ROSIGLITAZONE FOR CLOZAPINE INDUCED GLUCOSE METABOLISM IMPAIRMENT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 与传统的抗精神病药物相比，非典型抗精神病药物引起的锥体外系副作用较少，但有各种其他副作用。肥胖是一种已知的抗精神病药物的副作用，最近的文献报道将氯氮平与体重增加联系在一起。 通过增加患者的肥胖风险，抗精神病药物可能会使患者面临相关的发病率和死亡率的风险。体重增加超过总体重10%的患者有发生与体重相关的疾病的风险，如高血压和非胰岛素依赖型糖尿病。 氯氮平仍然是治疗难治性精神分裂症最有效的药物，开发干预措施以防止与氯氮平相关的严重医学发病率至关重要。糖尿病是一种毁灭性的疾病，其并发症包括心血管疾病、肾脏疾病、神经病变和视网膜病变。除精神分裂症外，糖尿病还严重影响这一人群的健康、生活质量和预期寿命。此外，在一个患有慢性精神疾病并随后难以跟进医疗护理的人群中，2型糖尿病的经济影响是深远的。 我们提出了一项为期八周的罗格列酮双盲安慰剂对照试验，用于使用Bergman的MINMOD FSIVGTT检查糖代谢，用于接受氯氮平治疗的精神分裂症患者。MINMOD确定胰岛素敏感性、胰岛素分泌和肥胖程度之间的关系，并可用于研究药物对这些变量的影响。该计算机程序估计葡萄糖有效性(SG)、胰岛素敏感指数(SI)和对葡萄糖的急性胰岛素反应(AIRG)。(见下文)。这些参数将根据FSIVGTT期间测量的血糖和胰岛素值来计算。 具体目标是： 1.比较罗格列酮和安慰剂对氯氮平治疗的精神分裂症患者胰岛素、血糖和空腹血糖的影响，并进行基线和8周的随访。 2.将SI、SG和AIRG的结果与BMI、身体成分、家族史、年龄、性别、种族、饮食、运动、体重增加和血脂异常的变化相关联。 3.确定与安慰剂相比，罗格列酮是否改善了与胰岛素抵抗相关的其他变量，如心血管疾病的生化标记物(纤溶酶原激活物抑制物-1[PAI-1]、低密度脂蛋白颗粒大小、C反应蛋白、可溶性细胞间黏附分子-1[sICAM-1]和von Willebrand因子[vWF])和认知缺陷。 4.检测胰岛素抵抗和高血糖对精神分裂症患者认知功能的影响 受试者登记、临床评估和血液采集的地点将在埃里希·林德曼精神健康中心的自由之路诊所。FSIVGTT和血液样本将在马萨诸塞州综合医院的Mallinckrodt综合临床研究中心进行。 将从自由之路诊所招募50名接受氯氮平治疗的受试者。患者年龄必须在18-65岁之间，并被诊断为精神分裂症、分裂情感障碍或分裂样障碍。患者将根据基线空腹血糖进行匹配。将受试者分为两组：空腹血糖正常组(血糖100 mg/dL)和空腹血糖受损组(血糖=100 mg/dL和126 mg/dL)。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Atypical antipsychotic agents cause fewer extrapyramidal side effects than conventional neuroleptics but have a variety of other side effects. Obesity is a known side effect of neuroleptics and recent reports in the literature have linked clozapine with weight gain. By increasing a patient's risk of obesity, antipsychotic agents may be placing patients at risk for associated morbidity and mortality. Patients who gain greater than 10% of their total body weight are at risk for developing weight associated conditions such as hypertension and non-insulin dependent diabetes. Clozapine remains the most effective agent for treatment-resistant schizophrenia, developing interventions to prevent serious clozapine-related medical morbidity is critical. Diabetes is a devastating disease with complications including cardiovascular disease, renal disease, neuropathy, and retinopathy. In addition to schizophrenia, diabetes significantly impacts the health, quality of life, and life expectancy of this population. Furthermore, in a population with chronic mental illness and subsequent difficulty in following up with medical care, the economic impact of type 2 diabetes mellitus is profound. We propose an eight-week, double-blind, placebo-controlled trial of rosiglitazone in schizophrenia subjects treated with clozapine using Bergman's MINMOD FSIVGTT for examination of glucose metabolism. The MINMOD determines the relationship between insulin sensitivity, insulin secretion and the degree of obesity and can be used to study drug effects upon these variables. The computer program estimates glucose effectiveness (SG), insulin sensitivity index (SI), and the acute insulin response to glucose (AIRG). (see below). These parameters will be calculated from glucose and insulin values measured during the FSIVGTT. The Specific Aims are to: 1. Compare the effects of treatment with rosiglitazone to placebo in schizophrenia subjects treated with clozapine on insulin SI, SG, and AIRG by performing baseline and 8-week follow-up FSIVGTT. 2. Correlate the findings on SI, SG and AIRG with change in BMI, body composition, family history, age, sex, race, diet, exercise, weight gain, and lipid abnormalities. 3. Determine if rosiglitazone, compared to placebo, improves other variables associated with insulin resistance such as biochemical makers for cardiovascular disease (plasminogen activator inhibitor-1 [PAI-1], LDL particle size, C-reactive protein, soluble intercellular adhesion molecule-1 [sICAM-1], and von Willebrand factor [vWF]) and cognitive deficits. 4. Examine the effects of insulin resistance and hyperglycemia on cognition in subjects with schizophrenia The site for subject enrollment, clinical assessment, and collection of blood will be at the Freedom Trail Clinic at the Erich Lindemann Mental Health Center. The FSIVGTT and blood samples will be conducted at the Mallinckrodt General Clinical Research Center at Massachusetts General Hospital. Fifty clozapine-treated subjects will be recruited from the Freedom Trail Clinic. Patients must be between the ages of 18-65, with the diagnosis of schizophrenia, schizoaffective disorder or schizophreniform disorder. Patients will be matched according to baseline fasting glucose. They will be stratified into two groups: normal fasting glucose (glucose <100 mg/dL) and impaired fasting glucose (glucose =100 mg/dL and < 126 mg/dL).