Concurrent and prospective associations of inflammatory signaling, specific depressive symptoms, and substance use in adolescence.

Substance use and depression frequently co-occur. Adolescence appears to be a vulnerable developmental period for increases in both substance use and depressive symptoms, often attributed to rapid maturation of reward and motivation systems. Another contributing factor could be inflammatory signaling, which has been associated with both substance use disorder and depression. Prior research indicates that an increase in inflammatory activity can cause physical and emotional malaise, which resembles depression, and the anhedonia and somatic symptoms could lead to substance use. This perspective that substance use is a type of self-medication in response to anhedonia and subjective experiencing of increased inflammatory physiology has not been investigated previously. To test these associations, we used path analysis to examine concurrent and prospective associations between three pro-inflammatory markers, specific depressive symptoms, and substance use frequency in a diverse sample of older adolescents. Participants completed repeated self-report measures of specific depressive symptoms (i.e., dysphoria, anhedonia, somatic concerns, negative cognitions, and functional difficulties) and substance use frequency. Blood was collected to quantify circulating levels of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). This analysis showed an indirect effect of IL-6 and TNF-α levels on future substance use, but only via functional difficulties. Substance use also predicted future functional difficulties. Only anhedonia directly predicted future substance use frequency. These findings help to more precisely identify pathways through which inflammatory physiology and specific depressive symptoms synergistically confer risk for substance use.

The Impact of Early and Recent Life Stress on Trajectories of Inflammatory Biomarkers in a Diverse Sample of Adolescents.

Elevated inflammatory activity is one possible pathway through which exposure to childhood adversity engenders risk for physical and psychiatric illnesses. Limited research has investigated the compounding effects of childhood and adolescent stress exposure on changes in circulating levels of inflammatory biomarkers. This study assessed whether childhood adversity interacted with chronic or acute stress during adolescence to affect the temporal trajectories of five inflammatory biomarkers across at least three blood draws in a diverse sample of adolescents (N = 134; observations = 462). Using multilevel modeling, the interaction of childhood adversity, time, and within-person variance of acute stressors significantly predicted trajectories of higher interleukin-10 levels, controlling for demographics, medication use, and body mass index. Adolescents with high levels of childhood adversity who were exposed to a higher frequency of acute stressors compared to their own average rate of stress exposure consistently had higher levels of IL-10 as they got older, but those with average and below frequency of acute stressors had decreasing trajectories of log IL-10 as they matured. The results demonstrate how events early in life shape biological responses to the adolescent environment. This study also highlights the importance of developmental timing on the body's enhanced reactivity to acute and sustained stressors following childhood adversity.

The Interplay between Reward-Relevant Life Events and Trait Reward Sensitivity in Neural Responses to Reward Cues.

The reward hypersensitivity model posits that trait reward hypersensitivity should elicit hyper/hypo approach motivation following exposure to recent life events that activate (goal-striving and goal-attainment) or deactivate (goal-failure) the reward system, respectively. To test these hypotheses, eighty-seven young adults with high (HRew) versus moderate (MRew) trait reward sensitivity reported frequency of life events via the Life Event Interview. Brain activation was assessed during the fMRI Monetary Incentive Delay task. Greater exposure to goal-striving events was associated with higher nucleus accumbens (NAc) reward anticipation among HRew participants and lower orbitofrontal cortex (OFC) reward anticipation among MRew participants. Greater exposure to goal-failure events was associated with higher NAc and OFC reward anticipation only among HRew participants. This study demonstrated different neural reward anticipation (but not outcome) following reward-relevant events for HRew versus MRew individuals. Trait reward sensitivity and reward-relevant life events may jointly modulate reward-related brain function, with implications for understanding psychopathology.

Residence in High-Crime Neighborhoods Moderates the Association Between Interleukin 6 and Social and Nonsocial Reward Brain Responses.

