Higher inflammatory proteins predict future depressive symptom severity among adolescents with lower emotional clarity.

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-α), 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.

Prenatal maternal Inflammation, childhood cognition and adolescent depressive symptoms.

BACKGROUND: Accumulating evidence indicates that higher prenatal maternal inflammation is associated with increased depression risk in adolescent and adult-aged offspring. Prenatal maternal inflammation (PNMI) may increase the likelihood for offspring to have lower cognitive performance, which, in turn, may heighten risk for depression onset. Therefore, this study explored the potential mediating role of childhood cognitive performance in the relationship between PNMI and adolescent depressive symptoms in offspring. METHODS: Participants included 696 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Biomarkers of maternal inflammation [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1RA) and soluble TNF receptor-II (sTNF-RII)] were assayed from first (T1) and second trimester (T2) sera. Childhood (ages 9-11) cognitive performance was assessed via standardized Peabody Picture Vocabulary Test (PPVT), a measure of receptive vocabulary correlated with general intelligence. Adolescent (ages 15-17) depressive symptoms were assessed via self-report. RESULTS: There were no significant associations between T1 biomarkers and childhood PPVT or adolescent depressive symptoms. Higher T2 IL1-RA was directly associated with lower childhood PPVT (b = -0.21, SE = 0.08, t = -2.55, p = 0.01), but not with adolescent depressive symptoms. T2 IL-6 was not directly associated with childhood PPVT, but higher T2 IL-6 was directly associated at borderline significance with greater depressive symptoms in adolescence (b = 0.05, SE = 0.03, t = 1.96, p = 0.05). Lower childhood PPVT predicted significantly higher adolescent depressive symptoms (b = -0.07, SE = 0.02, t = -2.99, p < 0.01). There was a significant indirect effect of T2 IL-1RA on adolescent depressive symptoms via childhood PPVT (b = 0.03, 95 % CI = 0.002-0.03) indicating a partially mediated effect. No significant associations were found with T2 sTNF-RII nor IL-8. CONCLUSIONS: Lower childhood cognitive performance, such as that indicated by a lower PPVT score, represents a potential mechanism through which prenatal maternal inflammation contributes to adolescent depression risk in offspring.

Annual Research Review: Neuroimmune network model of depression: a developmental perspective.

Depression is a serious public health problem, and adolescence is an 'age of risk' for the onset of Major Depressive Disorder. Recently, we and others have proposed neuroimmune network models that highlight bidirectional communication between the brain and the immune system in both mental and physical health, including depression. These models draw on research indicating that the cellular actors (particularly monocytes) and signaling molecules (particularly cytokines) that orchestrate inflammation in the periphery can directly modulate the structure and function of the brain. In the brain, inflammatory activity heightens sensitivity to threats in the cortico-amygdala circuit, lowers sensitivity to rewards in the cortico-striatal circuit, and alters executive control and emotion regulation in the prefrontal cortex. When dysregulated, and particularly under conditions of chronic stress, inflammation can generate feelings of dysphoria, distress, and anhedonia. This is proposed to initiate unhealthy, self-medicating behaviors (e.g. substance use, poor diet) to manage the dysphoria, which further heighten inflammation. Over time, dysregulation in these brain circuits and the inflammatory response may compound each other to form a positive feedback loop, whereby dysregulation in one organ system exacerbates the other. We and others suggest that this neuroimmune dysregulation is a dynamic joint vulnerability for depression, particularly during adolescence. We have three goals for the present paper. First, we extend neuroimmune network models of mental and physical health to generate a developmental framework of risk for the onset of depression during adolescence. Second, we examine how a neuroimmune network perspective can help explain the high rates of comorbidity between depression and other psychiatric disorders across development, and multimorbidity between depression and stress-related medical illnesses. Finally, we consider how identifying neuroimmune pathways to depression can facilitate a 'next generation' of behavioral and biological interventions that target neuroimmune signaling to treat, and ideally prevent, depression in youth and adolescents.

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.

Unconsidered issues of measurement noninvariance in biological psychiatry: A focus on biological phenotypes of psychopathology.

