Overview
This project aims to identify immunobiological mechanisms underlying the development of depression during the perimenopause. 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 the investigators 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 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 the 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, the investigators will enroll 180 perimenopausal women aged 40-55, approximately half with depression and half without a diagnosis of depression. All participants will complete psychiatric assessments and provide blood samples to measure sex hormones, inflammation and immune cell changes. Women with depression will be reassessed approximately eight weeks later to identify blood markers that change as depressive symptoms improve.
This project seeks to improve understanding of the biological mechanisms of depression during perimenopause and aid the development of predictive biomarkers and more effective treatments.
Description
Perimenopause constitutes a high-risk period for developing depressive symptoms and recurrence of depression. Although hormonal changes are considered to trigger symptom development, little is known about the underlying biological mechanisms or why some women are at increased risk. Since both estrogen and progesterone induce changes in the immune response, this project focuses on the immunobiological mechanisms underlying depression in perimenopause.
The investigators' working hypothesis is that perimenopausal hormonal shifts induce a pro-inflammatory state, modulated by intrinsic chromatin properties in lymphocytes, that contributes to depression. The investigators propose that the risk of developing perimenopausal depression depends on levels of aryl hydrocarbon receptor (AhR)-binding ligands in plasma, the chromatin landscape of immune cells affected by these ligands, and sex hormone levels that act in concert with the ligands to sustain a pro-inflammatory state.
- Aims
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- Determine plasma tryptophan metabolite and cytokine patterns in perimenopausal depression.
- Define epigenetic mechanisms in lymphocytes that confer vulnerability to developing depression in perimenopause.
- Identify inflammatory and metabolic markers that normalize in recovering women.
To test these hypotheses, the investigators will enroll 180 perimenopausal women aged 40-55 years at Weill Cornell Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, and Pine Rest Christian Mental Health Services. Approximately 90 women will have depression, and 90 will have no or mild depressive symptoms without a diagnosis of depression. Perimenopausal status will be established using the Stages of Reproductive Aging Workshop criteria. A structured diagnostic interview using DSM-5 criteria will confirm or rule out a diagnosis of depression.
Participants will undergo clinical assessments and blood sampling. The Hamilton Depression Rating Scale will be the primary measure of depression severity. Additional assessments will measure menopausal symptoms, anxiety, trauma history, suicidal thoughts and behaviors, and functioning. Blood samples will be collected between 7:00 and 10:00 AM.
For Aim 1, the investigators will quantify plasma tryptophan metabolites, inflammatory cytokines and sex hormones. The working hypothesis is that women with depression in perimenopause have reduced levels of immunoregulatory tryptophan metabolites, worsening peripheral inflammation. Biomarker levels will be compared between groups and examined in relation to depression severity and sex hormone levels.
For Aim 2, peripheral immune cell populations will be characterized using flow cytometry. ATAC sequencing, Illumina EPIC arrays and RNA sequencing will assess chromatin accessibility, DNA methylation and gene expression in sorted naïve T-cells. The investigators expect to detect differences in transcriptional regulation, reflected in distinct inflammatory responses in women with depression in perimenopause.
For Aim 3, the approximately 90 women with depression will be reassessed eight weeks after the first visit, with repeat clinical assessments and blood sampling. This observational follow-up will include women starting hormone therapy as part of their clinical care and women who do not. The working hypothesis is that women receiving hormone therapy will show reduced pro-inflammatory cytokines and increased regulatory T-cells, along with improvement of depressive symptoms.
The findings may aid the identification of women at risk and the development of more effective treatments. The investigators predict that these distinct inflammatory responses will be linked to the development of depression. The investigators also expect improvement of depressive symptoms and reversal of immunobiological markers in women receiving hormonal therapy. The investigators envision that the 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.
Eligibility
Inclusion Criteria:
- • Biological women, age 40 to 55.
- Undergoing perimenopause according to STRAW criteria \[1\].
- All races and national origins can be included.
- English speaking (since all clinical rating scales to be used here have not been developed and validated for non-English speaking populations).
- Able to give informed consent.
- Able to comply with and complete study procedures.
- Willing and able to take part of the different steps in the study, including follow-up research visit after 8 weeks and blood draws.
Exclusion Criteria:
- • Pregnant, nursing or transgender women (due to their hormonal status being different than what is investigated in this project).
- Incarcerated individuals.
- Subjects with dementia or otherwise cognitively impaired subjects with difficulty understanding the study procedures.
- Patients with an active somatic disorder primarily involving the immune system (autoimmune diseases such as Crohn's disease, multiple sclerosis, or rheumatoid arthritis; or hematological diseases such as lymphoma or leukemia or HIV). Research staff will consult with the PIs in cases of uncertainty.
- Patients with untreated hormonal conditions affecting the reproductive system.
- Patients on chronic and systemic immunomodulatory treatment. Examples are patients with a liver or kidney transplant and medications used for disorders involving the immune system, as mentioned above. Examples of immunomodulatory treatments are cyclosporin, azathioprine, infliximab and chronic corticosteroid treatment.
- Women already taking hormonal substitution before the research visit (either for perimenopause or/and as contraceptive) or replacement will be excluded,
- Patients taking lithium, neuroleptic- or mood stabilizing medications (antidepressants, such as SSRIs and SNRIs, are allowed).
- Patients undergoing active treatment for any form of cancer (chemotherapy or immunomodulatory treatments).