BACKGROUND: Residence in high-crime neighborhoods, especially in childhood, is linked to mental health issues later. Detecting distinct neurobiological processes underlying the effects of this environmental stressor may be critical to identifying prevention and intervention targets. This study examined the relationships of levels of a circulating inflammatory protein with social and monetary reward-related brain function among adolescents who lived in high- versus low-crime neighborhoods during childhood. METHODS: A total of 70 participants (mean age = 16.3 years; 57% female) completed measures of inflammatory markers, depression history, and health and 2 functional magnetic resonance imaging tasks assessing responsivity to monetary and social rewards. Multivariate linear regression tested whether individuals with higher interleukin 6, an inflammatory cytokine, who also lived in neighborhoods with higher crime had distinct orbitofrontal cortex and nucleus accumbens activation to monetary reward and social acceptance. RESULTS: For adolescents who lived in neighborhoods with more crime, higher interleukin 6 was associated with higher nucleus accumbens responses to social acceptance. We did not detect significant moderating effects of neighborhood crime rates on the associations of interleukin 6 with orbitofrontal cortex responses to social acceptance or orbitofrontal cortex/nucleus accumbens activation during monetary reward anticipation or outcome. These results were obtained before and after adjusting for neighborhood income and other covariates. We did not detect significant moderating effects of neighborhood income. CONCLUSIONS: High-threat residence environment and specific demands of the social context in childhood may have shaped the effect of peripheral immune activation on reward-related neural function in adolescence. The prevailing view that inflammation-associated behaviors are characterized by blunted responsiveness to reward may be oversimplistic.

Attention, rumination and depression in youth with negative inferential styles: A prospective study.

BACKGROUND: Negative inferential style, rumination and attention are cognitive vulnerabilities implicated in depression that first emerge in childhood and adolescence. METHODS: The current study used a prospective longitudinal design to examine whether rumination mediates the relationship between attention (selective attention, sustained attention, attentional switching, and divided attention) and depression (depressive symptoms and depressive episode onset) conditional on negative inferential style. A diverse community sample of adolescents (n = 364) completed semi-structured diagnostic interviews, behavioral measures of attention, and self-report measures of rumination, negative inferential style, and depression annually for three consecutive years. RESULTS: Rumination mediated the relationship between strong sustained attention and both depressive symptoms and disorder onset conditional on negative inferential style. Specifically, adolescents high in negative inferential style with strong sustained attention were more likely to experience increased subsequent rumination that, in turn, led to increased depressive symptoms and episode onset. In contrast to study hypotheses, there were no significant effects for models that included selective attention, attentional switching, or divided attention. LIMITATIONS: Significant effects were relatively small, and therefore, should be interpreted with caution and require replication. We were unable to control for intelligence, and as a result, stronger sustained attention may be indicative of higher intelligence. CONCLUSIONS: Stronger sustained attention in early adolescence compared to peers may facilitate rumination on negative self-evaluation and subsequent depression. Use of non-emotion-relevant stimuli to assess attention may account for the lack of findings for selective attention, attentional switching, or divided attention. Implications and directions for future research are discussed.

Negative Inferential Style Mediates the Association between Racial Identity and Depressive Symptoms among African American Adolescents.

Negative inferential style is a cognitive vulnerability for depression. Yet, few studies have explored how this risk factor intersects with culturally-specific protective factors, such as racial identity, in a unified cognitive risk-cultural asset model in youth of color. The current study addressed this gap by exploring the interplay between negative inferential style, racial identity, and depressive symptoms in an urban African-American adolescent community sample (N = 233; 51.9% female). Cross-lagged panel analyses estimated concurrent and prospective relationships between study variables. Racial identity dimensions of regard, but not centrality, were significant predictors of inferential style, and buffered against the development of depressive symptoms via the development of a less negative inferential style. Implications for the study of racial identity and cognition, and treatment of African-American adolescents are discussed.

Concurrent and Longitudinal Associations of Sex and Race with Inflammatory Biomarkers during Adolescence.

Chronic, systemic inflammation is implicated in physical and mental health; little is known about whether sex and racial differences detected in adulthood are observed during adolescence or about normative changes occurring during adolescence. This longitudinal, United States-based study examined four biomarkers of systemic inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and IL-8) in 315 adolescents (51% female; 58% black; baseline age = 16.49 years (SD = 1.56; range: 12.14-21.28)] at three timepoints. Notable results included: general decline in inflammatory biomarkers in older adolescents, lower levels of TNF-α/IL-8 in black adolescents, elevated CRP/IL-6 in females, and especially higher levels of IL-6 in black, female adolescents. Implications are discussed, particularly the potential health implications of elevated IL-6 in black females.

Linking Maternal Depression to Adolescent Internalizing Symptoms: Transmission of Cognitive Vulnerabilities.

The mechanisms of the well-documented relationship between maternal depression and offspring psychopathology are not yet fully understood. Building upon cognitive theories of depression and the modeling hypothesis, path analyses tested whether maternal depression history predicted adolescent internalizing symptoms via the transmission of cognitive vulnerabilities within a sample of 635 adolescents (Mage = 13.1 years, range = 11.2-17.2 years; 53% female; 48% African American/Black) and their primary female caregivers. Maternal depression history did not directly predict adolescent symptoms. Two significant indirect effects were found; maternal depression history was associated with maternal negative cognitive style, which predicted greater adolescent negative generalization, which, in turn, predicted adolescents' greater depressive and anxiety symptoms. These findings suggest that the transmission of cognitive vulnerabilities may link maternal depression and offspring internalizing psychopathology.

