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.