Theoretical Framework
A theoretical framework that views health as the result of multiple determinants interacting in nested environmental, behavioral, and biological contexts guide the work of the NCDMHR. In this model of health development, different health trajectories arise from multiple transactions between community/social, cognitive-behavioral, and neurobiological mechanisms.
Therefore, one of the explicit aims of this work is to investigate the neurobiologic processes that are associated with wellness after disasters. We will do that by focusing on both genetic and neuroendocrine factors. With respect to genes, the central psychopathologies of interest in the aftermath of disasters, including PTSD, depression, and anxiety likely represent an end result of the interplay between multiple small-effect genetic risk loci coupled with traumatic exposure. Support for genetic influences on psychopathology comes from both animal models and human studies.
Genetic Determinants and Environmental Exposures
Emerging evidence has suggested that there is interplay between genetic determinants and environmental exposures, including of central interest here, to traumatic event experience. In the proposed study we will evaluate a specified set of candidate genes and assess their role in determining both specific psychopathology (e.g., PTSD, depression) and also patterns of comorbidity.
With respect to neuroendocrine determinants, there is an emerging literature suggesting that dehydroepiandrosterone (DHEA) plays an important role in the mediation of stress resilience and wellness. Further, it appears that achievement of higher DHEA/cortisol levels during adrenal activation by stress may mitigate stress-induced degradation of cognition, mood, and behavioral function.
More recent studies suggest that the ratio of DHEA or the sulfated metabolite of DHEA (DHEAS) to cortisol may be a more robust indictor of psychological health and resistance to the negative effects of stress. In this work we hypothesize that a higher ratio of DHEA or DHEAS, collectively termed DHEA(S), to cortisol is associated with increased individual resistance and resilience patterns measured at the time of sampling, two months after the disaster, independent of severity of individual-level exposure.
Aims for the Center's Neurobiologic Work
There are then two aims for the neurobiologic work that is being conducted by the center. First, we aim to assess the role played by gene x environment (G x E) interactions in shaping components and trajectories of wellness postdisaster. Specifically, we will sample DNA from all subjects who consent, assess whether genotypes at specific loci (e.g., SLC6A4, BDNF, A2CAR, HTR2C, GABRA2), and specific gene-gene interactions (e.g., interaction of SLC6A4 and BDNF), moderate the relation between exposure to disaster stressors and trajectories of PTSD/MD and the extent to which these relations are modified by the presence or absence of social support.
Second, as an exploratory aim, we will assess differences in components and trajectories of wellness between subgroups characterized by differences in neuroendocrine measures related to stress resistance, resilience, and adaptive functioning. Salivary levels of the neuroactive steroids of interest, DHEA(S), and cortisol, will be measured post-awakening (a sampling time that reflects maximum adrenal capacity) two months after the disaster and related to patterns of resistance at the time of the disaster and with wellness at two and twelve months after the disaster.
All persons who participate in the epidemiologic study will be asked to contribute a biologic (salivary) specimen that can be used for genotyping and for neuroendocrine assays. Selection of genes is guided primarily by research associated with depression, PTSD, and other forms of fear or anxiety. Gene candidates also are selected to address our secondary aim of examining G x E interactions associated with exposure to postdisaster traumatic events.
As in the epidemiologic analyses, growth mixture models also will be used to examine G x E interactions with PTSD, MD, and substance use as phenotypes analyzed separately, and genotypes, traumatic stressors and/or social supports as main effects, and ancestral proportion scores, age and sex utilized as covariates over time. The analytic approach for the neuroendocrine analyses is similar, where the central determinants of interest include DHEA and DHEA/cortisol ratio.