Major depressive disorder (MDD) has a lifetime prevalence rate of approximately 20% in the United States and is the leading cause of non-fatal disease burden worldwide. MDD can be debilitating for all, but beginning in early adolescence, women are twice as likely to experience MDD relative to men. Moreover, as they age, they are at disproportionately high risk for developing several serious medical conditions that frequently co-occur with MDD and presage early mortality, such as hypertension, heart disease, certain cancers, neurodegeneration, and stroke. Understanding mechanisms that may underlie the initial development of depression, especially among women, is therefore of paramount public importance. To address this issue, I will elucidate neural, inflammatory, and genomic processes associated with risk for MDD in adolescence. Recent studies have shown that social stress engages a network of brain regions involved in processing physical and social threat. Social stress also up regulates components of the immune system involved in inflammation, which has been implicated in the pathophysiology of depression. To examine for the first time social stress-induced alterations in neural activity and connectivity, pro-inflammatory cytokine activity, and genome-wide transcriptional activity that are associated with risk for MDD, I will conduct a study in which 25 adolescent girls at high risk for MDD (i.e., no personal history of any affective Axis I disorder, but a positive maternal history of MDD) and 25 adolescent girls at low risk for MDD (i.e., no personal or maternal history of any Axis I disorder) will be exposed to a brief episode of social rejection while undergoing an fMRI scan. In addition, blood samples will be obtained at four time-points during the study to test for social stress-induced changes in (a) levels of the pro-inflammatory cytokines TNF-?, IL-1?, and IL-6, and (b) inflammatory gene expression, using microarray-based genome-wide transcriptional profiling. As such, this study will be the first to examine neural, inflammatory, and genomic responses to social stress that are associated with differential risk for depression (Aims 1 & 2). The study will also be the firstto examine relations between these different stress-related mechanisms in adolescent girls at high and low risk for MDD (Aim 3). Finally, the study will allow me to obtain mentored training in several areas that are critical for pursuing this line of research independently, including: neuroscience and neuroimaging methods, fMRI data analysis, and functional genomics. My goal as a clinical psychologist is to identify mechanisms that underlie the initial emergence of risk fo depression and related disorders in adolescence, which can in turn be modified to reduce the enormous disease burden that is associated with these conditions. This Mentored Clinical Scientist Development Award will enable me to pursue this goal by providing me with protected time to obtain state-of-the-art training at UCLA. This award will also allow me to conduct the firs multi-method, experimental fMRI study on neural, inflammatory, and genomic mechanisms underlying risk for depression in adolescence, which will in turn inform the development of novel strategies for reducing the mounting disease burden associated with depression and depression-related diseases.

Public Health Relevance

Women in the United States currently rank last in health quality and second-to-last in life expectancy at birth, relative to their counterparts in sixteen other developed countries. This poor health trajectory originates in childhood and early adolescence, as females become twice as likely to develop depression as men and are at disproportionally high risk for a wide range of serious medical conditions that frequently co-occur with depression, including heart disease, certain cancers, neurodegeneration, and stroke. This interdisciplinary neuroimaging study aims to address this important public health problem by applying state-of-the-art methods to examine neural and immune system processes that may underlie the initial emergence of disease risk in adolescence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH103443-03
Application #
9199100
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Sarampote, Christopher S
Project Start
2014-12-01
Project End
2018-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Cuneo, Michaela G; Schrepf, Andrew; Slavich, George M et al. (2017) Diurnal cortisol rhythms, fatigue and psychosocial factors in five-year survivors of ovarian cancer. Psychoneuroendocrinology 84:139-142
Shields, Grant S; Slavich, George M (2017) Lifetime Stress Exposure and Health: A Review of Contemporary Assessment Methods and Biological Mechanisms. Soc Personal Psychol Compass 11:
Shields, Grant S; Moons, Wesley G; Slavich, George M (2017) Better executive function under stress mitigates the effects of recent life stress exposure on health in young adults. Stress 20:75-85
Lutgendorf, Susan K; Shinn, Eileen; Carter, Jeanne et al. (2017) Quality of life among long-term survivors of advanced stage ovarian cancer: A cross-sectional approach. Gynecol Oncol 146:101-108
Shields, Grant S; Moons, Wesley G; Slavich, George M (2017) Inflammation, Self-Regulation, and Health: An Immunologic Model of Self-Regulatory Failure. Perspect Psychol Sci 12:588-612
Dooley, Larissa N; Slavich, George M; Moreno, Patricia I et al. (2017) Strength through adversity: Moderate lifetime stress exposure is associated with psychological resilience in breast cancer survivors. Stress Health 33:549-557
Malat, Jennifer; Jacquez, Farrah; Slavich, George M (2017) Measuring lifetime stress exposure and protective factors in life course research on racial inequality and birth outcomes. Stress 20:379-385
Goldfarb, Elizabeth V; Shields, Grant S; Daw, Nathaniel D et al. (2017) Low lifetime stress exposure is associated with reduced stimulus-response memory. Learn Mem 24:162-168
Slavich, George M (2016) Life Stress and Health: A Review of Conceptual Issues and Recent Findings. Teach Psychol 43:346-355
Shields, Grant S; Toussaint, Loren L; Slavich, George M (2016) Stress-related changes in personality: A longitudinal study of perceived stress and trait pessimism. J Res Pers 64:61-68

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