Pubertal Synchrony and Depressive Symptoms: Differences by Race and Sex.

Individual differences in the timing and tempo of pubertal development have been shown to be related to depressive symptoms during adolescence, particularly among girls. Another measure of variability in pubertal development is pubertal synchrony, the degree to which the development of pubertal indicators (e.g., breast growth and ancillary hair growth) are synchronized within the individual. Pubertal synchrony also has been hypothesized to be related to depressive symptoms, but, to date, only one study has tested this hypothesis. However, it remains unclear whether pubertal synchrony confers risk for depressive symptoms more proximally in time or differentially among boys or non-White youth. The current study examined the relation between pubertal synchrony and depressive symptoms concurrently and six months later as a function of race and sex in a community sample of 215 youth (53% female, 44.7% African American; mean age = 12.90 years (SD = 0.86)). Girls with asynchronous development at Time 1 reported significantly higher depressive symptoms at Time 2 than girls with synchronous development and boys with asynchronous development. In addition, boys with asynchronous development at Time 1 had lower depressive symptoms at Time 2 than boys with synchronous development. Race did not moderate pubertal synchrony-depression relations. These results suggest that pubertal asynchrony is a risk factor for girls, but a protective factor for boys, and lend support for pubertal synchrony as a potential contributor to the gender gap in depression that emerges during adolescence.

Bidirectional Associations Between Inflammatory Biomarkers and Depressive Symptoms in Adolescents: Potential Causal Relationships.

There are inconsistent findings in the literature about the directionality and magnitude of the association between inflammation and depressive symptoms. This analysis separates predictors into between-person and within-person components to gain greater clarity about this relationship. Blood samples were collected and depressive symptoms assessed in 140 adolescents (54% female, 59% Black, Mage = 16.1 years) with at least three blood draws and a total of 394 follow-up observations. Multi-level modeling indicated that the within-person effect of tumor necrosis factor alpha (TNF-α) predicted change in total depressive symptoms, suggesting a potential causal relationship. There were no significant within-person effects of total depressive symptoms on change in biomarkers. Exploratory analyses examined associations between inflammatory biomarkers and subsets of depressive symptoms. These findings inform modeling decisions that may explain inconsistencies in the extant literature as well as suggest potential causal relationships between certain proteins with significant within-person effects on depressive symptoms, and vice-versa.

Reward Sensitivity, Cognitive Response Style, and Inflammatory Response to an Acute Stressor in Adolescents.

Inflammation is gaining support as a biological mediator between stress and many negative outcomes that have heightened risk during adolescence (e.g., mood disorders). Thus, an important line of inquiry is evaluating whether risk factors for mood psychopathology also are associated with heightened inflammatory responses to stress during this developmental period. Two prominent risk factors that interact to predict mood psychopathology are reward sensitivity and perseverative cognitive response styles, which also have been associated with heightened inflammatory proteins. These factors could influence inflammation by synergistically amplifying stress reactivity. Ninety-nine late adolescents (Mage = 18.3 years, range = 15.6-21.9 years) completed measures of reward sensitivity, cognitive response style, and blood draws before and 60-min after a modified Trier Social Stress Task to determine levels of inflammation. Higher reward drive interacted with more perseverative response style ratios (rumination relative to distraction + problem-solving) to predict larger increases in interleukin-6 (a proinflammatory protein). Follow-up analyses found that reward drive interacted with all three components of the ratio to predict change in interleukin-6. Thus, these results suggest that high reward drive and perseverative cognitive response styles are associated with increased inflammatory response to social stress in adolescents, a potential physiological mechanism linking these risk factors to mood psychopathology during this developmental period.

Early Pubertal Timing Mediates the Association between Low Socioeconomic Status and Poor Attention and Executive Functioning in a Diverse Community Sample of Adolescents.

Low socioeconomic status (SES) may be associated with earlier pubertal timing and impaired attention and executive function (EF) in youth; however, whether pubertal timing mediates the relation between SES and attention or executive functioning remains unclear. Structural equation models tested concurrent and prospective relations between SES, pubertal timing, and attention and executive functioning measures in a gender and racially diverse sample of adolescents (N = 281, 45.6% male, 50.5% White/Caucasian, 46.3% Black/African American, 3.2% Biracial/other, and 44.5% low SES; complete data were not available on some measures). Youth from low SES families experienced earlier pubertal timing, and this accelerated development was associated with worse performance on attention and executive functioning tasks, both concurrently and longitudinally. These findings highlight a pathway by which youth from low socioeconomic backgrounds may develop worse attention and executive functioning abilities during adolescence.