There is increasing appreciation that certain biological processes may not be equally related to all psychiatric symptoms in a given diagnostic category. Research on the biological phenotyping of psychopathology has begun examining the etiological and treatment implications of identified biotypes; however, little attention has been paid to a critical methodological implication of these results: measurement noninvariance. Measurement invariance is the ability of an instrument to measure the same construct, the same way, across different people, or across different time points for the same individual. If what a measure quantifies differs across different people (e.g., those with or without a particular biotype) or time points, then it is invalid to directly compare means on that measure. Using a running example of inflammatory phenotypes of depression, we first describe the biological phenotyping of psychopathology. Second, we discuss three types of measurement invariance. Third, we demonstrate how differential biology-symptom associations invariably creates measurement noninvariance using a theoretical example and simulated data (for which code is provided). We also show how this issue can lead to false conclusions about the broader diagnostic construct. Finally, we provide several suggestions for addressing these important issues to help advance the field of biological psychiatry.

Circadian, Reward, and Emotion Systems in Teens prospective longitudinal study: protocol overview of an integrative reward-circadian rhythm model of first onset of bipolar spectrum disorder in adolescence.

BACKGROUND: Bipolar spectrum disorders (BSDs) are associated with a heightened sensitivity to rewards and elevated reward-related brain function in cortico-striatal circuitry. A separate literature documents social and circadian rhythm disruption in BSDs. Recently, integrated reward-circadian models of BSDs have been proposed. These models draw on work indicating that the two systems influence each other and interact to affect mood functioning. When dysregulated, reward and circadian system signaling may combine to form a positive feedback loop, whereby dysregulation in one system exacerbates dysregulation in the other. Project CREST (Circadian, Reward, and Emotion Systems in Teens) provides a first systematic test of reward-circadian dysregulation as a synergistic and dynamic vulnerability for first onset of BSD and increases in bipolar symptoms during adolescence. METHODS: This NIMH-funded R01 study is a 3-year prospective, longitudinal investigation of approximately 320 community adolescents from the broader Philadelphia area, United States of America. Eligible participants must be 13-16 years old, fluent in English, and without a prior BSD or hypomanic episode. They are being selected along the entire dimension of self-reported reward responsiveness, with oversampling at the high tail of the dimension in order to increase the likelihood of BSD onsets. At Times 1-6, every 6 months, participants will complete assessments of reward-relevant and social rhythm disruption life events and self-report and diagnostic assessments of bipolar symptoms and episodes. Yearly, at Times 1, 3, and 5, participants also will complete self-report measures of circadian chronotype (morningness-eveningness) and social rhythm regularity, a salivary dim light melatonin onset (DLMO) procedure to assess circadian phase, self-report, behavioral, and neural (fMRI) assessments of monetary and social reward responsiveness, and a 7-day ecological momentary assessment (EMA) period. During each EMA period, participants will complete continuous measures of sleep/wake and activity (actigraphy), a daily sleep diary, and three within-day (morning, afternoon, evening) measures of life events coded for reward-relevance and social rhythm disruption, monetary and social reward responsiveness, positive and negative affect, and hypo/manic and depressive symptoms. The fMRI scan will occur on the day before and the DLMO procedure will occur on the first evening of the 7-day EMA period. DISCUSSION: This study is an innovative integration of research on multi-organ systems involved in reward and circadian signaling in understanding first onset of BSD in adolescence. It has the potential to facilitate novel pharmacological, neural, and behavioral interventions to treat, and ideally prevent, bipolar conditions.

Associations Between Pubertal Stage and Depression: A Systematic Review of the Literature.

The current article systematically reviews the literature and provides results from 36 studies testing the relation between pubertal stage and depression, as well as moderators and mediators of this relation. Results indicate that there is a significant relation between advancing pubertal stage and depression among girls, and this effect is strongest among White girls. Among boys, risk for depression does not increase with pubertal stage. Importantly, gonadal development appears to be driving the pubertal stage effect. Increasing hormone concentrations, shared environmental stressors, and body esteem appear to be mechanisms of this relation; increases in nonshared environmental stressors (negative life events, peer victimization) moderate the relation between pubertal stage and depression. Inconsistencies in findings across studies can be explained by methodological differences. Future work on this topic should control for age, examine differences by sex, and utilize within-person analyses to evaluate the effect of pubertal stage on depression over time.

