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.

Despite the great public health significance of bipolar disorder (BD), it has been understudied, especially from an integrative biopsychosocial perspective. This project is relevant to NIMH’s mission to understand the causes of BD and targets for prevention. Although current work underscores the strong promise of the Behavioral Approach System (BAS)/reward system hypersensitivity theory of BD, research designs to date are inadequate to determine whether “BAS/reward hypersensitivity” indeed provides vulnerability to BD. Thus, the overarching goal of this project is to use a biobehavioral high-risk design to test whether BAS/reward hypersensitivity, either alone or in combination with BAS/reward-relevant life events, provides vulnerability to 1st onset of BD during a critical “age of risk.”

To this end, a large-scale prospective, longitudinal study of 400 14-19 year old adolescents (including males and females and Caucasian and minority Ps), selected to be at high vs. low risk for BD based on high BAS (n = 200) vs. moderate BAS (n = 200) sensitivity, but with no prior history of BD, is being conducted. At Time 1, we comprehensively assess these Ps’ BAS (and BIS) sensitivity vulnerability profiles (with EEG, behavioral task, cognitive style, and self-report), as well as their impulsivity, social/circadian rhythms, lifetime and family history of psychopathology, and current symptoms/impairment.  Ps’ family history of psychopathology is also assessed.  Ps are followed prospectively every 6 months with assessments of BAS/reward-relevant life events, cognitions, and the development of 1st onsets and recurrences of BD episodes, symptoms, and/or course and progression of their BD.

Results will contribute to the development of assessments that may identify individuals with a bipolar endophenotype who are likely to develop BD before such dysfunction occurs and, thus, who can most benefit from early preventive interventions. Finally, the project will contribute to development of BAS-targeted interventions for treatment and prevention of BD.

Adolescence is a developmental period involving both heightened reward sensitivity and risk for bipolar spectrum disorders (BSDs). Despite their prevalence and public health significance, major unanswered questions exist regarding the mechanisms involved in vulnerability to BSDs.

Recent exciting research provides strong and consistent support for a Behavioral Approach System (BAS)/reward hypersensitivity theory of BSDs that shows great promise for elucidating and integrating the neurobiological, behavioral, and environmental mechanisms underlying risk along the bipolar spectrum. In addition, research on social and circadian rhythm models of BSDs is also very promising, but has proceeded independently of research on reward sensitivity. Yet, our recent work demonstrates influences of reward sensitivity on social rhythm disruption and mood symptoms, leading us to a novel integration of reward sensitivity and social rhythm dysregulation in this application. Thus, the overarching goal of this project is to use an innovative biobehavioral high-risk design in adolescents to examine two interrelated processes that may help explain the association between reward hypersensitivity and BSDs: 1) heightened activation of a “reward-related” neural network involving the ventral striatum and orbitofrontal cortex; and 2) influences of reward sensitivity/activation on social rhythm disruption.

We are continuing to follow High and Moderate BAS/reward sensitive adolescents as they further age into the period of risk for BSDs with self-report and behavioral measures of reward sensitivity/processing, BAS-relevant cognitive styles, social rhythms, BAS-relevant and social rhythm disruption life events, and mood symptoms/diagnoses. We also are conducting a new and novel neuroimaging study. We are comparing High BAS adolescents who have developed BSD (HBAS+BSD), High BAS adolescents who have not yet exhibited, but are at risk for, BSD (HBAS), and Moderate BAS adolescents without BSD (MBAS) on reward-related brain activity and connectivity in response to the anticipation and receipt of monetary rewards in an fMRI study. In addition, we are examining the influence of reward sensitivity/ activation and social rhythm dysregulation on mood symptoms in these same three groups of adolescents.

This research program is the first to examine neural trait markers and social rhythm dysregulation in adolescents at risk for BSDs based on a hypothesized psychobiological vulnerability. It will provide tools for the early identification of adolescents at risk for first onset and a worse course of BSD, inform our understanding of specific etiological pathways and biobehavioral mechanisms involved in illness onset, recurrence, and progression, and contribute to the development of early psychosocial, pharmacological, and neuroprotective strategies targeted at ameliorating reward processing abnormalities.

Despite their prevalence and public health significance, major unanswered questions exist regarding the mechanisms involved in vulnerability to bipolar spectrum disorders (BSDs).

Social and circadian (24-h) rhythm models of BSD risk hypothesize that mood episodes may be a result of circadian rhythm abnormalities caused by life events that disrupt social rhythms (e.g., bedtimes, mealtimes) that normally entrain circadian rhythms. Recent research also provides strong support for a Behavioral Approach System (BAS)/reward hypersensitivity theory of BSDs. Although research on these distinctive theoretical models has proceeded in parallel, our recent work demonstrates influences of reward sensitivity on social rhythm disruption and mood symptoms, leading us to a novel integration of reward sensitivity and social/circadian disruption in this project. Our overarching goal is to use an innovative biobehavioral high-risk design to examine bidirectional influences of reward sensitivity and social and circadian rhythm disruption as risk factors for BSD mood symptoms/ episodes.

We plan to prospectively follow 210 participants (Ps) drawn in part from an existing sample of High and Moderate BAS/reward sensitive Ps at an age of risk for BSDs. We will compare High BAS Ps with a BSD diagnosis, High BAS Ps who have not yet exhibited but are at risk for BSD, and Moderate BAS Ps with no BSD to determine whether reward hypersensitivity influences social and circadian rhythm disruption following the occurrence of reward-relevant events to predict manic and depressive symptoms/episodes. This 3-group design will allow us to test whether reward hypersensitivity and its relationship with social and circadian rhythm disruption are pre-existing vulnerabilities or consequences of BSD, or both. Social rhythm regularity and reward sensitivity will be assessed at baseline. Reward-relevant life events, social rhythm disruption from these events, and mood symptoms/episodes will be assessed prospectively for up to 4 years. Ps will complete a 20-day ecological momentary assessment (EMA) study including 5 day baseline, 10 day high BAS/reward activation, and 5 day reward-outcome periods to assess bidirectional influences between social and circadian rhythm disruption and reward sensitivity and their synergistic effects on BSD symptoms. In the EMA study, Ps will complete daily measures of life events, social rhythms, and sleep diaries, continuous measures of sleep/wake (actigraphy) and circadian rhythms (skin temperature), and repeated within-day measures of mood, symptoms, and reward motivation. Dim light melatonin onset will be assessed three times to determine circadian melatonin phase changes.

This research program will provide valuable insights into the mechanisms underlying vulnerability to BSDs and contribute to the development of targeted intervention and prevention strategies.