Hormonal Mechanisms of Perimenopausal Risk for Psychosis in Women

项目总结 女性在中年表现出患精神病的高风险，这在男性中是没有观察到的。更年期过渡 (即围绝经期)被推定为这些中年风险变化的原因，但检验这一点的数据 可能性是完全没有的。关于中年风险机制的信息也很少。卵巢 荷尔蒙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，理论上认为，围绝经期这些荷尔蒙的变化会驱动中年。 女性的精神病风险，以及在其他生殖事件(如月经周期)期间的研究表明 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，还没有研究 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作为关键的 风险期(目标1)，并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、多种方法(行为、神经内分泌、多种信息者)，并且每天密集进行 研究设计采用基于人口的大样本妇女(N=750)，其绝经状态不同(即， 绝经前、围绝经期、绝经后)，并增加精神病风险。女性每天都会收到 连续35天的精神病(及相关)症状的数据，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(如中年压力)，会增加精神病风险 妇女(目标1)。然后，我们将通过收集每日唾液中的雌激素和 在为期35天的研究期间，围绝经期妇女的黄体酮水平和 这些激素的变化是女性中年精神病风险的潜在机制(目标2)。我们会 评估研究期间的一系列精神病症状，以捕捉精神病风险的全部范围， 我们将收集告密者和临床医生的症状评分，以验证和确认症状报告。 重要的是，我们建议的研究解决了RFA的高优先级领域--研究澄清机制 生殖类固醇在产生、缓和或减轻情绪和精神病症状中的作用 在更年期过渡期间。“事实上，我们新颖的纵向研究将使我们能够量化人口- 降低中年精神病的风险，并阐明必要的关键激素机制 为妇女的健康政策提供信息，并制定预防和干预的转换方法。

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.