Grief, depressive symptoms, and inflammation in the spousally bereaved

Grief is conceptualized by strong negative emotions, which include longing, sadness, and preoccupations with thoughts, recollections, and images of the spouse. In the initial months after the loss of a spouse, those who are widowed are at risk for cardiovascular problems and premature mortality. In the general population, depression is characterized by chronic low-grade inflammation, a key predictor of cardiovascular problems, morbidity, and mortality. Although depression and grief share similarities, they are distinct constructs. We aimed to identify if grief was related to inflammation among those who had a spouse recently die. We also sought to determine if those who are widowed and already experience elevated levels of depressive symptoms compared with the general population had higher levels of inflammation compared with those who are widowed who report fewer depressive symptoms. Ninety-nine recently bereaved individuals (M = 84.74 days since passing, SD = 18.17) completed a blood draw and psychological assessments. Proinflammatory T cell-derived cytokines were assessed, which included interferon gamma (IFN-γ), interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL17-A, and IL-2. Bereaved individuals with a higher grief severity (using an established cut-score) had higher levels of the proinflammatory cytokines IFN-γ, IL-6, and TNF-α than those with less grief severity. Those who experienced higher levels of depression exhibited elevated levels of proinflammatory cytokines compared with those who had lower levels of depression (using a continuous measure of depressive symptoms, as well as an established cut score). This is the first study to demonstrate that inflammatory markers can distinguish those who are widowed based on grief severity such that those who are higher on grief severity have higher levels of inflammation compared with those who are lower on grief severity. These findings also add to the broader literature on depression and inflammation by showing that even in a population with high levels of depressive symptoms, there is a positive relationship between depression and inflammation.

Related papers:

title: Mortality After Bereavement: The Role of Cardiovascular Disease and Depression
abstract: Late-life bereavement is associated with an increased risk of mortality. This study assesses the associations among bereavement, cardiovascular disease (CVD), and depressive symptoms on mortality in older men and women.  We examined data from the Cardiovascular Health Study, a prospective population-based cohort study of older adults. We compared mortality in those who became bereaved from 1989 to 1999 (n = 593) to an age- and sex-matched sample of individuals who remained married (n = 593). Cox regression was used to examine the association between bereavement and 3-year all-cause mortality and whether or not the association differed by sex, presence of CVD, or postbereavement depressive symptoms.  One hundred ninety-nine (16.8%) individuals died. There was no association of bereavement with mortality (hazard ratio [HR] = 0.98 [0.74–1.30]). However, there were significant interaction effects of bereavement with participant sex (p < .001) and CVD (p = .010). Bereavement decreased the risk of mortality in women (HR = 0.67 [0.46–0.97]) and increased the risk of mortality in men (HR = 1.77 [1.14–2.75]). Within sex, the association of bereavement with mortality differed according to CVD status. The reduced risk of mortality associated with bereavement in women was only observed in women with CVD, and the increased risk in men was only observed in men without CVD. High levels of depressive symptoms attenuated the relation between bereavement and mortality in men without CVD.  The relation between bereavement and mortality was different in men and women and varied by CVD status. Bereavement decreased mortality in women with CVD and increased mortality in men without CVD.

title: Short- and long-term associations between widowhood and mortality in the United States: longitudinal analyses.
abstract: Past research shows that spousal death results in elevated mortality risk for the surviving spouse. However, most prior studies have inadequately controlled for socioeconomic status (SES), and it is unclear whether this 'widowhood effect' persists over time.



Health and Retirement Study participants aged 50+ years and married in 1998 (n = 12 316) were followed through 2008 for widowhood status and mortality (2912 deaths). Discrete-time survival analysis was used to compare mortality for the widowed versus the married.



Odds of mortality during the first 3 months post-widowhood were significantly higher than in the continuously married (odds ratio (OR) for men = 1.87, 95% CI: 1.27, 2.75; OR for women = 1.47, 95% CI: 0.96, 2.24) in models adjusted for age, gender, race and baseline SES (education, household wealth and household income), behavioral risk factors and co-morbidities. Twelve months following bereavement, men experienced borderline elevated mortality (OR = 1.16, 95% CI: 1.00, 1.35), whereas women did not (OR = 1.07, 95% CI: 0.90, 1.28), though the gender difference was non-significant.



The 'widowhood effect' was not fully explained by adjusting for pre-widowhood SES and particularly elevated within the first few months after widowhood. These associations did not differ by sex.

title: Effect of conjugal bereavement on mortality of the bereaved spouse in participants of the Renfrew/Paisley Study
abstract: To investigate how loss of a spouse affects mortality risk in the bereaved partner.  Prospective cohort study in Renfrew and Paisley in Scotland.  4395 married couples aged 45–64 years when the study was carried out between 1972 and 1976.  The date of bereavement for the bereaved spouse was the date of death of his or her spouse. Bereavement could occur at any time during the follow-up period, so it was considered as a time-dependent exposure variable and the Cox proportional hazards model for time-dependent variables was used. The relative rate (RR) of mortality was calculated for bereaved versus non-bereaved spouses and adjusted for confounding variables.  Causes of death to 31 March 2004.  Bereaved participants were at higher risk than non-bereaved participants of dying from any cause (RR 1.27; 95% CI 1.2 to 1.35). These risks remained but were attenuated after adjustment for confounding variables. There were raised RRs for bereaved participants dying of cardiovascular disease, coronary heart disease, stroke, all cancer, lung cancer, smoking-related cancer, and accidents or violence. After adjustment for confounding variables, RRs remained higher for bereaved participants for all these causes except for mortality from lung cancer. There was no strong statistical evidence that the increased risks of death associated with bereavement changed with time after bereavement.  Conjugal bereavement, in addition to existing risk factors, is related to mortality risk for major causes of death.

title: Widowhood and Mortality: A Meta-Analysis and Meta-Regression
abstract: The study of spousal bereavement and mortality has long been a major topic of interest for social scientists, but much remains unknown with respect to important moderating factors, such as age, follow-up duration, and geographic region. The present study examines these factors using meta-analysis. Keyword searches were conducted in multiple electronic databases, supplemented by extensive iterative hand searches. We extracted 1,377 mortality risk estimates from 123 publications, providing data on more than 500 million persons. Compared with married people, widowers had a mean hazard ratio (HR) of 1.23 (95% confidence interval (CI), 1.19–1.28) among HRs adjusted for age and additional covariates and a high subjective quality score. The mean HR was higher for men (HR, 1.27; 95% CI, 1.19–1.35) than for women (HR, 1.15; 95% CI, 1.08–1.22). A significant interaction effect was found between gender and mean age, with HRs decreasing more rapidly for men than for women as age increased. Other significant predictors of HR magnitude included sample size, geographic region, level of statistical adjustment, and study quality.

