CLINICAL TRIAL: ARIPIPRAZOLE FOR CLOZAPINE ASSOCIATED MEDICAL MORBIDITY

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。 与传统抗精神病药物相比，非典型抗精神病药物在副作用方面有显著改善，特别是在锥体外系症状(EPS)方面。氯氮平是一种非典型的抗精神病药物，仍然是治疗难治性精神分裂症人群中最有效的药物。虽然氯氮平产生的锥体外系副作用较少，但它也不是没有副作用。一些文献报道表明氯氮平与高脂血症、体重增加、高血压、胰岛素抵抗、高血糖、糖尿病酮症酸中毒(DKA)和2型糖尿病(DM)有关。在一项为期五年的观察性研究中，我们发现接受氯氮平治疗的82名患者中有30名(36.6%)患上了糖尿病，这与体重增加无关。观察到总胆固醇和甘油三酯显著增加。我们还采用横断面设计研究了氯氮平、奥氮平和利培酮的作用，采用频繁取样静脉葡萄糖耐量试验(FSIVGTT)，测量胰岛素敏感指数(SI)、葡萄糖有效性(SG)和急性胰岛素反应(AIR)。结果表明，服用氯氮平和奥氮平的非肥胖受试者的SI和SG异常，表明胰岛素抵抗和葡萄糖利用受损，两者都增加了糖尿病的风险。高胰岛素血症或胰岛素抵抗被认为会损害脂质代谢，是糖尿病的先兆。氯氮平治疗所观察到的血脂异常可能继发于药物引起的胰岛素抵抗。 很少有干预措施能成功预防或逆转氯氮平治疗的医学并发症。我们对10名接受氯氮平治疗的患者进行了一项为期六周的阿立哌唑辅助治疗开放研究，阿立哌唑是一种非典型抗精神病药物。与研究终点相比，观察到空腹甘油三酯、总胆固醇、体重和体重指数(BMI)显著降低。 我们现在提议对新型抗精神病药物阿立哌唑进行为期8周的安慰剂对照试验，并对70名接受氯氮平治疗的精神分裂症患者进行为期4周的辅助治疗，以检查阿立哌唑对血脂和葡萄糖代谢以及身体成分的影响。我们还将进行一系列症状评分，以检验联合治疗的临床相关性。这项研究的结果应该有助于阐明氯氮平治疗患者中阿立哌唑辅助治疗的有效性，以及高脂血症与胰岛素抵抗和氯氮平治疗后体重增加的关系。 具体目标： 主要： 1.通过对70名接受氯氮平治疗的精神分裂症患者进行为期8周的15毫克阿立哌唑的安慰剂对照试验，检验阿立哌唑降低包括甘油三酯和总胆固醇在内的空腹血脂的有效性。 2.检测阿立哌唑的减肥和降低BMI的疗效。 3.通过检测空腹胰岛素、稳态模型评估-胰岛素抵抗(HOMA-IR)和FSIVGTT的SI、SG的变化来检验阿立哌唑改善胰岛素抵抗和糖代谢的有效性。 4.分析改善血脂、体重减轻和胰岛素抵抗的潜在预测因素，包括基线血脂、体重、年龄、性别、种族、活动水平和吸烟状况。 次要： 1.研究阿立哌唑对食物摄入量和能量消耗的影响。 2.用SAFTEE和生命体征评价阿立哌唑与氯氮平配伍的耐受性和安全性。 3.将FSIVGTT、SI和SG的结果与年龄、性别、种族以及BMI、身体成分、家族史、饮食、锻炼、体重增加和血脂异常的变化相关联。 4.通过连续检测纤溶酶原激活物分子-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)和血管性假血友病因子(VWF)，将血脂和糖代谢的改善与动脉粥样硬化生化指标的变化联系起来。 5.用载脂蛋白和脂蛋白密度分级来表征基线血脂异常的变化。 6.评价阿立哌唑对阴性症状(SANS总分)、阳性症状(PANSS总分和阳性症状子分)和抑郁症状(汉密尔顿抑郁量表)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。

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 offer significant improvements in side effect profiles relative to conventional antipsychotic agents, particularly concerning extrapyramidal symptoms (EPS). Clozapine, an atypical antipsychotic agent, remains the most effective agent for the treatment-resistant schizophrenia population. Though clozapine produces fewer extrapyramidal side effects, it is not without side effects. Several reports in the literature suggest an association of clozapine with hyperlipidemia, weight gain, hypertension, insulin resistance, hyperglycemia, diabetic ketoacidosis (DKA) and type 2 diabetes mellitus (DM). In a five-year observational study, we found that 30 of 82 (36.6%) patients treated with clozapine developed diabetes mellitus, which was not correlated with weight gain. Significant increases in total cholesterol and triglyceride was observed. We also studied the effects of clozapine, olanzapine, and risperidone in a cross-sectional design, using a frequent sampled intravenous glucose intolerance test (FSIVGTT) which allowed for the measurement of insulin sensitivity index (SI), glucose effectiveness (SG,) and the acute insulin response (AIRG). Results suggested abnormalities in SI and SG in clozapine- and olanzapine- non-obese treated subjects, suggesting insulin resistance and an impairment of glucose utilization, both increasing the risk for DM. Hyperinsulinemia or insulin resistance is thought to impair lipid metabolism