Depression is the fourth leading cause of disease burden worldwide, and the incidence of major depressive disorder (MDD) in women is twice that of men. Further, MDD has a high rate of comorbidity with general medical disorders such as cardiovascular disease (CVD), metabolic syndrome (MetS), dementias, and other psychiatric disorders, all of which exhibit significant sex differences. Thus there is a high cost to the medical system and society associated with depression that differs for men and women. We believe that risk factors for adult-onset MDD occur prenatally during mid-to-late gestation, and therefore we study fetal and neonatal neurodevelopmental pathways that we hypothesize are implicated in sex-specific adult brain abnormalities and endocrine dysfunction associated with depression and related comorbid conditions.

Our current work focuses on investigating the pathophysiology of sex differences in the comorbidity of MDD, CVD, and MetS. Our hypotheses are based on the assumption that some of the key brain regions involved in the regulation of mood also regulate metabolism, the hypothalamic-pituitary-adrenal (HPA) axis, inflammatory responses, and autonomic nervous system (ANS), which controls heart rate and blood pressure. We propose that hormones and polypeptides that these shared brain regions express are important links in understanding the comorbidity of MDD and risk for CVD and MetS. 

Recently, as part of a multi-site, collaborative, interdisciplinary, basic and translational research center examining the biological causes of sex differences in depression, we tested hypotheses regarding the roles of adrenal and gonadal signaling pathways regulating growth factors and their interactions with GABA-ergic, GLU-tamatergic, and nitric oxide (NO) mechanisms in the development of regions in the stress response circuitry (known to be abnormal in depression). The human studies in this project (directed by Dr. Goldstein) involved functional brain imaging, endocrinology, immunology, and genetics. We believe that findings from this work will lead to the development of novel sex-specific treatments and/or prevention strategies.

Examples of findings:

  1. Stress response circuitry in the brain is disrupted in MDD in women and men and significantly associated with gonadal and adrenal hormone dysregulation. MDD versus healthy control women show distinct brain-hormone relationships at early follicular compared with mid-cycle menstral time periods. Further, brain-hormone associations differ in premenopausal compared to perimenopausal MDD women.

  2. Brain activity deficits in stress response circuitry in MDD are significantly associated with lower parasympathetic cardiac regulation (or less inhibitory ANS control).

  3. Abnormal maternal immune responses are associated with fetal growth restriction and offspring deficits in age 7 cognitive, affective, and behavioral outcomes known to be associated with depression.

  4. Fetal growth restriction and preeclampsia are significantly associated with sex-specific risk for MDD and less parasympathetic control of the heart, an effect that was modulated by childhood socioeconomic status.

  5. Maternal immune dysregulation during mid-gestation is a significant sex-dependent risk for MDD,
    i.e., higher in female offspring.