Executive dysfunction in depression in adolescence: the role of inflammation and higher body mass.

BACKGROUND: There is substantial evidence that many depressed individuals experience impaired executive functioning. Understanding the causes of executive dysfunction in depression is clinically important because cognitive impairment is a substantial contributor to functional impairment. This study investigated whether elevated levels of an inflammatory cytokine [interleukin-6 (IL-6)] and/or higher body mass index (BMI) concurrently and/or prospectively accounted for the relationship between depressive symptoms and impaired executive functioning in adolescents. METHODS: A diverse, community sample of adolescents (N = 288; mean age = 16.33; 51.4% female; 59.0% African-American) completed assessments of height and weight, IL-6, depressive symptoms, and self-report/behavioral measures of executive functioning (selective attention, switching attention) and future orientation annually over 3 years. Adolescents experiencing acute illness or medical conditions that affect inflammation were excluded from analyses. Path analysis within a structural equation modeling framework simultaneously examined the concurrent and prospective relationships between BMI, IL-6, depressive symptoms, and the measures of cognitive functioning across three timepoints. RESULTS: Across all timepoints, higher BMI was prospectively associated with higher levels of IL-6 and depressive symptoms, while higher levels of IL-6 were associated with worse performance on three behavioral and self-report measures of cognitive functioning. Higher depressive symptoms also were prospectively associated with elevated IL-6 and both higher depressive symptoms and a higher BMI predicted worse future executive functioning via increased IL-6. CONCLUSIONS: More severe depressive symptoms and increased BMI may disrupt executive functioning via elevated IL-6.

Longitudinal changes of inflammatory biomarkers moderate the relationship between recent stressful life events and prospective symptoms of depression in a diverse sample of urban adolescents.

This study investigated whether longitudinal changes in inflammatory physiology moderated the relationship between recent stressful life events and subsequent depressive symptoms in adolescence. A diverse sample of adolescents representative of an urban community (N = 129; Age at baseline = 12.5 years; 48.8% female; 55.0% African American) completed measures of stressful life events, depressive symptoms, and two annual blood draws (BD1 and BD2). Controlling for inflammatory activity at BD1, depression at BD1, demographics and the time between assessments, increases in interleukin-6 (IL-6; b = 0.878, p = .007) and C-reactive protein (CRP; b = 0.252, p = .024) from BD1 to BD2 interacted with recent stressful life events before BD1 to predict severity of depressive symptoms at BD2. Similar associations were evident for IL-6 (b = 2.074, p = .040) and CRP (b = 0.919, p = .050) when considering acute stressful life events that had occurred within the two weeks before the first blood collection. More frequent stressful life events before BD1 predicted significantly more severe depressive symptoms at BD2, but only for adolescents with moderate (50th percentile) and high (84th percentile) levels of IL-6 and CRP at BD2. In conclusion, adolescents who experienced both recent stressful life events and larger increases in inflammatory activity following these stressors were at increased risk for more severe depressive symptoms after approximately one year. The findings indicate that the interaction of stress and larger changes in inflammatory activity following these stressors are prognostic risk factors for depression severity in adolescents.

Pubertal Status and Age are Differentially Associated with Inflammatory Biomarkers in Female and Male Adolescents.

A better understanding of the maturational correlates of inflammatory activity during adolescence is needed to more appropriately study both normal and abnormal development. Inflammation is the immune system's first response to infection, injury, or psychological stress, and it has been shown to be elevated in individuals with both physical and psychological conditions. This study examined unique associations between (1) pubertal status and inflammatory biomarkers, and (2) age and inflammatory biomarkers, and whether these relationships differed by sex in a diverse sample of 155 adolescents (54.2% female, 45.8% male; Mage = 16.22) from a northeastern city in the US. A more advanced pubertal status was uniquely associated with lower levels of tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8). Chronological age was uniquely associated with lower IL-8 levels. The association between pubertal status and C-reactive protein (CRP) levels differed by sex: more mature females had higher CRP, whereas pubertal status and CRP were not significantly associated in males. These findings highlight an important relation between pubertal development and inflammatory activity during adolescence.

The Combination of Living in High Crime Neighborhoods and High Rumination Predicts Depressive Symptoms among Adolescents.

