Gregory E. Miller

Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry

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.

If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans.

The notion that chronic stress fosters disease by activating the hypothalamic-pituitary-adrenocortical (HPA) axis is featured prominently in many theories. The research linking chronic stress and HPA function is contradictory, however, with some studies reporting increased activation, and others reporting the opposite. This meta-analysis showed that much of the variability is attributable to stressor and person features. Timing is an especially critical element, as hormonal activity is elevated at stressor onset but reduces as time passes. Stressors that threaten physical integrity, involve trauma, and are uncontrollable elicit a high, flat diurnal profile of cortisol secretion. Finally, HPA activity is shaped by a persons response to the situation; it increases with subjective distress but is lower in persons with posttraumatic stress disorder.

Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms.

Depression increases the risk of cardiac mortality and morbidity in patients with coronary heart disease (CHD), but the mechanisms that underlie this association remain unclear. This review considers the evidence for several behavioral and physiological mechanisms that might explain how depression increases the risk for incident coronary disease and for subsequent cardiac morbidity and mortality. The candidate mechanisms include: (1). antidepressant cardiotoxicity; (2). association of depression with cardiac risk factors such as cigarette smoking, hypertension, diabetes, and reduced functional capacity; (3). association of depression with greater coronary disease severity; (4). nonadherence to cardiac prevention and treatment regimens; (5). lower heart rate variability (HRV) reflecting altered cardiac autonomic tone; (6). increased platelet aggregation; and (7). inflammatory processes. Despite recent advances in our understanding of these potential mechanisms, further research is needed to determine how depression increases risk for cardiac morbidity and mortality.

Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model

This study examined whether chronic stress impairs the immune systems capacity to respond to hormonal signals that terminate inflammation. Fifty healthy adults were studied; half were parents of cancer patients, and half were parents of healthy children. Parents of cancer patients reported more psychological distress than parents of healthy children. They also had flatter diurnal slopes of cortisol secretion, primarily because of reduced output during the morning hours. There was also evidence that chronic stress impaired the immune systems response to anti-inflammatory signals: The capacity of a synthetic glucocorticoid hormone to suppress in vitro production of the pro-inflammatory cytokine interleukin-6 was diminished among parents of cancer patients. Findings suggest a novel pathway by which chronic stress might alter the course of inflammatory disease.

Adaptive Self-Regulation of Unattainable Goals: Goal Disengagement, Goal Reengagement, and Subjective Well-Being

Three studies examined associations between goal disengagement, goal reengagement, and subjective well-being. In Study 1, 115 undergraduates reported on the extent to which they were able to abandon unattainable goals and reengage their efforts in alternative goals. Study 2 examined the importance of goal disengagement and goal reengagement in groups of young adults and older adults (N = 120). In Study 3, a sample of parents of children with cancer and parents of medically healthy children was examined (N = 45). The findings confirmed that goal disengagement and goal reengagement can be associated with ratings of high subjective well-being. In addition, the results showed that goal disengagement and goal reengagement can have interactive effects on subjective well-being. The importance of the findings for effective self-regulation and successful development are discussed.

Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research.

Objectives: To summarize quantitatively the literature comparing hypothalamic-pituitary-adrenal (HPA) axis function between depressed and nondepressed individuals and to describe the important sources of variability in this literature. These sources include methodological differences between studies, as well as demographic or clinical differences between depressed samples. Methods: The current study used meta-analytic techniques to compare 671 effect sizes (cortisol, adrenocorticotropic hormone, or corticotropin-releasing hormone) across 361 studies, including 18,454 individuals. Results: Although depressed individuals tended to display increased cortisol (d = 0.60; 95% confidence interval [CI], 0.54-0.66) and adrenocorticotropic hormone levels (d = 0.28; 95% CI, 0.16-0.41), they did not display elevations in corticotropin-releasing hormone (d = 0.02; 95% CI, −0.47-0.51). The magnitude of the cortisol effect was reduced by almost half (d = 0.33; 95% CI, 0.21-0.45) when analyses were limited to studies that met minimal methodological standards. Gender did not significantly modify any HPA outcome. Studies that included older hospitalized individuals reported significantly greater cortisol differences between depressed and nondepressed groups compared with studies with younger outpatient samples. Important cortisol differences also emerged for atypical, endogenous, melancholic, and psychotic forms of depression. Conclusions: The current study suggests that the degree of HPA hyperactivity can vary considerably across patient groups. Results are consistent with HPA hyperactivity as a link between depression and increased risk for conditions, such as diabetes, dementia, coronary heart disease, and osteoporosis. Such a link is strongest among older inpatients who display melancholic or psychotic features of depression. HPA = hypothalamic-pituitary-adrenal; ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; dex = dexamethasone; CI = confidence interval.

Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.

Clinical depression and inflammatory risk markers for coronary heart disease

Despite mounting evidence that psychiatric depression heightens risk for cardiac morbidity and mortality, little is known about the mechanisms responsible for this association. The present study examined the relation between depression and the expression of inflammatory risk markers implicated in the pathogenesis of coronary heart disease (CHD). One hundred adults were enrolled (68% women, 48% Caucasian, 48% African-American, mean age 30 +/- 2 years). Fifty subjects met the diagnostic criteria for clinical depression; the remaining 50 were demographically matched controls with no history of psychiatric illness. All subjects were in excellent health, defined as having no acute infectious disease, chronic medical illness, or regular medication regimen aside from oral contraceptives. The depressed subjects exhibited significantly higher levels of the inflammatory markers C-reactive protein (3.5 +/- 0.5 vs 2.5 +/- 5 mg/L, p = 0.04) and interleukin-6 (3.0 +/- 0.3 vs 1.9 +/- 0.2 pg/ml, p = 0.007) compared with control subjects. Mediational analyses aimed at identifying the pathways contributing to this association revealed that neither cigarette smoking nor subclinical infection with cytomegalovirus or Chlamydia pneumoniae had been responsible. However, depressed subjects exhibited greater body mass than control subjects, and analyses were consistent with adiposity accounting for a portion of the relation between clinical depression and increased expression of inflammatory markers. These findings indicate that in otherwise healthy adults, depression is associated with heightened expression of inflammatory markers implicated in the pathogenesis of CHD. Increased body mass appears to be partially, although not completely, responsible for this relation.

Is it beneficial to involve a family member? A meta-analysis of psychosocial interventions for chronic illness.

Links between chronic illness and family relationships have led to psychosocial interventions targeted at the patients closest family member or both patient and family member. The authors conducted a meta-analytic review of randomized studies comparing these interventions with usual medical care (k=70), focusing on patient outcomes (depression, anxiety, relationship satisfaction, disability, and mortality) and family member outcomes (depression, anxiety, relationship satisfaction, and caregiving burden). Among patients, interventions had positive effects on depression when the spouse was included and, in some cases, on mortality. Among family members, positive effects were found for caregiving burden, depression, and anxiety; these effects were strongest for nondementing illnesses and for interventions that targeted only the family member and that addressed relationship issues. Although statistically significant aggregate effects were found, they were generally small in magnitude. These findings provide guidance in developing future interventions in this area.

Loneliness, Social Network Size, and Immune Response to Influenza Vaccination in College Freshmen.

Antibody response to the influenza immunization was investigated in 83 1st-semester healthy university freshmen. Elevated levels of loneliness throughout the semester and small social networks were independently associated with poorer antibody response to 1 component of the vaccine. Those with both high levels of loneliness and a small social network had the lowest antibody response. Loneliness was also associated with greater psychological stress and negative affect, less positive affect, poorer sleep efficiency and quality, and elevations in circulating levels of cortisol. However, only the stress data were consistent with mediation of the loneliness-antibody response relation. None of these variables were associated with social network size, and hence none were potential mediators of the relation between network size and immunization response.