Perinatal SMILES (Synergistic Multi-component Intervention to alLeviate dEpressive Symptoms)

David Monks, MBBS, Assistant Professor, Anesthesiology

We propose a novel intervention to harness the potential of combined ketamine and psychotherapy to improve postcesarean mood in marginalized and underserved communities. Postpartum depression (PPD) complicates 6‐19% of pregnancies. Women undergoing cesarean delivery (CD) have 33% increased odds of developing PPD and risk at our institution may be even greater due to social inequities. Interventions to improve mood after CD are urgently needed to protect such women as they traverse a high‐risk period for new or worsening depression. Ketamine has been shown to improve depressive symptoms after CD, but the 2‐day infusions employed are impractical and the benefit, transient. We propose to solve these problems by promoting synergy between psychotherapy and a more practical administration strategy of ketamine to produce durable efficacy. Psychotherapy can optimize ketamine therapy by guiding the mindset of the recipients. In turn, it is hypothesized that ketamine can provide an “opportune window” of enhanced cortical plasticity for psychotherapy. Psychotherapy may also encourage solidification of these beneficial neuroplastic changes. We have modified Interpersonal Therapy (IPT) to include pre‐ and post‐ketamine sessions. Identifying a mechanistic target of ketamine could facilitate adaptation of the intervention to individual response in future studies. Enhanced neuroplasticity in the prefrontal cortex (PFC) is a proposed mechanism of ketamine and Transcranial Magnetic Stimulation‐EEG (TMS‐EEG) has been used to assess neuroplasticity, as indexed through Paired Associative Stimulation (PAS)‐induced potentiation of cortical‐evoked activity (CEA).

The Perinatal Synergistic Multimodal Intervention to alLeviate dEpressive Symptoms (SMILES) consists of a) Five sessions of IPT and additional pre‐, and post‐, ketamine sessions on postoperative day (POD) 1 and 2, respectively; b) SC ketamine, 0.5 mg/kg, on POD 1 & 2. We hypothesize that Perinatal SMILES will enhance PFC neuroplasticity to provide sustained improvements in postcesarean mood. To help plan an RCT to test this, we propose an open‐label case series to assess the feasibility of participant enrollment, administration of the intervention, and data collection. We aim to enroll 15 low‐income women with depressive symptoms. We will approach third trimester women who are “scheduled” for CD, and women on POD 1 after an “unscheduled” CD. IPT sessions will be administered either during the third trimester to immediate postpartum (scheduled) or the first 4 postpartum weeks (unscheduled). Depression scores will be assessed during the first 12 postpartum weeks. We will employ TMS‐EEG to measure PASinduced potentiation of CEA pre‐, and 2, 4 & 6 hours after, SC ketamine therapy. “Perinatal SMILES” has the potential to reduce the considerable societal burden of this devastating disease.