ARIPIPRAZOLE FOR CLOZAPINE ASSOCIATED MEDICAL MORBIDITY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 非典型抗精神病药物相对于常规抗精神病药物在副作用方面提供显著改善，特别是关于锥体外系症状（EPS）。氯氮平是一种非典型抗精神病药物，仍然是治疗难治性精神分裂症人群最有效的药物。虽然氯氮平产生较少的锥体外系副作用，它不是没有副作用。文献中的一些报告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）相关。 在一项为期5年的观察性研究中，我们发现82例接受氯氮平治疗的患者中有30例（36.6%）发生了糖尿病，而糖尿病与体重增加无关。观察到总胆固醇和甘油三酯显著增加。我们还研究了氯氮平，奥氮平和利培酮的影响，在一个横断面设计，使用频繁采样静脉葡萄糖耐量试验（FSIVGTT），允许测量胰岛素敏感性指数（SI），葡萄糖有效性（SG）和急性胰岛素反应（AIRG）。结果表明，氯氮平和奥氮平治疗的非肥胖受试者的SI和SG异常，提示胰岛素抵抗和葡萄糖利用受损，均增加了DM的风险。高胰岛素血症或胰岛素抵抗被认为损害脂质代谢，是DM的前兆。氯氮平治疗中观察到的脂质异常可能继发于药物诱导的胰岛素抵抗。 很少有干预措施能够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6周的阿立哌唑（一种非典型抗精神病药）连续治疗的开放标签研究。基线与研究终点相比，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。 我们现在提出了一个为期8周的安慰剂对照试验的新的抗精神病药物，阿立哌唑，4周的后续治疗70氯氮平治疗的精神分裂症受试者检查阿立哌唑对脂质和葡萄糖代谢的影响，以及身体组成。我们还将进行一系列症状量表，以检查联合治疗的临床相关性。本研究的结果有助于阐明阿立哌唑连续治疗在氯氮平治疗患者中的有效性，以及高脂血症与胰岛素抵抗和体重增加与氯氮平治疗的关系。 具体目标： 主要： 1.通过在70名氯氮平治疗的精神分裂症受试者中进行为期8周的15 mg阿立哌唑安慰剂对照试验，检查阿立哌唑降低空腹血脂（包括甘油三酯和总胆固醇）的疗效。 2.检查阿立哌唑减肥和降低BMI的疗效。 3.通过检查空腹胰岛素、稳态模型评估-胰岛素抵抗（HOMA-IR）和FSIVGTT的SI、SG的变化，检查阿立哌唑改善胰岛素抵抗和葡萄糖代谢的疗效。 4.分析血脂、体重减轻和胰岛素抵抗改善的潜在反应预测因素，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.检查阿立哌唑对食物摄入和能量消耗的影响。 2.使用SAFTEE和生命体征评价阿立哌唑加用氯氮平的耐受性和安全性。 3.将FSIVGTT、SI和SG的结果与年龄、性别、种族和BMI、身体成分、家族史、饮食、运动、体重增加和血脂异常的变化相关联。 4.通过连续测量纤溶酶原激活物分子-1（派-1）、低密度脂蛋白颗粒大小、C反应蛋白、可溶性细胞间粘附分子-1（sICAM-1）和血管性血友病因子（vWF），将脂质和葡萄糖代谢的改善与动脉粥样硬化生化预测因子的变化相关联。 5.使用载脂蛋白和脂蛋白密度分类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总分和阳性症状分项评分）和抑郁症状（汉密尔顿抑郁量表）的影响。 受试者入组、临床评估和血液采集的研究中心将位于Erich Lindemann Mental Health Center的Freedom Trail Clinic。 FSIVGTT和血样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.