Ketamine to reduce postpartum depression and pain after cesarean delivery

项目概要（摘要） 产后抑郁症（PPD）影响了全球2800万母亲在出生后的第一年，有自杀的风险- 这是全球产妇死亡的主要原因，并使儿童面临未来心理健康问题的风险。 剖腹产（CD）是世界上最常见的腹部大手术，缺乏关于新的 妊娠期和哺乳期的疼痛治疗使每年120万美国妇女在CD后处于疼痛风险中 情绪低落，恢复不佳。尽管CD后疼痛的个体差异性很高，但目前的CD 治疗忽视了疼痛的多维度性。已知NMDA受体拮抗剂如氯胺酮 减少非产科手术人群的术后疼痛和阿片类药物的使用，最近，氯胺酮 被认为是治疗抑郁症的有效药物。尽管产后氯胺酮的限量使用研究表明 没有严重副作用的证据，氯胺酮具有已知的和不希望的副作用（例如，恶心， 烦躁不安），这可能会干扰新生儿护理。对妊娠/哺乳期女性的研究因缺乏 关于最佳剂量和长期PPD和疼痛恢复结果的数据。这种知识差距阻碍了 了解氯胺酮如何减少这一人群的PPD和疼痛。迫切需要更好地 减少PPD风险和CD后疼痛的治疗。为了满足这些需求，我们将确定氯胺酮的耐受性 剂量、药代动力学和药效学，以便将来的随机试验使用适当的 可以对产后妇女进行氯胺酮给药。我们的长期目标是减轻负担， 抑郁症和疼痛对特殊人群的影响。我们的中心假设是CD后氯胺酮减少了 通过多方面减少疼痛来降低PPD风险。具体目的：A1：量化产后可耐受剂量 氯胺酮使用MTD设计。A2：确定开放标签中产后氯胺酮输注的PK/PD 观察性研究A3：确定PPD症状的变化点/轨迹，为未来产后提供信息 氯胺酮试验结果。这项建议有可能改变实践，因为预防性治疗 PPD缺乏，CD后替代非阿片类镇痛的缺乏一直是CD治疗的关键障碍。 产后疼痛恢复的进展。我们的方法是创新的，因为它采用了新的理论 产后多模式疼痛管理策略的概念。它解决了以前研究中的空白， 氯胺酮的最佳猜测剂量，导致疗效和副作用的可变结果。这项工作将确定 降低PPD风险和产后疼痛的新治疗策略。它将直接通知下一步 一项关于CD后氯胺酮耐受剂量的随机试验，用于PPD和疼痛恢复结局。

PROJECT SUMMARY (ABSTRACT) Postpartum depression (PPD) affects 28 million mothers worldwide in the first year after birth, risking suicide— a leading cause of maternal death globally—and placing children at risk for future mental health problems. Cesarean delivery (CD) is the most common major abdominal surgery in the world, and a lack of data on new pain treatments in pregnancy and lactation puts 1.2 million US women every year after CD at risk for poor pain control, depressed mood, and poor recovery. Despite high individual variability in pain after CD, current CD treatments ignore the multidimensionality of pain. NMDA receptor antagonists like ketamine are known to reduce postoperative pain and opioid use in non-obstetric surgical populations, and recently, ketamine has been recognized for its utility in treating depression. Although limited-use postpartum ketamine studies show no evidence of serious negative effects, ketamine has known and undesirable side effects (e.g., nausea, dysphoria) which can interfere with newborn care. Studies on pregnant/lactating women are limited by lack of data on optimal dose and long-term PPD and pain recovery outcomes. This knowledge gap precludes understanding how ketamine might reduce PPD and pain in this population. There is a critical need for better treatments to reduce PPD risk and pain after CD. To address these needs, we will identify ketamine’s tolerable dose, pharmacokinetics, and pharmacodynamics after CD so that future randomized trials using appropriately dosed ketamine in postpartum women can be conducted. Our long-term goal is to reduce the burden and impact of depression and pain in special populations. Our central hypothesis is that post-CD ketamine reduces PPD risk by reducing pain in multiple dimensions. Specific Aims: A1: Quantify tolerable dose of postpartum ketamine using MTD design. A2: Identify PK/PD of postpartum ketamine infusion in an open-label observational study. A3: Identify change points/trajectories of PPD symptoms to inform future postpartum ketamine trial outcomes. This proposal has the potential to change practice because preventive therapies for PPD are lacking, and the dearth of alternative non-opioid analgesia after CD has been a critical barrier to progress in postpartum pain recovery. Our approach is innovative because it employs novel theoretical concepts to postpartum multimodal pain management strategies. It addresses gaps in prior studies that used best-guess doses of ketamine, leading to variable results on efficacy and side effects. This work will identify new therapeutic strategies that reduce both PPD risk and postpartum pain. It will directly inform the next steps for a randomized trial on post-CD ketamine at a tolerable dose, for PPD and pain recovery outcomes.