Sleep Disturbance as a Mediator of Lung Cancer Stigma on Psychological Distress and Physical Symptom Burden.

OBJECTIVE: This study tested sleep disturbance as a mediator through which stigma and discrimination predict psychological distress and physical symptom burden in adults with lung cancer. METHODS: Lung cancer patients on active oncological treatment ( N = 108; 74.1% stage IV) completed questionnaires on lung cancer stigma, sleep, distress, and physical symptoms at study entry and at 6- and 12-week follow-up. Mediation analyses were conducted to investigate whether stigma and discrimination predicted distress and physical symptoms at study entry and across 12 weeks through disrupted sleep. RESULTS: Higher discrimination ( b = 5.52, 95% confidence interval [CI] = 2.10-8.94) and constrained disclosure ( b = 0.45, 95% CI = 0.05-0.85) were associated significantly with higher sleep disruption at study entry. Sleep disruption, in turn, was associated with higher distress ( b = 0.19, 95% CI = 0.09-0.29) and physical symptoms ( b = 0.28, 95% CI = 0.17-0.40) at study entry. Sleep disruption significantly mediated relationships between higher discrimination and the outcomes of distress (indirect effect = 1.04, 95% CI = 0.13-1.96) and physical symptoms (indirect effect = 1.58, 95% CI = 0.37-2.79) at study entry. Sleep disruption also mediated relationships between constrained disclosure and the outcomes of distress (indirect effect = 0.85, 95% CI = < 0.01-0.17) and physical symptoms (indirect effect = 0.13, 95% CI = 0.01-0.25). CONCLUSIONS: Lung cancer patients evidenced pronounced sleep disruption, which mediated relationships between indicators of lung cancer stigma and distress and physical symptoms at study entry. Research is needed to test additional mechanisms through which lung cancer stigma predicts these outcomes longitudinally.

Structural brain plasticity and inflammation are independently related to changes in depressive symptoms six months after an index ECT course.

BACKGROUND: Electroconvulsive therapy (ECT) is effective for treatment-resistant depression and leads to short-term structural brain changes and decreases in the inflammatory response. However, little is known about how brain structure and inflammation relate to the heterogeneity of treatment response in the months following an index ECT course. METHODS: A naturalistic six-month study following an index ECT course included 20 subjects with treatment-resistant depression. Upon conclusion of the index ECT course and again after six months, structural magnetic resonance imaging scans and peripheral inflammation measures [interleukin-6 (IL-6), IL-8, tumor necrosis factor (TNF-α), and C-reactive protein] were obtained. Voxel-based morphometry processed with the CAT-12 Toolbox was used to estimate changes in gray matter volume. RESULTS: Between the end of the index ECT course and the end of follow-up, we found four clusters of significant decreases in gray matter volume (p < 0.01, FWE) and no regions of increased volume. Decreased HAM-D scores were significantly related only to reduced IL-8 level. Decreased volume in one cluster, which included the right insula and Brodmann's Area 22, was related to increased HAM-D scores over six months. IL-8 levels did not mediate or moderate the relationship between volumetric change and depression. CONCLUSIONS: Six months after an index ECT course, multiple regions of decreased gray matter volume were observed in a naturalistic setting. The independent relations between brain volume and inflammation to depressive symptoms suggest novel explanations of the heterogeneity of longer-term ECT treatment response.

Tai Chi compared with cognitive behavioral therapy and the reversal of systemic, cellular and genomic markers of inflammation in breast cancer survivors with insomnia: A randomized clinical trial.

