Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study.

Background: Low-grade systemic inflammation is implicated in the pathogenesis of various neuropsychiatric conditions affecting mood and cognition. While much of the evidence concerns depression, large-scale population studies of anxiety, affect, and cognitive function are scarce. Importantly, causality remains unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognitive performance in the Lifelines Cohort; and whether associations are likely to be causal. Methods: Using data from up to 55,098 (59% female) individuals from the Dutch Lifelines cohort, we tested the cross-sectional and longitudinal associations of C-reactive protein (CRP) with (i) depressive and anxiety disorders; (ii) positive and negative affect scores, and (iii) five cognitive measures assessing attention, psychomotor speed, episodic memory, and executive functioning (figural fluency and working memory). Additionally, we examined the association between inflammatory marker GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (Nmax=57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (Nmax=23,268). In genetic analyses, all GRSs and outcomes were z-transformed. Results: In non-genetic analyses, higher CRP was associated with diagnosis of any depressive disorder, lower positive and higher negative affect scores, and worse performance on tests of figural fluency, attention, and psychomotor speed after adjusting for potential confounders, although the magnitude of these associations was small. In genetic analyses, CRPGRS was associated with any anxiety disorder (ß=0.002, p=0.037, N=57,047) whereas GlycAGRS was associated with major depressive disorder (ß=0.001, p=0.036; N=57,047). Both CRPGRS (ß=0.006, p=0.035, N=57,946) and GlycAGRS (ß=0.006, p=0.049; N=57,946) were associated with higher negative affect score. Inflammatory marker GRSs were not associated with cognitive performance, except sIL-6RGRS which was associated with poorer memory performance (ß=-0.009, p=0.018, N=36,783). Further examination of the CRP-anxiety association using MR provided some weak evidence of causality (ß=0.12; p=0.054). Conclusions: Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. Genetic analyses suggest that IL-6 signaling could be relevant for memory, and that the association between CRP and anxiety disorders could be causal. These results suggest that dysregulated immune physiology may impact a broad range of trans-diagnostic affective symptoms. However, given the small effect sizes and multiple tests conducted, future studies are required to investigate whether effects are moderated by sub-groups and whether these findings replicate in other cohorts.

A Randomized Controlled Trial of Community-Delivered Heated Hatha Yoga for Moderate-to-Severe Depression.

Objective: To evaluate feasibility, acceptability, and preliminary efficacy of heated yoga to treat moderate-to-severe depression.Design: An 8-week randomized controlled trial (RCT) of heated yoga versus waitlist control was conducted from March 2017 to August 2019.Methods: Participants in the yoga condition were asked to attend heated yoga classes at 2 community heated yoga studios at least twice weekly. We assessed acceptability and feasibility using exit interview and attendance data, respectively. The primary intervention efficacy outcome variable was change in the Inventory of Depressive Symptomatology-Clinician Rated (IDS-CR) score from baseline to post-intervention (week 8).Results: We randomized 80 participants and included 65 (mean [± SD] age 32.7 [± 11.7] years; 81.5% female) in the analyses (yoga n = 33, waitlist n = 32). The mean IDS-CR score at baseline was 35.6 (± 7.9) for the full sample, 36.9 (± 8.8) for yoga participants, and 34.4 (± 6.7) for waitlist participants. Participants attended an average of 10.3 (± 7.1) total classes over the 8-week intervention period. Yoga participants had a significantly greater pre- to post-intervention reduction in IDS-CR scores than waitlist participants (Cohen d = 1.04, P < .001). More yoga participants (59.3%; n = 16) than waitlist participants (6.3%; n = 2) evidenced larger treatment responses (IDS-CR ≥ 50% decrease in symptoms). Participants rated the heated yoga and its aftereffects positively in exit interviews.Conclusions: Approximately 1 heated yoga session per week (mean of 10.3 classes over 8 weeks) was associated with significantly greater reduction in depression symptoms than a waitlist control. Participants rated heated yoga positively. Taken together, results suggest feasibility, acceptability, and preliminary efficacy for patients with depression and warrant further research using active control conditions.Trial Registration: ClinicalTrials.gov identifier: NCT02607514.

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.

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.

Is Worse Attention a Risk Factor for or a Consequence of Depression, or Are Worse Attention and Depression Better Accounted for by Stress? A Prospective Test of Three Hypotheses.

It is unclear whether impaired cognition is a risk factor for depression, a consequence of depression, or whether both depression and impaired cognition are caused by a third underlying process (e.g., stress). These three hypotheses were tested in 523 adolescents assessed annually for depression, attentional functioning, and childhood/recent life stress. Baseline switching, sustained, and selective attention did not predict first onset of depression (foD) or depressive symptoms. Divided attention predicted depressive symptoms only. Piecewise growth modelling indicated that the trajectory of switching attention declined prior to foD; there was evidence of significant recovery in switching attention following foD. Structural equation modelling indicated that impaired switching attention prospectively predicted higher depressive symptoms and that higher depressive symptoms predicted worse selective and switching attention. Further, childhood stress prospectively predicted higher depressive symptoms via switching attention and worse switching attention via depressive symptoms.