Reproductive Endocrine Related Mood Disorders-Differential Sensitivity

生殖内分泌相关情绪障碍-敏感性差异

• 批准号: 9152113
• 负责人: Peter Schmidt
• 金额: $ 63.11万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9152113
• 关键词: Affect; Affective; Age of Onset; Agonist; Androgen Metabolism; Animals; Antidepressive Agents; Behavior; Behavioral; Biological; Biology; Brain region; Cell physiology; Cells; Characteristics; Child; Chromatin; Clinic; Clinical; Clinical Management; Clinical Protocols; Collaborations; Comorbidity; Complement; Complex; Counseling; Data; Diagnosis; Diagnostic and Statistical Manual of Mental Disorders; Disease; Disease Outcome; Disease remission; Double-Blind Method; Dutasteride; Enantone; Endocrine; Enzymes; Estradiol; Estrogen Receptor alpha; Estrogens; Exhibits; Experimental Models; Exposure to; Frequencies; Functional disorder; Future; Gene Expression; Gene Expression Profile; General Population; Genes; Genomic Segment; Gestational Diabetes; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Health; Hormonal; Hormones; Human; Hypogonadism; Incidence; Injury; Interview; Investigation; Laboratories; Liquid Chromatography; Literature; Major Depressive Disorder; Mass Spectrum Analysis; Measures; Medial; Medical; Menstrual cycle; Mental Depression; Metabolic Pathway; Methodology; Minor; Mood Disorders; Moods; Morbidity - disease rate; National Institute of Mental Health; Nature; Neuroglia; Neurons; Neurosciences; Ovarian; Ovarian Ablation; Pathway interactions; Pattern; Perimenopause; Perinatal; Phenotype; Physiological; Placebo Control; Plasma; Positron-Emission Tomography; Postpartum Depression; Predisposition; Prefrontal Cortex; Premenstrual syndrome; Process; Progesterone; Publications; RNA Sequences; Recording of previous events; Reporting; Research; Rest; Risk; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Severities; Signal Transduction; Steroids; Steryl-sulfatase; Structure; Subgroup; Symptoms; Time; Treatment Efficacy; Woman; Women' s Group; Work; base; behavioral response; brain behavior; burden of illness; child bearing; control trial; disability; disorder control; experience; frontal lobe; functional disability; functional genomics; gene repression; hormone therapy; interest; meetings; metabolomics; minor depressive disorder; mood regulation; neuroimaging; neurosteroids; premenstrual dysphoric disorder; relating to nervous system; reproductive; research study; response; trait; transcriptome sequencing; treatment response

This report includes work arising from the following clinical protocols: NCT00005011, NCT00056901, NCT00059228, NCT00082043, NCT00100360, NCT00001177, NCT00001259, and NCT00001481 Overlapping co-morbidities between premenstrual dysphoric disorder (PMDD) and postpartum depression (PPD) indicate that these disorders could represent a continuum of vulnerability with shared pathophysiology. Indeed, the results of some studies suggest that women with PMDD are at increased risk for developing PPD. These observations have important implications for both the clinical management of women with PMDD (specifically regarding risk counseling) and for research directions. Nonetheless, comorbidity does not necessarily indicate similar pathophysiology, and the comorbidity shared between PMDD and PPD could be uninformative about pathophysiology, analogous to the comorbidity shared between PMDD and non-reproductive depression. We examined the past histories of PPD in a clinic-based sample of women meeting criteria for PMDD. Two hundred and fifteen women who attended the NIMH mood disorders clinic seeking treatment for PMDD and in whom we confirmed the diagnosis of PMDD, were administered the Structured Clinical Interview for DSM. The frequency of PPD (major or minor) was established in the subgroup of women (n=137) who had delivered at least one child. Ninety-three women (43.3%) had a past history of a mood disorder (i.e. either major (MDE) or minor depression). Of these women only 16 (i.e., 11.7%) of the 137 childbearing women with prospectively confirmed PMDD met criteria for a past PPD, not substantially different from the reported incidence of PPD in the general population of women. Our data demonstrate that PMDD and PPD do not frequently co-occur, and do not suggest that PMDD and PPD share similar pathophysiology beyond both being ovarian-steroid triggered mood disorders. In our studies we have developed experimental models for the triggering of symptoms in PMDD and PPD that we employ in our efforts to identify the underlying biology of these conditions. In our gonadotropin releasing hormone (GnRH) agonist-induced ovarian suppression studies (henceforth referred to as the Lupron paradigm) we have demonstrated that the change in ovarian steroid level not the absolute level itself is the trigger for affective destabilization in these women. In addition to our studies on the behavioral effects of changes in ovarian