Psychobiology and Treatment of Perimenopausal Mood Disorders

National Institute Of Mental Health

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Abstract

This report includes work arising from the following clinical protocols: NCT00030147, NCT00060736, NCT00001231, NCT03689543 and NCT00001322. Our cross-sectional findings to date show that episodes of perimenopause-related depression (PMD) cluster during the late menopause transition, a stage of life accompanied by the largest declines in estradiol secretion. However, ovarian steroid levels (including estradiol) do not differ between women with PMD and reproductively matched women without PMD; thus, women with PMD are not simply more estrogen deficient. Moreover, hormone therapy (HT) can alleviate or prevent depression in perimenopausal women, whereas women who stop HT often have a reoccurrence of depressive symptoms. In a placebo-controlled, double-blind clinical study, we previously demonstrated that asymptomatic postmenopausal women with past PMD who were blindly withdrawn from estradiol-treatment experienced a significant recurrence of depressive symptoms, whereas women who had never experienced depression during perimenopause or those with past PMD who continued receiving estradiol-treatment had no change in symptoms. These findings suggest that women who experience PMD have a differential affective response to otherwise identical changes in estradiol specifically, and independently, of other events accompanying the menopause transition. These data also suggest that blinded estradiol study design could be employed to identify potentially novel therapeutics for PMD. To clarify the relative relationship of several potential accompaniments of PMD we have completed a high-density, prospective, longitudinal study of healthy asymptomatic women who were followed during and after their transition through the menopause with diagnostic interviews, symptom ratings (daily, weekly and at semi-annual clinic visits) and blood hormone measures. Eighty-nine asymptomatic, premenopausal, healthy women were monitored for a mean of 6.0 years (SD=2.7 years) until 6-12 months after their final menstrual periods (FMP). Outcomes included SCID-IV, early follicular phase blood hormone levels, and daily logs of menses and symptoms. Twenty-nine episodes of major or minor depression occurred in twenty-two women, fifteen of whom had 1st lifetime event. Twenty episodes occurred within the 24 months surrounding FMP; the relative risk for depression was approximately 5-fold greater during the perimenopause compared to earlier or later timeframes. Prior history of major depressive episodes was associated with PMD, while the presence of hotflushes (HF) was not. In women with PMD compared with those without PMD, the secretory patterns of plasma estradiol and FSH differed over time: PMD had lower estradiol levels throughout the perimenopause with higher FSH levels early which then diverged further 1 year pre-FMP. Thus, our preliminary results suggest the following: episodes of PMD cluster around FMP; HFs are not necessary accompaniments of PMD; and alterations in the patterns of ovarian steroid secretion e.g., lower estradiol exposure throughout the perimenopause and a more rapid increase of FSH around FMP, were associated with the development of PMD. Finally, we will employ this longitudinal sample to evaluate several potential markers in blood of PMD including several measures identified in our functional genomics studies. Our initial evidence that estradiol therapy is an effective treatment for PMD has been confirmed by the results of three randomized, placebo-controlled trials. Nonetheless, concerns about the long-term safety of any formulation of estrogen therapy remain after the results of the Women's Health Initiative. Given our prior demonstration that estradiol withdrawal precipitates depressive symptoms in women with past PMD (behavioral changes not observed in controls undergoing the same hormone manipulation), we employ this study design to examine the ability of a selective estrogen receptor beta (ER beta) agonist (LY300507) to prevent estradiol withdrawal-induced depressive symptoms in women with past PMD. The role of ER beta is suggested to be more involved in brain and behavior that estrogen receptor alpha and to have a lower impact on tissue growth and metabolism within the body. Thus, it could be predicted that this estrogen receptor beta agonist prevents estradiol withdrawal-induced depressive symptoms in women with past PMD, that this compound could have more selective antidepressant actions in women with current PMD and have a more acceptable long term safety profile that would not require women to augment estradiol therapy with a progestin. We are now recruiting the last few women to be enrolled in this study and we intend to complete the trial in 2024 after which we will break the blind. Finally, steroid hormone signaling, such as occurs with estradiol, traditionally involves actions at the cellular level to alter gene transcription and neural signaling, we hypothesized that we could observe differences in cellular response, both innately (i.e., in the absence of ovarian steroids) and during estradiol-withdrawal, in PMD. The therapeutic benefits of estradiol and symptom-provoking effects of estradiol-withdrawal suggest that a greater sensitivity to changes in estradiol at the cellular level contribute to PMD. We developed an in vitro model of PMD with lymphoblastoid cell lines (LCLs) derived from participants of a prior estradiol-withdrawal clinical study. LCLs from women with past PMD or control women were cultured in three experimental conditions: at vehicle baseline, during estradiol treatment, and following estradiol-withdrawal. Whole transcriptome analysis revealed significant differences in transcript expression in PMD in all experimental conditions, and significant overlap in genes which were changed in PMD regardless of experimental condition. Of these, CXCL10, previously linked to an increased risk of cardiovascular disease, was upregulated in women with PMD, but most robustly after estradiol-withdrawal. A second gene, CYP7B1, an enzyme intrinsic to DHEA metabolism, was upregulated in PMD across all three experimental conditions. These differences in CYP7B1/CXCL10 expression provide evidence that both intrinsic cellular differences (hormone state-independent) as well as differential sensitivity to estradiol-withdrawal (hormone state-dependent) could contribute to the onset and/or sequella of the estradiol-withdrawal-related affective state in PMD. More recent gene network and data driven analyses also identify differential expressions of genes involved in circadian clock regulation (e.g., PER1) and the age of onset of menopause. These latter findings are of interest given both the frequent reports of sleep disturbance in women with PMD and reports of an earlier age of menopause in women with PMD compared with euthymic controls. Finally, our in vitro model allows for future investigations into the mechanisms of genes and gene networks involved in the vulnerability to, and consequences of, PMD. To this end, we currently perform whole exome and genome wide sequencing of women with and without PMD. We intend these data to identify further characteristics of the underlying pathophysiology of PMD and contribute to large scale studies of the genetic basis of both depression in women and more specifically PMD. Plans are underway to collaborate with groups at Stanford employing several large-scale efforts including NIHs All of Us Research Program in which the PMD phenotype is examined.