PULSE LOADED IV CLOMIPRAMINE IN UNRESPONSIVE OCD

强迫症(OCD)是美国第四种最常见的精神障碍，经常导致残疾。20%到40%的强迫症患者对口服药物的反应不令人满意，需要进行8到10周的试验，以确定给定的药物对患者是否有效。这项研究的广泛的、长期的目标是调查一种新的治疗方法对这些患者的有效性、安全性和起效速度。我们建议对76名对治疗无效的DSM-IV强迫症患者进行两点随机双盲对照试验，比较脉冲加载静脉注射氯丙咪嗪(CMI)(第1天，150 mg；第2天，200 mg；第3-5天，零)和脉冲加载口服CMI(相同剂量)，然后口服CMI治疗12周。我们的主要假设是：1.双盲静脉注射脉冲负荷CMI将在第6天前产生临床上有意义的改善，即强迫症患者对先前抗强迫症药物试验的反应大于或等于2次；2.这一改善将显著超过口服脉冲负荷CMI产生的改善；以及3.在为期12周的开放标签口服CMI维持试验结束时，静脉脉冲负荷患者将比口服脉冲负荷患者体验到更大的改善。我们的双盲初步研究结果与这些假设是一致的。基于保守效应大小0.7的功率计算表明，76名患者将提供80%的功率来检验p小于或等于0.05的主要假设。我们还将探索：1.第6天和第12周的结果是否与血浆CMI及其代谢物水平有关；2.根据基线临床信息是否可以预测结果。(在这份修订的拨款申请中，除了新的介绍是普通字体外，修改都是用粗体表示的)。

Obsessive-compulsive disorder (OCD) is the 4th most common mental disorder in the U.S. and is frequently disabling. From 20 percent to 40 percent of OCD patients do not respond satisfactorily to oral medications and an 8- to 10-week trial is needed to determine whether a given drug is effective for the patient. This study's broad, long-term objective is to investigate the efficacy, safety and rapidity of effect of a new treatment for these patients. We propose a 2-site, randomized, double-blind controlled trial in 76 patients with treatment-unresponsive DSM-IV OCD comparing pulse loaded intravenous clomipramine (CMI), (day 1, 150 mg; day 2, 200 mg; days 3-5, zero) to pulse loaded oral CMI (in identical doses) followed by 12 weeks of oral CMI treatment. Our primary Hypotheses are: 1. double-blind intravenous pulse loaded CMI will produce by day 6 a clinically meaningful improvement in OCD patients unresponsive to greater than or equal to 2 prior anti-OCD drug trials; 2. this improvement will significantly exceed that produced by oral pulse loaded CMI; and, 3. intravenous pulse loading patients will have experienced greater improvement by the end of a 12-week open-label oral CMI maintenance trial than oral pulse loading patients. Results of our double-blind Preliminary Study are consistent with these hypotheses. Power calculations based on a conservative effect size of 0.7 indicate that 76 patients would provide 80 percent power to test the Primary Hypotheses at p less than or equal to 0.05. We will also explore whether: 1. day 6 and week 12 outcomes are related to plasma levels Of CMI and its metabolites; and, 2. outcome can be predicted from baseline clinical information. (Throughout this revised grant application, revisions are indicated by bold type face, except that the new Introduction is in ordinary typeface).