interested	  in	  hearing	  about	  our	  future	  studies:	  □	  Yes	   	   	   	   	   	   □	  No	  	  	  	  17.	  WHAT	  WILL	  THE	  STUDY	  COST	  ME?	  	   Costs	  You	  may	  need	  to	  cover	  the	  costs	  of	  commuting	  to	  UBC	  Hospital	  when	  you	  come	  in	  for	  your	  visits,	  which	  might	  include	  gas	  costs,	  or	  transit	  costs.	  	  However,	  if	  you	  drive	  to	  the	  hospital,	  we	  will	  reimburse	  your	  parking	  fees.	  	  	  	  Honorariums	  All	  subjects	  will	  receive	  an	  honorarium	  of	  $75	  CAD	  at	  the	  end	  of	  the	  first	  visit,	  and	  at	  the	  end	  of	  your	  third	  visit.	  	  For	  subjects	  who	  are	  taking	  antipsychotics,	  you	  will	  also	  receive	  $50	  CAD	  at	  the	  end	  of	  your	  second	  visit,	  and	  at	  the	  end	  of	  your	  fourth	  visit	  (healthy	  volunteers	  do	  not	  come	  to	  these	  visits;	  thus,	  they	  will	  not	  receive	  these	  honorariums).	  	  All	  subjects	  will	  also	  receive	  with	  an	  honorarium	  for	  each	  of	  the	  three	   87 telephone	  interviews	  completed	  between	  visits	  ($10	  CAD	  for	  first	  month,	  $10	  CAD	  for	  the	  second	  month,	  and	  $15	  CAD	  for	  the	  third	  month).	  	  These	  payments	  will	  be	  prorated	  if	  you	  withdraw	  from	  the	  study.	  	  	  	  	  	  	  18.  WHO	  DO	  I	  CONTACT	  IF	  I	  HAVE	  QUESTIONS	  ABOUT	  THE	  STUDY	  DURING	  MY	  PARTICIPATION?  	  If	  you	  have	  any	  questions	  or	  desire	  further	  information	  about	  this	  study	  before	  or	  during	  participation,	  or	  if	  you	  experience	  any	  adverse	  effects,	  you	  can	  contact	  Dr.	  Alasdair	  Barr	  at	  any	  time	  at	  the	  numbers	  listed	  in	  the	  title	  page.	  	  	  Or,	  you	  can	  speak	  to	  one	  of	  the	  Research	  Assistants,	  Delrae	  Fawcett	  or	  Heidi	  Boyda,	  at	  any	  time	  at	  the	  numbers	  listed	  in	  the	  title	  page.	  	  19.	  	  WHO	  DO	  I	  CONTACT	  IF	  I	  HAVE	  ANY	  QUESTIONS	  OR	  CONCERNS	  ABOUT	  MY	  RIGHTS	  AS	  A	  SUBJECT?	  	  If	  you	  have	  any	  concerns	  or	  complaints	  about	  your	  rights	  as	  a	  research	  subject	  and/or	  your	  experiences	  while	  participating	  in	  this	  study,	  contact	  the	  Research	  Subject	  Information	  Line	  in	  the	  University	  of	  British	  Columbia	  Office	  of	  Research	  Services	  by	  e-­‐mail	  at	  	  RSIL@ors.ubc.ca	  or	  by	  phone	  at	  604-­‐822-­‐8598	  (Toll	  Free:	  1-­‐877-­‐822-­‐8598).A	  Longitudinal	  Comparison	  of	  Aripiprazole	  versus	  Higher	  Metabolic	  Risk	  Antipsychotic	  Drugs	  on	  Adiposity	  Using	  MRI	  (The	  CALM	  Study)	  Principal	  Investigators:	  	  Dr.	  Alasdair	  Barr,	  Assistant	  Professor;	  Dr.	  Lili	  Kopala,	  Psychiatrist	  	  Subject	  Consent	  • I	  have	  read	  and	  understood	  the	  subject	  information	  and	  consent	  form.	  	  • I	  have	  had	  sufficient	  time	  to	  consider	  the	  information	  provided	  and	  to	  ask	  for	  advice	  if	  necessary.	  	  • I	  have	  had	  the	  opportunity	  to	  ask	  questions	  and	  have	  had	  satisfactory	  responses	  to	  my	  questions.	  	  • I	  understand	  that	  all	  of	  the	  information	  collected	  will	  be	  kept	  confidential	  and	  that	  the	  results	  will	  only	  be	  used	  for	  scientific	  objectives.	  	  • I	  understand	  that	  my	  participation	  in	  this	  study	  is	  voluntary	  and	  that	  I	  am	  completely	  free	  to	  refuse	  to	  participate	  or	  withdraw	  from	  this	  study	  at	  any	  time	  without	  changing	  the	  quality	  of	  care	  that	  I	  receive.	  • I	  authorize	  access	  to	  my	  medical	  record,	  Pharmanet	  record,	  and	  blood	  samples	  as	  described	  in	  this	  consent	  form.	  	  • I	  understand	  that	  I	  am	  not	  waiving	  any	  of	  my	  legal	  rights	  by	  signing	  this	  consent	  form.	  	  • I	  understand	  that	  there	  is	  no	  guarantee	  that	  this	  study	  will	  provide	  any	  benefits.	  • I	  understand	  that	  I	  will	  be	  receiving	  MRI	  scans.	  	   88 The	  parent(s)/guardian(s)/substitute	  decision-­‐maker	  (legally	  authorized	  representative)	  and	  the	  investigator	  are	  satisfied	  that	  the	  information	  contained	  in	  this	  consent	  form	  was	  explained	  to	  the	  child/subject	  to	  the	  extent	  that	  he/she	  is	  able	  to	  understand	  it,	  that	  all	  questions	  have	  been	  answered,	  and	  that	  the	  child/subject	  assents	  to	  participating	  in	  the	  research.	  	  I	  will	  receive	  a	  signed	  copy	  of	  this	  consent	  form	  for	  my	  own	  records.	  I	  consent	  to	  participate	  in	  this	  study.	  	  	  	   	   	   	   	   	   	   	   	   	   	   	  	   	  Participant/Parent/Guardian	  Signature	   	   	  	  	  	  	  	  Printed	  Name	   	   	   	  	  	  	  	  	  	  Date	  	  	  	   	   	   	   	   	   	   	   	   	   	  	  	  	  	  	  	  	   	   	  Signature	  of	  Person	  Obtaining	  Consent	   	  	  	  	  	  	  	  	  	  	  Printed	  name	   	  	  	  	  	  	  	  	  	  	  	  	  Study	  Role	   	  	  	  	  	  	  	  	  Date	  	  	   	   	   	   	   	   	   	   	   	   	   	   	  	  	  Investigator	  Signature	   	   	   	  	  	  	  	  	  	  	  	  	  Printed	  name	   	   	   	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  Date	  Investigator:	  My	  signature	  above	  signifies	  that	  the	  study	  has	  been	  reviewed	  with	  the	  study	  subject	  by	  me	  and/or	  by	  my	  delegated	  staff.	  	  My	  signature	  may	  have	  been	  added	  at	  a	  later	  date,	  as	  I	  may	  not	  have	  been	  present	  at	  the	  time	  the	  subject’s	  signature	  was	  obtained.	  	         	   89 Appendix III: Short Form 36 (SF-36)  This survey asks for your views about your health. This information will help keep track of how you feel and how well you are able to do your usual activities.  For each of the following questions, please mark an ? in the one box that best describes your answer. 1. In general, would you say your health is: Excellent o Very Good o Good o Fair o Poor o 2. Compared to one year ago, how would you rate your health in general now? Much better now than one year ago o Somewhat better now than one year ago o About the same as one year ago  o Somewhat worse now than one year ago o Much worse now than one year ago o 3. The following questions are about activities you might do during a typical day. Does your health now limit you in these activities? If so, how much?   Yes, limited a lot Yes, limited a little No, not limited at all a.  Vigorous activities, such as running, lifting heavy objects, participating in strenuous sports… o o o b.  Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf… o o o c.  Lifting or carrying groceries… o o o d. Climbing several flights of stairs… o o o e. Climbing one flight of stairs… o o o f.  Bending, kneeling, or stooping… o o o g. Walking more than a mile… o o o h. Walking several hundred yards… o o o i.  Walking one hundred yards… o o o j.  Bathing or dressing yourself… o o o 4. During the past 4 weeks, how much of the time have you had any of the following problems with your work or other regular daily activities as a result of your physical health?  All of the time Most of the time Some of the time A little of the time None of the time a. Cut down on the amount of time you spent on work or other activities… o o o o o b. Accomplished less than you would like… o o o o o c. Were limited in the kind or work or other activities… o o o o o d. Had difficulty performing the work or other activities (for example, it took extra effort)… o o o o o  5. During the past 4 weeks, how much of the time have you had any of the following problems with your work or other regular daily activities as a result of any emotional problems (such as feeling depressed or anxious)?  