BACKGROUND: Insomnia contributes to inflammation in breast cancer survivors. This study evaluates whether insomnia treatment reverses inflammation in breast cancer survivors with insomnia. METHODS: Participants (n = 90) were randomized to 3 months of Tai Chi (n = 45) or cognitive behavioral therapy for insomnia (CBT-I)(n = 45), and followed for one year post-intervention to 15 month endpoint. Our previous report found that Tai Chi as compared to CBT-I resulted in similar rates of insomnia response and remission over 15 months. Here, we analyze changes in plasma C-reactive protein and pro- and anti-inflammatory cytokines, Toll-like receptor (TLR)-4 stimulated monocyte production of interleukin (IL)-6 and tumor necrosis factor-α (TNF), and cellular pro-inflammatory and anti-viral gene expression (Conserved Transcriptional Response to Adversity RNA profile; CTRA) over 15 months. RESULTS: Insomnia treatment resulted in decreases in the TLR-4 stimulated monocyte production of IL-6, TNF, and their co-expression, as well as decreases in the CTRA profile, decreases inflammatory gene transcripts, and increases in anti-viral gene transcripts over 15 months (all P's < 0.01). In addition, as compared to CBT-I, Tai Chi resulted in greater decreases in plasma IL-6 (P < 0.05), and greater decreases in TLR-4 activated monocyte production of IL-6 and co-expression of IL-6 and TNF at 15 month endpoint. CBT-I resulted in greater increases in anti-viral gene transcripts. CONCLUSIONS: Administration of either CBT-I or Tai Chi effectively treats insomnia, and shows additional benefits of reducing cellular and genomic markers of inflammation, and increasing anti-viral genomic markers in breast cancer survivors with insomnia. Tai Chi, as compared to CBT-I, yields greater and more durable decreases in systemic- and cellular inflammation. Targeting insomnia might mitigate the risk of inflammation-related co-morbidities in breast cancer survivors.

Type I interferons, inflammation, and fatigue in a longitudinal RNA study of women with breast cancer.

BACKGROUND: Fatigue is a common side effect of cancer and its treatment and is thought to be driven in part by activation of the proinflammatory cytokine network. However, the cellular and molecular underpinnings of cancer-related fatigue (CRF) have not been determined, nor have immune pathways beyond inflammation been carefully investigated. The goal of this study was to examine the association between CRF and activation of canonical proinflammatory gene regulation pathways and Type I interferon (IFN) signaling pathways in breast cancer patients during and after treatment. METHODS: Women diagnosed with early-stage breast cancer (n = 181) completed assessments before and after treatment with radiation and/or chemotherapy and at 6, 12, and 18-month post-treatment follow-ups. Assessments included self-reported fatigue (Multidimensional Fatigue Symptom Inventory - Short Form) and expression of pre-specified sets of Type I IFN and pro-inflammatory immune response genes determined from mRNA sequencing of PBMCs. Mixed effect linear models examined changes in fatigue and immune gene expression over time and tested the hypothesis that fatigue would be associated with increased expression of Type I IFN and inflammatory response genes. RESULTS: There were significant changes in fatigue and immune gene expression across the assessment period; all measures increased from pre- to post-treatment but showed diverging patterns over the follow-up, with declines in fatigue and persistent elevations in Type I IFN and proinflammatory gene expression. In mixed effect linear models, expression of Type I IFN response genes was elevated in association with fatigue across the assessment period, from pre-treatment to 18-month follow-up. In contrast, pro-inflammatory gene expression was associated with fatigue only at 6, 12, and 18-month follow-ups. Analyses controlling for changes in leukocyte subsets continued to show a significant association between fatigue and Type I IFN gene expression but reduced the time-dependent association with pro-inflammatory gene expression to non-significant. CONCLUSIONS: Results revealed unexpected complexity in the immune underpinnings of CRF and identify a novel role for IFN signaling as a robust contributor to this symptom before, during, and after treatment. Pro-inflammatory gene expression emerged as a predictor of fatigue later in the cancer trajectory, and that effect was primarily accounted for by a concurrent increase in monocyte prevalence.

Efficacy of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction for Depression Symptoms and Sleep-Wake Disruption in Older and Younger Adults: Secondary Age-Stratified Analysis of a Randomized Controlled Trial.