title: Clinical practice. Complicated grief.
abstract: A 68-year-old woman seeks care from her primary physician because of trouble sleeping 4 years after the death of her husband. On questioning, she reveals that she is sleeping on a couch in her living room because she cannot bear to sleep in the bed she shared with him. She has stopped eating regular meals because preparing them makes her miss him too much; she still has meals that she cooked for him in her freezer. The patient often ruminates about how unfair it was for her husband to die, and she is alternately angry with the medical staff who cared for him and angry at herself for not recognizing his illness earlier. She finds it too painful to do things that she and her husband used to do together, and she thinks about him constantly and often wishes she could die to be with him. How should this patient be evaluated and treated?

title: Determinants and Predictors of Grief Severity and Persistence: The Rotterdam Study
abstract: We aimed to explore correlates and predictors of bereavement severity and persistence (triggered by “loss of a loved one”; referent group partner loss) in the Rotterdam cohort.  We used linear regression to examine factors associated with grief severity using a cross-sectional analysis and logistic regression to determine prospective associations.  Cross-sectionaly, females, child-lost, higher depressive symptoms, lower education, and difficulties in daily activities were independently associated with a higher bereavement severity. Prospectively (6 years; response rate 71%), the baseline value of the grief severity was the single predictor significantly associated with grief persistence.  Our results suggest that only grief severity is independently associated with grief persistence. Further studies are needed to confirm our findings.

title: Depressive symptoms enhance stress-induced inflammatory responses
abstract: Depression is a risk factor for morbidity and mortality, and immune dysregulation may be partially responsible for this link. Proinflammatory cytokines such as interleukin 6 (IL-6) are reliable predictors of quality of life, morbidity, and many causes of mortality. The current study evaluated relationships between depressive symptoms, as assessed by the CES-D, and stress-induced inflammation. The participants, 138 healthy adults, were evaluated at rest, and after a standardized laboratory speech and mental arithmetic stressor. Compared with individuals with fewer depressive symptoms, those with more depressive symptoms produced more IL-6 in response to the stressor, as well as significantly higher levels of IL-6 both 45 min and 2 h after the stressor. These findings add to our emerging understanding of the complex interactions among stress, depression, and immune dysregulation, and provide one potential pathway to explain relationships between depressive symptoms and disease.

title: Inflammation: depression fans the flames and feasts on the heat.
abstract: Depression and inflammation fuel one another. Inflammation plays a key role in depression's pathogenesis for a subset of depressed individuals; depression also primes larger cytokine responses to stressors and pathogens that do not appear to habituate. Accordingly, treatment decisions may be informed by attention to questions of how (pathways) and for whom (predispositions) these links exist, which are the focus of this article. When combined with predisposing factors (moderators such as childhood adversity and obesity), stressors and pathogens can lead to exaggerated or prolonged inflammatory responses. The resulting sickness behaviors (e.g., pain, disturbed sleep), depressive symptoms, and negative health behaviors (e.g., poor diet, a sedentary lifestyle) may act as mediating pathways that lead to further, unrestrained inflammation and depression. Depression, childhood adversity, stressors, and diet can all influence the gut microbiome and promote intestinal permeability, another pathway to enhanced inflammatory responses. Larger, more frequent, or more prolonged inflammatory responses could have negative mental and physical health consequences. In clinical practice, inflammation provides a guide to potential targets for symptom management by signaling responsiveness to certain therapeutic strategies. For example, a theme across research with cytokine antagonists, omega-3 fatty acids, celecoxib, and exercise is that anti-inflammatory interventions have a substantially greater impact on mood in individuals with heightened inflammation. Thus, when inflammation and depression co-occur, treating them in tandem may enhance recovery and reduce the risk of recurrence. The bidirectional links between depression, inflammation, and disease suggest that effective depression treatments could have a far-reaching impact on mood, inflammation, and health.

title: Turning Up the Heat
abstract: Mounting evidence indicates that chronic stressors and depressive symptoms contribute to morbidity and mortality from cardiac disease. However, little is known about the underlying mechanisms responsible for these effects or about why depressive symptoms and cardiac disease co-occur so frequently. In this article we outline a novel model that seeks to address these issues. It asserts that chronic stressors activate the immune system in a way that leads to persistent inflammation. With long-term exposure to the products of inflammation, people develop symptoms of depression and experience progression of atherosclerosis, the pathologic condition that underlies cardiac disease.

title: Depression through the first year after the death of a spouse.
abstract: This study assesses the frequency of depressive syndromes during the first 13 months after the death of a spouse.



Men and women whose spouses had recently died were identified through death certificate records. These subjects completed a multidimensional questionnaire and were interviewed 7-8 weeks (2 months) after the death. Follow-up questionnaires were completed 7 and 13 months after the death. The questionnaires contained specific items corresponding to DSM-III-R criteria for depressive episodes as well as other widely used measures of depressive symptoms such as the Zung Depression Scale and the Hopkins Symptom Checklist.



Eighty-four (24%) of 350 widows and widowers met criteria for depressive episodes at 2 months, 72 (23%) of 308 did so at 7 months, and 46 (16%) of 286 did so at 13 months. At each time period, the prevalence was substantially higher than the 4% rate of depressive episodes observed in a comparison group of 126 subjects whose spouses were still living. Widows and widowers most likely to meet criteria for depressive episodes 13 months after the bereavement were younger, had past histories of major depression, were still grieving 2 months after the loss, and met DSM-III-R criteria for depressive episodes 2 and/or 7 months after the death.



Depressive episodes are common after the death of a spouse. Clinicians should maintain a high index of suspicion for the possibility of depression, particularly in young widows and widowers who have a past history of depression or who experience a full depressive syndrome soon after the loss.

title: Making of romantic attachment bonds: Longitudinal trajectories and implications for relationship stability
abstract: The current study outlined the timing of romantic attachment formation and its implications for relationship stability. People came to prefer their romantic partners for proximity and as a safe haven roughly 4 months after commitment; it took over 2 years to prefer them as their primary secure base. More anxiously attached people preferred their partner for proximity earlier than less anxiously attached people; more avoidantly attached people reported less preference for their romantic partner for all attachment components at the time of initial commitment compared to less avoidantly attached people. Those who more quickly represented their romantic partner as a secure base were less likely to subsequently break up; accordingly, normative attachment development may be prognostic for relationship stability.

title: Inflammatory biomarkers for persistent fatigue in breast cancer survivors
abstract: This study seeks to define immunologic and inflammatory variables associated with persistent post-treatment fatigue in breast cancer survivors.



Leukocyte subsets, plasma inflammatory markers, and ex vivo proinflammatory cytokine production were assessed in 50 fatigued and nonfatigued breast cancer survivors recruited > or = 2 years after successful primary therapy. Multivariate statistical analyses were used to define a composite immunologic biomarker of fatigue risk.



