The immunobiological mechanisms of depression in perimenopause - PROJECT SUMMARY/ABSTRACT This project aims to identify immunobiological mechanisms underlying the development of depression during the perimenopause, in response to the NIMH funding opportunity “Mood and Psychosis Symptoms during the Menopause Transition”. During the perimenopause, the risk for recurrence of depression is increased 13-fold among women who previously had depression. Moreover, perimenopause overlaps with the age span exhibiting the highest suicide rate for women. The perimenopause can last for several years and starts when estrogen and progesterone levels begin to fluctuate, gradually declining. Sex hormones are powerful modulators of the immune response and we therefore propose that changes in lymphocytes play a central role in depression during this time. Notably, our previous work has demonstrated deficient regulatory T-cell responses in women with post- partum depression and identified a specific pro-inflammatory profile (composed of cytokines and tryptophan metabolites) that predicts depression during pregnancy. Importantly, our new pilot data derived from women with severe depression in the perimenopausal age span reveals alterations in tryptophan metabolites that control T- cell responses as well as in the methylation of genes involved in T-cell fate and chromatin remodeling. Taken together, these data support our hypothesis that the perimenopausal hormonal shifts induce a pro-inflammatory state, regulated by chromatin modifications in T-cells, that triggers depression in vulnerable women. To test this hypothesis, we will enroll 150 perimenopausal women in a multi-site study to: 1) determine plasma tryptophan metabolite and cytokine patterns in perimenopausal depression; 2) define epigenetic mechanisms in lymphocytes that confer vulnerability to developing depression in perimenopause; and 3) identify inflammatory and metabolic markers that normalize in a subset of 60 women recovering from depression (re-assessed 8 weeks after their initial visit), either treated with hormonal substitution therapy or untreated. We will undertake careful clinical diagnostics and confirm perimenopausal status using established criteria. In all participants, we will quantify plasma tryptophan metabolites, cytokines, and sex hormones. We will also define peripheral immune cell populations and determine changes in DNA-methylation, chromatin accessibility and gene expression in naïve T-cells. Finally, we will test the functional response to inflammatory stimulation in cultured lymphocytes derived from the same women. We expect that women with perimenopausal depression will exhibit reduced levels of immunoregulatory tryptophan metabolites and signs of peripheral inflammation as well as differences in transcriptional regulation in lymphocytes. We predict that these distinct inflammatory responses will be linked to the development of depression. We also expect improvement of depressive symptoms and reversal of immunobiological markers in women receiving hormonal therapy. We envision that our project will lead to an improved understanding of the molecular underpinnings of depression during perimenopause, aiding the future identification of biomarkers of women at risk as well as the development of more effective treatments.