The longitudinal associations of inflammatory biomarkers and depression revisited: systematic review, meta-analysis, and meta-regression.

The innate immune system is dysregulated in depression; however, less is known about the longitudinal associations of depression and inflammatory biomarkers. We investigated the prospective associations of depression and inflammatory biomarkers [interleukin-6 (IL-6), Tumor Necrosis Factor-Alpha (TNF-α), and C-reactive protein (CRP)] in community samples, both unadjusted and adjusted for covariates. The review, registered with PROSPERO, searched for published and unpublished studies via MEDLINE/PsycINFO/PsycARTICLES/EMBASE/Proquest Dissertation. Standardized Fisher transformations of the correlation/beta coefficients, both unadjusted and adjusted for covariates, were extracted from studies examining the prospective associations of depression and inflammatory biomarkers. Systematic review conducted in January, 2019 included 38 studies representing 58,256 participants, with up to 27 studies included in random-effects meta-analysis. Higher CRP/IL-6 were associated with future depressive symptoms, and higher depressive symptoms were associated with higher future CRP/IL-6 in both unadjusted and adjusted analyses - this is the first meta-analysis reporting an adjusted association of IL-6 with future depression. The adjusted prospective associations of depression with CRP/CRP with depression were substantially attenuated and small in magnitude. No significant associations were observed for TNF-α. No conclusive results were observed in studies of clinical depression. Meta-regression indicated that the association of CRP and future depression was larger in older samples and in studies not controlling for possible infection. Small, prospective associations of depression and inflammatory biomarkers are observed in both directions, particularly for IL-6; however, the strength and importance of this relationship is likely obscured by the heterogeneity in depression and profound study/methodological differences. Implications for future studies are discussed.

Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi-disciplinary literature review and agenda for future research from the ISBD task force on chronobiology.

AIM: Symptoms of bipolar disorder (BD) include changes in mood, activity, energy, sleep, and appetite. Since many of these processes are regulated by circadian function, circadian rhythm disturbance has been examined as a biological feature underlying BD. The International Society for Bipolar Disorders Chronobiology Task Force (CTF) was commissioned to review evidence for neurobiological and behavioral mechanisms pertinent to BD. METHOD: Drawing upon expertise in animal models, biomarkers, physiology, and behavior, CTF analyzed the relevant cross-disciplinary literature to precisely frame the discussion around circadian rhythm disruption in BD, highlight key findings, and for the first time integrate findings across levels of analysis to develop an internally consistent, coherent theoretical framework. RESULTS: Evidence from multiple sources implicates the circadian system in mood regulation, with corresponding associations with BD diagnoses and mood-related traits reported across genetic, cellular, physiological, and behavioral domains. However, circadian disruption does not appear to be specific to BD and is present across a variety of high-risk, prodromal, and syndromic psychiatric disorders. Substantial variability and ambiguity among the definitions, concepts and assumptions underlying the research have limited replication and the emergence of consensus findings. CONCLUSIONS: Future research in circadian rhythms and its role in BD is warranted. Well-powered studies that carefully define associations between BD-related and chronobiologically-related constructs, and integrate across levels of analysis will be most illuminating.

The relationship between physical activity states and depressive symptoms: Using ambulatory assessment to characterize day-to-day associations among individuals with and without bipolar spectrum disorder.

