Sleep and biological rhythms after fetal exposure to antidepressants

描述（由申请人提供）：胎儿在怀孕期间暴露于母体重度抑郁症（MDD）与新生儿医学和神经行为缺陷以及儿童的长期情绪、行为和社会问题一致相关。产前重度抑郁症的治疗至关重要。选择性5 -羟色胺再摄取抑制剂（SSRIs）和双作用5 -羟色胺和去甲肾上腺素再摄取抑制剂（SNRIs）是重度抑郁症（统称为SRIs）的药物治疗选择，估计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。这给孕妇及其卫生保健提供者在选择重度抑郁症的治疗方案时造成了一个重大的困境。产前暴露于SRI有助于改变发育中的胎儿血清素可用性。血清素是超昼夜睡眠状态变化和昼夜睡眠-觉醒节律的关键调节因子；SRIs改变了血清素的可用性和这些过程。动物研究表明，早期暴露于SRI会改变胎儿的睡眠状态发育，并在以后的发育中导致永久性的负面影响。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（R01）研究，以确定产前SRI和MDD暴露对胎儿和30天大的新生儿的影响，并系统地测量胎儿和婴儿在生命的第一个月的睡眠状态和神经行为。在目前的建议中，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-觉醒节律以及硫酸褪黑激素、皮质醇、肾上腺素和去甲肾上腺素的日尿排泄的长期影响。将测量可能影响结果的变量，包括产后母亲情绪、焦虑、压力、母乳喂养状况和环境变量。主要目的是确定产前暴露于SRI是否会改变婴儿18个月大时的睡眠状态组织、昼夜节律和神经行为发育。这包括确定如果母亲的重度抑郁症在怀孕期间和产后得到缓解，结果是否会改变。探索性目的包括确定SRI或MDD暴露婴儿尿液中硫酸褪黑激素、皮质醇、去甲肾上腺素和肾上腺素排泄的量和日模式是否改变，以及尿中硫酸褪黑激素排泄是否与婴儿的昼夜模式、外化行为和活动水平有关。

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.