Substantial evidence demonstrates that inflammatory processes may underlie depression for a subset of patients, including work showing that healthy subjects exposed to an inflammatory challenge show ...increases in depressed mood and feelings of social disconnection. However, despite the fact that depression is two times as likely to occur in females than males, the vast majority of this work has been carried out in males. Thus, the objective of this study was to determine whether females (vs males) would show greater increases in proinflammatory cytokines, depressed mood, and social disconnection in response to an inflammatory challenge. One hundred and fifteen healthy participants (69 female) completed this double-blind, placebo-controlled, randomized clinical trial in which participants were randomly assigned to receive either a single infusion of low-dose endotoxin (derived from Escherichia coli; 0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline). Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), depressed mood, and feelings of social disconnection were assessed hourly. Results showed that endotoxin (vs placebo) led to increases in proinflammatory cytokines (TNF-α, IL-6), depressed mood, and feelings of social disconnection. Females exposed to endotoxin showed greater increases in depressed mood and feelings of social disconnection. Furthermore, increases in TNF-α and IL-6 were correlated with increases in social disconnection for females but not for males. These sex differences in the relationships between inflammatory and socioemotional responses to an inflammatory challenge may be particularly important for understanding why females are two times as likely as males to develop depressive disorders.
IMPORTANCE: Older adults with insomnia have a high risk of incident and recurrent depression. Depression prevention is urgently needed, and such efforts have been neglected for older adults. ...OBJECTIVE: To examine whether treatment of insomnia disorder with cognitive behavioral therapy for insomnia (CBT-I) compared with an active comparator condition, sleep education therapy (SET), prevents major depressive disorder in older adults. DESIGN, SETTING, AND PARTICIPANTS: This assessor-blinded, parallel-group, single-site randomized clinical trial assessed a community-based sample of 431 people and enrolled 291 adults 60 years or older with insomnia disorder who had no major depression or major health events in past year. Study recruitment was performed from July 1, 2012, to April 30, 2015. The trial protocol was modified to extend follow-up from 24 to 36 months, with follow-up completion in July 2018. Data analysis was performed from March 1, 2019, to March 30, 2020. INTERVENTIONS: Participants were randomized to 2 months of CBT-I (n = 156) or SET (n = 135). MAIN OUTCOMES AND MEASURES: The primary outcome was time to incident major depressive disorder as diagnosed by interview and Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria. Secondary outcome was sustained remission of insomnia disorder before depression event or duration of follow-up. RESULTS: Among 291 randomized participants (mean SD age, 70.1 6.7 years; 168 57.7% female; 7 2.4% Asian, 32 11.0% Black, 3 1.0% Pacific Islander, 241 82.8% White, 6 2.1% multiracial, and 2 0.7% unknown), 156 were randomized to CBT-I and 135 to SET. A total of 140 participants (89.7%) completed CBT-I and 130 (96.3%) participants completed SET (χ2 = 4.9, P = .03), with 114 (73.1%) completing 24 months of follow-up in the CBT-I group and 117 (86.7%) in the SET group (χ2 = 8.4, P = .004). After protocol modification, 92 (59.0%) of the CBT-I participants and 86 (63.7%) of the SET participants agreed to extended follow-up (χ2 = 0.7, P = .41), with 81 (51.9%) of the CBT-I participants and 77 (57.0%) of the SET group completing 36 months of follow-up (χ2 = 0.8; P = .39). Incident or recurrent major depression occurred in 19 participants (12.2%) in the CBT-I group and in 35 participants (25.9%) in the SET group, with an overall benefit (hazard ratio, 0.51; 95%, CI 0.29-0.88; P = .02) consistent across subgroups. Remission of insomnia disorder continuously sustained before depression event or during follow-up was more likely in CBT-I participants (41 26.3%) compared with the SET participants (26 19.3%, P = .03). Those in the CBT-I group with sustained remission of insomnia disorder had an 82.6% decreased likelihood of depression (hazard ratio, 0.17; 95%, CI 0.04-0.73; P = .02) compared with those in the SET group without sustained remission of insomnia disorder. CONCLUSIONS AND RELEVANCE: The findings of this randomized clinical trial indicate that treatment of insomnia with CBT-I has an overall benefit in the prevention of incident and recurrent major depression in older adults with insomnia disorder. Community-level screening for insomnia concerns in older adults and wide delivery of CBT-I–based treatment for insomnia could substantially advance public health efforts to treat insomnia and prevent depression in this vulnerable older adult population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01641263
Fatigue, depression, and sleep disturbance are common adverse effects of cancer treatment and frequently co-occur. However, the possibility that inflammatory processes may underlie this constellation ...of symptoms has not been examined.
