Combined Mirtazapine and SSRI Treatment of PTSD: A Placebo-Controlled Trial

描述（由申请人提供）：创伤后应激障碍是一种常见的、严重的、致残的疾病，抑郁和失眠往往是突出的特征。创伤后应激障碍的最佳治疗方法是认知行为疗法（CBT），但有些患者更喜欢药物治疗，训练有素的CBT治疗师并非在所有领域都可用，而且CBT并不总是有效的。选择性5 -羟色胺再摄取抑制剂（SSRIs）是最成熟的药物治疗方法，但它们的疗效有限。高辍学率、延迟反应、相对较差的失眠治疗和性不良反应是SSRIs的常见缺点，尽管有证据表明能够继续SSRI治疗长达36周的患者获得高反应率。创伤后应激障碍迫切需要更有效的药物治疗。改善创伤后应激障碍药物治疗的一种方法是建立在已知的SSRIs部分疗效的基础上，通过开发一种联合治疗策略来抵消SSRIs的局限性。理想的增强剂是一种药物，当与SSRI一起开始时，它可以通过以下方式提高可接受性、耐受性和疗效：1)加速反应时间；2)加强整体应对；3)改善ptsd相关的失眠和性功能障碍，并抵消SSRIs常见的副作用，如失眠和性功能障碍；4)使用SSRI是安全的。米氮平是一种已上市的抗抑郁药，其拮抗剂是5 -羟色胺5HT2和5HT3, 2-肾上腺素能和组胺H1受体，它符合上述标准，通过加性和协同机制成为SSRI治疗PTSD的潜在增强剂。这种组合对PTSD来说是新颖的，其安全性和高可接受性已在其他疾病和非临床样本中得到证实。本研究的总体目标是通过安慰剂对照试验，探讨米氮平与SSRI联合治疗PTSD的可行性、可接受性、安全性、有效性和风险/获益比。结果将告知米氮平和SSRI联合治疗是否适合于其疗效、有效性和作用机制的大规模研究，并将建立用于此类研究的方法。该提案解决了NIMH战略计划的目标，即开发创新干预措施，检查干预措施的不利影响和有益影响之间的平衡，并检查如何将副作用最小化。长期目标是通过开发新的有利的药物治疗策略来改善创伤后应激障碍的治疗效果。在本研究中，60例平民PTSD患者将被随机分为舍曲林+米氮平与舍曲林+安慰剂的双盲治疗，为期24周。12周后表现出至少最小反应的患者将继续进行另外12周的相同双盲研究治疗。结果将由治疗精神病医生和患者的独立评估人员进行评估。结果测量将包括创伤后应激障碍、失眠和抑郁症状的严重程度评分；反应与缓解；停药和治疗持续时间、生活质量和不良反应，包括性功能评估。改善将在治疗的前12周和整个24周内进行评估。

DESCRIPTION (provided by applicant): PTSD is common, severe, and disabling, and depression and insomnia are often prominent features. The best-established treatments for PTSD are cognitive behavioral therapies (CBT), but some patients prefer medication treatment, trained CBT therapists are not available in all areas, and CBT is not always effective. The selective serotonin reuptake inhibitors (SSRIs) are the best-established medication treatment, but they are of modest efficacy. High dropout rates, delayed response, relatively poor treatment of insomnia, and sexual adverse effects are common drawbacks to SSRIs, although there is evidence that patients who are able to continue SSRI treatment for up to 36 weeks achieve high rates of response. More-effective medication treatments are urgently needed for PTSD. One approach to improving medication treatment of PTSD is to build upon the known partial efficacy of SSRIs by developing a combination treatment strategy that counteracts the limitations of SSRIs. An ideal augmenting agent would be a medication that when initiated with an SSRI improves acceptability, tolerability and efficacy by: 1) accelerating time to response; 2) enhancing overall response; 3) improving PTSD-related insomnia and sexual dysfunction, and counteracting common side effects of SSRIs, such as insomnia and sexual dysfunction; and 4) being safe to administer with an SSRI. Mirtazapine is a marketed antidepressant with antagonist at serotonin 5HT2 and 5HT3, 2-adrenergic and histamine H1 receptors, and it meets each of the above criteria for a potential augmenter of SSRI treatment for PTSD through additive and synergistic mechanisms. This combination is novel to PTSD, and its safety and high acceptability has been documented in other disorders and in nonclinical samples. The overall goal of this study is to examine feasibility, acceptability, safety, efficacy and risk/benefit ratio of combined mirtazapine and SSRI treatment for PTSD in a placebo-controlled trial. Results will inform whether combined mirtazapine and SSRI treatment is suitable for larger-scale study of its efficacy, effectiveness, and mechanisms of action, and will establish methods to be used in such studies. This proposal addresses NIMH Strategic Plan goals of developing innovative interventions that examine the balance between adverse effects and beneficial effects of interventions and examine how to minimize side effects. The long-term goal is to improve the treatment outcome of PTSD by developing new and advantageous pharmacological treatment strategies. In this study, 60 patients with civilian PTSD will be randomized to 24 weeks of double-blind treatment with sertraline + mirtazapine versus sertraline + placebo. Patients who show at least a minimal response after 12 weeks will continue for another 12 weeks on the same double-blind study treatment. Outcome will be assessed by independent assessors, treating psychiatrists and patients. Outcome measures will include ratings of severity of PTSD, insomnia, and depression symptoms; response and remission; dropout and duration of persistence in treatment, quality of life, and adverse effects, including assessment of sexual functioning. Improvement will be assessed over the first 12 weeks of treatment, and over the full 24 weeks. PUBLIC HEALTH RELEVANCE: PTSD is common, severe, and disabling. The SSRIs are the best-established medication treatment, but they are of modest efficacy. This study examines a strategy for augmenting the effect of treatment with the SSRI sertraline, by combining it with another antidepressant mirtazapine, or placebo, over 24 weeks of treatment.