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

描述（由申请人提供）：创伤后应激障碍是常见的，严重的，致残的，抑郁和失眠往往是突出的特点。PTSD最好的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（SSRIs）是最好的药物治疗，但它们的疗效有限。高脱落率，延迟响应，失眠治疗相对较差，以及性副作用是SSRI的常见缺点，尽管有证据表明，能够持续SSRI治疗长达36周的患者达到高应答率。PTSD迫切需要更有效的药物治疗。 改善PTSD药物治疗的一种方法是通过开发一种抵消SSRIs局限性的联合治疗策略来建立SSRIs已知的部分疗效。理想的增强剂是一种药物，当用SSRI开始时，通过以下方式改善可接受性、耐受性和疗效：1）加速反应时间; 2）增强总体反应; 3）改善PTSD相关的失眠和性功能障碍，并抵消SSRI的常见副作用，如失眠和性功能障碍; 4）与SSRI一起安全给药。米氮平是一种市售的抗抑郁药，具有5-羟色胺5-HT 2和5-HT 3、2-肾上腺素能和组胺H1受体拮抗剂，通过叠加和协同机制，符合上述SSRI治疗PTSD的潜在增强剂的标准。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在安慰剂对照试验中检查米氮平和SSRI联合治疗PTSD的可行性、可接受性、安全性、有效性和风险/效益比。结果将告知联合米氮平和SSRI治疗是否适合其疗效，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。该提案涉及NIMH战略计划的目标，即制定创新干预措施，研究干预措施的不利影响和有利影响之间的平衡，并研究如何最大限度地减少副作用。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例平民PTSD患者将被随机分配至24周的双盲治疗组，分别接受舍曲林+米氮平和舍曲林+安慰剂治疗。12周后至少出现轻微缓解的患者将继续接受相同的双盲研究治疗12周。结果将由独立评估员、治疗精神科医生和患者进行评估。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级;反应和缓解;脱落和持续治疗的持续时间，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：PTSD是常见的，严重的，致残的。SSRIs是最好的药物治疗，但它们的疗效不高。这项研究探讨了一种策略，通过将SSRI舍曲林与另一种抗抑郁药米氮平或安慰剂联合治疗24周，来增强舍曲林治疗的效果。

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.