steroids, we employ methodologies to investigate the underlying biological mechanisms of these conditions including neuroimaging studies, as well as both metabolomics platforms for evaluating neurosteroid synthesis, and functional genomics studies examining the effects of a change in ovarian steroid on cellular function. First, our neuroimaging studies have identified both a neural substrate of risk in PMDD as well as a brain-region specific response that could underlie the differential behavioral response to ovarian steroids in this condition. In a previous study, we observed that women with PMDD show abnormal prefrontal recruitment, specifically greater activation than controls throughout the dorsolateral prefrontal cortex (DLPFC) bilaterally. DLPFC activations in PMDD were independent of hormone condition, and correlated negatively with measures of PMDD functional impairment, age of onset of PMDD, and pre-treatment symptom severity measures. These findings suggest an enduring, trait-like predisposition to this hormonally-triggered disorder. In a second completed study, in women with PMDD and controls who underwent resting state PET studies during each of the three hormone conditions in the Lupron paradigm, we observed differences in resting rCBF in women with PMDD compared with controls in the subgenual cingulate (BA25), and medial orbital frontal cortex (mOFC). Higher resting state rCBF in PMDD was present during hypogonadism (when PMDD symptoms are in remission) compared with estradiol or progesterone replacement (when PMDD symptoms are at risk of recurring), whereas no hormone-related changes were observed in controls in either brain region. These data demonstrate for the first time a differential pattern of rCBF within neuroanatomical loci implicated in the process of affective adaptation. Additionally, the fact that the changes in rCBF correspond in time to the hormone state-related changes in symptoms raises the possibility that the changes in rCBF may reflect the altered mood state rather than a direct effect of ovarian steroid hormonal exposure. One possible trigger for the abnormal ovarian steroid-triggered mood state in PMDD is an altered profile of neurosteroid metabolites during exposure to estradiol or progesterone. This possibility is also suggested by our demonstration of the therapeutic efficacy of dutasteride to mitigate symptoms of PMDD since dutasteride inhibits the rate limiting enzymatic step in neurosteroid synthesis. Thus, we next examined the profile of steroid and neurosteroid metabolites in women with PMDD using a metabolomics platform. Metabolomic studies (employing liquid chromatography-tandem mass spectroscopy) are performed in women with PMDD who respond to Lupron with elimination of symptoms and who experience return of symptoms during progesterone or estradiol replacement, as well as controls who experience no change in mood during the identical experimental paradigm. Preliminary data suggest that women with PMDD exhibit differences from control women in a key enzyme involved with steroid (both estrogen and androgen) metabolism, steroid sulphatase. However, in this sample of women, we observed no differences in progesterone-derived neurosteroid levels in plasma. Thus, we plan to expand this study in a larger group of women with PMDD and controls to permit confirmation that no differences in neurosteroid levels exist between women with PMDD and controls (consistent with previous naturalistic studies across the menstrual cycle), and to allow us to examine steroid metabolic pathways in more detail. Our metabolomic and neuroimaging studies are complemented by functional genomic studies, performed in collaboration with David Goldman's laboratory, in which we employ lymphoblastoid and induced pluripotent cells obtained from women with PMDD and controls who participate in our Lupron studies. These experiments allow us to explore the nature of the differential behavioral response by examining gene expression and changes in cellular behaviors associated with the exposure to physiologic levels of either estradiol or progesterone across the two different behavioral phenotypes (i.e., women with PMDD and controls). Results show that women with PMDD express more estrogen receptor (ER) alpha (but not beta) compared with controls. Additionally, RNA sequencing studies show statistically significant, quantitative differences in the PMDD transcriptome compared to control women. We identified significant differences in the expression of the chromatin modifying ESC/E(Z) complex genes, which is of particular interest as a potential candidate since it is regulated by ovarian steroids and leads to genomic regions of transcriptional repression. The mechanism by which these pathways converge and possibly alter CNS function sufficient to manifest in PMDD will be the focus of our future studies in induced neuronal and glial cells.

