2/2-Ziprasidone Augmentation of SSRIs for Treatment-Resistant Depression (TRD)

描述（由申请人提供）：迫切需要确定耐药性抑郁症（TRD）的新治疗方法，以帮助提高护理标准。迄今为止，一些初步研究已经检查了使用非典型抗精神病药物作为标准抗抑郁药治疗TRD的替代品。然而，这种流行的标签外治疗策略的有效性尚未得到确定，而关于这种治疗策略的长期效果（在有效性，耐受性和安全性方面）知之甚少。特别是非典型抗精神病药物齐拉西酮，可以提供一个独特的机会，研究作为TRD的辅助治疗，主要有两个原因：I）其独特的受体亲和力特征，II）与该类药物相比，其有利的副作用特征。然而，不幸的是，齐拉西酮增加TRD的双盲，安慰剂对照试验至今尚未进行。如果齐拉西酮作为抗抑郁药的辅助治疗安全有效，那么对于许多对标准治疗的初始反应不满意的患者来说，它将是一个有吸引力的选择。如果未发现安全或有效，则该拟议试验的结果也将具有高度信息性，因为尽管来自独立资助的严格设计研究的数据相对较少，但TRD患者中有相当大比例的患者接受了非典型抗精神病药物的标签外治疗。拟议的研究包括三个阶段。第一阶段是一项为期8周的SSRI治疗MDD的开放标签试验。在该开放标签试验后没有经历足够症状改善的患者将被招募到齐拉西酮增强的8周、双盲、安慰剂对照试验（2期）中。齐拉西酮和安慰剂缓解者将进入为期12个月的双盲扩展期（第3期）。本研究的目的是评估齐拉西酮（20- 80 mg，每日两次;灵活剂量）作为SSRI耐药MDD的连续治疗的有效性、安全性和耐受性。次要目标包括：I）确定齐拉西酮增强是否有效缓解抑郁症的共病焦虑和疼痛症状，和，II）获得关于齐拉西酮辅助治疗的长期安全性和有效性的初步数据。该研究包括在马萨诸塞州总医院或范德比尔特大学医学院精神病学系门诊部招募总共400名MDD患者，为期5年。我们估计其中180名患者将进入双盲期。

DESCRIPTION (provided by applicant): Identifying novel treatments for resistant depression (TRD) is urgently needed to help improve the standard of care. To date, several preliminary studies have examined the use of atypical antipsychotic agents as adjuncts to standard antidepressants for TRD. However, the efficacy of this popular off-label treatment strategy has yet to be firmly established, while very little is known regarding the long-term effects (in terms of efficacy, tolerability and safety) of this treatment strategy. The atypical antipsychotic agent ziprasidone, in particular, may offer a unique opportunity to study as an adjunct for TRD for two principal reasons: I) its unique receptor-affinity profile, and, II) its favorable side-effect profile compared to the other agents in the class. Unfortunately, however, double-blind, placebo controlled trials of ziprasidone augmentation for TRD have not been conducted to date. If safe and effective as an antidepressant adjunct, ziprasidone would represent an attractive option for many of these patients who have had unsatisfactory initial response to standard treatment. If not found to be either safe or effective, the results of this proposed trial would also be highly informative given the significant proportion of TRD patients who, despite the relative paucity of data from independently-funded studies of rigorous design, are prescribed atypical antipsychotic agents off-label. The proposed study involves three phases. The first phase is an 8-week, open-label trial of an SSRI for MDD. Patients who do not experience sufficient symptom improvement following this open-label trial will be enrolled in an 8-week, double-blind, placebo controlled trial of ziprasidone augmentation (phase 2). Ziprasidone and placebo-remitters will then enter a 12-month, double-blind, extension phase (phase 3). The purpose of our study is to evaluate the efficacy, safety and tolerability of ziprasidone (20- 80mg twice-daily; flexible dose) as an adjunctive treatment in SSRI-resistant MDD. Secondary aims include: I) to determine whether ziprasidone augmentation is effective in relieving co-morbid anxious and painful symptoms of depression, and, II) to obtain preliminary data on the long-term safety and efficacy of adjunct ziprasidone. The study involves the enrollment of a total of 400 patients with MDD over the course of 5 years at either the Massachusetts General Hospital or the outpatient clinic of the department of Psychiatry at the Vanderbilt University School of Medicine. We estimate that 180 of these patients will enter the double-blind phase.