Psychobiology And Treatment Of Perimenopausal Mood Disorders

心理生物学和围绝经期情绪障碍的治疗

• 批准号: 7969304
• 负责人: Peter Schmidt
• 金额: $ 77.07万
• 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/7969304
• 关键词: Acute; Adrenal Glands; Adverse effects; Affect; Affective; Affinity; Age; Aging; Agonist; Androgen Therapy; Anti-Anxiety Agents; Antidepressive Agents; Appearance; Area; Behavior; Behavioral; Biology; Brain; Brain region; Breast; Cardiovascular Diseases; Cerebrovascular Circulation; Cessation of life; Classification; Communities; Data; Development; Disease; Disease remission; Double-Blind Method; Endocrine; Endometrial Carcinoma; Epidemiologic Studies; Equipment and supply inventories; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Therapy; Estrogens; Evaluation; Event; Failure; Functional disorder; Future; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Health; Hormones; Hot flushes; Human; Hypogonadism; Investigation; Knowledge; Lead; Libido; Life; Measures; Medical; Menopause; Metabolic syndrome; Mood Disorders; Moods; Morbidity - disease rate; Osteoporosis; Osteoporosis prevention; Ovarian; Pattern; Perception; Perimenopause; Physicians; Phytoestrogens; Placebos; Plants; Population; Postmenopause; Postpartum Depression; Precipitation; Predisposition; Premenopause; Prevalence; Public Health; Raloxifene; Recording of previous events; Regulation; Relative (related person); Reporting; Research; Research Personnel; Risk; Risk Marker; Role; Sampling; Selective Estrogen Receptor Modulators; Sex Functioning; Sleep; Sleep disturbances; Staging; Steroids; Subgroup; Substance Withdrawal Syndrome; Symptoms; Therapeutic; Therapeutic Agents; Tissues; Withdrawal; Woman; Work; age effect; base; cardiovascular risk factor; clinically significant; depression; depressive symptoms; design; dietary supplements; disability; effectiveness trial; hormone therapy; infancy; men; middle age; mortality; negative mood; novel; novel therapeutics; older women; psychobiology; reproductive; response

A role of estradiol withdrawal in the onset of mood disorders in some perimenopausal women has been suggested indirectly by the clustering of depressive episodes during the late menopause transition (the stage of ovarian aging associated with maximal decline of ovarian estradiol secretion) and by estradiol's antidepressant efficacy in perimenopausal depression. Nonetheless, there is no direct evidence that estradiol withdrawal precipitates depressive episodes in those women who develop depression during the perimenopause. In these studies, first we examine the effects of estradiol withdrawal and the recent onset of hypogonadism on mood symptoms in asymptomatic premenopausal women. Second, we investigate what factors influence the development of depression during estradiol withdrawal. We administered a gonadotropin releasing hormone (GnRH) agonist for two to three months to 60 regular cycling, asymptomatic, healthy, premenopausal women (age - mean (SD) = 33.4 (8.1) years). Only three women (5.0% of the sample) reported clinically significant symptoms of depression. In contrast to the relative absence of depressive symptoms in these women, we did observe the significant appearance of several symptoms including hot flushes, disturbed sleep, and diminished libido. The latter finding is consistent with a prior study performed in a smaller subsample of these women in whom significant reductions in libido (as measured by a modified Derogatis Inventory of Sexual Functioning Scale) was observed in approximately 30% of the sample. Thus, in otherwise healthy women, the induction of neither hypogonadism nor hot flushes (with an accompanying sleep disturbance) uniformly precipitates depressive symptoms. In these studies, we also investigate two factors that could impact the appearance of depression during estradiol withdrawal - age and a previous episode of depression. We evaluate the effects of the acute withdrawal of estradiol therapy in older postmenopausal women with and those without a past perimenopausal depression. Preliminary results suggest that estradiol withdrawal induces depressive symptoms in women with a past perimenopausal depression, but not in those without such a history. In women with a past depression during the perimenopause, estradiol withdrawal is associated with a significant increase in depressive symptoms compared with those women who were maintained on estradiol therapy under double-blind conditions. Additionally, no significant depressive symptoms emerged in the women lacking a history of depression who were either withdrawn or maintained on estradiol therapy. Thus, in contrast to our findings with GnRH agonist-induced hypogonadism in premenopausal women with no past psychiatric history, estradiol withdrawal in women with a history of