Depression Susceptibility in Adolescent Females: Estrogen Variability, Stress Exposure, and Fronto-Limbic Brain Dynamics

2018 Award: $38,710

Puberty is characterized by dramatic reproductive hormone instability, heightened interpersonal stress and an increased risk for depression, especially for girls. A sensitivity to normal changes in ovarian hormones (e.g., estrogen) during reproductive events has been shown to provoke mood symptoms in vulnerable women; however, the relationship between hormone changes and depression symptoms has not been examined in girls during the pubertal transition. This study will determine the impact of hormone variability on neurobiological systems (brain activity and cortisol stress responses) known to influence affective (mood) states. Foundation of Hope funding provides the opportunity to use a novel multimodal approach involving precise measures of hormone variability and neurophysiological responses to acute challenge (laboratory stress task) to advance our understanding of the neurobiological basis of depression at a critical developmental window for intervention and prevention efforts.

Need/Problem: Dramatic fluctuations in reproductive hormones (e.g., estrogen), refinement of brain circuitry involved in cognitive and emotional processing, and elevated psychosocial stress during the pubertal transition (peripuberty) accompany a substantially increased risk for depression, particularly for adolescent girls. Although normal changes in estrogen provoke affective symptoms in vulnerable women during reproductive events, the role of changing estrogen levels in depression risk has not been studied in peripubertal girls. Furthermore, the neurophysiologic mechanisms underlying the vulnerability to estrogen fluctuations have yet to be identified.

Grant Summary: : Estrogen exerts significant modulatory effects on the cortisol stress response and brain circuitry involved in regulating affective (mood) state. With the Foundation of Hope’s support, this research will use a novel multimodal approach involving precise ovarian hormone measurements, neurophysiological assessments of cognitive and emotional processing, and neuroendocrine (e.g., cortisol) responses to acute psychosocial stress to begin constructing a comprehensive model of depression susceptibility in girls during the pubertal transition.

Goals and Projected Outcomes: The primary goal of this study is to advance our understanding of the neurophysiological mechanisms whereby hormone variability increases the risk for depression in peripubertal girls. Specifically, this project investigates whether: 1) brain activity involved in regulating emotion and cognition and; 2) cortisol stress reactivity partially explain (mediate) the relationship between weekly estrogen fluctuation and depression symptoms in peripubertal girls, particularly for girls who have experienced recent stressful life events.

Elizabeth Andersen, PhD

Grant Details: We will enroll 48 mid-pubertal girls between the ages of 11 and 14 who are pre-or-post menarche (within one year). 24 girls will have familial risk for depression (first-degree family member with depression) to achieve a broader range of depression symptomatology. Over 8 weeks, salivary estrogen samples and depression symptom ratings will be collected weekly, followed by a test session involving recordings of brain activity during a computerized cognitive-emotional processing task, and saliva measures of the cortisol stress response to an acute laboratory social stress test. The weekly salivary hormone measurements will be analyzed using an ultrasensitive hormone assay (in collaboration with Dr. Zava at the ZRT laboratory, OR), and the standard deviation in estrogen across the 8 measurements will be used to index hormone variability. Greater estrogen variability is expected to predict brain activity associated with weakened emotional and cognitive processing and impaired regulation of the cortisol stress response and, in turn, elevated symptoms of depression, especially in girls who have experienced recent stressful life events.

This research examines a pivotal developmental window, associated with naturally fluctuating ovarian hormones and increased life stress, to provide insight on the neurophysiological mechanisms linking stress exposure and sensitivity to hormone fluctuations to the onset and maintenance of depression in peripubertal girls. In doing so, this research will also have significant implications for understanding the pathophysiology of affective state change, a phenomenon common to all psychiatric illnesses, including reproductive mood disorders.