Fatigued breast cancer survivors were distinguished from nonfatigued survivors by increased ex vivo monocyte production of interleukin (IL)-6 and tumor necrosis factor-alpha following lipopolysaccharide stimulation, elevated plasma IL-1ra and soluble IL-6 receptor (sIL-6R/CD126), decreased monocyte cell-surface IL-6R, and decreased frequencies of activated T lymphocytes and myeloid dendritic cells in peripheral blood (all P < 0.05). An inverse correlation between sIL-6R and cell-surface IL-6R was consistent with inflammation-mediated shedding of IL-6R, and in vitro studies confirmed that proinflammatory cytokines induced such shedding. Multivariate linear discriminant function analysis identified two immunologic markers, the ratio of sIL-6R to monocyte-associated IL-6R and decreased circulating CD69+ T lymphocytes, as highly diagnostic of fatigue (P = 0.0005), with cross-validation estimates indicating 87% classification accuracy (sensitivity = 0.83; specificity = 0.83).



These results extend links between fatigue and inflammatory markers to show a functional alteration in proinflammatory cytokine response to lipopolysaccharide and define a prognostic biomarker of behavioral fatigue.

title: Complicated grief and bereavement-related depression as distinct disorders: preliminary empirical validation in elderly bereaved spouses.
abstract: This study sought to determine whether a set of symptoms interpreted as complicated grief could be identified and distinguished from bereavement-related depression and whether the presence of complicated grief would predict enduring functional impairments.



Data were derived from a study group of 82 recently widowed elderly individuals recruited for an investigation of physiological changes in bereaved persons. Baseline data were collected 3-6 months after the deaths of the subjects' spouses, and follow-up data were collected from 56 of the subjects 18 months after the baseline assessments. Candidate items for assessing complicated grief came from a variety of scales used to evaluate emotional functioning (e.g., the Hamilton Depression Rating Scale, the Brief Symptom Inventory). The outcome variables measured were global functioning, medical illness burden, sleep, mood, self-esteem, and anxiety.



A principal-components analysis conducted on intake data (N = 82) revealed a complicated grief factor and a bereavement-depression factor. Seven symptoms constituted complicated grief: searching, yearning, preoccupation with thoughts of the deceased, crying, disbelief regarding the death, feeling stunned by the death, and lack of acceptance of the death. Baseline complicated grief scores were significantly associated with impairments in global functioning, mood, sleep, and self-esteem in the 56 subjects available for follow-up.



The symptoms of complicated grief may be distinct from depressive symptoms and appear to be associated with enduring functional impairments. The symptoms of complicated grief, therefore, appear to define a unique disorder deserving of specialized treatment.

title: The CES-D Scale
abstract: The CES-D scale is a short self-report scale designed to measure depressive symptomatology in the general population. The items of the scale are symptoms associated with depression which have been used in previously validated longer scales. The new scale was tested in household interview surveys and in psychiatric settings. It was found to have very high internal consistency and adequate test- retest repeatability. Validity was established by pat terns of correlations with other self-report measures, by correlations with clinical ratings of depression, and by relationships with other variables which support its construct validity. Reliability, validity, and factor structure were similar across a wide variety of demographic characteristics in the general population samples tested. The scale should be a useful tool for epidemiologic studies of de pression.

title: The effects of acute psychological stress on circulating and stimulated inflammatory markers: A systematic review and meta-analysis
abstract: Inflammatory reactivity to acute laboratory stress is thought to reflect individual differences in responsivity to environmental stressors and may confer future health risk. To characterize this response, we conducted a meta-analysis of 34 studies that measured circulating inflammatory markers and 15 studies that measured stimulated production of inflammatory markers before and after exposure to laboratory challenge. Results showed significant stress-related increases in circulating interleukin (IL)-1β (d=0.66, p<0.001), IL-6 (d=0.35, p<0.001), IL-10 (d=0.69, p<0.001), and tumor necrosis factor(TNF)-α (d=0.28, p<0.001), but not IL-1ra, IL-2, interferon-γ, or C-reactive protein. There were sufficient data to assess the time course of IL-6, IL-1β, and TNF-α reactivity. IL-6 increased from baseline to measures taken 40-50, 60-75, 90, and 120min following stress, with the largest effect at 90min post-stress (d=0.70, p<0.001). IL-1β increased from baseline to 20-30, 40-50, and 60-70min following stress, with the largest effect between 40 and 50min post-stress (d=0.73, p=0.02). For TNF-α, there was a significant increase from baseline to 31-50min post stress (d=0.44, p=0.01), but not at later times. There was no difference in magnitude of IL-6 reactivity as a function of type of stress (social-evaluative versus other). For stimulated inflammatory markers, results showed stress-related increases in IL-1β when measured 20-120min post-stress (d=1.09, p<0.001), and in IL-4 and interferon-γ when measured 0-10min post stressor (d=-0.42, p<0.001 and d=0.47, p<0.001). These results extend findings from a prior meta-analysis (Steptoe et al., 2007) to show reliable increases in circulating IL-6, IL-1β, IL-10 and TNF-α and stimulated IL-1β, IL-4 and interferon-γ in response to acute stress. It is possible that these responses contribute to associations between exposure to life challenges and vulnerability to inflammatory disease.

title: Reduced Th2 cytokine production by sarcoidosis patients in clinical remission with chronic fatigue
abstract: When the inflammatory phase of sarcoidosis has resolved, complaints of chronic fatigue frequently persist. Low-grade residual inflammatory activity may play a role in maintaining chronic fatigue. The aim of this study was to compare in vitro cytokine/chemokine production and plasma cytokine/chemokine levels between chronically fatigued and non-fatigued patients with sarcoidosis in clinical remission. Patients with sarcoidosis in clinical remission were assigned to a non-fatigued group (n=38) or a fatigued group (n=34) based on the standardized cut-off of the fatigue questionnaire Checklist Individual Strength. Cytokines/chemokines in plasma and in supernatants of whole blood cultures stimulated with either a T cell mitogen or lipopolysaccharide were quantified by multiplex analysis. Associations of cytokine/chemokine profiles with chronic fatigue were analyzed by multivariate analysis of variance and principal component analysis followed by logistic regression. Principal component analysis of T cell mitogen-induced cytokine/chemokine production identified three components that explained 76% of the variance in the cytokine/chemokine data. Logistic regression revealed that the 'Th2 cytokine'-component which mainly consists of interleukin (IL)-4, IL-5 and IL-10 was significantly and negatively associated with chronic fatigue. In addition, multivariate analysis revealed higher levels of LPS-induced IL-8 and lower levels of plasma monocyte chemoattractant protein (MCP)-1 in the fatigued group compared to the non-fatigued group. In chronically fatigued sarcoidosis patients in clinical remission, we found a cytokine/chemokine profile which is suggestive for a less competent Th2 counterbalancing capacity, that may contribute to the persistence of chronic fatigue.

