Sleep and biological rhythms after fetal exposure to antidepressants

描述(由申请人提供)：胎儿在怀孕期间接触母体严重抑郁障碍(MDD)一直与新生儿的医学和神经行为缺陷以及儿童长期的情感、行为和社会问题有关。产前MDD的治疗是至关重要的。选择性5-羟色胺再摄取抑制剂(SSRIs)和双重作用的5-羟色胺和去甲肾上腺素再摄取抑制剂(SNRI)是治疗MDD(统称SRI)的首选药物，估计有37%的抑郁孕妇使用这些药物。产前MDD和SRI暴露都会改变胎盘和宫内环境，并对发育结果构成风险。这给孕妇和她们的卫生保健提供者在选择MDD的治疗方法时造成了严重的两难境地。产前SRI暴露有助于改变发育中胎儿的5-羟色胺供应。5-羟色胺是极端睡眠状态变化和昼夜睡眠-觉醒节律的关键调节器；SRI改变5-羟色胺的供应和这些过程。动物研究表明，早期SRI暴露会改变胎儿的睡眠状态，并在发育后期导致永久性的负面后果。早期睡眠状态模式预示着神经发育异常和儿童行为问题。因此，睡眠过程的改变不仅是与产前暴露有关的潜在结果，也可能是其他长期影响的潜在机制。然而，到目前为止，还没有关于产前SRI暴露后人类婴儿睡眠的前瞻性、长期研究。我们目前正在进行一项由NIMH资助的研究(R01)，以确定产前SRI和MDD暴露对胎儿和新生儿的影响，直到30天，系统地测量胎儿和婴儿在出生第一个月期间的睡眠状态和神经行为。在目前的提案中，我们计划评估至少153名18-20个月大的产前研究队列中的婴儿，以检查早期SRI或MDD暴露对睡眠状态组织、24小时睡眠-觉醒节律以及每日尿液中褪黑素硫酸盐、皮质醇、肾上腺素和去甲肾上腺素排泄的长期影响。将测量可能影响结局的变量，包括产后母亲的情绪、焦虑、压力、母乳喂养状况和环境变量。主要目的是确定产前SRI暴露是否会改变18个月大的婴儿的睡眠状态、昼夜节律和神经行为发育。这包括确定如果孕妇的MDD在孕期和产后缓解，结果是否会改变。研究目的包括确定暴露于SRI或MDD的婴儿尿中硫酸褪黑素、皮质醇、去甲肾上腺素和肾上腺素的排泄量和昼夜模式是否发生改变，以及尿中硫酸褪黑素的排泄是否与婴儿的超常和昼夜节律模式、外在行为和活动水平有关。 公共卫生相关性：产前接触抗抑郁药物与婴儿和动物的不良后果有关，动物研究表明，长期后果可能包括睡眠、昼夜节律、情绪和行为的改变。我们计划研究产前使用抗抑郁药物对18-20个月大的儿童的睡眠和生物节律的影响，这些儿童之前曾参加过一项从产前到新生儿的研究。这项研究的信息与产前研究数据相结合，将为妊娠期抑郁症的治疗提供更好的指导方针。

DESCRIPTION (provided by applicant): Fetal exposure to maternal Major Depressive Disorder (MDD) during pregnancy is consistently associated with newborn medical and neurobehavioral deficits and long-term emotional, behavioral, and social problems in the child. Treatment of prenatal MDD is critical. Selective serotonin reuptake inhibitors (SSRIs) and dual-action serotonin and norepinephrine reuptake inhibitors (SNRIs) are the pharmacological treatment of choice for MDD (collectively SRIs), and are used by an estimated 37% of depressed pregnant women. Both prenatal MDD and SRI exposure alter the placenta and intrauterine environment and pose risks to developmental outcomes. This creates a significant dilemma for pregnant women and their health care providers when making choices about treatment for MDD. Prenatal SRI exposure contributes to altered serotonin availability in the developing fetus. Serotonin is a key regulator of ultradian sleep-state alternations and circadian sleep-wake rhythms; SRIs alter serotonin availability and these processes. Animal studies show that early SRI exposure alters fetal sleep state development and leads to permanent negative consequences later in development. Early sleep state patterns predict abnormal neurodevelopment and child behavior problems. Therefore, alterations in sleep processes are not only a potential outcome related to prenatal exposure, but may also be a potential mechanism for other long term effects. However, to date, there are no prospective, long term studies on human infant sleep following prenatal SRI exposure. We are currently conducting a NIMH funded (R01) study to determine the effects of prenatal SRI and MDD exposure on the fetus and newborn through 30 days of age, with systematic measures of sleep state and neurobehavior in the fetus and infant through the first month of life. In the current proposal we plan to assess at least 153 of the infants from the prenatal study cohort when they are 18-20 months of age to examine the longer term effects from early SRI or MDD exposure on sleep-state organization, 24-hour sleep-wake rhythms, and diurnal urinary excretion of melatonin sulfate, cortisol, epinephrine, and norepinephrine. Variables that may influence outcomes will be measured, including postpartum maternal mood, anxiety, stress, breastfeeding status, and environmental variables. The primary aim is to determine if prenatal SRI exposure alters infant sleep state organization, circadian rhythms, and neurobehavioral development at 18 months of age. This includes determining if the outcomes are altered if maternal MDD is remitted during the pregnancy and postpartum. Exploratory aims include determining if the magnitude and diurnal pattern of urinary excretion of melatonin sulfate, cortisol, norepinephrine, and epinephrine excretion is altered in SRI or MDD exposed infants and whether urinary melatonin sulfate excretion is associated with ultradian and circadian patterns, externalizing behaviors, and activity level in infants. PUBLIC HEALTH RELEVANCE: Prenatal exposure to antidepressant medications is related to adverse outcomes in infants and animal studies show that long term outcomes may include changes in sleep, circadian rhythms, mood and behavior. We plan to study the effects of prenatal antidepressant exposure on sleep and biological rhythms in children 18-20 months of age who were previously enrolled in a prenatal to newborn study. The information from this study, combined with the prenatal study data, will lead to better guidelines for the treatment of depression during pregnancy.