INTRODUCTION: The role of activation in the pathogenesis of bipolar spectrum disorders (BSD) is of growing interest. Physical activity is known to improve mood, but it is unclear whether low activity levels contribute to inter-episode depressive symptoms observed in BSD. This study examined whether sedentary and vigorous activity, as well as the timing of the activity, were differentially associated with next-day depressive symptoms for individuals at low risk for BSD, high-risk for BSD, and diagnosed with BSD. METHODS: Young adults (n = 111, ages 18-27) from three groups (low BSD risk, high BSD risk, and BSD diagnosis), participated in a 20-day ecological momentary assessment study. Physical activity was measured via wrist actigraphy counts. The percentage of time awake spent in sedentary, light, moderate, and vigorous activity states was calculated, as was the percentage of morning hours and evening hours in each activity state. Multilevel models examined whether the BSD risk group moderated associations between sedentary and vigorous activity and depressive symptoms, which were assessed three times daily. RESULTS: There were no between-group differences in time spent in each activity state, nor were there main effects of sedentary or vigorous activity on depression. Increased time spent engaging in vigorous activity was associated with a greater reduction in subsequent depressive symptoms for the BSD group. An increase in the evening, but not morning, vigorous activity was significantly associated with a reduction in subsequent depressive symptoms for the BSD group after controlling for chronotype. CONCLUSIONS: Interventions targeting physical activity may effectively help regulate inter-episode mood disturbances in BSD.

Intergenerational Transmission of Rumination via Parenting Behaviors and Family Characteristics: The Impact on Adolescent Internalizing Symptoms.

The relationship between rumination and internalizing psychopathology across the lifespan is robustly documented, yet the development of rumination is not well understood. In a prospective study of adolescents (N = 629, M age = 13.05 years, 51.5% female, 48.3% African American/Black) and their primary female caregivers (90.6% biological mothers), self-report measures of rumination, parental behaviors, family characteristics, and internalizing symptoms were completed. Maternal rumination was not predictive of adolescent rumination, but was associated with less effective parenting and maladaptive family characteristics. Neither parenting behaviors nor family characteristics predicted adolescent rumination. The indirect effects of maternal rumination on adolescent rumination through parenting behaviors and family characteristics were non-significant. The well-established relationship between adolescent rumination and internalizing symptoms was replicated, but there was no evidence of the intergenerational process impacting these symptoms. The findings do not support intergenerational transmission of rumination via parenting behaviors and family characteristics.

Investigating whether depressed youth exhibiting elevated C reactive protein perform worse on measures of executive functioning, verbal fluency and episodic memory in a large, population based sample of Dutch adolescents.

Cognitive functioning is disrupted during a depressive episode and cognitive dysfunction persists when depression is in remission. A subtype of depressed individuals who exhibit elevated inflammatory biomarkers may be at particular risk for cognitive dysfunction. We examined whether an elevated inflammatory biomarker (C-reactive protein: CRP) in acute and/or remitted depression was associated with specific deficits in executive functioning, episodic memory, and verbal fluency. Data were drawn from a population-based sample of Dutch adolescents (N = 1066; 46% male) recruited at the age of 11 and followed over the course of eight years. We tested whether adolescents with either, (i) a history of depression (Wave 1-3) or (ii) current depression (Wave 4), and elevated levels of C-reactive protein measured in blood at Wave 3 performed worse on cognitive assessments at Wave 4. Eight measures of cognitive functioning were hypothesized to load on to one of three dimensions of cognitive functioning (executive functioning, episodic memory, and verbal fluency) within a structural equation model framework. Higher levels of CRP were associated with worse future executive functioning in adolescents with and without current/prior depression. A current depression diagnosis also was associated with worse executive functioning. There was consistent evidence linking low socioeconomic status and health-related covariates (high body mass index/sedentary behavior) with worse performance across multiple measures of cognitive functioning and, importantly, the association of depression/CRP and executive functioning was no longer significant when controlling for these covariates. Future studies may benefit from investigating whether specific depressogenic behaviors (e.g., sedentary behavior/substance use) mediate a relationship between depression and worse executive functioning, potentially via a prospective pathway through elevated inflammation.

Inflammatory phenotype of depression symptom structure: A network perspective.