90  All of the time Most of the time Some of the time A little of the time None of the time a. Cut down on the amount of time you spent on work or other activities…  o  o  o  o  o b. Accomplished less than you would like… o o o o o c. Did work or other activities less carefully than usual…  o  o  o  o  o 6. During the past 4 weeks, to what extent has your physical health or emotional problems interfered with your normal social activities with family, friends, neighbors, or groups? Not at all o Slightly o Moderately o Quite a bit o Extremely o 7. How much bodily pain have you had during the past 4 weeks? None o Very mild o Mild o Moderate o Severe o Very severe o 8. During the past 4 weeks, how much did pain interfere with your normal work (including both outside the home and housework)? Not at all o A little bit o Moderately o Quite a bit o Extremely o 9. These questions are about how you feel and how things have been with you during the past 4 weeks. For each question, please give the one answer that comes closest to the way you have been feeling. How much of the time during the past 4 weeks…  All of the time Most of the time Some of the time A little of the time None of the time Did you feel full of life? o o o o o Have you been very nervous? o o o o o Have you felt so down in the dumps that nothing could cheer you up? o o o o o Have you felt calm and peaceful? o o o o o Did you have a lot of energy? o o o o o Have you felt downhearted and depressed? o o o o o Did you feel worn out? o o o o o Have you been happy? o o o o o Did you feel tired? o o o o o  10. During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with your social activities (like visiting friends, relatives, etc.)? All of the time o Most off the time o Some of the time o A little of the time o None of the time o 11. How TRUE or FALSE is each of the following statements for you?  Definitely true Mostly true Don’t know Mostly false Definitely false  91 I seem to get sick a little easier than other people. o o o o o I am as healthy as anybody I know. o o o o o I expect my health to get worse. o o o o o My health is excellent. o o o o o  Comments:  ________________________________________________________________________________________________________________________________________________________________________________________________________________________                        92 Appendix IV: International Physical Activity Questionnaire (IPAQ)  READ:  I am going to ask you about the time you spent being physically active in the last 7 days.  Please answer each question even if you do not consider yourself to be an active person.  Think about the activities you do at work, as part of your house and yard work, to get from place to place, and in your spare time for recreation, exercise, or sport.  READ:  Now, think about all the vigorous activities which take hard physical effort that you did in the last 7 days.  Vigorous activities make you breathe much harder than normal and may include heavy lifting, digging, aerobics, or fast bicycling.  Think only about those physical activities that you did for at least 10 minutes at a time.  1. During the last 7 days, on how many days did you do vigorous physical activities? ___________Days per week [range 0-7, 8, 9] 8.  Don’t know/Not sure 9.  Refused  [Interviewer clarification: Think only about those physical activities that you do for at least 10 minutes at a time.]   [Interviewer note: If respondent answers zero, refuses, or does not know, skip to Question 3.]  2. How much time did you usually spend doing vigorous physical activities on one of those days? ___________Hours per day [range 0-16] ___________Minutes per day [range 0-960, 998, 999] 998.  Don’t know/Not sure 999.  Refused   [Interviewer clarification: Think only about those physical activities you do for at least 10 minutes at a  time.]  [Interviewer probe: An average time for one of the days on which you do vigorous activity is being sought.  If the respondent can’t answer because the pattern of time spent varies widely from day to day, ask: “How much time in total would you spend over the last 7 days doing vigorous physical activities?”    ___________Hours per week [range 0-112]  ___________Minutes per week [range 0-6720, 9998, 9999]  9998.  Don’t know/Not sure  9999.  