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.

绝经后期过渡期间抑郁发作的聚集（与卵巢雌二醇分泌最大程度下降相关的卵巢衰老阶段）以及雌二醇的抗抑郁功效间接表明雌二醇戒断在一些围绝经期女性情绪障碍发作中的作用在围绝经期抑郁症中。 尽管如此，没有直接证据表明雌二醇戒断会导致围绝经期抑郁症女性的抑郁发作。 在这些研究中，我们首先检查雌二醇戒断和最近发生的性腺功能减退症对无症状绝经前女性情绪症状的影响。 其次，我们研究了哪些因素会影响雌二醇戒断期间抑郁症的发展。 我们对 60 名定期骑车、无症状、健康的绝经前女性（年龄 - 平均 (SD) = 33.4 (8.1) 岁）施用促性腺激素释放激素 (GnRH) 激动剂两到三个月。 只有三名女性（样本的 5.0%）报告了临床上显着的抑郁症状。 与这些女性相对不存在抑郁症状相反，我们确实观察到一些症状的显着出现，包括潮热、睡眠不安和性欲减退。 后一个发现与先前在这些女性的较小子样本中进行的研究一致，在这些女性中，约 30% 的样本观察到性欲显着下降（通过改良的 Derogatis 性功能量表测量）。 因此，在其他方面健康的女性中，性腺功能减退症和潮热（伴有睡眠障碍）的诱发均不会导致抑郁症状。 在这些研究中，我们还调查了两个可能影响雌二醇戒断期间抑郁症出现的因素——年龄和既往抑郁症发作情况。 我们评估了急性停用雌二醇治疗对患有和没有既往围绝经期抑郁症的老年绝经后女性的影响。 初步结果表明，雌二醇戒断会导致既往有围绝经期抑郁症的女性出现抑郁症状，但对于没有围绝经期抑郁史的女性则不会。 在围绝经期期间患有抑郁症的女性中，与双盲条件下维持雌二醇治疗的女性相比，雌二醇戒断与抑郁症状显着增加相关。 此外，没有抑郁病史、停药或维持雌二醇治疗的女性没有出现明显的抑郁症状。 因此，与我们在没有既往精神病史的绝经前女性中 GnRH 激动剂诱发的性腺功能减退症的研究结果相反，有围绝经期抑郁病史的女性中雌二醇戒断会引发情绪症状。 这些数据与流行病学研究的数据一致，流行病学研究表明，对于女性亚群来说，绝经后期过渡的内分泌事件可能是情绪不稳定和抑郁症发作的重要触发因素。 这种风险的标志以及雌二醇戒断引起的抑郁症状的机制仍有待确定。 仅在围绝经期期间有过抑郁症的老年女性在雌二醇戒断期间出现抑郁症状，但在没有既往抑郁症的年轻或老年女性中则不会出现。 因此，在雌二醇停药期间，与过去的抑郁症发作相比，女性的年龄似乎对抑郁症状的发展影响较小。 在第二项正在进行的研究中，我们正在调查过去的抑郁症（与围绝经期无关）对雌二醇戒断对情绪的影响。 初步观察表明，对于既往有抑郁症发作的无症状绝经前女性，GnRH 激动剂诱发的性腺功能减退症伴随着抑郁症状的发作。 如果在更大的样本中得到证实，这些数据表明，与在无抑郁病史的无症状绝经前女性中观察到的 GnRH 激动剂诱发的性腺功能减退症的影响相反，单次抑郁发作（无论是否与围绝经期相关）可能会增加女性在诱发性腺功能减退症/雌二醇戒断期间容易出现负面情绪症状。 女性健康倡议 (WHI) 的结果阻止了许多女性使用雌激素治疗。 尽管关于 WHI 研究结果对年轻围绝经期女性的适用性存在相当大的争议，但许多女性及其医生担心雌激素治疗的长期风险。 在之前的一项研究中，我们证明了短期服用雌二醇对患有围绝经期抑郁症的女性具有抗抑郁作用。 在一项正在进行的研究中，我们现在正在研究两种化合物对情绪和行为的影响，对于许多女性来说，这两种化合物代表了传统雌激素疗法的替代品。 具体来说，选择性雌激素受体调节剂（SERM）和植物雌激素（植物源性雌激素样化合物）已成为可用的，并且据报道显示出雌激素激动剂和拮抗剂作用的组织特异性特征以及雌二醇对两种形式雌激素的不同亲和力受体。 对于许多女性来说，这些新型化合物代表了雌激素疗法的更安全替代品，可预防骨质疏松症，并可能治疗围绝经期症状。 SERM 和植物雌激素的使用可能是首选，因为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，并且人们认为其中一些化合物（植物雌激素）是膳食补充剂。 初步结果表明，服用雌二醇或雷洛昔芬八周后，情绪评分与基线评分相比显着下降，并且显着低于接受安慰剂的女性的评分。 接受植物雌激素或安慰剂的女性与基线评分相比没有显着改善。 如果在更大的女性样本中得到证实，雷洛昔芬与雌二醇的功效相同，将提供一种替代治疗选择，且长期副作用更容易接受。 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。 具体来说，我们将检查选择性雌激素受体β激动剂（当可供人类使用时）对患有围绝经期抑郁症的女性的抗抑郁/抗焦虑功效。 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制中的作用，而且可以确定一类有前途的新型治疗药物，它们比雌激素更安全、更容易接受，并且可能没有与传统药物相关的副作用或戒断综合征。精神药物。 最后，将雷洛昔芬和植物雌激素与雌二醇对情绪和行为的影响进行比较，可以对参与雌二醇抗抑郁作用的特定大脑区域和雌激素受体亚型做出更精确的推断。 此外，这些化合物对雌激素受体α和β的选择性可能会确定雌二醇对特定目标症状的功效机制。 最后，由于植物雌激素已经被普遍推荐、广泛接受并广泛用于治疗情绪症状，进一步阐明其情绪影响可能会对公共健康产生重大影响。