title: The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research
abstract: Despite the prevalence of sleep complaints among psychiatric patients, few questionnaires have been specifically designed to measure sleep quality in clinical populations. The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1-month time interval. Nineteen individual items generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these seven components yields one global score. Clinical and clinimetric properties of the PSQI were assessed over an 18-month period with "good" sleepers (healthy subjects, n = 52) and "poor" sleepers (depressed patients, n = 54; sleep-disorder patients, n = 62). Acceptable measures of internal homogeneity, consistency (test-retest reliability), and validity were obtained. A global PSQI score greater than 5 yielded a diagnostic sensitivity of 89.6% and specificity of 86.5% (kappa = 0.75, p less than 0.001) in distinguishing good and poor sleepers. The clinimetric and clinical properties of the PSQI suggest its utility both in psychiatric clinical practice and research activities.

title: Risk adjustment in outcome assessment: the Charlson comorbidity index.
abstract: To measure the burden of comorbid diseases using the MED-ECHO database (Quebec), the so-called Charlson index was adapted to International Classification of Disease (ICD-9) codes. The resulting comorbidity index was applied to the study of inpatient death in a group of 62,456 patients having one of the following conditions: ischemic heart disease, congestive heart failure, stroke, or bacterial pneumonia. Multiple logistic regression was used to relate inpatient death to its predictors, including gender, principal diagnosis, age, and the comorbidity index. Various transformations of the comorbidity score were performed, and their effect on predictive accuracy was assessed. The comorbidity index was constantly and strongly associated with death. When gender, age, comorbidity and the principal diagnoses were taken into account, the area under the receiver-operating curve was 0.83. Therefore, the Charlson Index is a useful approach to risk adjustment in outcomes research from administrative databases.

title: Attachment anxiety is related to Epstein–Barr virus latency
abstract: Attachment theory provides a framework for understanding individual differences in chronic interpersonal stress. Attachment anxiety, a type of relationship insecurity characterized by worry about rejection and abandonment, is a chronic interpersonal stressor. Stress impacts cellular immunity, including herpesvirus reactivation. We investigated whether attachment anxiety was related to the expression of a latent herpesvirus, Epstein-Barr virus (EBV), when individuals were being tested for breast or colon cancer and approximately 1 year later. Participants (N=183) completed a standard attachment questionnaire and provided blood to assess EBV viral capsid antigen (VCA) IgG antibody titers. Individuals with more attachment anxiety had higher EBV VCA IgG antibody titers than those with less attachment anxiety. The strength of the association between attachment anxiety and antibody titers was the same at both assessments. This study is the first to show an association between latent herpesvirus reactivation and attachment anxiety. Because elevated herpesvirus antibody titers reflect poorer cellular immune system control over the latent virus, these data suggest that high attachment anxiety is associated with cellular immune dysregulation.

title: International physical activity questionnaire: 12-country reliability and validity.
abstract: Physical inactivity is a global concern, but diverse physical activity measures in use prevent international comparisons. The International Physical Activity Questionnaire (IPAQ) was developed as an instrument for cross-national monitoring of physical activity and inactivity.



Between 1997 and 1998, an International Consensus Group developed four long and four short forms of the IPAQ instruments (administered by telephone interview or self-administration, with two alternate reference periods, either the "last 7 d" or a "usual week" of recalled physical activity). During 2000, 14 centers from 12 countries collected reliability and/or validity data on at least two of the eight IPAQ instruments. Test-retest repeatability was assessed within the same week. Concurrent (inter-method) validity was assessed at the same administration, and criterion IPAQ validity was assessed against the CSA (now MTI) accelerometer. Spearman's correlation coefficients are reported, based on the total reported physical activity.



Overall, the IPAQ questionnaires produced repeatable data (Spearman's rho clustered around 0.8), with comparable data from short and long forms. Criterion validity had a median rho of about 0.30, which was comparable to most other self-report validation studies. The "usual week" and "last 7 d" reference periods performed similarly, and the reliability of telephone administration was similar to the self-administered mode.



The IPAQ instruments have acceptable measurement properties, at least as good as other established self-reports. Considering the diverse samples in this study, IPAQ has reasonable measurement properties for monitoring population levels of physical activity among 18- to 65-yr-old adults in diverse settings. The short IPAQ form "last 7 d recall" is recommended for national monitoring and the long form for research requiring more detailed assessment.

title: Better cognitive control of emotional information is associated with reduced pro-inflammatory cytokine reactivity to emotional stress
abstract: Stress is strongly associated with several mental and physical health problems that involve inflammation, including asthma, cardiovascular disease, certain types of cancer, and depression. It has been hypothesized that better cognitive control of emotional information may lead to reduced inflammatory reactivity to stress and thus better health, but to date no studies have examined whether differences in cognitive control predict pro-inflammatory cytokine responses to stress. To address this issue, we conducted a laboratory-based experimental study in which we randomly assigned healthy young-adult females to either an acute emotional stress (emotionally evocative video) or no-stress (control video) condition. Salivary levels of the key pro-inflammatory cytokines IL-1β, IL-6, and IL-8 were measured before and after the experimental manipulation, and following the last cytokine sample, we assessed participants’ cognitive control of emotional information using an emotional Stroop task. We also assessed participants’ cortisol levels before and after the manipulation to verify that documented effects were specific to cytokines and not simply due to increased nonwater salivary output. As hypothesized, the emotional stressor triggered significant increases in IL-1β, IL-6, and IL-8. Moreover, even in fully adjusted models, better cognitive control following the emotional (but not control) video predicted less pronounced cytokine responses to that stressor. In contrast, no effects were observed for cortisol. These data thus indicate that better cognitive control specifically following an emotional stressor is uniquely associated with less pronounced pro-inflammatory cytokine reactivity to such stress. These findings may therefore help explain why superior cognitive control portends better health over the lifespan.

title: Multiple imputation as a flexible tool for missing data handling in clinical research.
abstract: The last 20 years has seen an uptick in research on missing data problems, and most software applications now implement one or more sophisticated missing data handling routines (e.g., multiple imputation or maximum likelihood estimation). Despite their superior statistical properties (e.g., less stringent assumptions, greater accuracy and power), the adoption of these modern analytic approaches is not uniform in psychology and related disciplines. Thus, the primary goal of this manuscript is to describe and illustrate the application of multiple imputation. Although maximum likelihood estimation is perhaps the easiest method to use in practice, psychological data sets often feature complexities that are currently difficult to handle appropriately in the likelihood framework (e.g., mixtures of categorical and continuous variables), but relatively simple to treat with imputation. The paper describes a number of practical issues that clinical researchers are likely to encounter when applying multiple imputation, including mixtures of categorical and continuous variables, item-level missing data in questionnaires, significance testing, interaction effects, and multilevel missing data. Analysis examples illustrate imputation with software packages that are freely available on the internet.