Refused]  READ: Now think about activities which take moderate physical effort that you did in the last 7 days.  Moderate physical activities make you breathe somewhat harder than normal and may include carrying light loads, bicycling at a regular pace, or doubles tennis.  Do not include walking.  Again, think about only those physical activities that you did for at least 10 minutes at a time.  3. During the last 7 days, on how many days did you do moderate physical activities? ___________Days per week [range 0-7, 8, 9]  93 8.  Don’t know/Not sure 9.  Refused  [Interviewer clarification: Think only about those physical activities that you do for at least 10 minutes at a time.]  [Interviewer note: If respondent answers zero, refuses, or does not know, skip to Question 5.]  How much time did you usually spend doing moderate physical activities on one of those days? ___________Hours per day [range 0-16] ___________Minutes per day [range 0-960, 998, 999] 998.  Don’t know/Not sure 999.  Refused  [Interviewer clarification: Think only about those physical activities that you do for at least 10 minutes at a time.]  [Interviewer probe: An average time for one of the days on which you do moderate activity is being sought.  If the respondent can’t answer because the pattern of time spent varies widely from day to day, or time spent in multiple jobs, ask: “How much time in total would you spend over the last 7 days doing moderate physical activities?”    ___________Hours per week [range 0-112]  ___________Minutes per week [range 0-6720, 9998, 9999]  9998.  Don’t know/Not sure  9999.  Refused]  READ: Now think about the time you spent walking in the last 7 days.  This includes at work and at home, walking to travel from place to place, and any other walking that you have done solely for recreation, sport, exercise, or leisure.  During the last 7 days how many days did you walk for at least 10 minutes at a time? ___________Days per week [range 0-7, 8, 9] 8.  Don’t know/Not sure 9.  Refused  [Interviewer clarification: Think only about those physical activities that you do for at least 10 minutes at a time.]  [Interviewer note: If respondent answers zero, refuses, or does not know, skip to Question 7.]  How much time did you usually spend walking on one of those days? ___________Hours per day [range 0-16] ___________Minutes per day [range 0-960, 998, 999] 998.  Don’t know/Not sure 999.  Refused   [Interviewer probe: An average time for one of the days on which you do moderate activity is being sought.  If the respondent can’t answer because the pattern of time spent  94 varies widely from day to day, ask: “What is the total amount of time you spent walking over the last 7 days?”    ___________Hours per week [range 0-112]  ___________Minutes per week [range 0-6720, 9998, 9999]  9998.  Don’t know/Not sure  9999.  Refused]  READ: Now think about the time you spent sitting on week days during the last 7 days.  Include time spent at work, at home, while doing course work, and during leisure time.  This may include time spent sitting at a desk, visiting friends, reading or sitting or lying down to watch television. During the last 7 days how many days did you spend sitting on a week day? ___________Hours per week day [range 0-16] ___________Minutes per week day [range 0-960, 998, 999] 998.  Don’t know/Not sure 999.  Refused   [Interviewer clarification: Include time spent lying down (awake) as well as sitting.]  [Interviewer probe: An average time per day spent sitting is being sought.  If the respondent can’t answer because the pattern of time spent varies widely from day to day, ask: “What is the total amount of time you spent sitting last Wednesday?”    ___________Hours on Wednesday [range 0-16]  ___________Minutes on Wednesday [range 0-960, 998, 999]  998.  Don’t know/Not sure  999.  Refused]    95 Appendix V: Three Factor Eating Questionnaire (TFEQ) 	  One point may be given to each item in Parts I and II.    The response that scores a point is underlined in Part I (either true/false), and the corresponding Factor that is measured by each item in Part I is located beside the question.    