Aripiprazole for Clozapine Associated Medical Morbidity

描述（由申请人提供）：氯氮平仍然是治疗难治性精神分裂症人群最有效的药物。虽然氯氮平产生的锥体外系副作用较少，但它也不是没有副作用，可能包括镇静和体重增加。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，并且体重、总胆固醇和甘油三酯也有所增加。我们最近完成了一项对36名非肥胖精神分裂症患者的研究，发现氯氮平和奥氮平治疗的非肥胖患者胰岛素敏感性和葡萄糖利用异常，表明糖代谢受损，糖尿病风险增加。我们还对10例氯氮平治疗的患者进行了为期6周的阿立哌唑（一种非典型抗精神病药物）辅助治疗的开放标签研究。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。方法：对70例氯氮平治疗的精神分裂症患者进行为期8周的阿立哌唑辅助治疗的安慰剂对照试验，以观察阿立哌唑对脂质代谢、葡萄糖代谢、身体成分和心血管危险因素的影响。我们将执行一系列症状量表来检查联合治疗的临床相关性。意义：本研究结果有助于阐明阿立哌唑辅助治疗氯氮平患者的有效性，以及高脂血症与胰岛素抵抗和体重的关系。临床辅助治疗可能使阿立哌唑成为精神分裂症和氯氮平相关疾病的一种新的治疗方法。

DESCRIPTION (provided by applicant): Clozapine remains the most effective agent for the treatment-resistant schizophrenia population. Though clozapine produces fewer extrapyramidal side effects, it is not without side effects, which may include sedation and weight gain. In a five year observational study, we found that 30 of 82 (36.6%) patients treated with clozapine developed diabetes mellitus, and increases in weight, total cholesterol and triglyceride was also observed. We recently completed a study of 36 nonobese schizophrenia patients and found abnormalities in insulin sensitivity and glucose utilization in clozapine- and olanzapine- non-obese treated patients suggesting an impairment of glucose metabolism and increased risk of diabetes. We also 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. Method: We propose an eight week, placebo-controlled trial of aripiprazole for adjunctive therapy in 70 clozapine-treated schizophrenia subjects to examine aripiprazole's affect on lipid metabolism, glucose metabolism, and body composition and cardiovascular risk factors. We will perform a battery of symptoms scales to exam clinical correlates of combination therapy. Significance: 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. Clinical adjunctive therapy may establish aripiprazole as a new therapeutic approach in schizophrenia and clozapine-associated medical disorders.