该报告包括由以下临床方案产生的工作：NCT00005011，NCT00056901，NCT00059228，NCT00082043，NCT00100360，NCT00001177，NCT0000001259和NCT0000001481 经前烦躁不安（PMDD）和产后抑郁症（PPD）之间的重叠合并症表明，这些疾病可以代表与共同的病理生理学的脆弱性连续性。 实际上，一些研究的结果表明，患有PMDD的女性患PPD的风险增加。 这些观察结果对PMDD女性的临床管理（特别是关于风险咨询）和研究方向都有重要意义。尽管如此，合并症并不一定表明相似的病理生理学，PMDD和PPD之间共享的合并症可能对病理生理学无关，类似于PMDD和非成熟性抑郁症之间的合并症。我们在符合PMDD标准的妇女妇女样本中检查了PPD的过去历史。参加了对PMDD治疗的NIMH情绪障碍诊所的215名妇女，我们确认了对PMDD的诊断，并接受了DSM的结构化临床访谈。 PPD（主要或小型）的频率是在至少一个孩子的女性亚组（n = 137）中建立的。九十3名妇女（43.3％）曾经有过情绪障碍的历史（即主要（MDE）或轻微抑郁症）。在这些妇女中，只有16名具有前瞻性确认PMDD的生育妇女中只有16名（即11.7％）符合过去PPD的标准，与普通妇女人群中PPD报告的发生率没有太大差异。我们的数据表明，PMDD和PPD不经常同时发生，并且不建议PMDD和PPD具有相似的病理生理学，而不是两者都是卵巢类触发的情绪障碍。 在我们的研究中，我们开发了用于触发PMDD和PPD症状的实验模型，这些模型是我们在识别这些疾病的潜在生物学努力中使用的。在我们的促性腺激素释放激素（GNRH）激动剂诱导的卵巢抑制研究（此后称为lupron范式）中，我们已经证明，卵巢类固醇水平的变化不是绝对水平本身的变化是这些妇女情感稳定的触发因素。除了我们对卵巢类固醇变化的行为影响的研究外，我们还采用方法来研究这些疾病的潜在生物学机制，包括神经影像学研究，以及代谢组学平台，用于评估神经类固醇的合成以及功能基因组学研究，以检查卵巢固醇对细胞固醇对细胞类固醇的影响的作用。 首先，我们的神经影像学研究已经确定了PMDD中风险的神经底物，也确定了在这种情况下对卵巢类固醇的差异行为反应的基础。 在先前的研究中，我们观察到患有PMDD的女性表现出异常的前额叶募集，特别是在双侧前额叶皮层（DLPFC）双侧的整个对照组中，其激活比对照更大。 PMDD中的DLPFC激活与激素条件无关，并且与PMDD功能障碍，PMDD发作年龄和治疗前症状严重程度测量的量度负相关。 这些发现表明，这种荷尔蒙触发的疾病存在持久的，类似于性状的倾向。 在第二次完成的研究中，在Lupron范式中三种激素条件中的每种激素条件中，在患有PMDD的女性和对照组中接受了静止状态宠物研究，我们观察到PMDD女性的静息RCBF与亚属性（BA25）的对照组相比（BA25）和内侧轨道额前的Cortex（MOFC）（MOFC）（MOFC）。 与雌二醇或孕激素替代相比（当PMDD症状发生重复发生的风险时，在做出PMDD症状处于缓解状态时（PMDD症状处于缓解时），PMDD中的静息状态较高（当PMDD症状处于缓解状态时），而在任何一个大脑区域的对照中均未观察到与激素相关的变化。 这些数据首次证明了与情感适应过程有关的神经解剖基因座中RCBF的差异模式。 此外，RCBF的变化在时间上对应于激素状态相关的症状变化这一事实增加了RCBF的变化可能反映了情绪状态的改变，而不是卵巢类固醇激素暴露的直接作用。 PMDD中卵巢类固醇触发的情绪状态异常的一种可能的触发因素是暴露于雌二醇或孕酮的神经类固醇代谢产物的变化。我们证明了Dutasteride可以减轻PMDD症状的治疗功效，这也表明了这种可能性，因为Dutasteride抑制了限制神经类固醇合成的酶促步骤的速率。因此，我们接下来研究了使用代谢组学平台的PMDD女性中类固醇和神经类固醇代谢产物的特征。 代谢组学研究（采用液相色谱串联质量光谱法）是在PMDD的女性中对lupron作出反应并消除症状并在孕酮或雌二醇替代过程中经历症状恢复的女性，以及在相同的实验中没有经历情绪变化的对照。初步数据表明，患有PMDD的女性与对照妇女在与类固醇（雌激素和雄激素）代谢相关的关键酶中表现出差异。 但是，在这个女性样本中，我们观察到血浆中孕激素衍生的神经类固醇水平没有差异。因此，我们计划将这项研究扩展到较大的PMDD女性和对照组中，以确认具有PMDD和对照的女性之间的神经类固醇水平不存在差异（与整个月经周期的先前自然主义研究一致），并允许我们更详细地检查类固醇代谢途径。我们的代谢组学和神经影像学研究得到了与David Goldman的实验室合作进行的功能基因组研究，在该研究中，我们采用了淋巴母细胞素和诱导的多能细胞，这些细胞从PMDD女性和参与我们的lupron研究的对照中获得。 这些实验使我们能够通过检查基因表达和与两种不同行为表型（即具有PMDD和对照的女性）相关的雌二醇或孕酮的生理水平相关的细胞行为的变化来探索差异行为反应的性质。 结果表明，患有PMDD的女性与对照组相比表达更多的雌激素受体（ER）α（但不是β）。 此外，与对照女性相比，RNA测序研究表明，PMDD转录组的统计学意义，定量差异。 我们确定了修饰ESC/E（Z）复合基因的染色质表达上的显着差异，这是潜在候选者的尤其令人感兴趣的，因为它受卵巢类固醇调节并导致转录抑制的基因组区域。 这些途径会融合并可能改变CNS功能足以在PMDD中表现出来的机制将是我们未来在诱导的神经元和神经胶质细胞中研究的重点。