For Part II, points are scored by splitting the responses down the middle.  If the question is labeled ‘+’, then responses above the middle (i.e., 3 or 4) are given a 0, and responses below the middle (i.e., 1 or 2) are given a 1.  The corresponding Factor that is measured by each item is located beside the question.   Part I     Factor Number 1. When I smell a sizzling steak or see a juicy piece of meat, I find it very difficult to keep from eating, even if I have just finished a meal. T            F 2 2. I usually eat too much at social occasions, like parties and picnics. T            F 2 3. I am usually so hungry that I eat more than three times a day. T            F 3 4. When I have eaten my quota of calories, I am usually good about not eating any more. T            F 1 5. Dieting is so hard for me because I just get too hungry. T            F 3 6. I deliberately take small helpings as a means of controlling my weight. T            F 1 7. Sometimes things just taste so good that I keep on eating even when I am no longer hungry. T            F 2 8. Since I am often hungry, I sometimes wish that while I am eating, an expert would tell me that I have had enough or that I can have something more to eat. T            F 3 9. When I feel anxious, I find myself eating. T            F 2 10. Life is too short to worry about dieting. T            F 1 11. Since my weight goes up and down, I have gone on reducing diets more than once. T            F 2 12. I often feel so hungry that I just have to eat something. T            F 2 13. When I am with someone who is overeating, I usually overeat too. T            F 3 14. I have a pretty good idea of the number of calories in common food. T            F 1 15. Sometimes when I start eating, I just can’t T            F 2  96 seem to stop. 16. It is not difficult for me to leave something on my plate. T            F 2 17. At certain times of the day, I get hungry because I have gotten used to eating then. T            F 3 18. While on a diet, if I eat food that is not allowed, I consciously eat less for a period of time to make up for it.   T            F   1 19. Being with someone who is eating often makes me hungry enough to eat also. T            F 3 20. When I feel blue, I often overeat. T            F 2 21. I enjoy eating too much to spoil it by counting calories or watching my weight. T            F 1 22. When I see a real delicacy, I often get so hungry that I have to eat right away. T            F 3 23. I often stop eating when I am not really full as a conscious means of limiting the amount that I eat. T            F 1 24. I get so hungry that my stomach often seems like a bottomless pit. T            F 3 25. My weight has hardly changed at all in the last ten years. T            F 2 26. I am always hungry so it is hard for me to stop eating before I finish the food on my plate. T            F 3 27. When I feel lonely, I console myself my eating. T            F 2 28. I consciously hold back at meals in order not to gain weight. T            F 1 29. I sometimes get very hungry late in the evening or at night. T            F 3 30. I eat anything I want, any time I want. T            F 1 31. Without even thinking about it, I take a long time to eat. T            F 2 32. I count calories as a conscious means of controlling my weight. T            F 1 33. I do not eat some foods because they make me fat. T            F 1 34. I am always hungry enough to eat at any time. T            F 3 35. I pay a great deal of attention to changes in my figure. T            F 1 36. While on a diet, if I eat a food that is not allowed, I often then splurge and eat other high calorie foods. T            F 2             Part II  Directions:  Please answer the following questions by circling the number above the response that is appropriate to you.  Factor Number  97 37. How often are you dieting in a conscious effort to control your weight?  1 2 3 4  Rarely Sometimes Usually Always +1  38. Would a weight fluctuation of 5 lbs affect the way you live your life?  1 2 3 4  Not at all Slightly Moderately Very much +1  39. How often do you feel hungry?  