Efficacy of Clozapine for Treatment-Resistant Mania

氯氮平治疗难治性躁狂症的疗效

• 批准号: 6982742
• 负责人: HUSSEINI K MANJI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6982742
• 关键词: antipsychotic agents; bipolar depression manic phase; brain mapping; brain metabolism; clinical trials; clozapine; deoxyglucose; drug screening /evaluation; glucose metabolism; human subject; human therapy evaluation; mental disorder chemotherapy; patient oriented research; pharmacokinetics; positron emission tomography

A significant proportion of manic patients either do not respond adequately to conventional treatment (lithium, valproate or carbamazepine (with or without antipsychotic drugs), or cannot tolerate the adverse effects associated with therapeutic doses of these agents. Thus, a need exists for additional effective treatments. Preliminary studies by our group suggest that clozapine may have antimanic actions and be effective in treatment-resistant bipolar disorder. However, the efficacy of clozapine as an alternative therapy in treatment-resistant mania has never been subjected to definitive study with an adequate numbers of subjects. Thus, we propose to conduct the largest and only double-blind, placebo-controlled trial to date, of clozapine, in bipolar manic patients who were unresponsive or intolerant to six weeks of treatment with lithium, valproate, carbamazepine and at least one antipsychotic drug. The specific aims of this investigation are to 1) assess the acute treatment efficacy of clozapine in treatment-resistant mania, 2) to investigate the functional anatomical correlates of mania, and 3) to investigate the effects of clozapine treatment on cerebral glucose metabolism and metabolic correlates of effective antimanic, clozapine treatment. Forty-two subjects (two groups of 21 each) will be randomly assigned to treatment with clozapine or placebo for three weeks. We anticipate that a maximum of 33% of patients will be withdrawn from the acute phase of the study due to reasons such as intolerable adverse effects or withdrawal of consent. Thus, we expect the entered sample to yield 14 completed subjects per cell. This sample size will allow for adequate statistical power to test the hypotheses stated above. Patients, ages 18 to 60, with a diagnosis of bipolar I disorder manic or mixed (with or without psychotic features), will be randomized to double-blind treatment to receive either clozapine (200-550 mg/day) or placebo, for a period of 3 weeks. Following this acute period, the patients will receive either open-label clozapine or treatment as clinically indicated. If clozapine is found effective in treatment-resistant mania, it would be a significant step forward in the treatment of these patients and would have major health implications. In addition, it would establish a gold standard against which newer treatments can be compared to. Finally, glucose metabolism images will be obtained using PET and [F-18] FDG at baseline and following 3 weeks of clozapine treatment to investigate the functional anatomical correlates of mania and to compare drug-induced metabolic changes between responders and nonresponders.

很大一部分躁狂患者对常规治疗（锂、丙戊酸盐或卡马西平（伴或不伴抗精神病药物））没有充分反应，或不能耐受与这些药物治疗剂量相关的不良反应。因此，需要额外的有效治疗。我们小组的初步研究表明，氯氮平可能有抗躁狂作用，对难治性双相情感障碍有效。然而，氯氮平作为难治性躁狂症的替代疗法的疗效从未在足够数量的受试者中进行过确定性研究。因此，我们建议进行最大的和唯一的双盲，安慰剂对照试验，氯氮平，在双相躁狂患者谁是无反应或不耐受的治疗6周锂，丙戊酸盐，卡马西平和至少一种抗精神病药物。本研究的具体目的是：1）评估氯氮平对难治性躁狂症的急性治疗效果，2）研究躁狂症的功能解剖学相关性，3）研究氯氮平治疗对脑葡萄糖代谢的影响以及有效抗躁狂剂氯氮平治疗的代谢相关性。42名受试者（两组，每组21名）将被随机分配接受氯氮平或安慰剂治疗三周。我们预计，最多33%的患者将因不可耐受的不良反应或撤回知情同意等原因退出研究的急性期。因此，我们预计输入的样本将产生每个单元14个完成的受试者。该样本量将允许足够的统计功效来检验上述假设。年龄18 - 60岁，诊断为躁狂或混合型I型双相情感障碍（伴或不伴精神病特征）的患者将随机接受双盲治疗，接受氯氮平（200-550 mg/天）或安慰剂，为期3周。急性期后，患者将接受开放标签氯氮平或临床指征治疗。如果发现氯氮平对难治性躁狂症有效，这将是治疗这些患者的重要一步，并将对健康产生重大影响。此外，它将建立一个黄金标准，可以与新的治疗方法进行比较。最后，将在基线和氯氮平治疗3周后使用PET和[F-18] FDG获得葡萄糖代谢图像，以研究躁狂症的功能解剖学相关性，并比较应答者和非应答者之间药物诱导的代谢变化。