OBJECTIVE: Perform a secondary analysis examining the efficacy of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for depression symptom responses, and explore changes in potential target mechanisms. DESIGN: Secondary analysis of a randomized controlled trial with convenience age subsamples (younger (20-49 year; n = 52) versus and older (50-71 years; n = 35)). SETTING: Community mental health clinics. PARTICIPANTS: Eighty-seven adults with serious mental illness. INTERVENTION: TranS-C versus treatment as usual (TAU). MEASUREMENTS: Outcomes were depression symptoms (Quick Inventory of Depression Symptoms), insomnia symptoms (Insomnia Severity Index), and objective sleep-wake rhythm measures (interdaily stability and relative amplitude). RESULTS: Depression response rates (≥50% symptom reductions) were higher in the TranS-C (35.0%) than the TAU (8.8%) group 6-months postintervention (χ2 = 10.3, p = 0.001). There was a medium effect of TranS-C versus TAU on depression symptoms 6-months postintervention (Cohen's d = -0.40, 95% confidence interval (CI): -0.81, 0.01). In both age groups, there were large treatment effects on insomnia symptoms post-treatment (Cohen's d >0.90). In the older subsample, there were additionally medium treatment effects on post-treatment interdaily stability (Cohen's d = 0.60, 95% CI: -0.11, 1.61). Post-treatment reductions in insomnia symptoms correlated with depression symptom reduction 6-months later in the younger subsample (Spearman rho = 0.59, n = 20, p = 0.008). In older adults, postintervention increases in interdaily stability correlated with depression symptom reductions 6-months later (Spearman rho = -0.52, n = 15, p = 0.049). CONCLUSION: Confirmatory trials are needed, given the low age-specific sample sizes here, to determine if TranS -C's produces durable depression responses by increasing sleep-wake rhythm stability in older adults and improving insomnia symptoms in younger adults. BRIEF ARTICLE SUMMARY: The authors evaluated preliminary efficacy of a behavioral intervention that targets sleep/sleep-wake rhythms, the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C), for depression symptoms in people with serious mental illness. TranS-C was associated with higher depression response rates than treatment as usual 6-months postintervention. The degree of depression symptom response 6-months later was related to the degree of treatment phase improvements in interdaily stability (in older adults) and reduction in insomnia severity (in younger adults). A pragmatic nonpharmacologic intervention, the Transdiagnostic Intervention for Sleep and Circadian Dysfunction, has preliminary efficacy for improving sleep-wake factors and depression symptoms.

Work Productivity Among Younger Breast Cancer Survivors: The Impact of Behavioral Interventions for Depression.

OBJECTIVES: The Pathways to Wellness randomized controlled trial found that 2 behavioral interventions, mindfulness awareness practices and survivorship education, reduced depressive symptoms in younger breast cancer survivors (BCSs) compared with wait-list control. This secondary analysis examines whether the interventions led to reduced loss of work productivity among younger BCSs and whether such reductions were mediated by reductions in depressive symptoms. METHODS: The Work Productivity and Activity Impairment scale was used to measure work productivity loss at 4 assessment time points. Correlates of productivity loss at enrollment were examined using multivariable linear regression. Differences in change over time in productivity loss between each intervention group and control were assessed using linear mixed models. Reduced depressive symptoms were tested as a mediator of reduced productivity loss. RESULTS: Of 247 trial participants, 199 were employed and included in the analyses. At enrollment, higher productivity loss was associated with chemotherapy receipt (P = .003), younger age (P = .021), more severe cognitive problems (P = .002), higher musculoskeletal pain severity (P = .002), more depressive symptoms (P = .016), and higher fatigue severity (P = .033). The mindfulness intervention led to significantly less productivity loss compared with control at all 3 postintervention assessment points (all P < .05), with about 54% of the effect mediated by reduction in depressive symptoms. Survivorship education was not associated with reduced loss of productivity. CONCLUSIONS: These findings suggest that addressing depressive symptoms through behavioral interventions, such as mindfulness, may mitigate impacts on work productivity in younger BCSs.

Everyday discrimination, emotion, and daily interactions during adolescence.

The present study examined whether everyday discrimination relates to the frequency of adolescents' positive and negative daily social interactions and whether these associations are driven by anger and positive emotion. Adolescents (N = 334) participated in a three-wave longitudinal study, in which they completed surveys regarding everyday discrimination, anger, and positive emotion, as well as 15 daily reports of conflict and getting along with friends and family. Higher everyday discrimination was related to more daily conflicts and fewer experiences of getting along with other people. Longitudinal models also provided preliminary evidence that everyday discrimination was associated with daily conflicts 4 years later indirectly through anger. Overall, results suggest everyday discrimination relates to adolescents' daily experiences, potentially through differences in emotion.

Interferon-γ moderation of poor sleep maintenance and depressed mood in community-dwelling older adults.