Women (N = 103) who had recently finished primary treatment (ie, surgery, radiation, chemotherapy) for early-stage breast cancer completed self-report scales and provided blood samples for determination of plasma levels of inflammatory markers: soluble tumor necrosis factor (TNF) receptor II (sTNF-RII), interleukin-1 receptor antagonist, and C-reactive protein.
Symptoms were elevated at the end of treatment; greater than 60% of participants reported clinically significant problems with fatigue and sleep, and 25% reported elevated depressive symptoms. Women treated with chemotherapy endorsed higher levels of all symptoms and also had higher plasma levels of sTNF-RII than women who did not receive chemotherapy (all P < .05). Fatigue was positively associated with sTNF-RII, particularly in the chemotherapy-treated group (P < .05). Depressive symptoms and sleep problems were correlated with fatigue but not with inflammatory markers.
This study confirms high rates of behavioral symptoms in breast cancer survivors, particularly those treated with chemotherapy, and indicates a role for TNF-α signaling as a contributor to postchemotherapy fatigue. Results also suggest that fatigue, sleep disturbance, and depression may stem from distinct biologic processes in post-treatment survivors, with inflammatory signaling contributing relatively specifically to fatigue.
•We examined race and HIV differences in transcription activity in pathways relevant to the CTRA.•Racial differences were found in activity of pro-inflammatory transcription control and ...stress-signaling pathways.•Discrimination explained more than 50% of total race-related difference in pro-inflammatory transcription factor activity.•HIV group differences were found in pro-inflammatory and antiviral transcription pathways.
Racial disparities in health outcomes between African Americans and European Americans have been well-documented, but not fully understood. Chronic inflammation contributes to several of the diseases showing racial disparities (e.g., Human Immunodeficiency Virus HIV), and racial differences in stress exposure (e.g., experiences of racial discrimination) that stimulate pro-inflammatory processes that may contribute to differential health outcomes.
We performed a cross-sectional bioinformatic analyses relating perceived discrimination (as measured by the Perceived Ethnic Discrimination Questionnaire PED-Q) to the activity of pro-inflammatory, neuroendocrine, and antiviral transcription control pathways relevant to the conserved transcriptional response to adversity (CTRA) in peripheral blood leukocytes. Subjects were 71 individuals (37 HIV-seropositive (HIV+); 34 HIV-seronegative (HIV-)) (mean age = 53 years, range 27–63), who self-identified either as African American/Black (n = 48) or European American/White (n = 23). This provided the opportunity to examine the independent effects of race and HIV, as well as the modifying role of perceived discrimination on pathways involved in CTRA. Exploratory analysis examined the interactive effects of HIV and race on pathways involved in CTRA. Relative to European Americans, African Americans showed increased activity of two key pro-inflammatory transcription control pathways (NF- кB and AP-1) and two stress-responsive signaling pathways (CREB and glucocorticoid receptor); these effects did not differ significantly as a function of HIV infection (HIV x Race interaction, all p > .10). Results suggested that differences in experiences of racial discrimination could potentially account for more than 50% of the total race-related difference in pro-inflammatory transcription factor activity. In sum, differential exposure to racial discrimination may contribute to racial disparities in health outcomes in part by activating threat-related molecular programs that stimulate inflammation and contribute to increased risk of chronic illnesses.
Electroconvulsive therapy (ECT) is the most robust acute treatment for severe major depressive disorder, yet clinical response is variable. Inflammation is associated with depression, especially in ...women, and levels of C-reactive protein (CRP) and interleukin (IL)-6 predict response to antidepressant medications. This study evaluated whether markers of inflammation predicted response to electroconvulsive therapy (ECT) in patients with treatment-resistant depression and to what extent this association differed between men and women.
In patients (N = 29) who had a current major depressive episode diagnosed using DSM-IV-TR criteria and were scheduled to undergo ECT at an academic referral center, levels of CRP, IL-6, IL-8, and tumor necrosis factor-α and severity of depressive symptoms (Montgomery-Asberg Depression Rating Scale MADRS) were prospectively evaluated before ECT treatment, after the second ECT session, and again at the completion of the index treatment series. Data were collected between December 2011 and December 2014. The primary outcome was end-of-treatment MADRS score.
In multivariate analyses, higher levels of IL-6 at baseline, but not other inflammatory markers or clinical variables, were associated with lower end-of-treatment MADRS score (P = .01). When stratified by sex, IL-6 remained a significant predictor of end-of-treatment MADRS for women (P = .02) but not men (P = .1), and CRP emerged as a significant predictor for women (P = .04) but not men (P = .66). CRP and IL-6 increased from baseline to the second ECT session (P values < .01) and returned to baseline levels at end of treatment; these changes did not relate to MADRS score over the course of ECT.
