Measuring allostatic load in an urban adolescent sample: The profile and role of biomarker dysregulation in depression outcomes

Accumulated, chronic stress exposure is well established as a precursor for allostatic load (AL). Both stress exposure and AL have been associated with depression in the existing literature. While many studies have focused on biomarkers representative of various physiological systems, a clear understanding of how physiological AL results in depression is yet unclear. Further, variability of hypoand hypercortisolemic profiles have been associated with depression. A review of the existing literature supports hypocortisolemic profiles in relation to female depression and hypercortisolemic profiles in male depression across both adolescent and adult populations. The function of alphaamylase (AA) dysregulation within the context of depression is even less well established. Previous research (Ali & Pruessner, 2012) has suggested a ratio of AA area under the curve with respect to ground (AUCg) over cortisol (CORT) AUCg, termed AOCg, as an indicator of the asymmetry between CORT and AA, and therefore, the hypothalamic pituitary adrenal (HPA) axis and sympathetic nervous system (SNS). Research supports an imbalance between these two systems may be representative of AL. AOCg has been correlated with major event exposure and depression in an adult sample. Adolescence is a sensitive biological period, perhaps posing even greater risk for the development of depressive symptoms within the context of AL. This provides rationale for use of the AOCg metric in an adolescent sample. A review of theory on stress research by Grant and colleagues (2003) posits a model for the etiology of psychopathology from stress exposure through the examination of potential biological mediators and moderators. The current study sought to further existing information on stress accumulation, AL, and depression by testing a path model with AUCg and area under the curve with respect to increase (AUCi) metrics of AA and CORT as mediators of the relationship between major events (ME), daily hassles (DH), and violent crime exposure (VC) with self-reported depression symptoms at two time points. We hypothesized that increased AUCg/AUCi of both CORT and AA would mediate the relationship between stressors and depression symptoms. We also hypothesized biological sex and parent depression severity would moderate the relationship between the physiological stress response and depression symptoms. In addition, the current study sought to replicate findings from the Ali & Pruessner study in an adolescent sample by running multiple regression analyses to identify associations between AOCg, stress, and depression symptoms. Results of the analyses indicate AUCg/AUCi metrics of AA and CORT do not mediate the relationship between stressors and depression symptoms. Regarding sex differences, female adolescents in the current sample exhibited a blunted response to the acute stressor task compared with males and presented with significantly more depression symptoms. AOCg was not significantly associated with depression symptoms in our adolescent sample but was significantly and positively associated with VC. Follow-up analyses indicate more VC is associated with lower COAg and that more COAg predicts less depression in adolescents. In addition, the use of more disengagement coping (DC) in response to more DH led to more depression symptoms at time one and lower AUCg AA values. Greater AUCg AA values in the current study were associated with less depression symptoms at time one and greater depression symptoms at time two. These results parallel previous studies demonstrating more SNS reactivity over time with STRESS, AA/CORT DYSREGULATION, & DEPRESSION 2 failure to habituate contributes to changes in neurobiological processes that create vulnerability for increased depression symptoms (McCarty, 2016). The current study provided further support for the need to utilize multiple measures of the stress response to elucidate associations between specific stressor types and specific parts of the stress response system that may be most impacted. In addition, the current study added to the topic of AA measurement in adolescents by identifying an association between AA with a chronic, uncontrollable distal stressor (VC) and identifying a positive association between AA and depression symptoms over time in a community sample of adolescents. STRESS, AA/CORT DYSREGULATION, & DEPRESSION 3 Measuring allostatic load in an urban adolescent sample: The profile and role of biomarker dysregulation in depression outcomes Introduction The role of allostatic load (AL) in psychopathology and pathophysiology is well established in the literature (McEwen, 1998). However, the mechanisms by which chronic stress results in the dysregulation of specific physiological systems and how the dysregulation, in turn, plays a direct or indirect role in the development of psychopathology is less well established. Biomedical and