PULSE LOADED IV CLOMIPRAMINE IN UNRESPONSIVE OCD

强迫症（OCD）是美国第四大最常见的精神障碍，经常导致致残。20%到40%的强迫症患者对口服药物的反应不满意，需要8到10周的试验来确定给定的药物是否对患者有效。这项研究的广泛、长期目标是研究一种新的治疗方法对这些患者的有效性、安全性和效果的快速性。我们建议在76例治疗无反应的DSM-IV OCD患者中进行一项2点、随机、双盲对照试验，比较脉冲负荷静脉注射氯丙咪嗪（CMI）（第1150 mg；第2200 mg；第3-5天，零）和脉冲负荷口服氯丙咪嗪（相同剂量），然后口服CMI治疗12周。我们的主要假设是：1。双盲静脉脉冲负荷CMI将在第6天对大于或等于2次抗强迫症药物试验无反应的强迫症患者产生有临床意义的改善；2. 这种改善将显著超过口服脉冲加载CMI所产生的改善；, 3。在为期12周的开放标签口服CMI维持试验结束时，静脉脉冲负荷患者比口服脉冲负荷患者有更大的改善。我们的双盲初步研究结果与这些假设一致。基于保守效应大小为0.7的功率计算表明，在p小于或等于0.05时，76名患者将提供80%的功率来检验主要假设。我们还将探讨：1；第6天和第12周的结局与血浆CMI及其代谢物水平有关；, 2。结果可以从基线临床信息预测。（在本修订后的拨款申请中，除了新的导言是普通字体外，所有修订均以粗体标示。）

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).