1 2 3 4  Only at mealtimes Sometimes between meals Often between meals Almost always +3 40. Do your feelings of guilt about overeating help you to control your food intake?  1 2 3 4  Never Rarely Often Always +1  41. How difficult would it be for you to stop eating halfway through dinner and not eat for the next four hours?  1 2 3 4  Easy Slightly difficult Moderately difficult Very difficult +3  42. How conscious are you of what you are eating?  1 2 3 4  Not at all Slightly Moderately Extremely +1  43. How frequently do you avoid ‘stocking up’ on tempting foods?  1 2 3 4  Almost never Seldom Usually Almost always +1  44. How likely are you to shop for low calorie foods?  1 2 3 4  Unlikely Slightly unlikely Moderately likely Very likely +1  45. Do you eat sensibly in front of others and splurge alone?  1 2 3 4  Never Rarely Often Always +2  46. How likely are you to consciously eat slowly in order to cut down on how much you eat?  1 2 3 4  Unlikely Slightly unlikely Moderately likely Very likely +1  47. How frequently do you skip dessert because you are no longer hungry?  1 2 3 4  Almost never Seldom At least once a week Almost every day -3  48. How likely are you to consciously eat less than you want?  1 2 3 4  Unlikely Slightly unlikely Moderately likely Very likely +1  49. Do you go on eating binges though you are not hungry?  1 2 3 4  Never Rarely Sometimes At least once a week +2   98 50. On a scale of 0 to 5, where 0 means no restraint in eating (eating whatever you want, whenever you want it) and 5 means total restraint (constantly limiting food intake and never ‘giving in’), what number would you give yourself?  0  +1              Eat whatever you want, whenever you want it  1               Usually eat whatever you want, whenever you want it  2               Often eat whatever you want, whenever you want it  3               Often limit food intake, but often ‘give in’  4               Usually limit food intake, rarely ‘give in’  5              Constantly limiting food intake, never ‘giving in’   51. To what extent does this statement describe your eating behaviour? ‘I start dieting in the morning, but because of any number of things that happen during the day, by evening I have given up and eat what I want, promising myself to start dieting again tomorrow.’  1 2 3 4  Not like me Little like me Pretty good description of me Describes me perfectly +2           99 Appendix VI: Medication Adherence rating Scale (MARS) 	  How closely you adhere to your medication plan affects the progression and outcome of your psychosis.   The Medication Adherence Rating Scale (MARS) is a self-report measure of medication adherence in psychosis.  Use the MARS tool to determine your willingness and ability to take oral medication every day.  For scoring purposes, answers that are assigned 1 point are filled in.   Yes No 1. Do you ever forget to take your medication? ☐ ☐ 2. Are you careless at times about taking your medicine? ☐ ☐ 3. When you feel better, do you sometimes stop taking your medicine? ☐ ☐ 4. Sometimes if you feel worse when you take the medicine, do you stop taking it? ☐ ☐ 5. I take my medication only when I am sick. ☐ ☐ 6. It is unnatural for my mind and body to be controlled by medication. ☐ ☐ 7. My thoughts are clearer on medication. ☐ ☐ 8. By staying on medication, I can prevent getting sick. ☐ ☐ 9. I feel weird, like a ‘zombie’, on medication. ☐ ☐ 10. Medication makes me feel tired and sluggish. ☐ ☐    If subject scores… 0 – 5: They are not adhering to the prescribed medication schedule. 6 – 10: It is likely that they are adhering to their medication.	   	   