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

描述(申请人提供)：创伤后应激障碍是常见的、严重的和致残的，抑郁和失眠通常是突出的特征。PTSD最成熟的治疗方法是认知行为疗法(CBT)，但一些患者更喜欢药物治疗，训练有素的CBT治疗师并不适用于所有领域，CBT并不总是有效的。选择性5-羟色胺再摄取抑制剂(SSRI)是最成熟的药物治疗方法，但它们的疗效不大。高辍学率、延迟反应、相对较差的失眠治疗和性不良反应是SSRI的常见缺点，尽管有证据表明，能够继续SSRI治疗长达36周的患者取得了高应答率。创伤后应激障碍急需更有效的药物治疗。改善创伤后应激障碍药物治疗的一种方法是在已知的SSRIs部分疗效的基础上，开发一种联合治疗策略，抵消SSRIs的局限性。一种理想的增强剂应该是这样一种药物，当与SSRI一起启动时，它通过以下方式提高可接受性、耐受性和有效性：1)加快反应时间；2)增强总体反应；3)改善与创伤后应激障碍相关的失眠和性功能障碍，并对抗SSRI的常见副作用，如失眠和性功能障碍；以及4)使用SSRI是安全的。米氮平是一种上市的抗抑郁药，具有5-HT2和5-HT3，2-肾上腺素能和组胺H1受体的拮抗剂，它符合上述标准中的每一个标准，通过添加和协同机制成为SSRI治疗PTSD的潜在增强剂。这种组合对创伤后应激障碍来说是新的，它的安全性和高可接受性已经在其他疾病和非临床样本中得到了证明。这项研究的总体目标是在安慰剂对照试验中检查米氮平和SSRI联合治疗创伤后应激障碍的可行性、可接受性、安全性、有效性和风险/收益比。结果将告知米氮平和SSRI联合治疗是否适合于对其疗效、有效性和作用机制进行更大规模的研究，并将建立用于此类研究的方法。这项建议涉及NIMH战略计划的目标，即开发创新的干预措施，审查干预措施的不利影响和有益影响之间的平衡，并审查如何将副作用降至最低。长期目标是通过开发新的和有利的药物治疗策略来改善PTSD的治疗结果。在这项研究中，60名平民创伤后应激障碍患者将被随机分成舍曲林+米氮平和舍曲林+安慰剂进行24周的双盲治疗。12周后至少表现出最小反应的患者将继续接受相同的双盲研究治疗12周。结果将由独立的评估员、治疗精神病医生和患者进行评估。结果衡量标准将包括创伤后应激障碍、失眠和抑郁症状的严重程度评级；反应和缓解；辍学和坚持治疗的时间、生活质量和不良反应，包括性功能评估。将在治疗的前12周和整个24周内评估改善情况。 公共卫生相关性：创伤后应激障碍是常见的、严重的和致残的。SSRI是最成熟的药物治疗方法，但它们的疗效不大。这项研究探讨了一种通过将SSRI舍曲林与另一种抗抑郁剂米氮平或安慰剂联合治疗24周来增强治疗效果的策略。

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.