title: A farewell to Bonferroni: the problems of low statistical power and publication bias
abstract: Recently, Jennions and Moller (2003) carried out a metaanalysis on statistical power in the field of behavioral ecology and animal behavior, reviewing 10 leading journals including Behavioral Ecology. Their results showed dismayingly low average statistical power (note that a meta-analytic review of statistical power is different from post hoc power analysis as criticized in Hoenig and Heisey, 2001). The statistical power of a null hypothesis (Ho) significance test is the probability that the test will reject Ho when a research hypothesis (Ha) is true. Knowledge of effect size is particularly important for statistical power analysis (for statistical power analysis, see Cohen, 1988; Nakagawa and Foster, in press). There are many kinds of effect size measures available (e.g., Pearson’s r, Cohen’s d, Hedges’s g), but most of these fall into one of two major types, namely the r family and the d family (Rosenthal, 1994). The r family shows the strength of relationship between two variables while the d family shows the size of difference between two variables. As a benchmark for research planning and evaluation, Cohen (1988) proposed ‘conventional’ values for small, medium, and large effects: r 1⁄4.10, .30, and .50 and d 1⁄4.20, .50, and .80, respectively (in the way that p values of .05, .01, and .001 are conventional points, although these conventional values of effect size have been criticized; e.g., Rosenthal et al., 2000). The meta-analysis on statistical power by Jennions and Moller (2003) revealed that, in the field of behavioral ecology and animal behavior, statistical power of less than 20% to detect a small effect and power of less than 50% to detect a medium effect existed. This means, for example, that the average behavioral scientist performing a statistical test has a greater probability of making a Type II error (or b) (i.e., not rejecting Ho when Ho is false; note that statistical power is equals to 1 2 b) than if they had flipped a coin, when an experiment effect is of medium size (i.e., r 1⁄4 .30, d 1⁄4 .50). Here, I highlight and discuss an implication of this low statistical power on one of the most widely used statistical procedures, Bonferroni correction (Cabin and Mitchell, 2000). Bonferroni corrections are employed to reduce Type I errors (i.e., rejecting Ho when Ho is true) when multiple tests or comparisons are conducted. Two kinds of Bonferroni procedures are commonly used. One is the standard Bonferroni procedure, where a modified significant criterion (a/k where k is the number of statistical tests conducted on given data) is used. The other is the sequential Bonferroni procedure, which was introduced by Holm (1979) and popularized in the field of ecology and evolution by Rice (1989) (see these papers for the procedure). For example, in a recent volume of Behavioral Ecology (vol. 13, 2002), nearly one-fifth of papers (23 out of 117) included Bonferroni corrections. Twelve articles employed the standard procedure while 11 articles employed the sequential procedure (10 citing Rice, 1989, and one citing Holm, 1979). A serious problem associated with the standard Bonferroni procedure is a substantial reduction in the statistical power of rejecting an incorrect Ho in each test (e.g., Holm, 1979; Perneger, 1998;  1989). The sequential Bonferroni procedure also incurs reduction in power, but to a lesser extent (which is the reason that the sequential procedure is used in preference by some researchers; Moran, 2003). Thus, both procedures exacerbate the existing problem of low power, identified by Jennions and Moller (2003). For example, suppose an experiment where both an experimental group and a control group consist of 30 subjects. After an experimental period, we measure five different variables and conduct a series of t tests on each variable. Even prior to applying Bonferroni corrections, the statistical power of each test to detect a medium effect is 61% (a 1⁄4 .05), which is less than a recommended acceptable 80% level (Cohen, 1988). In the field of behavioral ecology and animal behavior, it is usually difficult to use large sample sizes (in many cases, n , 30) because of practical and ethical reasons (see Still, 1992). When standard Bonferroni corrections are applied, the statistical power of each t test drops to as low as 33% (to detect a medium effect at a/5 1⁄4 .01). Although sequential Bonferroni corrections do not reduce the power of the tests to the same extent, on average (33–61% per t test), the probability of making a Type II error for some of the tests (b 1⁄4 1 2 power, so 39–66%) remains unacceptably high. Furthermore, statistical power would be even lower if we measured more than five variables or if we were interested in detecting a small effect. Bonferroni procedures appear to raise another set of problems. There is no formal consensus for when Bonferroni procedures should be used, even among statisticians (Perneger, 1998). It seems, in some cases, that Bonferroni corrections are applied only when their results remain significant. Some researchers may think that their results are ‘more significant’ if the results pass the rigor of Bonferroni corrections, although this is logically incorrect (Cohen, 1990, 1994; Yoccoz, 1991). Many researchers are already reluctant to report nonsignificant results ( Jennions and Moller, 2002a,b). The wide use of Bonferroni procedures may be aggravating the tendency of researchers not to present nonsignificant results, because presentation of more tests with nonsignificant results may make previously ‘significant’ results ‘nonsignificant’ under Bonferroni procedures. The more detailed research (i.e., research measuring more variables) researchers do, the less probability they have of finding significant results. Moran (2003) recently named this paradox as a hyper-Red Queen phenomenon (see the paper for more discussion on problems with the sequential method). Imagine that we conduct a study where we measure as many relevant variables as possible, 10 variables, for example. We find only two variables statistically significant. Then, what should we do? We could decide to write a paper highlighting these two variables (and not reporting the other eight at all) as if we had hypotheses about the two significant variables in the first place. Subsequently, our paper would be published. Alternatively, we could write a paper including all 10 variables. When the paper is reviewed, referees might tell us that there were no significant results if we had ‘appropriately’ employed Bonferroni corrections, so that our study would not be advisable for publication. However, the latter paper is Behavioral Ecology Vol. 15 No. 6: 1044–1045 doi:10.1093/beheco/arh107 Advance Access publication on June 30, 2004

title: Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models
abstract: Hypotheses involving mediation are common in the behavioral sciences. Mediation exists when a predictor affects a dependent variable indirectly through at least one intervening variable, or mediator. Methods to assess mediation involving multiple simultaneous mediators have received little attention in the methodological literature despite a clear need. We provide an overview of simple and multiple mediation and explore three approaches that can be used to investigate indirect processes, as well as methods for contrasting two or more mediators within a single model. We present an illustrative example, assessing and contrasting potential mediators of the relationship between the helpfulness of socialization agents and job satisfaction. We also provide SAS and SPSS macros, as well as Mplus and LISREL syntax, to facilitate the use of these methods in applications.

title: From inflammation to sickness and depression: when the immune system subjugates the brain
abstract: In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.

title: Prolonged Grief Disorder, depression, and posttraumatic stress disorder are distinguishable syndromes.
abstract: This study examined the distinctiveness of symptoms of Prolonged Grief Disorder (PGD), depression, and posttraumatic stress disorder (PTSD). We compared the fit of a one-factor model with the fit of four hierarchical models in which symptoms formed three distinct correlated higher-order dimensions, and PTSD-items were modeled in different ways.