100 Appendix VII: Positive and Negative Syndromes Scale (PANSS)  Instructions for Rating: 1 = Absent     2 = Minimal     3 = Mild     4 = Moderate     5 = Moderate Severe     6 = Severe     7 = Extreme   POSITIVE SCALE                                                                      (Circle one)  1 Delusions 1 2 3 4 5 6 7  2 Conceptual Disorganization 1 2 3 4 5 6 7  3 Hallucinatory Behavior 1 2 3 4 5 6 7  4 Excitement 1 2 3 4 5 6 7  5 Grandiosity 1 2 3 4 5 6 7  6 Suspiciousness / Persecution 1 2 3 4 5 6 7  7 Hostility 1 2 3 4 5 6 7  NEGATIVE SUBSCALE                                                                                           (Circle one)  1 Blunted Affect 1 2 3 4 5 6 7  2 Emotional Withdrawal 1 2 3 4 5 6 7  3 Poor Rapport 1 2 3 4 5 6 7  4 Passive Apathetic Withdrawal 1 2 3 4 5 6 7  5 Difficulty in Abstract Thinking 1 2 3 4 5 6 7  6 Lack of Spontaneity and Flow of Conversation 1 2 3 4 5 6 7  7 Stereotyped Thinking 1 2 3 4 5 6 7  GENERAL PSYCHOPATHOLOGY SUBSCALE                                  (Circle one) 	   1 Somatic Concern 1 2 3 4 5 6 7  2 Anxiety 1 2 3 4 5 6 7  3 Guilt Feelings 1 2 3 4 5 6 7  4 Tension 1 2 3 4 5 6 7  5 Mannerism and Posturing 1 2 3 4 5 6 7  6 Depression 1 2 3 4 5 6 7  7 Motor Retardation  1 2 3 4 5 6 7  8 Uncooperative 1 2 3 4 5 6 7  9 Unusual Thought Content 1 2 3 4 5 6 7 10 Disorientation 1 2 3 4 5 6 7 11 Poor Attention 1 2 3 4 5 6 7 12 Lack of Judgment and Insight 1 2 3 4 5 6 7 13 Disturbance of Volition 1 2 3 4 5 6 7 14 Poor Impulse Control 1 2 3 4 5 6 7 15 Preoccupation 1 2 3 4 5 6 7 16 Active Social Avoidance 1 2 3 4 5 6 7 	  	   	   	   	   	   	   	  TOTAL SCORE: ________________.	    101 Appendix IX:  Calgary Depression Scale (CDS) INSTRUCTIONS: Ask the following questions as written. Use the follow up probes or qualifiers at your discretion. Time frame refers to the last two weeks unless stipulated. N.B. the last item, #9, is based on observation of the entire interview. Circle the appropriate rating for each item following the clinical interview.	  0 = None      1 = Mild              2 = Moderate    3 = Severe  • Depression: How would you describe your mood over the last two seeks? Do you keep reasonably cheerful of have you been very depressed or low spirited recently? In the last two weeks how often have you (own words) every day? All day? 0 = Absent 1	  =	   Expresses	  some	  sadness	  or	  discouragement	  on	  questioning.	  2 = Distinct depressed mood persisting up to half the time over the last two weeks: present daily. 3 = Marked depressed mood persisting daily over half the time interfering with normal motor and social functioning. • Hopelessness: How do you see the future for yourself? Can you see any future? – or has life seemed quite hopelessness? Have you given up or does there still seem some reason for trying? 0 = Absent 1	  =	   Has	  at	  times	  felt	  hopelessness	  over	  the	  past	  two	  weeks	  but	  still	  has	  some	  degree	  of	  hope	  for	  the	  future.	  2	  =	   Persistent,	  moderate	  sense	  of	  hopelessness	  over	  last	  week.	  Can	  be	  persuaded	  to	  acknowledge	  possibility	  of	  things	  being	  better.	  3 = Persisting and distressing sense of hopelessness. • Self Depreciation: What is your opinion of your self compared to other people? Do you feel better, not as good, or about the same as other people? Do you feel inferior or even worthless? 0 = Absent 1	  =	   Some	  inferiority;	  not	  amounting	  to	  feeling	  of	  worthlessness.	  2 = Subject feels worthless, but less the 50% of the time. 3 =  subject feels worthless more than 50% of the time. May be challenged to acknowledge otherwise. • Guilt Ideas of Reference: Do you have the feeling that you are being blamed for something or even wrongly accused? What about? (Do not include justifiable blame or accusation. Exclude delusions of guilt) 0 = Absent 1	  =	   Subject	  feels	  blamed	  but	  not	  accused	  less	  than	  50%	  of	  the	  time.	  2	  =	   Persisting	  sense	  of	  being	  blamed,	  and/or	  occasional	  sense	  of	  being	  accused.	  3 = Persistent sense of being accused. When challenged, acknowledges that it is not so. • Pathological Guilt: Do you tend to blame yourself for little things you may have done in the past? Do you think that you deserve to be so concerned about this? 0 = Absent 1	  =	   Subject	  sometimes	  feels	  over	  guilty	  about	  some	  minor	  peccadillo,	  but	  less	  than	  50%	  of	  the	  time.	  2 = Subject usually (over 50% of time) feels guilty about past actions the significance of which he exaggerates. 