Hormonal Mechanisms of Perimenopausal Risk for Psychosis in Women

项目摘要 妇女在中年时患精神病的风险更高，而在男子中没有观察到。绝经过渡期 (i.e.,围绝经期）被认为是这些中年风险变化的原因，但研究这一点的数据显示， 可能性是完全缺乏的。关于中年风险机制的信息也基本上缺乏。卵巢 激素是女性更年期变化的关键，已知对大脑有广泛的影响。 和行为。因此，理论上，这些激素在围绝经期的变化驱动中年 女性精神病风险以及其他生殖事件期间的研究（例如，月经周期）显示 卵巢激素水平较低的女性精神病症状增加。然而，到目前为止，没有研究 研究了卵巢激素的变化是否是女性中年精神病风险的机制。 因此，拟议项目的具体目标是将围绝经期隔离为关键期， 风险期（目标1）和检查卵巢激素作为作用机制（目标2）。我们将解决 这些目标使用创新的，多方法（行为，神经内分泌，多信息），和密集的日常 研究设计在一个大的，基于人群的妇女样本（N = 750）中进行，这些妇女的绝经状态不同（即， 绝经前、围绝经期、绝经后），并且富含精神病风险。女人们每天都会收集 连续35天的精神病（和相关）症状数据，我们将使用这些数据来确认 围绝经期阶段，而不是年龄或其他因素（例如，中年压力），增加精神病风险 妇女（目标1）。然后，我们将通过收集雌激素和雌激素水平的日常唾液样本来扩展这些数据。 孕激素在35天的研究期间，在围绝经期妇女，并检查是否水平和 这些激素的变化是女性中年精神病风险的潜在机制（目的2）。我们将 评估整个研究期间的一系列精神病症状，以捕获精神病风险的全谱， 我们将收集举报人和临床医生的症状评级，以验证和确认症状报告。 重要的是，我们提出的研究解决了RFA的高优先级领域“研究阐明了 生殖类固醇在产生、调节或减轻情绪和精神病症状中的作用 在更年期过渡期”实际上，我们新颖的纵向研究将使我们能够量化人口数量- 水平风险中年精神病以及阐明关键的激素机制，是必要的， 为妇女保健政策提供信息，并制定预防和干预转化办法。

PROJECT SUMMARY Women show a heightened risk for psychosis in midlife that is not observed in men. The menopausal transition (i.e., perimenopause) is presumed to account for these midlife changes in risk, but data examining this possibility are wholly lacking. Information on mechanisms of midlife risk is largely absent as well. Ovarian hormones are key to menopausal changes in women and are known to have wide-reaching effects on brain and behavior. Thus, it has been theorized that changes in these hormones during perimenopause drive midlife psychosis risk in women, and studies during other reproductive events (e.g., the menstrual cycle) show increased psychotic symptoms in women with lower levels of ovarian hormones. However, to date, no studies have examined if changes in ovarian hormones are mechanisms of midlife psychosis risk in women. Consequently, the Specific Aims of the proposed project are to isolate the perimenopausal period as a critical period of risk (Aim 1) and examine ovarian hormones as mechanisms of effects (Aim 2). We will address these aims using an innovative, multi-method (behavioral, neuroendocrine, multi-informant), and intensive daily study design in a large, population-based sample of women (N = 750) that varies in menopausal status (i.e., premenopause, perimenopause, postmenopause) and is enriched for psychosis risk. Women will collect daily data on psychotic (and related) symptoms across 35 consecutive days, and we will use these data to confirm that perimenopausal stage, rather than age or other factors (e.g., midlife stress), drive increased psychosis risk in women (Aim 1). We will then extend these data by collecting daily saliva samples of estrogen and progesterone across the 35-day study period in the perimenopausal women and examining whether levels and changes in these hormones are mechanisms underlying midlife psychosis risk in women (Aim 2). We will assess a range of psychotic symptoms across the study period to capture the full spectrum of psychosis risk, and we will collect informant and clinician symptom ratings to validate and confirm symptom reports. Importantly, our proposed study addresses the RFA high priority area “Research clarifying the mechanistic role of reproductive steroids in generating, moderating, or mitigating mood and psychosis symptoms during the menopausal transition.” Indeed, our novel, longitudinal study will allow us to quantify population- level risk for midlife psychosis as well as elucidate the critical hormonal mechanisms that are necessary to inform women's health policy and devise translational approaches to prevention and intervention.