Self-reported data were available from two samples; 572 mourners recruited via the internet and 408 mourners recruited via healthcare workers.



In Sample 1, the unitary model did not fit the data. The four hierarchical models all fit better. The model in which PTSD-items constituted four lower-order factors of reexperiencing, avoidance, dysphoria, and hyperarousal fit the data best. The fit was further improved, when one weak PGD-item and one weak PTSD-item were removed, and error-terms of similar items were allowed to correlate. Findings from Sample 1 were replicated in Sample 2.



This study relied on self-reported data. Not all PGD-criteria and depression-criteria were assessed.



This is the first confirmatory factor analysis study showing that symptoms of PGD, depression, and PTSD represent distinguishable syndromes. PGD-symptoms should be addressed in the assessment and treatment of bereaved people seeking treatment.

title: Anxiety among widowed elders: is it distinct from depression and grief?
abstract: The purpose of this study was to test the validity and utility of distinguishing symptoms of anxiety from those of depression and grief in recently spousally bereaved elders. We also examined pathways from baseline (six months or less post-spousal death) to follow-up (12 and 18 months post-death) levels of anxiety, depression and grief-related symptoms. Baseline and follow-up data were available from 56 recently widowed elderly subjects recruited for an investigation of physiological changes in bereavement. Confirmatory factor analyses indicated that a model in which anxiety was specified as a third factor, apart from depression and grief factors, fit the data well and significantly better than either the one or two factor models. Path analyses revealed that both baseline severity of grief and anxiety had significant lagged effects and predicted follow-up severity of depression. Symptoms of anxiety appeared distinct from those of depression and grief, and the anxiety, depression and grief factors differentially predicted subsequent symptomatology. These findings suggest a need for more specific identification and treatment of anxiety, depression and grief symptoms within the context of late-life spousal bereavement.

title: Bereavement-related depression: Did the changes induced by DSM-V make a difference? Results from a large population-based survey of French residents.
abstract: DSM-V has been criticized for excessively expanding criteria for bereavement-related depression. The aim of this study was to quantify a potential increase in depression prevalence due to changes in diagnostic criteria and to assess the severity, clinical profile and healthcare use of new cases.  A cross-sectional telephone survey was performed in 2005–2006 in four French regions. Twelve-month prevalence of psychiatric disorders was measured by CIDI-SF. Bereavement was assessed in those who endorsed the gate question to the depression module. Persons with bereavement-related depression according to DSM-IV and DSM-V diagnosis criteria were compared.  Of the 22,138 respondents, 692 were bereaved. The prevalence of depression among those bereaved was 54.2% (95% CI=50.5–57.9) according to DSM-IV and 64.3% (60.7–67.9) according to DSM-V. The overall prevalence of major depression increased from 9.5% (9.1–9.9) with DSM-IV to 9.8% (9.4–10.2) with DSM-V. Cases diagnosed using DSM-IV presented more symptoms than cases diagnosed using DSM-V but clinical features were similar except regarding criterion E׳s symptoms. Healthcare use was similar between the two groups regarding consultations and psychotropic drug prescription.  Some DSM-IV and DSM-V criteria were difficult to operationalize in the survey. The observed difference in prevalence according to DSM-IV and DSM-V may be reduced when clinical judgment is taken into account.  The overall prevalence of major depression is only marginally increased by the new criteria. However, diagnostic changes increase the prevalence by 10 points among those bereaved. Diagnostic changes do not appear to modify service use.

title: Depression subtyping based on evolutionary psychiatry: Proximate mechanisms and ultimate functions
abstract: Major depressive disorder constitutes one of the leading causes of disability worldwide. However, it is not a unitary disease-it is a heterogeneous syndrome, with patients differing remarkably in symptom profile, pathophysiology and treatment responsiveness. Previous attempts to subtype major depressive disorder have showed limited clinical applicability. We present a classification of major depressive disorder episodes based on the proximate mechanisms that led to the original mood change that caused the depressive episode. We identify discrete depression subtypes that are induced by: 1) infection, 2) long-term stress, 3) loneliness, 4) traumatic experience, 5) hierarchy conflict, 6) grief, 7) romantic rejection, 8) postpartum events, 9) the season, 10) chemicals, 11) somatic diseases and 12) starvation. We further examine the ultimate functions of these subtypes and show that not all types of mood changes that trigger depression are adaptive. Instead, some are clearly maladaptive and some are byproducts of other adaptations. In modern societies, low mood after adverse life events may turn into a pathological depressive state. Modern lifestyle increases susceptibility to inflammatory dysregulation and chronic stress, both of which increase the amount of proinflammatory cytokines in peripheral blood, leading to low mood and sickness behaviour. Proinflammatory cytokines may aggravate the previously adaptive short-term mood changes to a chronic maladaptive depressive state by preventing the normalization of mood after adverse life events. Subtyping depression enables an effective and intelligent long-term treatment of patients in each subtype by treating the underlying causes of depression.

title: Inflammation in atherosclerosis: from pathophysiology to practice.
abstract: Until recently, most envisaged atherosclerosis as a bland arterial collection of cholesterol, complicated by smooth muscle cell accumulation. According to that concept, endothelial denuding injury led to platelet aggregation and release of platelet factors which would trigger the proliferation of smooth muscle cells in the arterial intima. These cells would then elaborate an extracellular matrix that would entrap lipoproteins, forming the nidus of the atherosclerotic plaque. Beyond the vascular smooth muscle cells long recognized in atherosclerotic lesions, subsequent investigations identified immune cells and mediators at work in atheromata, implicating inflammation in this disease. Multiple independent pathways of evidence now pinpoint inflammation as a key regulatory process that links multiple risk factors for atherosclerosis and its complications with altered arterial biology. Knowledge has burgeoned regarding the operation of both innate and adaptive arms of immunity in atherogenesis, their interplay, and the balance of stimulatory and inhibitory pathways that regulate their participation in atheroma formation and complication. This revolution in our thinking about the pathophysiology of atherosclerosis has now begun to provide clinical insight and practical tools that may aid patient management. This review provides an update of the role of inflammation in atherogenesis and highlights how translation of these advances in basic science promises to change clinical practice.

title: Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment.
abstract: The development of posttraumatic stress disorder (PTSD) is influenced by preexisting vulnerability factors. The authors aimed at identifying a preexisting biomarker representing a vulnerability factor for the development of PTSD. To that end, they determined whether the dexamethasone binding capacity of leukocytes, as a measure of glucocorticoid receptor (GR) number, before exposure to trauma was a predictor of development of PTSD symptoms. In addition, the authors analyzed mRNA expression for GR subtypes and GR target genes.



