Efficacy of Clozapine for Treatment-Resistant Mania

相当大比例的躁狂患者要么对常规治疗（锂、丙戊酸盐或卡马西平（有或没有抗精神病药物））没有充分反应，要么不能忍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方法。我们小组的初步研究表明氯氮平可能具有抗躁狂作用，对治疗难治性双相情感障碍有效。然而，氯氮平作为治疗难治性躁狂症的替代疗法的有效性从未在足够数量的受试者中进行过明确的研究。因此，我们建议在对锂、丙戊酸盐、卡马西平和至少一种抗精神病药物治疗6周无反应或不耐受的双相躁狂患者中进行迄今为止规模最大、唯一的氯氮平双盲安慰剂对照试验。本研究的具体目的是：1)评估氯氮平治疗难治性躁狂的急性疗效；2)研究躁狂的功能解剖学相关性；3)研究氯氮平治疗对脑糖代谢的影响以及有效抗躁狂、氯氮平治疗的代谢相关性。42名受试者（每组21人）将被随机分配使用氯氮平或安慰剂治疗三周。我们预计，由于无法忍受的不良反应或撤回同意等原因，最多33%的患者将退出研究的急性期。因此，我们期望输入的样本每个细胞产生14个完整的受试者。这个样本量将允许有足够的统计能力来检验上述假设。年龄在18岁到60岁之间，诊断为双相I型躁狂症或混合型（伴有或不伴有精神病性特征）的患者将随机分为双盲治疗组，接受氯氮平（200-550 mg/天）或安慰剂治疗，为期3周。在这个急性期之后，患者将接受开放标签氯氮平或临床指征治疗。如果氯氮平被发现对难治性躁狂有效，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，它还将建立一个黄金标准，可供比较新的治疗方法。最后，在基线和氯氮平治疗3周后，将使用PET和[F-18] FDG获得糖代谢图像，以研究躁狂的功能解剖学相关性，并比较有反应者和无反应者之间药物诱导的代谢变化。

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 We anticipate that a maximum of 33% of patients will be withdrawn from the acute phase of the study due to reasons such as intolerable adverse effects or withdrawal of consent.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.