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Novel pharmacotherapy strategies for obesity in schizophrenia

治疗精神分裂症肥胖症的新药物治疗策略

基本信息

批准号：
9262922
负责人：
Lars FREDRIK JARSKOG
金额：
$ 66.85万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262922
关键词：
Accelerometer Address Adult Adverse effects Agonist Antipsychotic Agents Appetite Regulation Behavior Therapy Behavior assessment Body Composition Body Weight Body Weight Changes Body Weight decreased Cardiovascular Diseases Cardiovascular system Chronic Disease Chronic Schizophrenia Clinical Controlled Study Data Desire for food Diabetes Mellitus Diagnosis Double-Blind Method Effectiveness Energy Intake Energy Metabolism Epilepsy Excess Mortality FDA approved Fatty acid glycerol esters Food Gastric Emptying General Population Hormones Hour Hyperlipidemia Hypertension Hypoglycemic Agents Individual Leptin Life Expectancy Longevity Measurement Measures Mediating Melanocortin 4 Receptor Melanocyte stimulating hormone Meta-Analysis Metabolic Metformin Morbidity - disease rate Obesity Outpatients Overweight Patients Peripheral Pharmaceutical Preparations Pharmacological Treatment Pharmacology Study Pharmacotherapy Phentermine Physical activity Placebos Plasma Population Premature Mortality Property Randomized Randomized Controlled Trials Risk Roentgen Rays Safety Schizophrenia Serotonin Receptor 5-HT2C Sympathomimetics Testing Vulnerable Populations Weight Weight-Loss Drugs base clinically significant ghrelin glucagon-like peptide 1 glucose metabolism good diet hypercholesterolemia improved lipid metabolism mortality non-diabetic novel patient population public health relevance randomized trial topiramate treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease represents a major cause of reduced lifespans in people with schizophrenia, which has been estimated at 15 - 25 years shorter than the general population. Obesity and associated metabolic problems, such as hypercholesterolemia and diabetes, are important contributors to cardiovascular disease, represent known side effects of antipsychotic medications, and are highly prevalent in schizophrenia. However, pharmacological treatment options for this patient group are limited given that many FDA-approved weight loss drugs are sympathomimetic, which can raise the risk of psychotic exacerbation. Metformin, an antihyperglycemic that acts in part via glucagon-like peptide-1 to reduce appetite and slow gastric emptying, has been found to safely reduce weight in non-diabetic overweight people with schizophrenia. Our group recently found that 16 weeks of adjunctive metformin led to 2 kg differential weight loss compared to placebo in 146 overweight people with schizophrenia. Because weight loss with metformin is modest, the identification of other safe, non-sympathomimetic options for this population is critical. Lorcaserin is a 5-HT2C agonist recently approved for weight loss. Lorcaserin is associated with ~5.5 kg weight loss compared to baseline and ~3 kg weight loss compared to placebo over 52 weeks in overweight, otherwise healthy adults. The appetite-reducing effect of lorcaserin is mediated in part through melanocortin receptor 4. Given significant weight loss from each of these two drugs with distinct mechanisms of action, this study will build on our preliminary data with metformin to test a strategy of metformin/lorcaserin combination treatment versus lorcaserin monotherapy versus placebo in overweight people with schizophrenia. In non-psychiatric populations, combination treatment has been used successfully for weight loss (i.e., phentermine/topiramate combination treatment) and for other chronic disorders such as hypertension, epilepsy, and diabetes when monotherapy was inadequate. 90 overweight people with schizophrenia (BMI>27) will participate in a 52-week double-blind, randomized study to assess the efficacy and safety of lorcaserin/metformin combination treatment, lorcaserin monotherapy and placebo on weight, body composition, and measures of glucose and lipid metabolism. Behavioral assessments of appetite and plasma levels of key appetite-regulating hormones including leptin, ghrelin and GLP-1 will be measured to examine mechanisms of action of lorcaserin and metformin for weight loss in this population. 24- hour food-recall assessments and accelerometer-based physical activity assessments will help determine the potentially confounding effects of energy intake and expenditure. All subjects will receive a behavioral intervention promoting a healthy diet and increased physical activity. The current proposal will help define new and safe long-term options for treating obesity in people with schizophrenia, critical for this vulnerable population with high rates of obesity and associated cardiovascular morbidity and mortality.