FETAL AND NEONATAL NEUROBEHAVIOR AND PRENATAL ANTIDEPRESSANT EXPOSURE: THE CHILD

描述（由申请人提供）：在美国，每年有超过40万名孕妇及其胎儿经历重度抑郁症（MDD）。它是发达国家疾病负担的第三大原因，与妊娠期缩短、儿童睡眠问题（睡眠周期缩短、频繁觉醒）和儿童精神病理学有关。婴儿和儿童时期母亲抑郁症的缓解与青春期问题的减少有关，突出了有效治疗的必要性。5-羟色胺/去甲肾上腺素再摄取抑制剂（SRI），抗抑郁药物仍然是妊娠期间MDD最常用的治疗方法; 8%的妊娠女性处方SRI药物。SRI改变神经递质信号，特别是血清素，它在运动控制，睡眠和昼夜节律以及情绪中发挥作用。母亲在怀孕期间服用SRI的新生儿更有可能在分娩后的第一个月内经历急性不良事件。虽然这些症状似乎是短暂的，但最近的证据表明，感觉运动发育存在持续的问题。缺乏产前SRI暴露后的长期结果数据。尽管有强有力的临床前证据表明，早期SRI暴露对运动、睡眠和行为结果有积极和消极的潜在影响，但据我们所知，产前SRI暴露对这些关键发育领域的影响尚无长期数据。缺乏关于产前SRI暴露与暴露于未经治疗的MDD的风险的信息，就后期发展而言，极大地阻碍了在妊娠期间做出MDD治疗的知情风险获益决策。获得这些信息对于促进该领域对暴露于母亲MDD和MDD加SRI的儿童的发育精神病理学机制的理解也至关重要。 本申请的目的是双重的：（1）确定产前SRI暴露和胎儿5-羟色胺的相关变化如何影响学龄前儿童的结局;（2）鉴定与这些影响相关的潜在生物标志物。中心假设是，与接受SRI治疗的产前MDD儿童相比，未接受SRI治疗的产前MDD儿童在5岁时将具有不同的发育轨迹和不同的神经行为结局。该研究将跟踪至少193名目前参加产前前瞻性纵向研究的婴儿至5岁，以检查产前MDD+SRI或仅MDD暴露对运动发育，睡眠状态组织，昼夜节律和精神病结局的长期影响。在MDD和SRI暴露导致发育性精神病理学风险的儿童中，尚未检查关键的阿托宁相关睡眠和昼夜节律过程。预期结果将产生积极影响，因为它们将导致MDD孕妇做出知情的风险-获益决策，并为儿童精神病理学提供新的预防和治疗目标，从而降低儿童期和后期精神疾病的患病率。这将进一步转化为大幅度减少由于这些条件可能导致的社会和功能残疾而产生的总体费用。

DESCRIPTION (provided by applicant): Over 400,000 pregnant women and their fetuses experience Major Depressive Disorder (MDD) every year in the United States. It is the third leading cause of disease burden in developed countries and is associated with shorter gestation, child sleep problems (shortened sleep cycles, frequent awakening), and child psychopathology. Remission of maternal depression in the infant and child years is associated with fewer problems in adolescence, highlighting the need for effective treatment. Serotonin/Norepinephrine Reuptake Inhibitors (SRIs), antidepressant medications remain the most commonly chosen treatment for MDD during pregnancy; 8% of all pregnant women are prescribed SRI medication. SRIs alter neurotransmitter signaling, particularly for serotonin, which plays a role in motor control, sleep and circadian rhythms, and emotion. Newborns whose mothers took SRIs in pregnancy are more likely to experience acute adverse events in the first month after delivery. Although these symptoms appear to be transient, recent evidence suggests there are continued problems with sensory-motor development. There is a lack of long-term data on outcomes following prenatal SRI exposure. Despite strong preclinical evidence of both positive and negative latent effects on motor, sleep, and behavioral outcomes from early SRI exposure, to our knowledge, there is no long-term data on the effects of prenatal SRI exposure on these key areas of development. Lack of information on the risks of prenatal SRI exposure versus exposure to untreated MDD, with respect to later development, greatly hinders informed risk-benefit decision making for MDD treatment during pregnancy. Obtaining this information is also critical to advancing the field's understanding of the mechanisms of developmental psychopathology in children exposed to maternal MDD and to MDD plus SRIs. The objective of this application is twofold: (1) to determine how prenatal SRI exposure and associated changes in fetal serotonin affect outcomes in preschool children; and (2) to identify potential biomarkers associated with these effects. The central hypothesis is that children who were exposed to prenatal maternal MDD without SRI treatment will have a different developmental trajectory and a different profile of neurobehavioral outcomes through age five, compared to children who were exposed to prenatal MDD with SRI treatment. The study will follow at least 193 of the infants currently enrolled in the prenatal prospective, longitudinal stuy through age 5 to examine the long-term effects from prenatal MDD+SRI or MDD-only exposure on motor development, sleep-state organization, circadian rhythms, and psychiatric outcomes. The critical serotonin-related processes of sleep and circadian rhythms have not been examined in children at risk for developmental psychopathology due to MDD and SRI exposure. The expected outcomes will have a positive impact because they will lead to informed risk-benefit decision-making for pregnant women with MDD and provide new preventive and therapeutic targets for psychopathology in children, resulting in a decrease in the prevalence of childhood and later psychiatric conditions. This will further translate into enormous reductions in overall costs due to the social and functional disability that may result from such conditions.