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 The review, registered with PROSPERO, searched for published and unpublished studies via MEDLINE/PsycINFO/PsycARTICLES/EMBASE/Proquest Dissertation.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.
There is convergent evidence that the immune system is dysregulated in some depressed individuals. A psychoneuroimmunology-based understanding of depression is advancing rapidly; however, a question ...of fundamental importance is poorly understood: does inflammation play a causal role in the etiology of depression or are elevated inflammatory biomarkers a downstream effect of depressive behaviors? Although longitudinal studies suggest that the relationship between depression and inflammation is characterized by complex bidirectional associations, existing prospective, longitudinal research designs are poorly equipped to investigate the dynamic interplay of depression and inflammation that unfolds over a relatively short time period. In addition, the precise role played by multiple, shared, and overlapping risk factors (e.g., diet, adiposity, stress, sleep dysregulation) in the etiology of depression and a pro-inflammatory phenotype (or both) is poorly understood. In this manuscript, I highlight the benefits of research designs that (i) manipulate constructs of interest (depression/inflammation) using intervention or treatment designs and (ii) use intensive sampling approaches with an ultimate goal of better understanding the temporal sequence and causal relationships of depression, inflammation, cognitive dysfunction, and their shared risk factors. For instance, are improved depressive symptoms a downstream effect of changes in inflammatory activity caused by increases in exercise or, alternatively, are changes in inflammatory activity and depression sequelae of improvements in sleep quality caused by increases in exercise? Potential benefits of these research designs are discussed in terms of their contribution to a better understanding of the etiology of depression and a pro-inflammatory phenotype, their relevance to structural health inequalities, and better characterizing the heterogeneous clinical presentation of depression, particularly relating to the etiology of cognitive dysfunction in depression.
•Evidence that inflammation plays a causal role in the etiology of depression (as well as the reverse) is reviewed.•The causal relationship between depression and inflammation is unclear due to multiple, shared, and overlapping risk factors.•Approaches to investigate the causal relationships of depression, inflammation, and cognitive dysfunction are discussed.
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.
Alcohol, tobacco and cannabis use in adolescence is associated with adverse outcomes. Characterizing adolescent substance misusers, however, is difficult due to the wide range of risk and protective ...factors linked to substance use. The aim of the present study was to examine the role of the Individual, Family, School, Peer, and Social Environment on alcohol (lifetime and risky), tobacco (risky only), and cannabis use (lifetime and riskiness).
Data were analyzed from a national sample of 5,680 adolescents, capturing substance use behavior alongside risk and protective factors across Individual, Family, School, Peer and Social domains. We applied a sophisticated machine learning classifier to develop models of alcohol, tobacco and cannabis initiation and misuse.
We found highly accurate (area under curve of receiver-operator-characteristic for out-of-sample performance was > .88) and replicable (over multiple iterations and in comparison with permuted outcomes) dissociable psychosocial profiles of alcohol, tobacco and cannabis use. Alongside common predictors (peer relations and externalizing behavior), dissociable risk and resilience factors were observed. Adolescent profiles of alcohol use were distinguished by the contribution of multiple domains. In contrast, tobacco use was characterized by a small number of individual variables, including female gender and poor perceived academic position. Cannabis use was differentiated by the distinct contribution of Individual risk factors, in particular male gender and feelings of anger. Differential associations were also evident, with the strength and direction of association differing substantially across substances.
This study indicates that the relationship between the environment and substance use is more complex than previously thought.
•Higher frequency of stressful life events predicts increased depression severity.•Change in inflammatory markers investigated as moderators of stress and depression.•Increases in IL-6 and CRP after ...these stressors enhance this relationship.•Adolescents with stressors and high inflammatory activity had increased depression.•Conditional effects of gender, race, and SES were examined in diverse sample of 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.
Prenatal maternal inflammation has been associated with major depressive disorder in offspring in adulthood as well as with internalizing and externalizing symptoms in childhood; however, the ...association between prenatal inflammation and offspring depression in adolescence has yet to be examined.
To determine whether maternal levels of inflammatory biomarkers during pregnancy are associated with depressive symptomatology in adolescent-aged offspring and to examine how gestational timing, offspring sex, and childhood psychiatric symptoms impact these associations.