3 = Subject usually feels s/he is to blame for everything that has gone wrong, even when not his/her fault. • Morning Depression: When you have felt depressed over the last 2 weeks, have you noticed the depression being worse at any particular time of the day? 0 = Absent 1 = Depression present but no diumal variation. 2	  =	   Depression	  spontaneously	  mentioned	  to	  be	  worse	  in	  a.m.	  3 = Depression markedly worse in a.m., with impaired functioning which improves in p.m. • Early Wakening: Do you awake earlier in the morning than is normal for you? How many times a week does this happen? 0 = Absent 1	  =	   Occasionally	  wakes	  (up	  to	  twice	  weekly)	  1	  hour	  or	  more	  before	  normal	  time	  to	  wake	  or	  alarm	  time.	  2	  =	   Often	  wakes	  early	  (up	  to	  5	  times	  weekly)	  1	  hour	  or	  more	  before	  normal	  time	  to	  wake	  or	  alarm	  time.	  3 = Daily wakes 1 hour or more before normal time. • Suicide: have you felt that life wasn’t worth living? Did you ever feel like ending it all? What did you think you might do? Did you actually try?  0 = Absent 1	  =	   Frequent	  thoughts	  of	  being	  better	  off	  dead,	  or	  occasional	  thoughts	  of	  suicide.	  2	  =	   Deliberately	  considered	  suicide	  with	  a	  plan,	  but	  made	  no	  attempt.	  3 = Suicidal attempt apparently designed to end in death (i.e., accidental discovery or inefficient means). • Observed Depression: Based on interview’s observations during the entire interview. The question “Do you feel like crying?” used at appropriate points in the interview, may elicit information useful to this observation. 0 = Absent 1	  =	   Subject	  appears	  sad	  and	  mournful	  even	  during	  parts	  of	  the	  interview,	  involving	  affectively	  neutral	  discussion.	  2 = Subject appears sad and mournful throughout the interview, with gloomy monotonous voice and is tearful or close to tears at times. 3 = Subject chokes on distressing topics, frequently sighs deeply and cries openly, or is persistently in a state of frozen misery if examiner is sure that this is present.  102 Appendix X: Social and Occupational Functioning Scale (SOFAS)  Consider social and occupational functioning on a continuum from excellent functioning to grossly impaired.  Include impairments in functioning due to physical limitations, as well as those due to mental impairments.  To be counted, impairment must be a direct consequence of mental and physical health problems; the effects of lack of opportunity and other environmental limitations are not to be considered. 	  	  100-91 Superior functioning in a wide range of activities.  90-81 Good functioning in all areas, occupationally and socially effective.  80-71 No more than slight impairment in social, occupational, or school functioning (e.g., infrequent interpersonal conflict, temporarily falling behind in schoolwork.  70-61 Some difficulty in social, occupational, or school functioning, but generally functioning well, has some meaningful interpersonal relationship.  60-51 Moderate difficulty in or school functioning (e.g., few friends, conflicts with peers or co-workers).  50-41 Serious impairment in social, occupational, or school functioning (e.g., no friends, unable to keep job).  40-31 Major impairment in several areas, such as work or school, family relations (e.g., depressed man avoids friends, neglects family, and is unable to work, child frequently beats up younger children, is defiant at home, and is failing in school).  30-21 Inability to function in almost all areas (e.g., stays in bed all day, no job, home or friends).  20-11 Occasionally fails to meet minimal personal hygiene; unable to function independently.  10-0 Persistent inability to maintain minimal personal hygiene. Unable to function without harming self or others or without considerable external support (e.g., nursing care and supervision). 	  	   	   	   	   	  	  	   	   	   	   	   Total SOFAS score: ___________.         

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