Living in high crime areas and rumination each have been identified as risk factors for depression among youth, yet it is unclear how crime and rumination may synergistically increase the risk of adolescent depression. Adolescents (N = 309; 51% female, Mage= 12.9, SD = 0.61) completed self-report measures of rumination, depressive symptoms, and provided local addresses, which were used to match police district crime statistics. Approximately one year later, participants again reported depressive symptoms. Moderation analyses indicated that the tendency to ruminate exacerbated the relationship between violent crime rates, but not non-violent crime, and higher prospective levels of depressive symptoms among adolescents. These findings suggest that individual-level interventions that promote more adaptive emotion response styles may lower the risk of depression among adolescents residing in high crime areas.

Unique and predictive relationships between components of cognitive vulnerability and symptoms of depression.

BACKGROUND: Cognitive vulnerability theories of depression outline multiple, distinct inferential biases constitutive of cognitive vulnerability to depression. These include attributing negative events to internal, stable, and global factors, assuming that negative events will lead to further negative consequences, and inferring that negative events reflect negative characteristics about the self. Extant research has insufficiently examined these biases as distinct, limiting our understanding of how the individual cognitive vulnerability components interrelate and confer risk for depression symptoms. Thus, we conducted exploratory network analyses to examine the relationships among the five components of negative cognitive style and explore how components may differentially relate to depressive symptoms in adolescents. METHODS: Participants completed measures of negative cognitive style twice over a two-year period. We estimated Graphical Gaussian Models using contemporaneous data and computed a cross-lagged panel network using temporal data from baseline and 2-year follow-up. RESULTS: Results reveal interesting structural dynamics among facets of negative cognitive style and depressive symptoms. For example, results point to biases towards stable and future-oriented inferences as highly influential among negative cognitive style components. The temporal model revealed the internal attributions component to be heavily influenced by depressive symptoms among adolescents, whereas stable and global attributions most influenced future symptoms. CONCLUSIONS: This study presents novel approaches for investigating cognitive style and depression. From this perspective, perhaps more precise predictions can be made about how cognitive risk factors will lead to the development or worsening of psychopathology.

Inflammatory Proteins Predict Change in Depressive Symptoms in Male and Female Adolescents.

Inflammation has been implicated in depressive symptoms, but few studies use longitudinal designs with adolescents. Furthermore, the extant literature has yielded inconsistent results. Blood was collected from a community sample of 201 adolescents (109 female, ages 12.3-20.0) and analyzed for inflammatory proteins. Up to five follow-up assessments of depressive symptoms were conducted. Multi-level modeling indicated that high C-reactive protein (CRP) (but no other proinflammatory markers) predicted depressive symptom increases. Three-way interactions between different inflammatory biomarkers, sex, and months-to-follow-up predicted change in depressive symptoms. Higher interleukin-6 predicted increased depressive symptoms at 13-31 months after baseline assessment of depression and inflammation for females. Higher tumor necrosis factor-alpha predicted increased depressive symptoms at < 1 month after baseline for males and 13-31 months after baseline for females. Higher interleukin-8 in males predicted lower depressive symptoms at 31 months after baseline. Exploratory post-hoc analyses examined these predictive associations for specific subsets of depressive symptoms. These findings are the first to support the predictive association of elevated CRP for depressive symptoms in a community adolescent sample and serve as preliminary evidence that the relationship between cytokines and later depressive symptoms differs by sex, time-to-follow-up, and the specific biomarker.

A Latent Structure Analysis of Cognitive Vulnerability to Depression in Adolescence.

Whether cognitive vulnerability to depression exists along a continuum of severity or as a qualitatively discrete phenomenological entity has direct bearing on theoretical formulations of risk for depression and clinical risk assessment. This question is of particular relevance to adolescence, given that cognitive vulnerability appears to coalesce and rates of depression begin to rise markedly during this period of development. Although a dimensional view is often assumed, it is necessary to submit this assumption to direct empirical evaluation. Taxometric analysis is a family of statistical techniques developed directly to test such assumptions. The present study applied taxometric methods to address this question in a community sample of early adolescents (n = 485), drawing on three indices of cognitive vulnerability to depression (i.e., negative inferential style, ruminative response style, self-referent information processing). The results of three taxometric analyses (i.e., mean above minus below a cut [MAMBAC], maximum eigenvalue [MAXEIG], and latent mode [L-Mode]) were consistent in unambiguously supporting a dimensional conceptualization of this construct. The latent structure of the tested indices of cognitive vulnerability to depression in adolescence appears to exist along a continuum of severity rather than as a discrete clinical entity.