Sex differences in the risk of developing co-occurring depression and cardiovascular disease in adulthood may result from disruptions during the development of the stress response circuitry in the fetal brain, according to findings from a longitudinal cohort study.
Specifically, fetal exposure to maternal immune activation resulting from preeclampsia or conditions that restricted fetal growth was shown in the 40-year study to be significantly associated the co-occurrence of major depressive disorder and cardiovascular diseases in adult women, Jill M. Goldstein, Ph.D., said during a press briefing held in conjunction with the annual meeting of the American College of Neuropsychopharmacology.
The findings have implications for the development of early interventions in adults who may be predisposed to this common co-occurrence, said Dr. Goldstein, professor of psychiatry and medicine at Harvard Medical School, Boston.
This is particularly important because co-occurring depression and cardiovascular disease, with a prevalence of about 20%, is predicted to be the leading cause of disability worldwide by 2020, she noted.
"Women are at greater risk than men, and we don’t understand why," said Dr. Goldstein, also director of research at the Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, Boston.
However, given that stress response circuitry involves a "perfect storm" of brain regions with some of the most striking sex differences, which both develop and function differently in men and women, and which regulate mood and cardiac function, Dr. Goldstein and her colleagues hypothesized that disruptions in this circuitry during fetal development might result in the sex-specific vulnerabilities to co-occurring depression and cardiovascular disease later in life.
Indeed, functional magnetic resonance imaging studies in 60 of the 295 adults with fetal exposure to maternal immune activation and their nonexposed siblings in the study cohort showed that fetal exposure was significantly associated with later sex-specific deficits on several measures of stress response brain activity, endocrine function, and autonomic nervous system function.
"Women are at greater risk than men, and we don’t understand why."
For example, the functional MRI scans, conducted in 30 exposed and 30 nonexposed subjects who viewed images with negative valence/high arousal vs. neutral valence/low arousal stimuli to assess stress response, indicated that exposure was significantly associated with low high-frequency R-R interval variability (HF-RRV) in response to stress 40 years later.
The association was threefold greater in those with major depressive disorder than in those without major depressive disorder, and exposed women had a significantly higher risk of comorbidity of major depressive disorder and HF-RRV, compared with men (relative risk 1.38). This comorbidity was significantly associated with tumor necrosis factor–alpha levels in the maternal sera of exposed women, compared with nonexposed women.
Also, significantly greater blood oxygen level-dependent (BOLD) signal changes in the hippocampus, anterior hypothalamus, and anterior cingulate cortex, and hypoactivity in the orbitofrontal cortex occurred in response to stress in fetal-exposed women. Only hypoactivity in the orbitofrontal cortex was significantly increased in exposed men.
Fetal-exposed women with major depressive disorder had the greatest hyperactivity in the anterior hypothalamus, and the greatest hypoactivity in the anterior cingulate cortex, the orbitofrontal cortex, and the hippocampus. This suggests hyperarousal, and lack of cortical and hippocampus control in fetal-exposed women who have major depressive disorder, Dr. Goldstein explained.
Significant associations also were seen between important stress response brain regions and loss of parasympathetic cardiac regulation, she noted.
Higher levels of TNF-alpha/interleukin-10 and interleukin-6 were significantly associated with lower BOLD changes in the hippocampus and anterior cingulate cortex, and these co-occurred with disruption in the hormones that were collected during the MRI scans (and timed to the stress response), including dehydroepiandrosterone or DHEAS, testosterone, estradiol or E2 (which were lowered), and progesterone, and cortisol (which increased) in response to stress.
This study was an expansion of a National Institutes of Health study initiated in the 1950s. Mothers were followed through pregnancy, their sera were stored at the NIH, and offspring were followed for 7 years. For this part of the study, Dr. Goldstein and her colleagues rerecruited exposed offspring and their nonexposed siblings, and followed them for 20 years, into their late 40s.
The findings suggest shared fetal risk factors for the co-occurrence of major depressive disorder and cardiovascular disease risk in women, and they suggest that fetal programming of the stress response circuitry might help explain sex-specific vulnerability to major depressive disorder and cardiovascular disease risk, Dr. Goldstein said.
Understanding the early signals and pathways could lead to early interventions that could lessen disability and perhaps even prevent the illnesses, she concluded.
This study was funded by the National Institute of Mental Health and the NIH Office of Research on Women’s Health. Dr. Goldstein reported no disclosures.