Background: A growing body of work has implicated inflammation in the pathogenesis of depression. As not all individuals with heightened levels of peripheral inflammation develop symptoms of depression, additional work is needed to identify other factors that catalyze the relationship between inflammation and depressive symptoms. Given that elevated levels of inflammatory activity can induce a variety of emotional changes, the present study examined whether emotional clarity, the trait-like ability to identify, discern, and express one's emotions, influences the strength of the association between inflammatory signaling and concurrent and prospective symptoms of depression. Methods: Community adolescents (N = 225, Mage = 16.63 years), drawn from a larger longitudinal project investigating sex and racial differences in depression onset, provided blood samples to determine peripheral levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) at a baseline visit, along with self-report measures of emotional clarity and depressive symptom severity. Depressive symptom severity was assessed again at a follow-up visit approximately 5-months after baseline. Results: Hierarchical multiple regressions detected a significant interaction between inflammatory markers and emotional clarity on future depression severity, controlling for baseline depressive symptoms. Specifically, among adolescents with low levels of emotional clarity, higher levels of IL-6, CRP, and inflammatory composite scores were significantly associated with greater future depression severity. Conclusions: These results indicate that low emotional clarity and high inflammatory signaling may jointly confer risk for prospective depressive symptom severity among adolescents. Therapeutic interventions that improve emotional clarity may reduce risk of depressive symptoms among adolescents with low-grade peripheral inflammation.

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.

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 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, we had 87 young adults with high trait reward (HRew) sensitivity or moderate trait reward (MRew) sensitivity report frequency of life events via the Life Event Interview. Brain activation was assessed during the functional MRI 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 individuals compared with MRew individuals. Trait reward sensitivity and reward-relevant life events may jointly modulate reward-related brain function, which has implications for understanding psychopathology.

Inflammation is complex with many components, often resulting in issues with multiple comparisons when they are analyzed separately. To navigate this, some researchers use composite measures of inflammation. Typically, composites are created without the guidance of factor analysis. The utility of these "a priori" composites and individual proteins has never been compared to empirically derived composites, despite potentially crucial differences.

Much inflammation research examines individual proteins; however, some studies have used summed score composites of all available inflammatory markers without first investigating dimensionality. Using three different samples (MIDUS-2: N = 1,255 adults, MIDUS-R: N =863 adults, and ACE: N = 315 adolescents), this study investigates the dimensionality of eight inflammatory proteins (C-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), fibrinogen, E-selectin, and intercellular adhesion molecule (ICAM)-1) and compares the resulting factor structure to a) an “a priori” factor structure in which all inflammatory proteins equally load onto a single dimension (a technique that has been used previously) and b) proteins modeled individually (i.e., no latent variable) in terms of model fit, replicability, reliability, temporal stability, and their associations with medical history and depression symptoms. A hierarchical factor structure with two first-order factors (Factor 1A: CRP, IL-6, fibrinogen; Factor 2A: TNF-α, IL-8, IL-10, ICAM-1, IL-6) and a second-order general inflammation factor was identified in MIDUS-2 and replicated in MIDUS-R and partially replicated in ACE (which unfortunately only had CRP, IL-6, IL-8, IL-10, and TNF-α but, unlike the other two, has longitudinal data). Both the empirically-identified structure and modeling proteins individually fit the data better compared to the one-dimensional “a priori” structure. Results did not clearly indicate whether the empirically-identified factor structure or the individual proteins modeled without a latent variable had superior model fit. Modeling the empirically-identified factors and individual proteins (without a latent factor) as outcomes of medical diagnoses resulted in comparable conclusions, but modeling empirically-identified factors resulted in fewer results “lost” to correction for multiple comparisons. Importantly, when the factor scores were recreated in a longitudinal dataset, none of the individual proteins, the “a priori” factor, or the empirically-identified general inflammation factor significantly predicted concurrent depression symptoms in multilevel models. However, both empirically-identified first-order factors were significantly associated with depression, in opposite directions. Measurement properties are reported for the different aggregates and individual proteins as appropriate, which can be used in the design and interpretation of future studies. These results indicate that modeling inflammation as a unidimensional construct equally associated with all available proteins does not fit the data well. Instead, empirically-supported aggregates of inflammation, or individual inflammatory markers, should be used in accordance with theory. Further, the aggregation of shared variance achieved by constructing empirically-supported aggregates might increase predictive validity compared to other modeling choices, maximizing statistical power.

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.

Serum levels of the astrocytic protein S100B have been reported to indicate disruption of the blood–brain barrier. In this study, we investigated the relationship between S100B levels and childhood trauma in a child psychiatric inpatient unit.Levels of S100B were measured in a group of youth with mood disorders or psychosis with and without history of childhood trauma as well as in healthy controls. Study participants were 93 inpatient adolescents admitted with a diagnosis of psychosis (N = 67), or mood disorder (N = 26) and 22 healthy adolescents with no history of trauma or psychiatric illness. Childhood trauma was documented using the Life Events Checklist (LEC) and Adverse Child Experiences (ACE).In a multivariate regression model, suicidality scores and trauma were the only two variables which were independently related to serum S100B levels. Patients with greater levels of childhood trauma had significantly higher S100B levels even after controlling for intensity of suicidal ideation. Patients with psychotic diagnoses and mood disorders did not significantly differ in their levels of S100B. Patients exposed to childhood trauma were significantly more likely to have elevated levels of S100B (p < .001) than patients without trauma, and patients with trauma had significantly higher S100B levels (p < .001) when compared to the control group. LEC (p = 0.046), and BPRS-C suicidality scores (p = 0.001) significantly predicted S100B levels.Childhood trauma can potentially affect the integrity of the blood–brain barrier as indicated by associated increased S100B levels.

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.

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.

There has been increasing interest in characterizing an inflammatory phenotype of depression. However, most studies have used cross-sectional data, precluding investigation of directionality, and univariate models, a serious limitation given covariance among both depression subscales and inflammatory proteins.

Inflammation is complex with many components, often resulting in issues with multiple comparisons when they are analyzed separately. To navigate this, some researchers use composite measures of inflammation. Typically, composites are created without the guidance of factor analysis. The utility of these theoretically derived composites and individual proteins has never been compared to empirically-derived composites, despite potentially crucial differences.

There are inconsistent findings in the literature about the directionality and magnitude of the association between inflammation and depressive symptoms. This study separates predictors into between-person and within-person components in an attempt 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 evaluations. Multi-level modeling indicated that the within-person effect of TNF-α predicted future total depressive symptoms, suggesting a potential causal relationship. Additionally, there were bidirectional, between-person effects of IL-6 on total depressive symptoms and vice-versa. Exploratory analyses examined the associations between five biomarkers and five subsets of depressive symptoms. These findings inform modeling decisions that may explain inconsistences in the extant literature as well as suggest potential causal relationships between certain biomarkers with significant within-person effects on depressive symptoms, and vice-versa.

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.

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 (M age = 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.

This research was supported by National Institute of Mental Health Grants MH079369 and MH101168 awarded to Lauren Alloy, National Institute of Mental Health Grant MH096478 awarded to Lauren Ellman and National Research Service Awards F31MH118808 to Naoise Mac Giollabhui.

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.

Both reward sensitivity and cognitive response styles are associated with heightened inflammatory physiology. Consistent with the immunocognitive model of mood disorders, these characteristics might influence inflammatory reactivity synergistically to confer risk for psychopathology. Reward hypersensitive individuals might have greater inflammatory responses to performance-related stressors, which could be amplified by perseverative response styles.