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

• 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
• 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

 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.

 描述（由申请人提供）：心血管疾病是精神分裂症患者寿命缩短的主要原因，估计比一般人群短15 - 25年。肥胖和相关的代谢问题，如高胆固醇血症和糖尿病，是心血管疾病的重要因素，代表抗精神病药物的已知副作用，在精神分裂症中非常普遍。然而，鉴于许多FDA批准的减肥药是拟交感神经药，这可能会增加精神病加重的风险，因此该患者组的药物治疗选择有限。二甲双胍是一种抗高血糖药，部分通过胰高血糖素样肽-1来降低食欲和减缓胃排空，已被发现可以安全地减轻非糖尿病超重精神分裂症患者的体重。我们的研究小组最近发现，在146名超重的精神分裂症患者中，与安慰剂相比，连续服用二甲双胍16周导致体重减轻2 kg。由于二甲双胍的体重减轻是适度的，因此为该人群确定其他安全的非拟交感神经药物选择至关重要。氯卡色林是一种5-HT 2C激动剂，最近被批准用于减肥。在超重、其他方面健康的成年人中，与基线相比，氯卡色林与约5.5 kg体重减轻相关，与安慰剂相比，在52周内与约3 kg体重减轻相关。氯卡色林的食欲降低作用部分通过黑皮质素受体4介导。鉴于这两种药物均具有显著的体重减轻作用，且作用机制不同，本研究将基于我们对二甲双胍的初步数据，在超重精神分裂症患者中检验二甲双胍/氯卡色林联合治疗与氯卡色林单药治疗与安慰剂治疗的策略。在非精神病人群中，联合治疗已成功用于减肥（即，芬特明/托吡酯组合治疗）和当单一疗法不足时用于其它慢性疾病如高血压、癫痫和糖尿病。90名超重的精神分裂症患者（BMI>27）将参加一项为期52周的双盲、随机研究，以评估氯卡色林/二甲双胍联合治疗、氯卡色林单药治疗和安慰剂对体重、身体组成以及葡萄糖和脂质代谢指标的有效性和安全性。将测量食欲行为评估和关键食欲调节激素（包括瘦素、胃饥饿素和GLP-1）的血浆水平，以检查氯卡色林和二甲双胍在该人群中减肥的作用机制。24-小时食物回忆评估和基于加速度计的体力活动评估将有助于确定能量摄入和消耗的潜在混杂效应。所有受试者将接受行为干预，促进健康饮食和增加体力活动。目前的提案将有助于确定治疗精神分裂症患者肥胖的新的和安全的长期选择，这对肥胖率高的脆弱人群以及相关的心血管发病率和死亡率至关重要。