Novel pharmacotherapy strategies for obesity in schizophrenia

 描述(申请人提供)：心血管疾病是导致精神分裂症患者寿命缩短的主要原因，据估计，精神分裂症患者的寿命比普通人群短15-25岁。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诱因，是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，这类患者的药物治疗选择有限，因为许多FDA批准的减肥药是交感神经仿制药，这可能会增加精神疾病恶化的风险。二甲双胍是一种抗高血糖药，部分通过胰升糖素样肽-1来降低食欲和减缓胃排空，已被发现可以安全地减轻患有精神分裂症的非糖尿病超重者的体重。我们的团队最近发现，在146名超重的精神分裂症患者中，服用16周的二甲双胍与安慰剂相比，体重减轻了2公斤。由于二甲双胍的减重效果不明显，因此为这一人群确定其他安全的、非交感神经替代方案是至关重要的。氯卡瑟林是一种5-HT2C激动剂，最近被批准用于减肥。在超重或其他健康的成年人中，氯酪蛋白在52周内与基线相比体重减轻约5.5公斤，与安慰剂相比体重减轻约3公斤。氯酪蛋白的食欲减少作用部分是通过黑素皮质素受体4介导的。鉴于这两种药物都有显著的体重减轻，作用机制不同，这项研究将以我们使用二甲双胍的初步数据为基础，在超重的精神分裂症患者中测试二甲双胍/氯酪蛋白联合治疗与氯酪蛋白单独治疗与安慰剂治疗的策略。在非精神病人群中，联合治疗已经成功地用于减肥(即，芬太尼/托吡酯联合治疗)和其他慢性疾病，如高血压、癫痫和糖尿病，当单一治疗不充分时。90名超重的精神分裂症患者(BMI&GT；27)将参加一项为期52周的双盲随机研究，以评估氯卡韦林/二甲双胍联合治疗、氯卡塞林单一治疗和安慰剂对体重、身体成分以及葡萄糖和脂代谢指标的疗效和安全性。将测量食欲和关键食欲调节激素(包括瘦素、Ghrelin和GLP-1)的血浆水平的行为评估，以研究氯酪蛋白和二甲双胍在该人群中减肥的作用机制。24小时食品召回评估和基于加速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影响。所有受试者都将接受促进健康饮食和增加体力活动的行为干预。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、安全的长期选择，这对肥胖率高以及相关的心血管发病率和死亡率高的脆弱人群至关重要。

 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.