BACKGROUND: Depressive symptoms, such as depressed mood, are common in older adults and associated with an increased risk for morbidity and mortality. Given the evidence that sleep disturbance and alterations in interferon (IFN)-γ biology are associated with depression risk, this study examines the separate and joint contributions of poor sleep maintenance and IFN-γ to depressed mood in older adults. METHODS: Community-dwelling, non-depressed older adults (n = 36, 72.1 ± 6.8 years) underwent a night of polysomnography to assess sleep maintenance [i.e. wake time after sleep onset (WASO)]. The morning after polysomnography, plasma levels of IFN-γ were evaluated along with self-reported depressed mood throughout the day. Multivariate linear regression tested associations of WASO and IFN-γ with the severity of depressed mood. In addition, moderation and mediation models examined the role of IFN-γ for the relationship between WASO and depressed mood. RESULTS: A greater amount of WASO (p < 0.05) and higher levels of IFN-γ (p < 0.01) were both associated with the severity of depressed mood. Moreover, IFN-γ moderated the relationship between WASO and depressed mood (p < 0.01), such that WASO was more strongly related to the depressed mood among those with higher IFN-γ, than among those with lower IFN-γ. However, IFN-γ did not mediate the relationship between WASO and depressed mood. CONCLUSION: In this study of older adults, poor sleep maintenance and higher levels of IFN-γ were both related to depressed mood. Moreover, IFN-γ moderated the relationship between poor sleep maintenance and depressed mood. Together, these findings suggest that older adults with higher IFN-γ are at heightened risk for depressive symptoms following sleep disturbance.

Null results of oxytocin and vasopressin administration on mentalizing in a large fMRI sample: evidence from a randomized controlled trial.

BACKGROUND: Although potential links between oxytocin (OT), vasopressin (AVP), and social cognition are well-grounded theoretically, most studies have included all male samples, and few have demonstrated consistent effects of either neuropeptide on mentalizing (i.e. understanding the mental states of others). To understand the potential of either neuropeptide as a pharmacological treatment for individuals with impairments in social cognition, it is important to demonstrate the beneficial effects of OT and AVP on mentalizing in healthy individuals. METHODS: In the present randomized, double-blind, placebo-controlled study (n = 186) of healthy individuals, we examined the effects of OT and AVP administration on behavioral responses and neural activity in response to a mentalizing task. RESULTS: Relative to placebo, neither drug showed an effect on task reaction time or accuracy, nor on whole-brain neural activation or functional connectivity observed within brain networks associated with mentalizing. Exploratory analyses included several variables previously shown to moderate OT's effects on social processes (e.g., self-reported empathy, alexithymia) but resulted in no significant interaction effects. CONCLUSIONS: Results add to a growing literature demonstrating that intranasal administration of OT and AVP may have a more limited effect on social cognition, at both the behavioral and neural level, than initially assumed. Randomized controlled trial registrations: ClinicalTrials.gov; NCT02393443; NCT02393456; NCT02394054.

The role of early life adversity and inflammation in stress-induced change in reward and risk processes among adolescents.

BACKGROUND: Early life adversity (ELA) has long been associated with increased risk for stress-related psychopathology, particularly depression. The neuroimmune network hypothesis posits that ELA increases sensitivity to psychosocial stress, moderating the association between increases in peripheral markers of inflammation and decreases in reward outcomes linked to anhedonia and risk-taking behaviors. The present study examined this hypothesis in a sample of adolescents by using acute psychosocial stress to probe the role of inflammatory signaling in behavioral measures of reward and risk processing. METHOD: 80 adolescents [13.86 years (SD = 1.54); 45 % female], oversampled for ELA, underwent the Trier Social Stress Test for Children while providing blood samples immediately before and 60-minutes after stress onset. Blood samples were assayed for plasma IL-6. One hour before stress onset, and then 60 min after, participants completed computer-administered behavioral tasks measuring reward (Pirate Task) and risk (Balloon Analog Risk Task). RESULTS: ELA moderated the association between increases in IL-6 and decreases in risk tolerance in pursuit of rewards (p = 0.003) and reward response bias (p = 0.04). Stress-induced increases in IL-6 were associated with decreases in pumps for rewards among adolescents exposed to high, relative to little or no, ELA. Further, greater IL-6 increases were associated with increases in bias toward high relative to low value rewards among adolescents with low adversity exposure but not among those exposed to higher adversity. CONCLUSIONS: The present study provides the first evidence in a pediatric sample that ELA may alter the role of stress-induced inflammation in reward and risk processing, and may extend our understanding of why stress leads to depression in this high-risk population.