BACKGROUND: There has been increasing interest in classifying inflammatory phenotypes of depression. Most investigations into inflammatory phenotypes only have tested whether elevated inflammation is associated with elevated levels of depression symptoms, or risk for a diagnosis. This study expanded the definition of phenotype to include the structure of depression symptoms as a function of inflammation. METHODS: Network models of depression symptoms were estimated in a sample of 4157 adults (mean age = 47.6, 51% female) from the 2015-2016 National Health and Nutrition Examination Survey (NHANES). Analyses included comparisons of networks between those with elevated (C-reactive protein (CRP) values ≥ 3.0 mg/L; N = 1696) and non-elevated CRP (N = 2841) as well as moderated network models with CRP group status and raw CRP values moderating the associations between depression symptoms. RESULTS: Differences emerged at all levels of analysis (global, symptom-specific, symptom-symptom associations). Specifically, the elevated CRP group had greater symptom connectivity (stronger total associations between symptoms). Further, difficulty concentrating and psychomotor difficulties had higher expected influence (concordance with other symptoms) in the elevated CRP group. Finally, there was evidence that several symptom-symptom associations were moderated by CRP. CONCLUSIONS: This study provides consistent evidence that the structure of depression symptoms varies as a function of CRP levels. Greater symptom connectivity might contribute to why elevated CRP is associated with treatment-resistant depression. Additionally, differences in symptom structure might highlight different maintenance mechanisms and treatment targets for individuals with compared to those without elevated CRP. Finally, differences in symptom structure as a function of CRP highlight a potential misalignment of standard depression measures (the structure of which are evaluated on groups unselected for CRP levels) and the presentation of depression symptoms in those with elevated CRP.

Investigating whether a combination of higher CRP and depression is differentially associated with worse executive functioning in a cohort of 43,896 adults.

Many depressed individuals experience difficulties in executive functioning that contribute substantially to functional impairment. It is unknown whether a subtype of depression characterized by chronic inflammation is differentially associated with worse executive functioning. This study examined whether the combination of depression and higher C reactive protein (CRP) is differentially associated with worse executive functioning and whether this association is stronger in older adults. This cross-sectional study analyzed data collected from a population-representative sample of 43,896 adults aged 44.13 years (SD = 13.52) who participated in the baseline assessment of the Lifelines cohort study. Multivariate regression models tested whether depressed individuals (established via structured interview) exhibiting higher levels of inflammation (indexed via high-sensitivity CRP assay following an overnight fast) performed worse on a behavioral test of executive functioning. Depression (B = -3.66, 95% CI: -4.82, -2.49, p < .001) and higher log-transformed CRP (B = -0.67, 95% CI: -0.87,-0.47, p < .001) were associated with worse executive functioning, after adjustment for age, sex, educational attainment, body mass index, smoking status, exposure to stressful life events and chronic stressors, sedentary behavior, and number of chronic medical conditions. Depressed individuals with higher log-transformed CRP exhibited differentially poorer executive functioning (B = -1.09, 95% CI: -2.07,-0.11, p < .001). This association did not differ based on age (B = 0.01, 95% CI: -0.08, 0.10, p = .82). Executive functioning is poorer in depressed individuals with higher CRP, even in early adulthood. Interventions that reduce inflammation may improve cognitive functioning in depression.

How handling extreme C-reactive protein (CRP) values and regularization influences CRP and depression criteria associations in network analyses.

Increasingly, it has been recognized that analysis at the symptom, rather than diagnostic, level will drive progress in the field of immunopsychiatry. Network analysis offers a useful tool in this pursuit with the ability to identify associations between immune markers and individual symptoms, independent of all other variables modeled. However, investigation into how methodological decisions (i.e., including vs. excluding participants with C-reactive protein (CRP) >10 mg/L, regularized vs. nonregularized networks) influence results is necessary to establish best practices for the use of network analysis in immunopsychiatry. In a sample of 3,464 adult participants from the 2015-2016 National Health and Nutrition Examination Survey dataset, this study found consistent support for associations between CRP and fatigue and changes in appetite and some support for additional CRP-criterion associations. Methodologically, results consistently demonstrated that including individuals with CRP >10 mg/L and estimating nonregularized networks provided better estimates of these associations. Thus, we recommend considering the use of nonregularized networks in immunopsychiatry and inclusion of cases with CRP values >10 mg/L when testing the association between CRP and depression criteria, unless contraindicated by the research question being tested. Additionally, results most consistently suggest that CRP is uniquely related to fatigue and changes in appetite, supporting their inclusion in an immunometabolic phenotype of depression. Finally, these associations suggest that fatigue and changes in appetite might be particularly receptive to anti-inflammatory treatments. However, future research with more nuanced measures is necessary to parse out whether appetite increases or decreases drive this association. Further, longitudinal research is an important next step to test how these relationships manifest over time.