and is a precursor to DM. It is possible that the lipid abnormalities observed with clozapine treatment is secondary to insulin resistance induced by the drug. Few interventions have been successful to prevent or reverse the medical complications of clozapine therapy. We conducted a six-week open label study of adjunctive therapy with aripiprazole, an atypical antipsychotic agent, in ten clozapine-treated patients. Significant reductions in fasting triglyceride, total cholesterol, weight and body mass index (BMI) were observed, comparing baseline to study endpoint. We now propose an 8-week, placebo-controlled trial of the novel antipsychotic agent, aripiprazole, with a 4-week follow-up for adjunctive therapy in 70 clozapine-treated schizophrenia subjects to examine aripiprazole's affect on lipid and glucose metabolism, as well as body composition. We will also perform a battery of symptoms scales to exam clinical correlates of combination therapy. The results of this study should help clarify the usefulness of adjunctive therapy with aripiprazole in clozapine-treated patients and the relationship of hyperlipidemia to insulin resistance and weight gain with clozapine treatment. Specific Aims: Primary: 1. Examine the efficacy of aripiprazole for reducing fasting lipids, including triglycerides and total cholesterol, by conducting an 8-week placebo-controlled trial of 15 mg aripiprazole in 70 clozapine-treated schizophrenia subjects. 2. Examine the efficacy of aripiprazole for weight loss and BMI reduction. 3. Examine the efficacy of aripiprazole for improving insulin resistance and glucose metabolism measured by examining changes in fasting insulin, homeostatic model assessment-insulin resistance (HOMA-IR), and SI, SG from FSIVGTT. 4. Analyze potential predictors of response for improvements in lipids, weight loss, and insulin resistance, including baseline lipids, weight, age, gender, race, activity levels, and smoking status. Secondary: 1. Examine the aripiprazole's effect on food intake and energy expenditure. 2. Evaluate tolerability and safety of aripiprazole added to clozapine using the SAFTEE and vital signs. 3. Correlate the findings from the FSIVGTT, SI, and SG with age, sex, race, and changes in BMI, body composition, family history, diet, exercise, weight gain, and lipid abnormalities. 4. Correlate improvements in lipid and glucose metabolism with change in biochemical predictors of atherosclerosis by sequential measurements of plasminogen activator moledcule-1 (PAI-1), LDL particle size, C-reactive protein, soluble intercellular adhesion molecule-1 (sICAM-1), and von Willebrand factor (vWF). 5. Characterize the changes of baseline lipid abnormalities using apolipoproteins and lipoprotein density classes. 6. Evaluate the effects of aripiprazole upon negative symptoms (SANS total score), positive symptoms (PANSS total score and positive symptom sub score) and depressive symptoms (Hamilton Depression Rating Scale). 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.