Baseline C-reactive protein levels are predictive of treatment response to a neuroimmune modulator in individuals with an alcohol use disorder: a preliminary study.

Background: Inflammation is implicated in alcohol use disorder (AUD). Ibudilast, a neuroimmune modulator, shows promise for the treatment of AUD. Elevated inflammation, indicated by high levels of C-reactive protein (CRP), represents a possible subtype of AUD, which may be associated with treatment response to ibudilast.Objectives: The current study evaluated CRP as a predictor of treatment response to ibudilast; hypothesizing that ibudilast would be more effective at reducing drinking and alcohol cue-reactivity in individuals with higher CRP levels.Methods: This is a secondary analysis of a clinical trial of ibudilast for AUD, which found that ibudilast reduced heavy drinking in individuals with AUD. Fifty-one individuals were randomized to receive ibudilast (n = 24 [16 M/8F]) or placebo (n = 27 [18 M/9F]) for two weeks. Participants provided blood samples at baseline to assess CRP levels, completed daily assessments of alcohol use, and an fMRI alcohol cue-reactivity task at study mid-point. Models tested the effects of medication, CRP levels, and their interaction on drinks per drinking day and alcohol cue-reactivity.Results: There was a significant interaction between medication and CRP (F = 3.80, p = .03), such that the ibudilast high CRP group had fewer drinks per drinking day compared to the ibudilast low CRP group. CRP moderated the effect of medication on brain activation in a cluster extending from the left inferior frontal gyrus to the right-dorsal striatum (Z = 4.55, p < .001). This interaction was driven by attenuated cue-reactivity in the ibudilast high CRP group relative to the ibudilast low CRP and placebo high CRP groups.Conclusions: This study serves as an initial investigation into predictors of clinical response to ibudilast treatment and suggests that a baseline proinflammatory profile may enhance clinical efficacy.

Hybrid Delivery of Mindfulness Meditation and Perceived Stress in Pediatric Resident Physicians: A Randomized Clinical Trial of In-Person and Digital Mindfulness Meditation.

Physicians are experiencing epidemic levels of work-related stress and burnout. Determine efficacy of mindfulness meditation delivered as a hybrid (in-person and digital) format to reduce perceived stress in pediatric residents. Pediatric residents (n = 66) were block randomized to a hybrid Mindful Awareness Practices (MAPs) intervention, comprised of one in-person 60-min session and 6-week access to a digitally delivered MAPs curriculum (n = 27) or wait-list control (n = 39). Perceived Stress Scale (PSS) was administered at baseline and post-intervention as the primary outcome measure. A priori secondary outcomes were measured using the Abbreviated Maslach Burnout Inventory-9, Beck Depression Inventory, Beck Anxiety Inventory, UCLA Loneliness Scale, and Pittsburgh Sleep Quality Index. After the first session, 58% participated at least one digital session (M = 2.0; SD = 1.3). MAPs participants showed significant decrease in PSS compared to controls, with between-group mean difference of 2.20 (95% CI 0.47-3.93) at post-intervention (effect size 0.91; 0.19-1.62). No secondary outcome group differences were detected. Exposure to a hybrid mindfulness intervention was associated with improvement in perceived stress among pediatric residents.Trial Registration: NCT03613441.

Effects of Tai Chi and cognitive behavioral therapy for insomnia on improving sleep in older adults: Study protocol for a non-inferiority trial.