Goal-striving tendencies moderate the relationship between reward-related brain function and peripheral inflammation.

Inflammation is associated with both lower and higher activity in brain regions that process rewarding stimuli. How can both low and high sensitivity to rewards be associated with higher inflammation? We propose that one potential mechanism underlying these apparently conflicting findings pertains to how people pursue goals in their environment. This prediction is based on evidence that both an inability to disengage from unattainable goals and low interest in and pursuit of important life goals are associated with poor health outcomes, including inflammation. Accordingly, this study examined the relationship between reward-related brain function and peripheral inflammation among individuals with different levels of ambitious goal-striving tendencies. Eighty-three participants completed an ambitious goal-striving tendency measure, an fMRI Monetary Incentive Delay task assessing orbitofrontal cortex (OFC) and nucleus accumbens (NAc) activation during reward anticipation and outcome, and a venous blood draw to assess the inflammatory biomarkers interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and C-reactive protein, from which we computed an inflammation composite score. We observed a reward anticipation by goal-striving interaction on inflammation, such that high OFC and NAc activation to reward anticipation (but not outcome) were associated with more inflammation, among high goal-striving individuals. By contrast, low NAc activation during reward anticipation (but not outcome) was associated with more inflammation, among low goal-striving individuals. The current study provides further evidence that both blunted and elevated reward function can be associated with inflammation. It also highlights the role that goal-striving tendencies may play in moderating the relationship between neural reward anticipation and inflammation.

Family history of depression is associated with alterations in task-dependent connectivity between the cerebellum and ventromedial prefrontal cortex.

BACKGROUND: A family history of major depressive disorder (MDD) increases the likelihood of a future depressive episode, which itself poses a significant risk for disruptions in reward processing and social cognition. However, it is unclear whether a family history of MDD is associated with alterations in the neural circuitry underlying reward processing and social cognition. METHODS: We subdivided 279 participants from the Human Connectome Project into three groups: 71 with a lifetime history of MDD, 103 with a family history (FH) of MDD, and 105 healthy controls (HCs). We then evaluated task-based functional magnetic resonance imaging data on a social cognition and a reward processing task and found a region of the ventromedial prefrontal cortex (vmPFC) that responded to both tasks, independent of the group. To investigate whether the vmPFC shows alterations in functional connectivity between groups, we conducted psychophysiological interaction analyses using the vmPFC as a seed region. RESULTS: We found that FH (relative to HC) was associated with increased sadness scores, and MDD (relative to both FH and HC) was associated with increased sadness and MDD symptoms. Additionally, the FH group had increased vmPFC functional connectivity within the nucleus accumbens, left dorsolateral PFC, and subregions of the cerebellum relative to HC during the social cognition task. CONCLUSIONS: These findings suggest that aberrant neural mechanisms among those with a familial risk of MDD may underlie vulnerability to altered social cognition.

The Role of Comorbid Depression in Youth Anxiety Treatment Outcomes.

Findings have been mixed regarding the relationship between comorbid depression and anxiety and treatment outcomes for anxious youth. The current study compared a sample of anxious youth with a comorbid depressive disorder (n = 20) and those without comorbid depression (n = 137). All participants received 16 weekly sessions of Coping Cat and completed measures assessing anxiety/depression severity, impairment, and functioning at pretreatment and posttreatment. Results indicated that anxiety-focused CBT is efficacious for anxious youth with and without comorbid depressive disorders, with a higher rate of symptom improvement for youth with comorbid depression during treatment. However, comorbid depression was associated with higher severity at baseline and after treatment. Thus, despite the higher rate of symptom improvement, anxious youth with comorbid depression may benefit from additional treatment to address remaining symptoms.

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.

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.