perimenopausal depression triggers mood symptoms. These data are consistent with those from epidemiologic studies showing that, for a subgroup of women, the endocrine events of the late menopause transition may represent important triggers for mood destabilization and the onset of depression. Both the markers of this risk and the mechanisms underlying estradiol withdrawal-induced depressive symptoms remain to be identified. Depressive symptoms emerged during estradiol withdrawal only in the older women with a past depression during the perimenopause, but not in either the younger or older women with no past depressions. Thus, during estradiol withdrawal, the ages of the women appear to be less of a contributor to the development of depressive symptoms than a past episode of depression. In a second ongoing study, we are investigating the impact of a past depression (not related to the perimenopause) on the effects of estradiol withdrawal on mood. Preliminary observations suggest that GnRH agonist-induced hypogonadism in asymptomatic premenopausal women with a past episode of depression is accompanied by the onset of depressive symptoms. If confirmed in a larger sample, these data suggest that in contrast to the effects of GnRH agonist-induced hypogonadism observed in asymptomatic premenopausal women with no history of depression, a single episode of depression (whether related to the perimenopause or not) could increase a womans susceptibility to develop negative mood symptoms during induced hypogonadism/estradiol withdrawal. The results of the Womens Health Initiative (WHI) have deterred many women from using estrogen therapy. Although considerable controversy exists regarding the applicability of the WHIs findings to younger perimenopausal women, many women and their physicians are concerned about the long-term risks of estrogen therapy. In a previous study, we demonstrated the antidepressant effects of the short-term administration of estradiol in women with perimenopausal depression. In an ongoing study, we now are examining the effects on mood and behavior of two compounds that for many women represent alternatives to traditional estrogen therapy. Specifically, selective estrogen receptor modulators (SERMs) and phytoestrogens (plant-derived estrogen-like compounds) have become available and are reported to display both tissue-specific profiles of estrogen agonist and antagonist actions and differential affinities from estradiol for the two forms of estrogen receptor. For many women, these novel compounds represent safer alternatives to estrogen therapy for the prevention of osteoporosis, and possibly, the treatment of perimenopausal symptoms. The use of SERMs and phytoestrogens may be preferred given their more favorable patterns of side effects, their lower risk of stimulating breast and endometrial cancers, and the perception that some of these compounds (phytoestrogens) are dietary supplements. Preliminary results demonstrate that after eight weeks of either estradiol or raloxifene, mood rating scores were significantly decreased compared with baseline scores and significantly lower than scores in women receiving placebo. Women receiving either phytoestrogen or placebo showed no significant improvement compared with their baseline scores. If confirmed in a larger sample of women, raloxifenes equal efficacy to that of estradiol would provide an alternative therapeutic option with a more acceptable profile of long-term side effects. In future studies, we intend to investigate the behavioral relevance of estrogen receptor beta in humans. Specifically, we will examine the antidepressant/anxiolytic efficacy of selective estrogen receptor beta agonists (when available for human use) in women with perimenopausal depression. These data will not only establish the role of estrogen receptor beta in the mechanism of estradiols antidepressant action, but could identify a promising new class of therapeutic agents that are safer and more acceptable than estrogen and potentially lack the side effects or withdrawal syndromes associated with traditional psychotropics. Finally, the comparison of the mood and behavioral effects of raloxifene and phytoestrogens to that of estradiol may allow more precise inferences to be made about the specific brain regions and estrogen receptor subtypes involved in estradiols antidepressant effects. Additionally, it is possible that the selectivity of these compounds for estrogen receptor alpha and beta may identify the mechanisms of efficacy of estradiol on specific target symptoms. Finally, as phytoestrogens are already commonly recommended, well accepted, and widely used for the treatment of mood symptoms, further clarification of their mood effects could have significant public health implications.