Background: Insomnia is a prevailing health problem among older adults. Tai Chi, a popular mind-body exercise practiced by older people in various oriental communities, has been shown to improve sleep. However, Tai Chi has not been directly compared to cognitive behavioral therapy for insomnia (CBT-I), which is the first-line non-pharmacological treatment for insomnia in older adults. This study aims to examine whether Tai Chi is non-inferior to CBT-I as a treatment for insomnia in older adults. Methods: This is a single-center, assessor-blinded, non-inferiority randomized controlled trial comparing Tai Chi and CBT-I in 180 older adults aged ≥50 years with chronic insomnia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Participants will be randomly assigned to either the Tai Chi or CBT-I group. Interventions will last for 3 months with a 12-month follow-up. The primary outcome is self-perceived insomnia severity measured by Insomnia Severity Index (ISI) at 3 months and at 15 months. The secondary outcomes include the remission rate of chronic insomnia, insomnia treatment response, subjective sleep quantity and quality, 7-day actigraphy, 7-day sleep diary, sleep medication, health-related quality of life, mental health, body balance and lower extremity function, adverse events, habitual physical activity, and dietary intake. Measurements will be conducted at baseline, 3 months, and 15 months by outcome assessors who are blinded to the group allocation. Discussion: This will be the first non-inferiority randomized controlled trial to compare the efficacy and long-term outcomes of Tai Chi versus CBT-I for treating insomnia in older adults. This study will be of clinical importance as it supports the use of Tai Chi as an alternative non-pharmacological approach for insomnia treatment and sustainable management.

Accelerated mononuclear cell telomere attrition in breast cancer survivors with depression history: A 2-year longitudinal cohort study.

BACKGROUND: Cancer treatments are thought to accelerate biological aging, although this trajectory is highly variable. Depression is more prevalent in breast cancer survivors and is thought to be a vulnerability factor for biological aging. A lifetime history of depression and cumulative lifetime number of depression episodes could hypothetically be associated with an accelerated rate of biological aging as indexed by attrition of telomere length in a prospective cohort of breast cancer survivors who were not currently depressed. METHODS: Breast cancer survivors (n = 206) without current depression were recruited from a large community-based health plan and were assessed for depression history by a structured diagnostic interview. Blood specimens were provided at baseline and every 8 months over 24 months to measure peripheral blood mononuclear cell (PBMC) telomere length. Mixed linear models examined associations of depression history and number of depression episodes with change in telomere length, adjusting for demographic, comorbidity, and cancer-specific factors. RESULTS: In the fully adjusted model, depression history predicted attrition of PBMC telomere length over 24 months (Beta [SE] = -.006 [.002], p = .001). Greater number of depressive episodes over the lifetime was also associated with accelerated attrition of PBMC telomere length over 24 months (Beta [SE] = -.004 [.001], p = .001). CONCLUSIONS: In breast cancer survivors without current depression, telomere attrition over 24 months was greatest in those with a lifetime depression history, particularly those with the greatest number of episodes of major depressive disorder over their lifetime. Depression history and its cumulative burden may contribute to accelerated biological aging, with implications for risk of morbidity and mortality in breast cancer survivors.

Antidepressant medication use and prostate cancer recurrence in men with depressive disorders.

PURPOSE: Whether treating prostate cancer survivors with a depressive disorder with antidepressants can affect their cancer outcomes is unknown. We evaluated the association between antidepressant use and prostate cancer recurrence, in survivors with comorbid depressive disorders. METHODS: We conducted a longitudinal cohort study of 10,017 men with prostate cancer (stages I-II) diagnosed who also had a comorbid depressive disorder followed a maximum of 22 years, and examined rates of biochemical recurrence by antidepressant medication use. We conducted multivariable Cox models based on time-dependent antidepressant drug use status, and examined the risk of biochemical recurrence by cumulative duration of antidepressant use. RESULTS: Of these 10,017 survivors, 1842 (18%) experienced biochemical recurrence over 69,500 person-years of follow-up. The prostate cancer biochemical recurrence rate was greater with antidepressant non-use (31.3/1000 person-years) compared to antidepressant use (23.5/1000 person-years). In Cox proportional hazards multivariable adjusted models, non-use of antidepressants was associated with a 34% increased risk of biochemical recurrence compared to antidepressant use (HR = 1.34, 95% CI: 1.24-1.44). Longer use of antidepressants was associated with a lower biochemical recurrence risk (P trend test < 0.001). CONCLUSION: Untreated depressive disorders in prostate cancer patients may be associated with an increased risk of biochemical recurrence.

The Relationship Between Family Socioeconomic Status and Adolescent Sleep and Diurnal Cortisol.