Participants were selected from a large prospective study on deployment-related disorders, in which peripheral blood mononuclear cells (PBMCs) were obtained prior to and 1 and 6 months after military deployment. Participants included armed forces personnel with high levels of PTSD symptoms 6 months after deployment (N=34) and comparison subjects without high levels of PTSD or depressive symptoms (N=34) matched for age, rank, previous deployments, educational level, and function during deployment.



Before military deployment, the GR number in PBMCs was significantly higher in participants who developed high levels of PTSD symptoms after deployment relative to matched comparison subjects. Logistic regression analysis showed that the risk for inclusion in the PTSD group after deployment increased 7.5-fold with each GR increase of 1,000. No group differences were observed in mRNA expression of GR-α, GR-P, GR-β, glucocorticoid-induced leucine zipper (GILZ), serum and glucocorticoid-inducible kinase-1 (SGK-1), and FKBP5. The higher GR number in the PTSD group was maintained at 1 and 6 months after deployment.



These results demonstrate that a preexisting high GR number in PBMCs is a vulnerability factor for subsequent development of PTSD symptoms.

title: Beta-adrenergic receptor mediated inflammation control by monocytes is associated with blood pressure and risk factors for cardiovascular disease
abstract: Overwhelming data indicate that individuals with even mildly elevated blood pressure (BP) are at great risk for developing clinical hypertension and future cardiovascular disease (CVD). There remains a lack of consensus regarding treatment strategies for mildly elevated BP, termed prehypertension, and the knowledge of pathophysiology and mechanisms of its clinical outcomes remains limited. Our primary aim was to investigate βAR-mediated inflammation control (BARIC) responses of blood monocytes to isoproterenol (Iso) in relation to BP and CVD risk factors, including obesity, depressive mood, fasting glucose, triglycerides, and cholesterol levels in the 64 prehypertensive compared to 84 individuals with normal BP. BARIC was determined by measuring the degree of inhibition in lipopolysaccharides-stimulated monocytic intracellular TNF production by ex vivo Iso treatment (10(-8)M). Depressive mood was assessed by Beck Depression Inventory (BDI). Fasting metabolic and lipid panels were assessed, and plasma levels of inflammatory cytokines TNF, IL-1β, IL-6 were measured in a subset to confirm proinflammatory state of prehypertensive participants. Prehypertensive participants were older, heavier, included more men, and presented higher levels of fasting glucose, triglycerides, cholesterol, and plasma TNF compared to normotensive participants (p's<.05). BARIC was significantly attenuated in the prehypertensive compared to normotensive group (p<.05). BARIC was negatively associated with systolic BP, diastolic BP, age, BMI, fasting glucose, triglycerides, total and low density cholesterol levels, and somatic depressive symptoms in all participants (p's<.0001 to .05). However, among the prehypertensive individuals BARIC was positively associated with SBP even after controlling for the covariates (age, gender, race, BMI, glucose and lipid panel, somatic BDI scores) (p<.05). This differing nature of the BARIC-SBP relationship between the two BP groups may be attributed to moderating factors such as cardiorespiratory fitness or depressive symptoms that could not be clearly deciphered in this current study. Nonetheless, our findings indicate the associations between inflammation dysregulation mediated by sympathoadrenal activation and BP that is observable even among individuals with normal to mildly elevated BP. BARIC may be a useful and sensitive indicator of elevated risk for vascular inflammatory disease that can be detected even at lower BP levels, especially given its associations with traditional CVD risk factors and the critical role of monocytes in atherogenic processes.

title: Effort–reward-imbalance in healthy teachers is associated with higher LPS-stimulated production and lower glucocorticoid sensitivity of interleukin-6 in vitro
abstract: According to the effort-reward-imbalance (ERI) model, a lack of reciprocity between costs and gains at work increases the risk for adverse health outcomes. Inflammation has been shown to play a crucial role in a variety of stress-related diseases and alterations in immune system glucocorticoid sensitivity may help to explain the increased risk for cardiovascular disease (CVD) and depression related to chronic work stress.



Changes in lipopolysaccharide (LPS)-induced interleukin (IL)-6 production and inhibition of IL-6 production by dexamethasone in reaction to the Trier Social Stress Test (TSST) were assessed in forty-six healthy school teachers to test whether chronic work stress is accompanied by alterations in inflammatory activity and glucocorticoid sensitivity of the innate immune system.



High ERI was associated with an increase in pro-inflammatory potential, reflected in elevated IL-6 production before and after stress and with a lower capacity of dexamethasone to suppress IL-6 production in vitro over all measurement time points. ERI was not associated with stress-related changes in GC sensitivity.



The present findings suggest a less effective anti-inflammatory regulation by glucocorticoids in teachers suffering from chronic work stress.

title: The role of anxious distress in immune dysregulation in patients with major depressive disorder
abstract: Although depression with anxious distress appears to be a clinically relevant subtype of major depressive disorder (MDD), whether it involves specific pathophysiology remains unclear. Inflammation has been implicated, but not comprehensively studied. We examined within a large MDD sample whether anxious distress and related anxiety features are associated with differential basal inflammation and innate cytokine production capacity. Data are from 1078 MDD patients from the Netherlands Study of Depression and Anxiety. In addition to the DSM-5 anxious distress specifier, we studied various dimensional anxiety scales (e.g. Inventory of Depressive Symptomatology anxiety arousal subscale [IDS-AA], Beck Anxiety Inventory [BAI], Mood and Anxiety Symptoms Questionnaire Anxious Arousal scale [MASQ-AA]). The specifier was constructed using five self-report items from the IDS and BAI. Basal inflammatory markers included C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Innate production capacity was assessed by 13 lipopolysaccharide (LPS)-stimulated inflammatory markers. Basal and LPS-stimulated inflammation index scores were created. Basal inflammation was not associated with anxious distress (prevalence = 54.3%) in MDD patients, except for a modest positive association for BAI score. However, anxious distress was associated with higher LPS-stimulated levels (interferon-γ, IL-6, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, matrix metalloproteinase (MMP)-2, TNF-α, LPS-stimulated index). Other anxiety indicators (anxious distress specifier score, BAI, MASQ-AA) were also associated with increased innate production capacity. Within a large MDD sample, the anxious distress specifier was associated with increased innate cytokine production capacity but not with basal inflammation. Results from dimensional anxiety indicators largely confirm these results. These findings provide new insight into the pathophysiology of anxious depression.