psychology researchers alike have contributed to this topic in various ways, though many previous studies have focused on one biomarker or physiological system at a time. Recently, research has expanded into the exploration of how different physiological systems, represented by various biomarkers, function in comparison to one another in response to acute and accumulated stress (Nederhof et al., 2015; Mauss et al., 2015; Mauss et al., 2016; Slopen et al., 2014). This has been done through the exploration of an overall allostatic load index (ALI), which includes multiple biomarker measurements across various physiological systems, and more precisely through the examination of interactions between the neuroendocrine and sympathetic nervous systems. The ALI is a representation of cumulative physiological risk comprised of one or several biomarker/s representing various physiological systems. Though the ALI method is more inclusive than the measurement of any one biomarker alone, it lacks specificity that may be acquired through the examination of the individual biomarkers/systems and interactions. Relatively little is known about the way these physiological systems work STRESS, AA/CORT DYSREGULATION, & DEPRESSION 4 together to promote risk for the onset of mental health problems. Further investigation of specific physiological systems and how asymmetry of their biomarker representatives interact with one another to influence mental health is needed to create a better overall understanding of this complex network of functioning. Adolescence is an important developmental period to explore in relation to the effects of chronic and acute stress exposure on biomarker functioning because it is characterized by many physiological, social, and emotional changes. Additionally, stress exposure in adolescence is associated with increased allostatic load in adulthood (Berg, Simons, Barr, Beach, Philbert, 2017). Adolescence is a particularly sensitive period in biological development, creating circumstances that may promote increased risk for the development of psychopathology (Chaby, Zhang, & Liberzon, 2017). Changes in physiological functioning during adolescence are hailed as a major component in this risk. This may be especially true for depression in which hormonal changes in female adolescents have been related to depression symptoms (Thapar, Collishaw, Pine, & Thapar, 2012), suggesting neurobiological factors play a role in the etiology of depression. Because of these sensitivities, study of the etiology of depression during adolescence is important. A recent study conducted by the National Institute of Mental Health (NIMH; 2019) found adolescents with depression make up of 13.3% of the U.S. population. Further, approximately 71% of these youth experience severe impairment. Depression rates are higher among female adolescents (20%) compared with their male peers (6.8%; NIMH, 2019), highlighting the importance of considering biological sex in methodology within depression studies. Additionally, Major Depressive Disorder (MDD) STRESS, AA/CORT DYSREGULATION, & DEPRESSION 5 is highly heritable, with rates of heritability in teens falling between 30 and 50 percent (NIMH, 2019). A review of epigenetics cites multiple gene polymorphisms within this age group as being associated with depression (Xia & Yao, 2015). Genetic vulnerability along with chronic stress has long been linked to the development of depressive symptoms, however, little is known about the specific role of stress response biomarker dysregulation in this equation beyond significant associations with stressors and depression. Taken together, it can be concluded exploration beyond that of associations between stress exposure and resulting physiological functioning in the etiology of depression in adolescent populations is needed. The present study is designed to aid in the development of understanding how stress exposure influences the physiological stress response, and how dysregulation of the stress response system may be involved in the development of depression symptoms in adolescent populations. Specific focus will be given to the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), through cortisol (CORT) and salivary alpha-amylase (AA) metrics. These biomarkers are well established as representative of these respective components of the stress response system. Additional elucidation of the physiological systems involved as impacted by stress exposure can aid in the possible development of prevention and intervention aimed at minimizing the effects of stress on the body and mental health in an adolescent population. Further, intervention at this period may be critical in minimizing a broad range of health outcomes across the lifespan. Allostatic Load STRESS, AA/CORT DYSREGULATION, & DEPRESSION 6 Allostatic load refers to the dysregulation of physiological mechanisms of the SNS and HPA axis in response to repeated exposure to stress (McEwen, 1998). The theory of allostasis can be thought of as an expans