OBJECTIVE: This study aimed to investigate the associations between indices of family socioeconomic status and sleep during adolescence and to examine whether measures of hypothalamic-pituitary-adrenal (HPA) axis functioning mediate the observed associations. METHODS: A total of 350 ethnically diverse adolescents (57% female; mean [standard deviation] age wave 1 = 16.4 [0.7] years) completed a three-wave longitudinal study in which sleep and cortisol data were collected at 2-year time intervals. Sleep duration, latency, and variability were assessed via actigraphy during a period of 8 days per study wave. Salivary cortisol was collected across 3 days per study wave to assess cortisol diurnal slope, area under the curve, and the cortisol awakening response. Adolescents' caregivers reported their education levels, family income, and economic hardship. RESULTS: A greater family income-to-needs ratio was associated with longer adolescent sleep duration ( b = 2.90, p = .023), whereas greater parental education was associated with shorter sleep duration ( b = -3.70, p = .030), less sleep latency ( b = -0.74, p = .016), and less variability across days ( b = -2.06, p = .010). Diurnal cortisol slope statistically mediated the association of parental education with sleep duration ( b = -0.48, 95% confidence interval = -1.099 to -0.042), but not the association of income-to-needs ratio with sleep duration. CONCLUSIONS: Findings suggest that parental education and family resources may have unique impacts upon sleep and HPA axis functioning during the period of adolescence. Future research is needed to examine family and behavioral factors that may underlie socioeconomic status associations with adolescent sleep and HPA axis functioning.

Psychosocial Resilience to Inflammation-Associated Depression: A Prospective Study of Breast-Cancer Survivors.

Stress can lead to depression, in part because of activation of inflammatory mechanisms. It is therefore critical to identify resilience factors that can buffer against these effects, but no research to date has evaluated whether psychosocial resilience mitigates the effects of stress on inflammation-associated depressive symptoms. We therefore examined psychosocial resources known to buffer against stress in a longitudinal study of women with breast cancer (N = 187). Depressive symptoms and inflammation were measured over a 2-year period extending from after diagnosis into survivorship. Cancer-related stress and psychosocial resources-social support, optimism, positive affect, mastery, self-esteem, and mindfulness-were measured after diagnosis. As hypothesized, women who reported having more psychosocial resources showed weaker associations between stress and depressive symptoms and weaker associations between stress and inflammation-related depressive symptoms. Results highlight the importance of psychosocial resilience by demonstrating a relationship between psychosocial resources and sensitivity to inflammation-associated depressive symptoms.

Behavioral activation therapy for depression is associated with a reduction in the concentration of circulating quinolinic acid.

BACKGROUND: An inflammation-induced imbalance in the kynurenine pathway (KP) has been reported in major depressive disorder but the utility of these metabolites as predictive or therapeutic biomarkers of behavioral activation (BA) therapy is unknown. METHODS: Serum samples were provided by 56 depressed individuals before BA therapy and 29 of these individuals also provided samples after 10 weeks of therapy to measure cytokines and KP metabolites. The PROMIS Depression Scale (PROMIS-D) and the Sheehan Disability Scale were administered weekly and the Beck depression inventory was administered pre- and post-therapy. Data were analyzed with linear mixed-effect, general linear, and logistic regression models. The primary outcome for the biomarker analyses was the ratio of kynurenic acid to quinolinic acid (KynA/QA). RESULTS: BA decreased depression and disability scores (p's < 0.001, Cohen's d's > 0.5). KynA/QA significantly increased at post-therapy relative to baseline (p < 0.001, d = 2.2), an effect driven by a decrease in QA post-therapy (p < 0.001, uncorrected, d = 3.39). A trend towards a decrease in the ratio of kynurenine to tryptophan (KYN/TRP) was also observed (p = 0.054, uncorrected, d = 0.78). Neither the change in KynA/QA, nor baseline KynA/QA were associated with response to BA therapy. CONCLUSION: The current findings together with previous research show that electronconvulsive therapy, escitalopram, and ketamine decrease concentrations of the neurotoxin, QA, raise the possibility that a common therapeutic mechanism underlies diverse forms of anti-depressant treatment but future controlled studies are needed to test this hypothesis.