This was an observational study of a population-based birth cohort from the Child Health and Development Studies (CHDS), which recruited almost all mothers receiving obstetric care from the Kaiser Foundation Health Plan (KFHP) in Alameda County, California, between June 1959 and September 1966. Pregnancy data and blood sera were collected from mothers, and offspring psychiatric symptom data were collected in childhood (ages 9-11 years) and adolescence (ages 15-17 years). Mother-offspring dyads with available maternal prenatal inflammatory biomarkers during first and/or second trimesters and offspring depressive symptom data at adolescent follow-up were included. Data analyses took place between March 2020 and June 2023.
Levels of inflammatory biomarkers (interleukin 6 IL-6, IL-8, IL-1 receptor antagonist IL-1RA, and soluble tumor necrosis factor receptor-II) assayed from maternal sera in the first and second trimesters of pregnancy.
Self-reported depressive symptoms at adolescent follow-up.
A total of 674 mothers (mean SD age, 28.1 5.9 years) and their offspring (350 male and 325 female) were included in this study. Higher second trimester IL-6 was significantly associated with greater depressive symptoms in offspring during adolescence (b, 0.57; SE, 0.26); P = .03). Moderated mediation analyses showed that childhood externalizing symptoms significantly mediated the association between first trimester IL-6 and adolescent depressive symptoms in male offspring (b, 0.18; 95% CI, 0.02-0.47), while childhood internalizing symptoms mediated the association between second trimester IL-1RA and adolescent depressive symptoms in female offspring (b, 0.80; 95% CI, 0.19-1.75).
In this study, prenatal maternal inflammation was associated with depressive symptoms in adolescent-aged offspring. The findings of the study suggest that pathways to adolescent depressive symptomatology from prenatal risk factors may differ based on both the timing of exposure to prenatal inflammation and offspring sex.
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.
•This study examines an immune mechanism that contributes to the antidepressant effects of whole-body hyperthermia.•Whole-body hyperthermia led to an acute, time-limited increase in the ratio of ...interleukin-6 (IL-6):soluble IL-6 receptor.•Increased ratio of IL-6:soluble IL-6 receptor was associated with the anti-depressant effect of whole-body hyperthermia.
There is urgent need for novel antidepressant treatments that confer therapeutic benefits via engagement with identified mechanistic targets. The objective of the study was to determine whether activation of the classical anti-inflammatory interleukin-6 signaling pathways is associated with the antidepressant effects of whole-body hyperthermia. A 6-week, randomized, double-blind study compared whole-body hyperthermia with a sham condition in a university-based medical center. Medically healthy participants aged 18–65 years who met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score ≥ 16 were randomized with 1-to-1 allocation in blocks of 6 to receive whole-body hyperthermia or sham. Of 338 individuals screened, 34 were randomized, 30 received interventions and 26 had ≥ 2 blood draws and depressive symptom assessments. Secondary data analysis examined change in the ratio of IL-6:soluble IL-6 receptor pre-intervention, post-intervention, and at weeks 1 and 4. Hierarchical linear modeling tested whether increased IL-6:soluble IL-6 receptor ratio post-intervention was associated with decreased depressive symptom at weeks 1, 2, 4 and 6 for those randomized to whole-body hyperthermia. Twenty-six individuals were randomized to whole-body hyperthermia n = 12; 75 % female; age = 37.9 years (SD = 15.3) or sham n = 14; 57.1 % female; age = 41.1 years (SD = 12.5). When compared to the sham condition, active whole-body hyperthermia only increased the IL-6:soluble IL-6 receptor ratio post-treatment F(3,72) = 11.73,p < .001, but not pre-intervention or at weeks 1 and 4. Using hierarchical linear modeling, increased IL-6:sIL-6R ratio following whole-body hyperthermia moderated depressive symptoms at weeks 1, 2, 4 and 6, such that increases in the IL-6:soluble IL-6 receptor ratio were associated with decreased depressive symptoms at weeks 1, 2, 4 and 6 for those receiving the active whole-body hyperthermia compared to sham treatment (B = –229.44, t = -3.82,p < .001). Acute activation of classical intereukin-6 signaling might emerge as a heretofore unrecognized novel mechanism that could be harnessed to expand the antidepressant armamentarium.
•Sustained attention predicts depression via rumination conditional on inferential style.•Adolescents with strong sustained attention and negative styles are at risk.•Stronger sustained attention may ...reflect advanced development relative to peers.
Negative inferential style, rumination and attention are cognitive vulnerabilities implicated in depression that first emerge in childhood and adolescence.
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.
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.
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.
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.
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