Levels of IL-6 prior to ECT treatment may be useful in identifying those depressed patients most likely to benefit from ECT treatment. In contrast, acute changes in IL-6 and CRP may reflect spikes in inflammatory response related to the initiation of seizure therapy, but not mood. Assessment of pretreatment inflammatory biomarkers, especially in women, might be useful in guiding treatment decision-making in treatment-resistant depression.
To investigate the comparative efficacy of cognitive behavioral therapy (CBT), Tai Chi Chih (TCC), and sleep seminar education control (SS) on the primary outcome of insomnia diagnosis, and secondary ...outcomes of sleep quality, fatigue, depressive symptoms, and inflammation in older adults with insomnia.
Randomized controlled, comparative efficacy trial.
Los Angeles community.
123 older adults with chronic and primary insomnia.
Random assignment to CBT, TCC, or SS for 2-hour group sessions weekly over 4 months with follow-up at 7 and 16 months.
Insomnia diagnosis, patient-reported outcomes, polysomnography (PSG), and high-sensitivity C-reactive protein (CRP) levels.
CBT performed better than TCC and SS in remission of clinical insomnia as ascertained by a clinician (P < 0.01), and also showed greater and more sustained improvement in sleep quality, sleep parameters, fatigue, and depressive symptoms than TCC and SS (all P values < 0.01). As compared to SS, CBT was associated with a reduced risk of high CRP levels (> 3.0 mg/L) at 16 months (odds ratio OR, 0.26 95% CI, 0.07-0.97 P < 0.05). Remission of insomnia was associated with lower levels of CRP (P < 0.05) at 16 months. TCC was associated with improvements in sleep quality, fatigue, and depressive symptoms as compared to SS (all P's < 0.05), but not insomnia remission. PSG measures did not change.
Treatment of late-life insomnia is better achieved and sustained by cognitive behavioral therapies. Insomnia treatment and remission reduces a marker of inflammatory risk, which has implications for cardiovascular morbidity and diabetes observed with sleep disturbance in epidemiologic surveys.
A growing body of work suggests that individuals with aggressive behavior and/or aggressive tendencies have evidence of chronic, low level, inflammation as manifested by elevated circulating levels ...of acute phase reactant proteins and pro-inflammatory cytokines. While animal studies report that direct application of pro-inflammatory proteins in brain increase aggressive behavior, there is no data on the relationship of central levels of these proteins and aggression in human subjects. We simultaneously measured levels of both plasma and lumbar cerebrospinal fluid (CSF) C-Reactive Protein (CRP) and IL-6, IL-8, and TNF-α in 77 medically healthy, drug-free, individuals with varying degrees of aggression including 22 individuals with DSM-5 Intermittent Explosive Disorder (IED). Aggression was assessed using the Life History of Aggression (LHA) and the Buss-Perry Aggression Questionnaire (BPAQ). Plasma and CSF levels of CRP, IL-8, and TNF-α, but not IL-6, correlated significantly with each other. Aggressive individuals with IED displayed elevated plasma, but not CSF, levels of proinflammatory markers and this relationship was specific to IED. Similarly, composite aggression scores correlated significantly with plasma, but not CSF, pro-inflammatory markers. Aggressive behavior in humans is correlated with Plasma, but not CSF, proinflammatory markers despite the observation that these two sets of markers are significantly correlated. Since the direct application of proinflammatory proteins in brains of animals increase aggressive behavior, proinflammatory proteins likely influence brain-based behavior in a manner not reflected in lumbar CSF.
Reply to S. Yang et al Carroll, Judith E; Mandelblatt, Jeanne S; Breen, Elizabeth C
Journal of clinical oncology,
2023-Apr-20, 2023-04-20, 20230420, Letnik:
41, Številka:
12
Journal Article
•Depression is common in breast cancer survivors.•Higher levels of interleukin-8 are associated with lower severity of depressive symptoms, and favorable treatment response.•High levels of ...interleukin-8 were associated with reduced risk of incident and recurrent major depression.•Interleukin-8 may have identify those who are resilient to depression during cancer survivorship.
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.
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.
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).
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.
Highlights • Inflammation leads to social withdrawal, but may also lead to approaching close others. • Endotoxin (vs. placebo) led to a greater desire to approach support figures. • Ventral striatum ...activity to support figures was greater in endotoxin participants. • Increases in IL-6 were associated with increased VS to support figures. • Results highlight a more nuanced view of changes in social behavior during sickness.
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