Psychobiology and Treatment of Perimenopausal Mood Disorders

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This report includes work arising from the following clinical protocols: NCT00030147, NCT00060736, NCT00001231, NCT03689543 and NCT00001322. Our cross-sectional findings to date show that perimenopause-related depression (PMD) is accompanied by a decreased QOL, decreased social adjustment, increased negative life events and impaired role functioning compared to matched asymptomatic perimenopausal women, but similar to depression occurring at other stages in a womans life. Additionally, depressive episodes during the perimenopause cluster during the late menopause transition, where there are usually the largest declines in estradiol secretion. This observation suggests that a subset of women could have a genetically predisposed sensitivity to rapidly declining estradiol. Moreover, hormone therapy (HT) can alleviate or prevent depression in perimenopausal women, whereas women who stop HT often have a reoccurrence of depressive symptoms. Intriguingly, ovarian steroid levels (including estradiol) are normal in PMD compared to reproductively matched women without PMD; thus, women with PMD are not simply more estrogen deficient. In a placebo-controlled, double-blind clinical study, we previously demonstrated that asymptomatic postmenopausal women with past PMD who were crossed over from estradiol-treatment to placebo experienced a significant recurrence of depressive symptoms, whereas women who had never experienced depression during perimenopause or 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. As steroid hormones such as estradiol traditionally act 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. These transcripts were further validated via qRT-PCR. Gene networks dysregulated in PMD included inflammatory response, early/late estradiol response, and cholesterol homeostasis. Our results provide evidence that differential behavioral responsivity to estradiol-withdrawal in PMD reflects intrinsic differences in cellular gene expression. Genes such as CXCL10, CYP7B1, and corresponding proinflammatory and steroid biosynthetic gene networks, may represent biomarkers and molecular targets for intervention in PMD. Finally, this in vitro model allows for future investigations into the mechanisms of genes and gene networks involved in the vulnerability to, and consequences of, PMD. Our initial evidence that estradiol therapy is an effective treatment for PMD was recently confirmed. Indeed, our recent findings replicate the results of three randomized, placebo-controlled trials, employing similar diagnostic criteria for PMD, documenting the beneficial effects of TE in this condition. Although all three trials were limited by relatively small samples, the combined sample size of over 170 women with well-characterized PMD strongly supports the efficacy of TE in this condition. Nonetheless, concerns about the long-term safety of any formulation of estrogen therapy remain even for TE, which is suggested to have lower safety risks especially in younger perimenopausal women. 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 now are employing this study design to examine the ability of a selective estrogen receptor beta agonist (LY300507) to prevent estradiol withdrawal-induced depressive symptoms in women with past PMD. The role of estrogen receptor 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 would be predicted that if this estrogen receptor beta agonist prevents estradiol withdrawal-induced depressive symptoms in women with past PMD that this compound could have antidepressant efficacy in women with current PMD. Finally, it remains unclear whether the clinical characteristics we identified in our cross-sectional studies reflect pre-existing risk factors for PMD or the negative impact of a current depression. To clarify the relative relationship of these potential accompaniments of (or antecedents to) 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 measures. Approximately, ninety-one asymptomatic, premenopausal women, ages 41-55 years, were monitored longitudinally for an average of 5.2 years (range of 2 10 years) until 6-12 months after their final menses (FMP). Preliminary results confirm the clustering of depressive episodes in proximity to the FMP. In the 24 months surrounding the FMP we observed the onset of twenty-five episodes of major or minor (subsyndromal) depression occurred in nineteen women. The clustering of depressions during the late menopause transition, a time associated with declining levels of ovarian estradiol secretion, consistent with our clinic-based estradiol manipulation studies. During the four years prior to the FMP, compared to women who remained asymptomatic, women with PMD reported significantly lower life satisfaction but did not report significant differences in overall QOL, marital satisfaction, experience of personal loss, or negative life events. Blood samples have been sent for assay and these longitudinal data will assess both the antecedents and accompaniments of PMD including day-to-day affective variability, plasma levels of ovarian hormones, adrenal androgens and inflammatory measures.