Adolescence is an “age of risk” for the emergence of 1st onset of major depressive disorder (MD). Despite its prevalence and public health significance, major unanswered questions exist regarding the mechanisms involved in vulnerability to MD. Depression (Dep) is associated with a reduced sensitivity to rewards and low reward-related brain function in cortico-striatal circuitry. However, research has not yet tested whether chronically low reward responsivity (RR) or attenuated RR development during adolescence predicts 1st onset of MD. A separate literature documents elevated peripheral inflammation in Dep. Yet, research also has not examined whether chronically elevated inflammation or increases in inflammation during adolescence predicts 1st onset of MD. Further, research on inflammation and RR mostly has proceeded in parallel.

Recently, however, we and others have proposed neuroimmune network models of Dep. These models draw on work indicating that peripheral inflammatory mediators (e.g., cytokines) access the brain, where they lower RR. When dysregulated, this immune-to-brain signaling can lead to chronic and worsening low RR, which is reflected in dysphoria and anhedonia. This low RR is proposed to initiate unhealthy behaviors (substance use, poor diet), as well as sleep disruption and stress generation, which further heighten inflammation. Over time, dysregulation in RR and immune signaling may synergize in a positive feedback loop, whereby dysregulation in each system exacerbates dysregulation in the other.

We propose that reward-immune dysregulation is a two-hit vulnerability for the 1st onset of MD and increases in Dep symptoms (Sxs) during adolescence. Moreover, childhood and adolescentadversity and recent stressors influence both RR and inflammation, and may set the foundation for reward-immune dysregulation. This proposal is the first systematic test of these hypotheses. We will use an innovative biobehavioral high-risk design to examine bidirectional relationships between peripheral inflammation and multiple indices and domains (monetary, social) of RR and their joint prediction of 1st onset of MD and increases in Dep Sxs, particularly anhedonia. Three hundred 14-15 year old participants (Ps) will complete a prospective 3-year longitudinal study. Ps with no prior MD will be selected along the entire dimension of self-reported RR, with oversampling at the low tail of the dimension in order to increase the likelihood of MD onsets. At Time 1 (T1), T3, and T5, each a year apart, Ps will complete blood draws to quantify inflammation, self-report and behavioral measures of RR, and fMRI scans of reward neural activity and functional connectivity. At T1-T5 (with T2 and T4 6 mo. between the yearly sessions), Ps also will complete diagnostic interviews, and measures of Dep Sxs, reward-relevant life events, and behaviors that increase inflammation. Adversity history will be assessed at T1 only. This proposal is an innovative integration of research on reward and inflammatory signaling in understanding 1st onset of MD in adolescence. It has the potential to facilitate novel neuroimmune and behavioral interventions to treat, and ideally prevent, MD.

Why does depression surge so dramatically in adolescence, especially for females?  Despite the great scientific and public health significance of this question, the mechanisms underlying the surge in depression and emergence of gender differences in depression during adolescence remain elusive.

This project is relevant to NIMH’s mission to understand the causes of depression in youth, role of minority and gender status in depression, and targets for early intervention.  The aims of this project are to examine the generality to African-Americans of this surge in depression and emergence of gender differences as well as to examine the mechanisms underlying these developmental phenomena from the perspective of an innovative cognitive vulnerability X transactional stress model, embedded within a normative adolescent brain and cognitive development context.

To this end, a large-scale prospective, longitudinal study of 12-13 year old community youth (evenly divided between males and females and Caucasians and African-Americans) and their parents is being conducted.  Assessments of the adolescents’ cognitive vulnerabilities (negative cognitive styles, rumination, self-referent information processing, autobiographical memories), normative cognitive development (executive functions – attention, working memory, decision-making, future orientation), early childhood stressors, racial identity, and psychiatric diagnoses are conducted at Time 1 and yearly thereafter.  Assessments of depressive and anxiety symptoms, stressful life events, hopelessness, emotional abuse and peer victimization, emotional clarity, body image, perceived discrimination, and pubertal status occur every 6 months.  In addition, assessments of parental psychopathology, maternal cognitive vulnerabilities, and parenting styles are also obtained at Time 1 and yearly.

Results will have very significant implications for prevention of depression.   Knowledge of mechanisms underlying the adolescent surge in depression would suggest interventions for short-circuiting it and the great impairment it portends for young adulthood.  Specifically, results will suggest optimal features of preventive interventions for depression in youth regarding: identification of youth to target, timing, psychological or biological processes to target, and interventions for girls vs. boys and African-Americans vs. Caucasians.

Rates of depressive symptoms and diagnoses rise markedly between ages 15-18. Despite the scientific and public health significance, the mechanisms responsible for the adolescent surge in depression are not fully understood.

Cognitive vulnerability – stress models have contributed importantly to our understanding of the increased incidence of depression in adolescence; however, these models do not adequately explain some of the somatic symptoms or incorporate biological stress mechanisms through which cognitive vulnerability evokes depression. A separate exciting body of research on immune correlates of depression has highlighted the role of proinflammatory pathways; yet, only some depressed individuals exhibit inflammation. This project provides a novel and compelling integration of the cognitive vulnerability – stress framework and the proinflammatory model of depression as applied to adolescence. The research has the potential to solve puzzles and limitations faced by both models when considered separately. The findings may help to account for the full spectrum of depressive symptoms and identify cognitively vulnerable individuals as especially likely to evince signs of cytokine dysregulation and increased reactivity to stressful events. Moreover, it is known that early childhood adversity contributes to both the development of cognitive vulnerability and a proinflammatory bias. The primary goal is to determine the role of inflammatory states in combination with cognitive vulnerabilities, stress, and childhood adversity as contributors that underlie the rise in adolescent depression.

A multiwave, 4-year prospective study will be conducted with an existing, well-characterized community sample of 300 adolescents, including similar numbers of males and females and Caucasians and African-Americans, just reaching the critical age when the dramatic rise in depression begins. We will conduct yearly blood draws to assess proinflammatory and regulatory cytokines (a multicytokine array of 7 cytokines) and C-reactive protein (CRP), in parallel with ongoing assessments of life stress and depression and anxiety symptoms every 6 months. Cognitive vulnerabilities and depression and anxiety diagnoses will be obtained yearly, along with a history of childhood adversity in this unique cohort of urban adolescents. We also will examine interleukin-6 (IL- 6) reactivity to an acute stressor (Trier Social Stress Test) to determine how individual variation in cognitive reactivity translates into increased IL-6 release.

This project fills a crucial knowledge gap about normal development of immunity in adolescence and its role in the dramatic rise in adolescent depression. It may lead to novel interventions for depression that target cognitive influences on cytokine responses to stress, as well as pharmacological manipulations of cytokines to address symptoms such as fatigue, anhedonia, and withdrawal.