Association of interleukin-8 and risk of incident and recurrent depression in long-term breast cancer survivors.

BACKGROUND: In cancer patients, an interleukin (IL)-8 gene variant that leads to higher production of IL-8, is associated with lower risk of depressive symptoms. In non-cancer adults, higher levels of IL-8 correlate with lower severity of depressive symptoms, decreased risk of suicide, and improved treatment response in females, but not males. This study evaluates the prospective association between circulating levels IL-8 and incident and recurrent major depressive disorder in breast cancer survivors. METHODS: In this single site, prospective cohort study with protocol modification extending follow-up from 24- to 32 months, recruitment occurred between September 2013 and January 2018, and follow-up was completed February 2021. Participants were identified from a Kaiser Permanente of Southern California health plan-based sample of 219 breast cancer survivors, who were two or more years since diagnosis of early stage breast cancer (TNM 0-II), aged 55 to 85 years, with no major depression or health events in last year. Circulating levels of IL-8 were obtained at enrollment. Primary outcome was time to incident or recurrent major depressive disorder as diagnosed by interview and DSM-5 criteria. RESULTS: Among 219 participants (mean age, 70 years; 100% female; 16 [7.3%] Asian, 42 [19.2%] Black, 161 [73.5%] White), 84% completed 24 months follow-up. After protocol modification, 59% completed 32 months follow-up. Median follow-up was 28.5 months. The primary endpoint occurred in 27 participants (12.4%, 5.7 events /100 person years; 95% CI 2.7 - 8.8). Higher IL-8 was associated with lower risk of incident and recurrent depression (hazard ratio, HR, 0.52, 95% CI 0.26 - 1.05). Among those with levels of IL-8 in the highest quartile, the primary endpoint occurred in 2 participants (3.6%; 1.6 events/100 person years; 95% CI 1.3 - 1.9), as compared to 25 participants in the pooled lower quartiles (15.2%; 7.2 events/100 persons years; 95%CI 7.0 - 7.4; rate difference, 5.6 per 100 person years, 95%CI 5.2 - 5.9; HR, 0.21, 95%CI 0.05 - 90, multivariable adjusted HR, 0.20, 95%CI 0.05 - 0.88). CONCLUSIONS: Among breast cancer survivors, higher IL-8 at enrollment was associated with a decreased risk of incident and recurrent major depression. These findings provide insights into mechanisms of depression risk and development of novel therapies for depression prevention, and suggest that testing for IL-8 may have prognostic value in identifying resilience or risk of depression.

Associations between peripheral inflammatory markers and amygdala activity and connectivity in response to emotional faces in adolescents.

Research in adults suggests that higher peripheral inflammation is associated with increased threat-related amygdala activity and reduced cortico-amygdala connectivity. However, there is limited research in adolescents, which is striking given the major developmental changes that occur in cortico-amygdala circuitry during adolescence. In this study, we examine the association between peripheral inflammation and amygdala activity and connectivity to emotional faces in a community sample of adolescents. Participants included 88 adolescents 12 to 15 years old who provided a blood sample and underwent fMRI scanning while completing a face and shape matching task that included fearful, angry, and happy faces. Blood samples were assayed for interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α); IL-6 and CRP were combined into a composite due to their high correlation and TNF-α was analyzed separately. Results indicated that higher TNF-α, but not the composite of IL-6 and CRP, was associated with increased amygdala activity to threatening (fearful and angry) faces and to happy faces, relative to shape matching. Whole-brain analyses also identified associations between TNF-α and neural activity to angry and happy faces in regions outside of the amygdala. Psychophysiological interaction analysis indicated that higher TNF-α was associated with reduced bilateral amygdala connectivity to the left cuneus, right cuneus/calcarine fissure/precuneus, and left supramarginal gyrus/inferior parietal gyrus during angry and fearful faces > shapes and higher IL-6/CRP was associated with reduced bilateral amygdala connectivity to the right postcentral gyrus and right precuneus. Results suggest that peripheral inflammation is associated with increased amygdala activity to emotional face stimuli and reduced amygdala connectivity with occipital and parietal regions. These findings enhance our understanding of the association between peripheral inflammation and neural response to emotional faces, which could inform the development of interventions targeting inflammation for adolescents.