title: Distinct inflammatory response patterns are evident among men and women with higher depressive symptoms
abstract: Extensive research links depression and inflammation, with emerging evidence suggesting some differences between males and females in these associations. However, relatively few studies have examined stimulated inflammatory responses (ex vivo) in depression. The present research investigated the associations between depressive symptoms, basal inflammation, and LPS-stimulated production of pro- (IL-1β, IL-6, IL-8, TNF-α) and an anti-inflammatory cytokine (IL-10), with a focus on the extent to which gender moderates these relationships. As part of a larger study, 162 socio-economically and racially diverse subjects (ages 25-65, 67% women) completed extensive self-report measures, including depressive symptoms. Whole blood was quantified for basal inflammation, or incubated with 1μg/mL lipopolysaccharide (LPS) for 2h (at 37°C, 5% CO2) to quantify inflammatory responses to bacterial challenge. We examined the associations between depression and inflammatory markers in regression analyses, controlling for age, BMI, race/ethnicity, income, education, and use of medications. No main effects were observed between depressive symptoms and basal or stimulated levels of inflammation. Moderation analyses revealed a significant interaction between depressive symptoms and gender for stimulated TNF-α, stimulated IL-6 (p<0.05), and a marginally significant interaction for stimulated IL-10 (p=0.07). For men, higher depressive symptoms were associated with significantly higher production of TNF-α (p<0.05) and marginally higher IL-6 (p=0.07), but not with the anti-inflammatory cytokine IL-10. For women, higher depressive symptoms were associated with significantly lower production of TNF-α and IL-10 (ps<0.05), and marginally lower IL-6 (p=0.06). These findings provide evidence for gender differences in the association of depressive symptoms with inflammatory response patterns, and highlight the utility of assessing ex vivo immune responses in blood. Implications for health are discussed.

title: Resilience to loss and chronic grief: a prospective study from preloss to 18-months postloss.
abstract: The vast majority of bereavement research is conducted after a loss has occurred. Thus, knowledge of the divergent trajectories of grieving or their antecedent predictors is lacking. This study gathered prospective data on 205 individuals several years prior to the death of their spouse and at 6- and 18-months postloss. Five core bereavement patterns were identified: common grief, chronic grief, chronic depression, improvement during bereavement, and resilience. Common grief was relatively infrequent, and the resilient pattern most frequent. The authors tested key hypotheses in the literature pertaining to chronic grief and resilience by identifying the preloss predictors of each pattern. Chronic grief was associated with preloss dependency and resilience with preloss acceptance of death and belief in a just world.

title: The Underlying Structure of Grief: A Taxometric Investigation of Prolonged and Normal Reactions to Loss
abstract: Recent studies have supported the distinctiveness of complicated and prolonged forms of grief as a cluster of symptoms that is separate from other psychiatric disorders. The distinction between prolonged and normal reactions to loss remains unclear, however, with some believing that prolonged grief represents a qualitatively distinct clinical entity and others conceptualizing it as the extreme end of a continuum. Thus, in this study a taxometric methodology was used to examine the underlying structure of grief. Participants included 1,069 bereaved individuals who had lost a first-degree relative. Each participant completed the Dutch version of the Inventory of Complicated Grief–Revised, which was used to create indicators of prolonged grief. The mean above and mean below a cut (MAMBAC) and maximum eigenvalue (MAXEIG) tests supported a dimensional conceptualization, indicating that pathological reactions might be best defined by the severity of grief symptoms rather than the presence or absence of specific symptoms.

title: The prevalence and characteristics of complicated grief in older adults.
abstract: Complicated grief is a prolongation of the normal grieving process with distinct characteristics. It impairs mental and physical health and can potentially greatly impact the quality of life of sufferers and their families. The prevalence and characteristics of complicated grief in the general population are currently unclear. The aims of the present study were therefore to evaluate the prevalence of complicated grief in a population-based cohort, examine the overlap between anxiety and depression and identify common bereavement-related and socio-demographic characteristics.



Based within the Rotterdam Study, 5741 older adults were evaluated. Complicated grief was assessed with a 17-item Inventory of Complicated Grief.



Prevalence within the general population was 4.8%. Current grief was reported by 1089 participants, and of these 277 (25.4%) were diagnosed with complicated grief. Inflated anxiety and depression rates were documented in people with complicated grief, but the vast majority remained free from co-morbidity. Time since bereavement and relationship to deceased, particularly when the source was a spouse or child, were predictive of complicated grief. People with complicated grief were older, had a lower level of education, and more cognitive impairment.



The prevalence of complicated grief in older adults in the general population was noteworthy. Several factors were predictive of complicated grief and it was demonstrated as a separate condition to anxiety and depression. These findings highlight the need for prevention, diagnosis and treatment options for older adults with complicated grief and for recognition of complicated grief as a distinct diagnosis.

title: When grief makes you sick: Bereavement induced systemic inflammation is a question of genotype
abstract: Although bereavement is associated with increased morbidity and mortality in the surviving spouse, some widow(er)s remain healthy. Genetic variability in expression of inflammatory markers in response to stress may be the key to this observation. The present study compares bereaved vs. married/partnered older adults, investigating the impact of bereavement status, pro-inflammatory cytokine single nucleotide polymorphisms (SNPs) on circulating markers of inflammation and hypothesizing a gene by environment (GxE) effect. The study sample included 64 older adults, of which 36 were widow(er)s. Circulating levels of inflammatory markers IL-6, IL-1RA and sTNFRII were measured. Participants were genotyped for SNPs in the IL-6 gene (IL-6 -174 and -572), the IL-1β gene (IL-1β -511), and TNF-α gene (TNF-α -308). Grief severity was assessed with the Inventory of Complicated Grief. Bereaved participants had higher circulating levels of IL-1RA and IL-6. This increase could not be explained by pro-inflammatory genotype frequency differences, or Complicated Grief diagnosis. However, a GxE effect with the IL-6 -174 SNP moderated individual vulnerability to higher circulating levels of inflammation resulting from bereavement exposure. These results suggest a possible mechanism for the increase in morbidity and mortality in the surviving spouse. Genetic variability interacts with an environmental stressor, leading to increased inflammatory markers in genetically susceptible subjects only. For these patients, clinical interventions for bereavement-related stressor reduction might be crucial for overall health.

title: Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry.
abstract: The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of specific immunity. Brief naturalistic stressors (such as exams) tended to suppress cellular immunity while preserving humoral immunity. Chronic stressors were associated with suppression of both cellular and humoral measures. Effects of event sequences varied according to the kind of event (trauma vs. loss). Subjective reports of stress generally did not associate with immune change. In some cases, physical vulnerability as a function of age or disease also increased vulnerability to immune change during stressors.