A role of estradiol withdrawal in the onset of mood disorders in some perimenopausal women has been suggested indirectly by the clustering of depressive episodes during the late menopause transition (the stage of ovarian aging associated with maximal decline of ovarian estradiol secretion) and by estradiol's antidepressant efficacy in perimenopausal depression. 尽管如此，没有直接的证据表明，雌二醇戒断会导致那些在围栏期间患抑郁症的妇女中的抑郁发作。 在这些研究中，首先，我们研究了雌二醇戒断的影响以及最近的性腺功能障碍对无症状绝经前妇女情绪症状的影响。 其次，我们研究哪些因素会影响雌二醇戒断期间抑郁症的发展。 我们管理了促性腺激素释放激素（GNRH）激动剂两到三个月，至60个常规循环，无症状，健康，绝经前女性（年龄 - 平均（SD）= 33.4（8.1）年）。 只有三名女性（占样本的5.0％）报告了临床上显着的抑郁症状。 与这些女性相对没有抑郁症状相反，我们确实观察到了几种症状的显着出现，包括热潮，扰乱的睡眠和性欲减少。 后一个发现与这些妇女的较小子样本中进行的先前研究一致，在这些女性的较小子样本中，在大约30％的样本中，观察到性欲大幅减少（通过修改的性功能功能量表库存来衡量）。 因此，在否则健康的女性中，诱导性腺负毒和潮热（随附的睡眠障碍）均不均匀地沉淀出抑郁症状。 在这些研究中，我们还研究了两个因素，这些因素可能会影响雌二醇戒断期间抑郁症的出现 - 年龄和先前的抑郁症发作。 我们评估雌二醇治疗急性戒断对绝经后妇女的急性戒断和没有过去的绝经性抑郁症患者的影响。 初步结果表明，雌二醇戒断会引起过去临床抑郁症的妇女的抑郁症状，但没有这种没有这种病史的女性。 在围膜期间过去患有抑郁症的女性中，与那些在双盲疾病中维持雌二醇治疗的女性相比，雌二醇戒断与抑郁症状的显着增加有关。 此外，缺乏抑郁史的女性没有出现明显的抑郁症状，这些抑郁史被撤回或维持雌二醇治疗。 因此，与我们在没有过去精神病史的绝经前妇女中与GNRH激动剂诱导的性腺功能减退相反，在具有上半月障碍抑郁症史的女性中，雌二醇戒断了雌激素。 这些数据与流行病学研究的数据一致，表明，对于女性的亚组，更年期过渡晚期的内分泌事件可能代表了情绪不稳定和抑郁症的重要触发因素。 这种风险的标记和雌二醇戒断引起的抑郁症状的基础机制尚待确定。 雌二醇在雌二醇戒断期间出现抑郁症状，仅在围栏期间患有过去抑郁症的老年妇女中，但在没有过去的抑郁症的年轻妇女或年龄较大的女性中。 因此，在雌二醇退出期间，女性的年龄似乎不如抑郁症状的发展，而不是过去的抑郁症。 在第二次正在进行的研究中，我们正在研究过去的抑郁症（与围膜无关）对雌二醇戒断对情绪的影响的影响。 初步观察表明，GNRH激动剂诱导的抑郁症抑郁症的无症状前女性妇女的性腺功能不全伴随​​着抑郁症状的发作。 如果在较大的样本中得到确认，这些数据表明，与无抑郁症的无症状绝经前妇女中观察到的GnRH激动剂诱导的性腺自然女性的影响相反，单个抑郁症（是否与上日上的抑郁症相关）可能会增加诱导降低降低降低率撤回的负面情绪症状的抑郁症。 女子健康计划（WHI）的结果阻止了许多妇女使用雌激素治疗。 尽管关于低语发现对年轻的绝经妇女的适用性​​存在很大的争议，但许多妇女及其医生都担心雌激素治疗的长期风险。 在先前的研究中，我们证明了雌二醇短期给药对绝经抑制抑郁症的女性的抗抑郁作用。 在一项正在进行的研究中，我们现在正在研究对许多女性代表传统雌激素疗法的替代品的两种化合物的情绪和行为的影响。 具体而言，选择性雌激素受体调节剂（SERM）和植物雌激素（植物来源的雌激素样化合物）已获得，并据报道显示出雌激素激动剂和拮抗剂作用的组织特异性谱，又显示了两种形式的雌激素受体的雌激素与雌激素产生的差异亲和力。 对于许多女性，这些新型化合物代表了预防骨质疏松症的雌激素疗法的更安全替代方法，可能是造成骨膜症的治疗。 鉴于它们的副作用更有利，刺激乳腺癌和子宫内膜癌的风险较低，并且认为这些化合物中的某些（植物雌激素）是饮食补充剂，因此可能首选Serm和植物雌激素的使用。 初步结果表明，与基线评分相比，雌二醇或r昔二八周后，情绪评分的评分显着降低，并且在接受安慰剂的女性中的评分显着降低。 与基线得分相比，接受植物雌激素或安慰剂的妇女没有显着改善。 如果在较大的女性样本中得到证实，则与雌二醇相等的疗效将提供替代性治疗选择，并具有更可接受的长期副作用概念。 在未来的研究中，我们打算研究人类雌激素受体β的行为相关性。 具体而言，我们将检查选择性雌激素受体β激动剂的抗抑郁药/抗焦虑症（如果可用的抗药性）在抑郁症的女性中。 这些数据不仅将确定雌激素受体β在雌二醇抗抑郁作用机理中的作用，而且可以鉴定出一种有希望的新的新型治疗剂，这些治疗剂比雌激素更安全，更可接受，并且潜在地缺乏与传统精神病相关的副作用或戒断综合症。 最后，比较雷昔二烯和植物雌激素与雌二醇的情绪和行为作用的比较可以使人们可以对参与雌二醇的特定脑区域和雌激素受体亚型进行更精确的推论。 此外，这些化合物对雌激素受体α和β的选择性可能可能识别雌二醇对特定靶症状的疗效机制。 最后，由于植物雌激素已经被推荐，被广泛接受并广泛用于治疗情绪症状，因此进一步澄清其情绪影响可能会产生重大的公共卫生影响。